AMINOPYRIMIDINE COMPOUNDS AND METHODS OF USE THEREOF

Abstract

Substituted aminopyrimidine compounds of formula I, and pharma- ceutically acceptable salts thereof, 1 , and R 2 have the meanings set forth herein), pharmaceutical compositions comprising such compounds, as well as methods of using such compounds are disclosed herein. JPEG2024509795000605.jpg29170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 154,409, filed February 26, 2021, U.S. Provisional Patent Application No. 63 / 216,868, filed June 30, 2021, and U.S. Provisional Patent Application No. 63 / 303,284, filed January 26, 2022. Each of the foregoing applications is incorporated herein by reference in its entirety.

[0002] Disclosed herein are substituted aminopyrimidine compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds. [Background technology]

[0003] Various approaches have been used in the past to block the activity of tyrosine kinases. These kinase inhibitors are often small molecules. These small molecules can be used to target these kinases to block the onset, growth, or spread of cancer.

[0004] Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate a wide range of physiological cellular processes, such as embryonic development, differentiation, proliferation, survival, migration, and angiogenesis. The FGF family includes 18 secreted ligands (FGFs) that are readily sequestered in the extracellular matrix by heparin sulfate proteoglycans (HPSGs). For signal propagation, FGFs are released from the extracellular matrix by proteases or specific FGF-binding proteins, and the free FGFs then bind to cell surface FGF-receptors (FGFRs) in a ternary complex consisting of FGFs, FGFRs, and HPSGs (Beenken, A., Nat. Rev. Drug Discov. 2009;8:235-253).

[0005] FGFR signaling components are frequently altered in human cancers, and several preclinical models have provided compelling evidence for the oncogenic potential of aberrant FGFR signaling in carcinogenesis, thereby validating FGFR signaling as an attractive target for cancer therapy. There is a need for compounds that inhibit FGFRs. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Provisional Patent Application No. 63 / 154,409 [Patent Document 2] U.S. Provisional Patent Application No. 63 / 216,868 [Patent Document 3] U.S. Provisional Patent Application No. 63 / 303,284 [Non-patent literature]

[0007] [Non-Patent Document 1] Beenken, A., Nat. Rev. Drug Discov. 2009;8:235-253 Summary of the Invention [Problem to be solved by the invention]

[0008] There is a need for compounds that inhibit FGFRs. [Means for solving the problem]

[0009] The present disclosure provides compounds that inhibit FGFR. In particular, the present disclosure provides compounds of formula I: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 1 H, F, Cl, Br, C 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 and R 2 but, a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E; or a 13-membered tricyclic heteroaryl containing a 6-5-6 fused ring system in which the 5-membered ring contains at least one nitrogen atom and one of the 6-membered rings is substituted with at least one E; or a 12- or 13-membered tricyclic group containing a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted by at least one E; Provided are compounds of formula I, or pharma- ceutically acceptable salts thereof, where E is an electrophilic moiety that can react with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

[0010] Pharmaceutical compositions and methods of using and making the disclosed compounds are also provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given its art-recognized meaning by a person of ordinary skill in the art applying the term in the context in which it is used in describing this disclosure.

[0012] The term "optionally substituted," as used herein to describe substituents defined herein, includes, but is not required to include, halo (i.e., -F, -Cl, -Br, -I), cyano (-CN), -OH, -C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, 5- to 7-membered heterocycloalkyl, 5- to 7-membered spirocycloalkyl or 5- to 7-membered spiroheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl (e.g., -CF 3 ;-CHF 2 , -CH 2 CF 3 etc.), -C 1 ~C 6 Alkoxy (e.g., -OC 1 ~C 6 Alkyl; -O(optionally substituted C 1 ~C 6 Alkyl), -C 1 ~C 6 Haloalkoxy (e.g., -OCF 3 ;-OCHF 2 , -OCH 2 CF 3 etc.), C 1 ~C 6 Alkylthio (e.g., -SCH 3 ;-SCH 2 CH 3 etc.), C 1 ~C 6 Alkylamino (e.g., -CH 2 NH 2 , -CH 2 CH 2 NH 2 etc.), -NH 2 , -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl)2 (For example, -N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl), -NH(C 1 ~C 6 Alkoxy), -C(O)NHC 1 ~C 6 Alkyl, -C(O)N(C 1 ~C 6 Alkyl) 2 , -COOH, -C 1 ~C 6 Alkyl COOH 、 -C 3~ C 6 CycloalkylCOOH, -C(O)NH 2 , -C 1~ C 6 AlkylCONH 2 -C 3~ C 6 CycloalkylCONH 2 , C 1~ C 6 Alkyl CONHC 1~ C 6 Alkyl 、 C 1~ C 6 Alkyl CON(C 1~ C 6 Alkyl) 2、 -C(O)C 1~ C 6 Alkyl, -C(O)OC 1 ~C 6 Alkyl, -NHCO(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl)C(O)(C 1 ~C 6 alkyl), -S(O)C 1 ~C 6 Alkyl, -S(O) 2 C 1 ~C 6 Alkyl, oxo (i.e., =O), -NHSO 2 (C 1 ~C 6 alkyl), -N(C 1 ~C6 Alkyl)SO 2 (C 1 ~C 6 Alkyl), SO 2 NH(C 1 ~C 6 Alkyl), SO 2 N(C 1 ~C 6 Alkyl) 2 , a 6- to 12-membered aryl group, a 4- to 6-membered heterocycloalkyl group, or a 5- to 12-membered heteroaryl group. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two of these groups.

[0013] Optionally substituted alkyl groups (e.g., optionally substituted C 1 ~C 6 In some embodiments where the alkyl is substituted with a halogen, the group is referred to as a haloalkyl group.

[0014] In some embodiments, excluded from the substituents encompassed by "optionally substituted" are substituents having the general formula: [ka] In the formula, W is -CH 2 -, -C(O)-, -CH(OH)-, or -N(R 10 )- and R 10 is -H, optionally substituted C 1 ~C 6 -alkyl, optionally substituted C 1 ~C 6 -alkenyl, or -C 3 ~C 6 -cycloalkyl, and each R 9 independently represents an optionally substituted C 1 ~C 6 -alkyl, optionally substituted C 1 ~C 6 -alkenyl, or C 3 ~C6 -cycloalkyl.

[0015] The range of carbon atoms, e.g., "C 1 ~C 6 ” (or equivalently “C 1~6 ") as used herein includes all ranges and individual numbers of carbon atoms. For example, "C 1 ~C 3 " is C 1 ~C 3 , C 1 ~C 2 , C 2 ~C 3 , C 1 , C 2 , and C 3 So, for example, "C 1 ~C 4 An "alkyl" group is one to four carbons (e.g., 1, 2, 3, or 4), i.e., CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 Refers to all alkyl groups having C-. 1 ~C 6 An "alkyl" group refers to any alkyl group having from 1 to 6 carbons (eg, 1, 2, 3, 4, 5, or 6).

[0016] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, t-butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. An alkyl group may have 1 to 30 carbon atoms (wherever it appears herein, a numerical range such as "1 to 30" refers to each integer within the given range, e.g., "1 to 30 carbon atoms" means that an alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified). An "alkyl" group may also be a medium-sized alkyl having 1 to 12 carbon atoms. An "alkyl" group may also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted. By way of example only, "C 1 ~C 5 "Alkyl" indicates that there are 1 to 5 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight chain), and the like. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. In some embodiments, "Me" is methyl (e.g., CH 3 ).

[0017] "C 1 ~C 6 The term "alkoxy" when used alone or as part of a substituent group refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g., -CH 2 -, -CH(CH 3 )-, -CH(CH 3)-CH 2 - and -C(CH 3 ) 2 -Includes "-C 0 The term "alk-" refers to a bond.

[0018] As used herein, "alkenyl" refers to an alkyl group that contains one or more double bonds in the straight or branched hydrocarbon chain. An alkenyl group can be unsubstituted or substituted.

[0019] As used herein, "alkynyl" refers to an alkyl group that contains one or more triple bonds in the straight or branched hydrocarbon chain. An alkynyl group can be unsubstituted or substituted.

[0020] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of two or more rings, the rings may be linked together in a fused fashion. Cycloalkyl groups may contain 3 to 12 carbon atoms. For example, C 3 ~C 6 A cycloalkyl group indicates that there are 3 to 6 carbon atoms in the ring, i.e., the ring is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. Cycloalkyl groups can be unsubstituted or substituted.

[0021] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C 6 ~C 14 Aryl group, C 6 ~C 10 Aryl group, or C 6 It may be an aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0022] The term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms have been replaced by one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of haloalkyl groups of the present disclosure include, for example, trifluoromethyl (-CF 3 ), chloromethyl (-CH 2 Cl) etc.

[0023] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized pi-electron system) containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the rings of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl rings may also contain bridgehead nitrogen atoms. For example, but not limited to, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine. Heteroaryl groups can be substituted or unsubstituted.

[0024] As used herein, "heterocycloalkyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms, together with 1 to 5 heteroatoms, constitute the ring system. However, heterocycloalkyls may optionally contain one or more unsaturated bonds positioned in such a way that a completely delocalized π-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycloalkyls may further contain one or more carbonyl or thiocarbonyl functional groups, and as defined, include oxo and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be linked together in a fused fashion. In addition, any nitrogen atom in a heterocycloalkyl may be quaternized. Heterocycloalkyl groups may be unsubstituted or substituted. Examples of such "heterocycloalkyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isopropyl alcohol ... These include, but are not limited to, soxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

[0025] As used herein, the term "amino" refers to -NH 2 Refers to the base.

[0026] As used herein, the term "hydroxy" refers to an --OH group.

[0027] As used herein, the term "halo" or "halogen" refers to atoms that are fluorine, chlorine, bromine and / or iodine.

[0028] As used herein, "alkoxy" and "alkylthio" (or thioalkoxy) refer to an alkyl group attached to the remainder of the molecule via an oxygen or sulfur atom, respectively.

[0029] The term "pharmaceutical acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with inorganic acids, hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and the like. Pharmaceutical salts can also be obtained by reacting the compound with organic acids, such as aliphatic or aromatic carboxylic or sulfonic acids, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Thus, pharma- ceutically acceptable salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate salts. Pharmaceutical salts also include ammonium salts, alkali metal salts, e.g., sodium salts or potassium salts, alkaline earth metal salts, e.g., calcium salts or magnesium salts, salts of organic bases, e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)-methylamine, C 1 ~C 7 Salts can be obtained with alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and amino acids, such as arginine and lysine.

[0030] In any compound described herein having one or more chiral centers, unless the absolute configuration is explicitly indicated, it is understood that each center may be independently in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixtures. In addition, in any compound described herein having one or more double bonds that produce geometric isomers that may be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. It is also understood that in any compound described herein, all isotopes of the atoms involved are envisioned. For example, any example of hydrogen may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium), or other isotopes; any example of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any example of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any example of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes; and any example of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0031] The term "gatekeeper mutation," as used herein, refers to a mutation in a kinase enzyme that modulates the accessibility of the kinase ATP-binding pocket.

[0032] The term "target sequence" or "target nucleic acid sequence" is given its ordinary meaning and includes and refers to the specific nucleotide sequence of a target nucleic acid to be detected (e.g., through amplification). A target sequence may include a probe hybridizing region contained within a target molecule to which a probe forms a stable hybrid under desired conditions. A "target sequence" may also include a complex sequence to which an oligonucleotide primer complexes and is extended using the target sequence as a template. If the target nucleic acid is originally single-stranded, the term "target sequence" also refers to a sequence complementary to the "target sequence" present in the target nucleic acid. If the "target nucleic acid" is originally double-stranded, the term "target sequence" refers to both the plus (+) and minus (-) strands.

[0033] As used herein, the term "kinase inhibitor" refers to any compound, molecule, or composition that inhibits or reduces the activity of a kinase. Inhibition can be achieved, for example, by blocking phosphorylation of the kinase (e.g., competing with adenosine triphosphate (ATP), a phosphorylating entity), by binding to a site outside the active site and affecting its activity by conformational changes, or by denying kinases access to molecular chaperoning systems that they depend on for cellular stability, leading to their ubiquitination and degradation.

[0034] As used herein, "subject," "host," "patient," and "individual" are used interchangeably and are given their ordinary meanings and are intended to refer to an organism that has an FGFR protein. This includes mammals, such as humans, non-human primates, ungulates, dogs, cats, horses, mice, rats, etc. The term "mammal" includes both human and non-human mammals. In some embodiments, a "subject," "host," "patient," or "individual" is a human.

[0035] "Diagnosis", as used herein, is to be given its ordinary meaning, and is intended to include determining a subject's susceptibility to a disease or disorder, determining whether a subject currently has a disease or disorder, prognosis of a subject suffering from a disease or disorder (e.g., identification of a cancer or cancer state, the stage of a cancer, or responsiveness to a cancer therapy), and the use of therametrics (e.g., monitoring a subject's condition to provide information regarding the efficacy or effectiveness of a therapy).

[0036] The term "sample" or "biological sample" shall be given its ordinary meaning and shall encompass a variety of sample types obtained from an organism and may be used in imaging, diagnostic, prognostic, or monitoring assays. The term encompasses blood and other liquid samples from an organism, solid tissue samples such as biopsy specimens or tissue cultures or cells derived therefrom, and the progeny thereof. The term encompasses samples that have been manipulated in any way after procurement, such as by treatment with reagents, solubilization, or enrichment for specific components. The term encompasses clinical samples, and also includes cell cultures, cell supernatants, cell lysates, serum, plasma, biological fluids, and cells in tissue samples.

[0037] The terms "treatment," "treating," "treat," and the like, shall be given their ordinary meaning and, as used herein, shall include reference generally to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, in that a disease or its symptoms are completely or partially prevented, and / or may be therapeutic, in that a partial or complete stabilization or cure for the disease and / or side effects resulting from the disease. "Treatment," as used herein, shall be given its ordinary meaning and shall include any treatment of disease in a mammal, particularly a human, including (a) preventing the disease or condition from occurring in a subject who may be predisposed to the disease or condition but has not yet been diagnosed as having it, (b) inhibiting the disease symptoms, e.g., arresting its onset, and / or (c) relieving the disease symptoms, e.g., causing regression of the disease or condition.

[0038] The terms "cancer," "neoplasm," and "tumor" are used interchangeably herein and are given their ordinary meanings and refer to cells that exhibit relatively autonomous growth and, as a result, an abnormal growth phenotype characterized by a marked loss of control of cell proliferation. In general, cells of interest for detection or treatment in this application include precursor, precancerous (e.g., benign), malignant, premetastatic, metastatic, and non-metastatic cells. As used herein, "FGFR-associated cancer" refers to those cancers that are associated with increased activity in mutant FGFR kinases, e.g., continuous activation of FGFR.

[0039] The term "control" is given its ordinary meaning and is intended to include a sample or standard used for comparison with a sample being tested, processed, characterized, analyzed, etc. In some embodiments, a control is a sample obtained from a healthy patient, or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In some embodiments, a control is a historical control or standard reference value or range of values. In some embodiments, a control is a comparison to a wild-type FGFR sequence or scenario.

[0040] The chapter headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described in any way. All literature and similar materials cited in this application, including but not limited to patents, patent applications, articles, books, papers, and Internet web pages, are expressly incorporated by reference in their entirety for any purpose. In the event that the definition of a term in an incorporated reference appears to differ from the definition provided in the present teachings, the definition provided in the present teachings shall prevail. It will be understood that there is an implied "about" before temperatures, concentrations, times, etc. discussed in the present teachings such that minor and insubstantial deviations are within the scope of the present teachings herein. In this application, the use of the singular includes the plural unless otherwise indicated. Also, the use of "comprise", "comprises", "comprising", "contain", "contains", "containing", "include", "includes", and "including" is not intended to be limiting. It should be understood that both the general description and the following detailed description are merely exemplary and explanatory and not restrictive. The term "and / or" indicates that the provided possibilities can be used together or as alternatives. Thus, the term "and / or" indicates that both options for the set of possibilities exist.

[0041] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, unless expressly stated otherwise, should be construed as open ended rather than limiting. As an example of the foregoing, the term "including" should be read to mean "including, without limitation," "including but not limited to," and the like, and the term "comprising," as used herein, is synonymous with "including," "containing," or "characterized by," and is inclusive or open ended and does not exclude additional, unrecited elements or method steps. The term "having" should be interpreted as "having at least." The term "includes" should be interpreted as "includes but is not limited to." The term "examples" is used to provide illustrative examples of the items in the discussion, rather than an exhaustive or exclusive enumeration thereof. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function of the invention, but instead should be understood as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. In addition, the term "comprising" should be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.Similarly, a group of items associated with the conjunction "and" should not be read as requiring each and every item to be present in the group, but rather as "and / or," unless expressly stated otherwise. Similarly, a group of items associated with the conjunction "or" should not be read as requiring mutual exclusivity between the groups, but rather as "and / or," unless expressly stated otherwise.

[0042] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art may interpret the plural to the singular and / or the singular to the plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not suggest that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0043] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 1 H, F, Cl, Br, C 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 and R 2or a 13-membered tricyclic heteroaryl comprising a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and one of the 6-membered rings is substituted by at least one E; or a 12- or 13-membered tricyclic group comprising a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl comprising a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and one of the 6-membered rings is substituted by at least one E; and E is an electrophilic moiety, which is capable of reacting with a nucleophile such as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

[0044] In some embodiments of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, each of which is optionally substituted; R 1 are H, F, Cl, Br, and C. 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 and R 2 is a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E, where E is an electrophilic moiety capable of reacting with a nucleophile such as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

[0045] In other embodiments of the compound of Formula I, or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, each of which is optionally substituted; R 1 are H, F, Cl, Br, and C. 1~6 Alkyl, CN, C 1~6Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 and R 2 is a 13-membered tricyclic heteroaryl containing a 6-5-6 fused ring system in which the 5-membered ring contains at least one nitrogen atom and one of the 6-membered rings is substituted with at least one E, where E is an electrophilic moiety capable of reacting with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

[0046] In other embodiments of the compound of Formula I, or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, each of which is optionally substituted; R 1 are H, F, Cl, Br, and C. 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 and R 2 is a 12- or 13-membered tricyclic group comprising a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl comprising a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E, where E is an electrophilic moiety capable of reacting with a nucleophile such as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

[0047] In some embodiments, Ar in formula I is each an optionally substituted 6-10 membered aryl group or a 5-10 membered heteroaryl group.

[0048] In some embodiments, Ar is an optionally substituted 6-10 membered aryl group. In some embodiments, Ar is an unsubstituted 6-10 membered aryl group, such as an unsubstituted phenyl group or an unsubstituted naphthyl group.

[0049] In other embodiments, Ar is a substituted 6-10 membered aryl group, such as a substituted phenyl group, or a substituted naphthyl group.

[0050] In some embodiments, Ar is an optionally substituted phenyl group.

[0051] In some embodiments, Ar is a substituted phenyl group.

[0052] In some embodiments where Ar is a substituted phenyl group, the phenyl group is selected from the group consisting of one or more optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 6 Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl), -O(optionally substituted C 1 ~C 6 substituted with -alkyl), -CN, or halogen.

[0053] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -C 1~6 Alkyl-cyclopropyl, -CH 2 -cyclopropyl, -C 1~6 Alkyl-(optionally substituted 5- or 6-membered heterocycloalkyl), -CH 2-(optionally substituted 5- or 6-membered heterocycloalkyl), or -CH 2 CH 2 It is OH.

[0054] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 3 It is.

[0055] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH 3 It is.

[0056] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 The alkyl is isopropyl.

[0057] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CF 3 It is.

[0058] Ar is one or more optionally substituted C 1 ~C 6In some embodiments, at least one optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is -CHF 2 It is.

[0059] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is -CF 3 It is.

[0060] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 -cyclopropyl.

[0061] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is, for example, [ka] -CH etc. 2 -(optionally substituted 5- or 6-membered heterocycloalkyl).

[0062] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, optionally substituted C is a substituted phenyl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH2 It is OH.

[0063] Ar is one or more optionally substituted C 3 ~C 6 In some embodiments, an optionally substituted C is a substituted phenyl group substituted with cycloalkyl. 3 ~C 6 Cycloalkyl is cyclopropyl or cyclobutyl.

[0064] Ar is one or more optionally substituted C 3 ~C 6 In some embodiments, an optionally substituted C is a substituted phenyl group substituted with cycloalkyl. 3 ~C 6 Cycloalkyl is cyclopropyl.

[0065] Ar is one or more optionally substituted C 3 ~C 6 In some embodiments, an optionally substituted C is a substituted phenyl group substituted with cycloalkyl. 3 ~C 6 Cycloalkyl is cyclobutyl.

[0066] In some embodiments where Ar is a substituted phenyl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0067] In some embodiments where Ar is a substituted phenyl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0068] In some embodiments where Ar is a substituted phenyl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0069] In some embodiments where Ar is a substituted phenyl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0070] In some embodiments where Ar is a substituted phenyl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0071] In some embodiments where Ar is a substituted phenyl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0072] In some embodiments where Ar is a substituted phenyl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0073] Ar is one or more N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 In some embodiments, N(C alkyl) is a substituted phenyl group. 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 Alkyl) is [ka] It is.

[0074] Ar is one or more -O(optionally substituted C 1 ~C 6 In some embodiments, -O(optionally substituted C alkyl) is a substituted phenyl group. 1 ~C 6 Alkyl) is -OCH 3 , -OCH 2 CH 3 or [ka] It is.

[0075] Ar is one or more -O(optionally substituted C 1 ~C 6 In some embodiments, -O(optionally substituted C alkyl) is a substituted phenyl group. 1 ~C 6 Alkyl) is -OCH 3 It is.

[0076] Ar is one or more -O(optionally substituted C 1 ~C 6 In some embodiments, -O(optionally substituted C alkyl) is a substituted phenyl group.1 ~C 6 Alkyl) is -OCH 2 CH 3 It is.

[0077] Ar is one or more -O(optionally substituted C 1 ~C 6 In some embodiments, -O(optionally substituted C alkyl) is a substituted phenyl group. 1 ~C 6 Alkyl) is [ka] It is.

[0078] In some embodiments where Ar is a substituted phenyl group, the phenyl group is substituted with --CN.

[0079] In some embodiments where Ar is a substituted phenyl group substituted with one or more halogens, at least one halogen is -F.

[0080] In some embodiments, Ar in formula I is [ka] It is.

[0081] In some embodiments, Ar in formula I is an optionally substituted 5-10 membered heteroaryl group such as, for example, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine, each of which is optionally substituted.

[0082] In some embodiments, each optionally substituted 5-10 membered heteroaryl group is an optionally substituted pyridinyl, pyrazolyl, triazolyl, imidazolyl, pyrazolopyrimidine, or triazolopyridine.

[0083] In some embodiments, Ar is an unsubstituted 5-10 membered heteroaryl group.

[0084] In some embodiments, Ar is a substituted 5-10 membered heteroaryl group.

[0085] In some embodiments, Ar is a substituted pyrazolyl group.

[0086] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group, the substituted 5-10 membered heteroaryl group is selected from the group consisting of one or more optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 6 Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C 1 ~C 6Alkyl) (optionally substituted C 1 ~C 6 alkyl), -O(optionally substituted C 1 ~C 6 substituted with -alkyl), -CN, or halogen.

[0087] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group, the substituted 5-10 membered heteroaryl group can have one or more -C(O)-O(optionally substituted C(O)-O) groups, such as, for example, -C(O)Ot-butyl. 1 ~C 6 The alkyl group is substituted with .

[0088] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl), or -CH 2 CH 2 It is OH.

[0089] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH(OH)CH 3 , -C(CN)(CH 3 ) 2 , -CH 2CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , C.H. 2 CH(OCH 3 )CH 3 , -CH 2 CHF 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl), or -CH 2 -optionally substituted cyclopropyl.

[0090] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 3 It is.

[0091] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH 3 It is.

[0092] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 The alkyl is isopropyl.

[0093] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one substituted C 1 ~C 6 Alkyl is -CH 2 CF 3 It is.

[0094] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one substituted C 1 ~C 6 Alkyl is -CHF 2 It is.

[0095] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one substituted C 1 ~C 6 Alkyl is -CF 3 It is.

[0096] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, at least one substituted C 1 ~C 6 Alkyl is -CH 2 -cyclopropyl.

[0097] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is, for example, [ka] -CH etc. 2 -(optionally substituted 5- or 6-membered heterocycloalkyl).

[0098] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH 2 It is OH.

[0099] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH(OH)CH 3 It is.

[0100] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -C(CN)(CH 3 ) 2 It is.

[0101] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH 2 CH 2 It is OH.

[0102] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH 2 OCH 3 It is.

[0103] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 C(OH)(CH 3 ) 2 It is.

[0104] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH 2 OCH 2 CH 3 It is.

[0105] Ar is one or more optionally substituted C 1 ~C6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH 2 OCH(CH 3 ) 2 It is.

[0106] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH(OCH 3 )CH 3 It is.

[0107] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CHF 2 It is.

[0108] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is -CH 2 CH 2 N(CH 3 ) 2 It is.

[0109] Ar is one or more optionally substituted C 1 ~C 6In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is, for example, [ka] -CH etc. 2 CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl).

[0110] Ar is one or more optionally substituted C 1 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with alkyl. 1 ~C 6 Alkyl is, for example, [ka] -CH etc. 2 -optionally substituted cyclopropyl.

[0111] Ar is one or more optionally substituted C 3 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with cycloalkyl. 3 ~C 6 Cycloalkyl is cyclopropyl or cyclobutyl.

[0112] Ar is one or more optionally substituted C 3 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with cycloalkyl. 3 ~C 6 Cycloalkyl is cyclopropyl.

[0113] Ar is one or more optionally substituted C3 ~C 6 In some embodiments, an optionally substituted C is a substituted 5-10 membered heteroaryl group substituted with cycloalkyl. 3 ~C 6 Cycloalkyl is cyclobutyl.

[0114] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0115] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0116] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0117] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0118] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0119] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0120] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group substituted with one or more optionally substituted 4-6 membered heterocycloalkyl, the optionally substituted 4-6 membered heterocycloalkyl is [ka] It is.

[0121] Ar is one or more N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 In some embodiments, N(C alkyl) is a substituted 5-10 membered heteroaryl group. 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 Alkyl) is [ka] It is.

[0122] Ar is one or more -O(optionally substituted C 1 ~C 6 In some embodiments, -O(optionally substituted C alkyl) is a substituted 5-10 membered heteroaryl group. 1 ~C 6 Alkyl) is -OCH 3 , -OCH 2 CH 3 or [ka] It is.

[0123] Ar is one or more -O(optionally substituted C 1 ~C 6 In some embodiments, -O(optionally substituted C alkyl) is a substituted 5-10 membered heteroaryl group. 1 ~C 6 Alkyl) is -OCH 3 It is.

[0124] Ar is one or more -O(optionally substituted C 1 ~C 6 In some embodiments, -O(optionally substituted C alkyl) is a substituted 5-10 membered heteroaryl group. 1 ~C 6 Alkyl) is -OCH 2 CH 3 It is.

[0125] Ar is one or more -O(optionally substituted C 1 ~C 6 In some embodiments, -O(optionally substituted C alkyl) is a substituted 5-10 membered heteroaryl group. 1 ~C 6 Alkyl) is [ka] It is.

[0126] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group, the phenyl group is substituted with -CN.

[0127] In some embodiments where Ar is a substituted 5-10 membered heteroaryl group substituted with one or more halogen, the halogen is -F.

[0128] In some embodiments, Ar in the compound of formula I is [ka] It is.

[0129] In some embodiments, Ar in the compound of formula I is [ka] It is.

[0130] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0131] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0132] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0133] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0134] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0135] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0136] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0137] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0138] In another embodiment, Ar in the compound of formula I is [ka] It is.

[0139] In some embodiments, R in formula I 1 are H, F, Cl, Br, and C. 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 It is.

[0140] In some embodiments, R 1 -H, -Cl, -F, -CH3 , or -CN.

[0141] In some embodiments, R 1 is -Cl or -CH 3 It is.

[0142] In some embodiments, R 1 is H.

[0143] In some embodiments, R 1 is F, where R 1 When is F, Ar is [ka] isn't it.

[0144] In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br.

[0145] In some embodiments, R 1 For example, C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 C such as alkyl, methyl, ethyl, and propyl 1~6 It is an alkyl.

[0146] In some embodiments, R 1 -CH 3 It is.

[0147] In some embodiments, R 1 is CN.

[0148] In some embodiments, R 1 For example, C 6 Haloalkyl, C 5 Haloalkyl, C 4 Haloalkyl, C 3Haloalkyl, C 2 Haloalkyl, C 1 Haloalkyl, -CF 3 , -CHF 2 , -CH 2 CF 3 C etc. 1~6 It is haloalkyl.

[0149] In some embodiments, R 1 is -C(O)NH 2 It is.

[0150] In some embodiments, R 1 For example, -C(O)NH(C 6 alkyl), -C(O)NH(C 5 alkyl), -C(O)NH(C 4 alkyl), -C(O)NH(C 3 alkyl), -C(O)NH(C 2 alkyl), -C(O)NH(C 1 alkyl), -C(O)NH(CH 3 ), -C(O)NH(CH 2 CH3), -C(O)NH(CH 2 CH 2 -C(O)NH(C 1~6 alkyl).

[0151] In some embodiments, R 1 is -C(O)N(C 1~6 Alkyl) 2 And each C 1~6 The alkyls may be the same or different, for example, -C(O)N(C 6 Alkyl) 2 , -C(O)N(C 5 Alkyl) 2 , -C(O)N(C 4 Alkyl) 2 , -C(O)N(C 3 Alkyl) 2 , -C(O)N(C 2 Alkyl) 2 , -C(O)N(C 1 Alkyl) 2, -C(O)N(CH 3 ) 2 , -C(O)N(CH 2 CH 3 ) 2 , -C(O)N(CH 2 CH 3 )(CH 3 ) etc.

[0152] In some embodiments, R in formula I 2 is a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E, where E is an electrophilic moiety capable of reacting with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety. Exemplary E groups are described herein.

[0153] R 2 In these embodiments, the 9-membered bicyclic heteroaryl, including the 6-5 fused ring system, is any fully aromatic 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom. The 5-membered ring may also contain, in addition to the nitrogen, one further additional heteroatom, which may be another nitrogen, oxygen, or sulfur. The 6-membered ring may contain one or more nitrogen atoms.

[0154] In another embodiment, R in formula I 2 is a 13-membered tricyclic heteroaryl containing a 6-5-6 fused ring system in which the 5-membered ring contains at least one nitrogen atom and one of the 6-membered rings is substituted with at least one E, where E is an electrophilic moiety capable of reacting with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

[0155] R 2In these embodiments, the 13-membered tricyclic heteroaryl, including the 6-5-6 fused ring system, is any fully aromatic 6-5-6 fused ring system in which the 5-membered ring contains at least one nitrogen atom. The 5-membered ring may also contain, in addition to nitrogen, one additional additional heteroatom, which may be another nitrogen, oxygen, or sulfur. The 6-membered ring may contain one or more nitrogen atoms.

[0156] In another embodiment, R in formula I 2 is a 12- or 13-membered tricyclic group comprising a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl comprising a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E, where E is an electrophilic moiety capable of reacting with a nucleophile such as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

[0157] R 2 In these embodiments, the 9-membered bicyclic heteroaryl, including the 6-5 fused ring system, is any fully aromatic 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom. The 5-membered ring may also contain one additional additional heteroatom in addition to the nitrogen, which may be another nitrogen, oxygen, or sulfur. The 6-membered ring may contain one or more nitrogen atoms. A 5- or 6-membered cycloalkyl or heterocycloalkyl ring is fused to the 5-membered ring of the 6-5 ring system.

[0158] In some embodiments of Formula I, R 2 teeth, [ka] where: Q 1 is N or CR 3A and Q 2 is N or CR 3A and R 3A , H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 Is it an alkyl group? Or Q 1 CR 3A And Q 2 CR 3A If so, Q 1 R 3A and Q 2 R 3A together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring, or a phenyl ring; Q 3 , Q 4 , Q 5 , and Q 6 are each independently N or CR 3B and Each R 3B are independently H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, C 3 ~C 7 cycloalkyl, or E, where Q 3 , Q 4 , Q 5 , and Q 6 at least one of is CE, where E is an electrophilic moiety capable of reacting with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety; R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO 2 (C1 ~C 6 alkyl) or Or Q 1 CR 3A If so, Q 1 R 3A and R 4 together with the atom to which they are attached form a 5- or 6-membered heterocycloalkyl ring.

[0159] In some embodiments of Formula I, R 2 teeth, [ka] where: Q 1 is N or CH, Q 2 is N or CR 3A and R 3A , H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 is alkyl, Q 3 , Q 4 , Q 5 , and Q 6 are each independently N or CR 3B and Each R 3B are independently H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, C 3 ~C 7 cycloalkyl, or E, where Q 3, Q 4 , Q 5 , and Q 6 at least one of is CE, where E is an electrophilic moiety capable of reacting with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety; R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO 2 (C 1 ~C 6 alkyl).

[0160] In some embodiments of Formula I, R 2 teeth, [ka] It is.

[0161] R 2 In some embodiments, Q 1 is N.

[0162] R 2 In another embodiment, Q 1 CR 3A In such an embodiment, R 3A , H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, each R is independently H or C. 1 ~C 6 It is an alkyl.

[0163] R 2In another embodiment, Q 1 is CH.

[0164] R 2 In another embodiment, Q 1 is C-CH 3 It is.

[0165] R 2 In some embodiments, Q 2 is N.

[0166] R 2 In another embodiment, Q 2 CR 3A It is.

[0167] In some embodiments, R 3A , H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, each R is independently H or C. 1 ~C 6 It is an alkyl.

[0168] In some embodiments, R 3A is H.

[0169] In other embodiments, R 3A For example, C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 C such as alkyl, methyl, ethyl, and propyl 1 ~C 6 It is an alkyl.

[0170] In some embodiments, R 3A is methyl.

[0171] In some embodiments, R 3A is ethyl.

[0172] In some embodiments, R 3A is -CN.

[0173] In other embodiments, R 3A For example, C 6 Haloalkyl, C 5 Haloalkyl, C 4 Haloalkyl, C 3 Haloalkyl, C 2 Haloalkyl, C 1 Haloalkyl, -CF 3 , -CHF 2 , -CH 2 CF 3 C etc. 1~6 It is haloalkyl.

[0174] In some embodiments, R 3A is halo, i.e., -F, -Cl, -Br, or -I.

[0175] In some embodiments, R 3A -CON(R) 2 and each R is independently H or C 1 ~C 6 Alkyl (e.g., C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 alkyl, methyl, ethyl, propyl, etc.). Therefore, R 3A -CON(R) 2 In some embodiments, R 3A For example, -CONH 2 , -CON(CH 3 ) 2 , -CON(CH 2 CH3 ) 2 , -CONH(CH 3 ), -CONH(CH 2 CH 3 ), -CON(CH 3 )(CH 2 CH 3 ) etc.

[0176] In some embodiments, R 3A -NR 2 and each R is independently H or C 1 ~C 6 Alkyl (e.g., C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 alkyl, methyl, ethyl, propyl, etc.). Therefore, R 3A Ga-NR 2 In some embodiments, R 3A For example, -NH 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NH(CH 3 ), -NH(CH 2 CH 3 ), -N(CH 3 )(CH 2 CH 3 ) etc.

[0177] In some embodiments, R 3A is, for example, -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0178] In some embodiments, R 3A For example, -CH 2 Cyclopropyl, -CH 2 Cyclobutyl, -CH 2 Cyclopentyl, -CH 2 -CH such as cyclohexyl 2It is cycloalkyl.

[0179] In some embodiments, R 3A is -COR, and R is independently H or C 1 ~C 6 Alkyl (e.g., C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 alkyl, methyl, ethyl, propyl, etc.). Therefore, R 3A In some embodiments, where R is -COR, 3A For example, -COH, -COCH 3 , -COCH 2 CH 3 And so on.

[0180] In some embodiments, R 3A is -CH(OH)R, where R is independently H or C 1 ~C 6 Alkyl (e.g., C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 alkyl, methyl, ethyl, propyl, etc.). Therefore, R 3A In some embodiments where R is -CH(OH)R, 3A For example, -CH 2 (OH), -CH(OH)CH 3 , -CH(OH)CH 2 CH 3 And so on.

[0181] In some embodiments, R 3A is -CO-cycloalkyl. Therefore, R 3A In some embodiments, where R is -CO-cycloalkyl, 3Ais, for example, --CO-cyclopropyl, --CO-cyclobutyl, --CO-cyclopentyl, --CO-cyclohexyl, and the like.

[0182] In some embodiments, R 3A is -CH(OH)-cycloalkyl. Thus, R 3A In some embodiments, where R is -CH(OH)-cycloalkyl, 3A is, for example, -CH(OH)-cyclopropyl, -CH(OH)-cyclobutyl, -CH(OH)-cyclopentyl, -CH(OH)-cyclohexyl, and the like.

[0183] In some embodiments, R 3A is -SR, and each R is independently H or C 1 ~C 6 Alkyl (e.g., C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 alkyl, methyl, ethyl, propyl, etc.). Therefore, R 3A In some embodiments, where R is -SR, 3A For example, -SH, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 And so on.

[0184] In some embodiments, R 3A -SO 2 R, each R is independently H or C. 1 ~C 6 Alkyl (e.g., C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 alkyl, methyl, ethyl, propyl, etc.). Therefore, R 3A-SO 2 In some embodiments where R, R 3A For example, -SO 2 H, -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -SO 2 CH 2 CH 2 CH 3 And so on.

[0185] R 2 In some embodiments, Q 3 is N or CR 3B It is.

[0186] Q 1 CR 3A And Q 2 CR 3A In some embodiments, Q 1 R 3A and Q 2 R 3A are both -CH 3 It is.

[0187] Q 1 CR 3A And Q 2 CR 3A In some embodiments, Q 1 R 3A and Q 2 R 3A together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring, or a 6-membered phenyl ring.

[0188] Q 1 CR 3A And Q 2 CR 3A In some embodiments, Q 1 R 3A and Q 2 R 3Atogether with the carbon atom to which they are attached form a 5-membered cycloalkyl ring. Thus, in some embodiments, R 2 teeth, [ka] It is.

[0189] Q 1 CR 3A And Q 2 CR 3A In other embodiments, Q 1 R 3A and Q 2 R 3A together with the carbon atom to which they are attached form a 6-membered cycloalkyl ring. Thus, in some embodiments, R 2 teeth, [ka] It is.

[0190] Q 1 CR 3A And Q 2 CR 3A In other embodiments, Q 1 R 3A and Q 2 R 3A together with the carbon atom to which they are attached form a phenyl ring. Thus, in some embodiments, R 2 teeth, [ka] It is.

[0191] In some embodiments, Q 3 is N.

[0192] In some embodiments, Q 3 CR 3B It is.

[0193] In some embodiments, Q 4is N.

[0194] In some embodiments, Q 4 CR 3B It is.

[0195] In some embodiments, Q 5 is N.

[0196] In some embodiments, Q 5 CR 3B It is.

[0197] In some embodiments, Q 6 is N.

[0198] In some embodiments, Q 6 CR 3B It is.

[0199] Q 3 , Q 4 , Q 5 , and / or Q 6 CR 3B In embodiments where R 3B are independently H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, C 3 ~C 7 cycloalkyl, or E.

[0200] In some embodiments, R 3B is H.

[0201] In other embodiments, R 3B For example, C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 C such as alkyl, methyl, ethyl, and propyl 1 ~C 6 It is an alkyl.

[0202] In some embodiments, R 3B is methyl.

[0203] In some embodiments, R 3B is -CN.

[0204] In other embodiments, R 3B For example, C 6 Haloalkyl, C 5 Haloalkyl, C 4 Haloalkyl, C 3 Haloalkyl, C 2 Haloalkyl, C 1 Haloalkyl, -CF 3 , -CHF 2 , -CH 2 CF 3 C etc. 1~6 It is haloalkyl.

[0205] In some embodiments, R 3B For example, -C 3 Cycloalkyl, -C 4 Cycloalkyl, -C 5 Cycloalkyl, -C 6 Cycloalkyl, -C 7 -C such as cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3 ~C 7 It is cycloalkyl.

[0206] In some embodiments, R 3B is E, where E is an electrophilic moiety that can react with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety. Exemplary E groups are described further herein.

[0207] In some embodiments, R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C3 ~C 7 Cycloalkyl or SO 2 (C 1 ~C 6 alkyl).

[0208] In some embodiments, R 4 For example, C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 C such as alkyl, methyl, ethyl, and propyl 1 ~C 6 It is an alkyl.

[0209] In some embodiments, R 4 For example, C 6 Haloalkyl, C 5 Haloalkyl, C 4 Haloalkyl, C 3 Haloalkyl, C 2 Haloalkyl, C 1 Haloalkyl, -CF 3 , -CHF 2 , -CH 2 CF 3 C etc. 1~6 It is haloalkyl.

[0210] In some embodiments, R 4 For example, -C 3 Cycloalkyl, -C 4 Cycloalkyl, -C 5 Cycloalkyl, -C 6 Cycloalkyl, -C 7 -C such as cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3 ~C 7 It is cycloalkyl.

[0211] In some embodiments, R 4 For example, -SO 2 (C 1 Alkyl), -SO 2(C 2 Alkyl), -SO 2 (C 3 Alkyl), -SO 2 (C 4 Alkyl), -SO 2 (C 5 Alkyl), -SO 2 (C 6 Alkyl), -SO 2 (CH 3 ), -SO 2 (CH 2 CH 3 ), -SO 2 (CH 2 CH 2 CH 3 ) and other -SO 2 (C 1 ~C 6 alkyl).

[0212] Q 1 CR 3A In some embodiments, Q 1 R 3A and R 4 together with the atom to which they are attached form a 5- or 6-membered heterocycloalkyl ring.

[0213] Q 1 CR 3A In some embodiments, Q 1 R 3A and R 4 together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring. Thus, in some embodiments, R 2 teeth, [ka] It is.

[0214] Q 1 CR 3A In some embodiments, Q 1 R 3A and R 4together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring. Thus, in some embodiments, R 2 teeth, [ka] It is.

[0215] Q 3 CR 3B In some embodiments, R 3B -CH 3 It is.

[0216] Q 5 CR 3B In some embodiments, R 3B -CH 3 It is.

[0217] In some embodiments, R 2 teeth, [ka] And so on.

[0218] In some embodiments, R 2 teeth, [ka] It is.

[0219] In some embodiments, R 2 teeth, [ka] It is.

[0220] In some embodiments, R 2 teeth, [ka] It is.

[0221] In some embodiments, R2 teeth, [ka] It is.

[0222] In some embodiments, R 2 teeth, [ka] It is.

[0223] In some embodiments, R 2 teeth, [ka] It is.

[0224] In some embodiments, R 2 teeth, [ka] It is.

[0225] In some embodiments, R 2 teeth, [ka] It is.

[0226] In some embodiments, R 2 teeth, [ka] It is.

[0227] In some embodiments, R 2 teeth, [ka] It is.

[0228] In some embodiments, R 2 teeth, [ka] It is.

[0229] In some embodiments, R 2 teeth, [ka] It is.

[0230] In some embodiments, R 2 teeth, [ka] It is.

[0231] In some embodiments, R 2 teeth, [ka] It is.

[0232] In some embodiments, R 2 teeth, [ka] It is.

[0233] In some embodiments, E in the compounds of the present disclosure is an electrophilic moiety that can react with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety. Such electrophilic moieties include, but are not limited to, α-β unsaturated amides, α-β unsaturated esters, α-β unsaturated ketones, α-β unsaturated sulfoxides, α-β unsaturated sulfones, α-β unsaturated sulfinates, α-β unsaturated sulfonates, α-β unsaturated sulfinamides, α-β unsaturated sulfonamides, α-β unsaturated succinimides, α-β epoxy amides, α-β epoxy esters, α-β epoxy ketones, α-halo amides, α-halo esters, α-haloketones, and the like.

[0234] In some embodiments, E is [ka] where each R 5 and each R 6 are independently H, optionally substituted C 1 ~C 6 alkyl or halogen; R 8 is H or C 1 ~C 6 alkyl and X is a halogen.

[0235] In some embodiments, R 5 is H.

[0236] In other embodiments, R 5 can be, for example, optionally substituted C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 Optionally substituted C such as alkyl, methyl, ethyl, propyl, etc. 1 ~C 6 It is an alkyl.

[0237] In other embodiments, R 5 is a halogen, i.e., -F, -Cl, -Br, or -I.

[0238] In some embodiments, R 6 is H.

[0239] In other embodiments, R 6 can be, for example, optionally substituted C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 Optionally substituted C such as alkyl, methyl, ethyl, propyl, etc. 1 ~C 6It is an alkyl.

[0240] In other embodiments, R 6 is a halogen, i.e., -F, -Cl, -Br, or -I.

[0241] In some embodiments, R 8 is H.

[0242] In other embodiments, R 8 For example, C 6 Alkyl, C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl, C 1 C such as alkyl, methyl, ethyl, and propyl 1 ~C 6 It is an alkyl.

[0243] In some embodiments, X is a halogen, i.e., -F, -Cl, -Br, or -I.

[0244] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0245] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0246] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0247] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0248] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0249] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0250] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0251] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0252] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0253] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0254] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0255] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0256] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0257] In some embodiments of the compounds of the present disclosure, E is [ka] It is.

[0258] In some embodiments of the disclosure, the compound of formula I is a compound of formula IA: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 and E have the definitions given above for formula I.

[0259] In some embodiments of the compound of formula IA, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0260] In some embodiments of the compound of formula IA, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 CR 3B and R 3A -CH 3 , each R 3B is H.

[0261] In another embodiment of the compound of formula IA, Q 1 is N and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0262] In some embodiments, the compound of formula IA is a compound of formula IA-1: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F.

[0263] In some embodiments of the compound of formula IA-1, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0264] In some embodiments of the compound of formula IA-1, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 CR 3B and R 3A -CH 3 , each R 3B is H.

[0265] In another embodiment of the compound of formula IA-1, Q 1 is N and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0266] In some embodiments of the compound of formula IA-1, R 7a Four of them are H and the other R 7a -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] Or -F.

[0267] In some embodiments of the compound of formula IA-1, R 7a Three or four of the R 7a -CH 3 , [ka] -OCH 3 , -OCH 2 CH 3 , [ka] Or -F.

[0268] In some embodiments, the compound of formula IA is a compound of formula IA-2: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c -H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] It is.

[0269] In some embodiments of the compound of formula IA-2, R 7c -CH 2 CHF 2 , -CH2 -CH(OH)-CH 3 , -CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OH, -C(CH 3 ) 2 -CN, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH 2 CH 2 O.C.H.F. 2 , -CH 2 CH 2 N(CH 3 ) 2 , [ka] It is.

[0270] In some embodiments of the compound of formula IA-2, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0271] In some embodiments of the compound of formula IA-2, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3BAnd Q 5 CR 3B and R 3A -CH 3 , each R 3B is H.

[0272] In another embodiment of the compound of formula IA-2, Q 1 is N and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0273] In some embodiments of the compound of formula IA-2, each R 7b are independently H, -CH 3 , -OCH 3 , -OCH 2 CH 3 or -CN, R 7c -CH 3 , -CH 2 CH 2 OH, [ka] It is.

[0274] In another embodiment of the compound of formula IA-2, each R 7b are independently H, -CH 3 and R 7c -CH 2 CHF 2 , -CH 2 -CH(OH)-CH 3 , -CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OH, -C(CH 3 )2 -CN, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH 2 CH 2 O.C.H.F. 2 , -CH 2 CH 2 N(CH 3 ) 2 , [ka] It is.

[0275] In some embodiments of the compound of formula (IA-2), Q 1 CR 3A And Q 2 CR 3A And Q 3 CR 3B And Q 4 CR 3B And Q 5 CR 3B And each R 3A are independently H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0276] In some embodiments of the compound of formula (IA-2), Q 1 CR 3A And Q 2 CR 3A And Q 3 CR 3B And Q 4 CR 3B And Q 5 CR 3B And each R 3B are independently H or -CH 3 And Q1 R 3A and Q 2 R 3A together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring, or a phenyl ring.

[0277] In some embodiments, the compound of formula IA is a compound of formula IA-3: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c -H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] It is.

[0278] In some embodiments of the compound of formula IA-3, R 7c is -C(O)OC(CH 3 ) 3 It is.

[0279] In some embodiments of the compound of formula IA-3, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0280] In some embodiments of the compound of formula IA-3, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 CR 3B and R 3A -CH 3 , each R 3B is H.

[0281] In another embodiment of the compound of formula IA-3, Q 1 is N and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0282] In some embodiments of the compound of formula IA-3, each R 7b are independently H or -CH 3 and R 7c -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, cyclopropyl, or [ka] It is.

[0283] In some embodiments, the compound of formula IA is a compound of formula IA-4: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c -H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] It is.

[0284] In some embodiments of the compound of formula IA-4, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0285] In some embodiments of the compound of formula IA-4, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 CR 3B and R 3A -CH 3 , each R 3B is H.

[0286] In another embodiment of the compound of formula IA-4, Q 1 is N and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0287] In some embodiments of the compound of formula IA-4, each R 7b are independently H or -CH 3 and R 7c is -CH 3 It is.

[0288] In some embodiments, the compound of formula IA is a compound of formula IA-5: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F.

[0289] In some embodiments of the compound of formula IA-5, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0290] In some embodiments of the compound of formula IA-5, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 CR 3B and R 3A -CH 3 , each R 3B is H.

[0291] In another embodiment of the compound of formula IA-5, Q 1 is N and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0292] In some embodiments of the compound of formula IA-5, R 7a Three of them are H and the other R 7a teeth, [ka] It is.

[0293] In another embodiment of the compound of formula IA-5, R 7a Three of them are H and the other R 7a is -CH 3 Or -F.

[0294] In some embodiments, the compound of formula IA is a compound of formula IA-6: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c -H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2-Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] It is.

[0295] In some embodiments of the compound of formula IA-6, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 It is.

[0296] In some embodiments of the compound of formula IA-6, Q 1 is CH and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 CR 3B and R 3A -CH 3 , each R 3B is H.

[0297] In another embodiment of the compound of formula IA-6, Q 1 is N and Q 2 CR 3A And Q 3 and Q 4 are respectively CR 3B And Q 5 is N or CR 3B and R 3A is H or -CH3 And each R 3B are independently H or -CH 3 It is.

[0298] In some embodiments of the compound of formula IA-6, each R 7b is H and R 7c is -CH 3 It is.

[0299] In some embodiments of the disclosure, the compound of formula I is a compound of formula IB: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Q 1 , R 4 , Q 3 , Q 4 , Q 5 and E have the definitions given above for formula I.

[0300] In some embodiments of the compound of formula IB, Q 1 is CH and R 4 is -CH 3 And Q 3 , Q 4 , and Q 5 are each independently N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0301] In some embodiments of the compound of formula IB, Q 1 is N and R 4 is -CH 3 And each Q 3 , Q 4 , and Q 5 is N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0302] In some embodiments, the compound of formula IB is a compound of formula IB-1: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F.

[0303] In some embodiments of the compound of formula IB-1, Q 1 is CH and R 4 is -CH 3 And Q 3 , Q 4 , and Q 5 are each independently N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0304] In some embodiments of the compound of formula IB-1, Q 1 is N and R 4 is -CH 3 And each Q 3 , Q 4 , and Q 5 is N or CR 3B And each R3B are independently H or -CH 3 It is.

[0305] In some embodiments of the compound of formula IB-1, each R 7a are independently H, [ka] or -OCH 3 It is.

[0306] In some embodiments, the compound of formula IB is a compound of formula IB-2: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c -H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3, -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] It is.

[0307] In some embodiments of the compound of formula IB-2, R 7c is -CH 2 CHF 2 It is.

[0308] In some embodiments of the compound of formula IB-2, Q 1 is CH and R 4 is -CH 3 And Q 3 , Q 4 , and Q 5 are each independently N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0309] In some embodiments of the compound of formula IB-2, Q 1 is N and R 4 is -CH 3 And each Q 3 , Q 4 , and Q 5 is N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0310] In some embodiments of the compound of formula IB-2, each R 7b is H and R 7c is -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 -cyclopropyl, or -CH2 CH 2 It is OH.

[0311] In some embodiments, the compound of formula IB is a compound of formula IB-3: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c -H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] It is.

[0312] In some embodiments of the compound of formula IB-3, Q 1 is CH and R 4 -CH 3 And Q 3 , Q 4 , and Q 5 are each independently N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0313] In some embodiments of the compound of formula IB-3, Q 1 is N and R 4 -CH 3 And each Q 3 , Q 4 , and Q 5 is N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0314] In some embodiments of the compound of formula IB-3, R 7b are independently H or -CH 3 and R 7c -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, or cyclopropyl.

[0315] In some embodiments, the compound of formula IB is a compound of formula IB-4: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2, -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c -H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] It is.

[0316] In some embodiments of the compound of formula IB-4, Q 1 is CH and R 4 is -CH 3 And Q 3 , Q 4 , and Q 5 are each independently N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0317] In some embodiments of the compound of formula IB-4, Q 1 is N and R 4 -CH 3 And each Q 3 , Q 4 , and Q 5 is N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0318] In some embodiments of the compound of formula IB-4, R 7b are independently H or -CH 3 and R 7c -CH 3 It is.

[0319] In some embodiments, the compound of formula IB is a compound of formula IB-5: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F.

[0320] In some embodiments of the compound of formula IB-5, Q 1 is CH and R 4 is -CH 3 And Q 3 , Q 4 , and Q 5 are each independently N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0321] In some embodiments of the compound of formula IB-5, Q 1 is N and R 4 is -CH 3 And each Q 3 , Q 4 , and Q 5 is N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0322] In some embodiments of the compound of formula IB-5, R 7a Three of them are H and the other R 7a teeth, [ka] It is.

[0323] In some embodiments, the compound of formula IB is a compound of formula IB-6: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c -H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] It is.

[0324] In some embodiments of the compound of formula IB-6, Q 1 is CH and R 4 -CH 3 And Q 3 , Q 4 , and Q 5 are each independently N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0325] In some embodiments of the compound of formula IB-6, Q 1 is N and R 4 -CH3 And each Q 3 , Q 4 , and Q 5 is N or CR 3B And each R 3B are independently H or -CH 3 It is.

[0326] In some embodiments of the compound of formula IB-6, each R 7b is H and R 7c -CH 3 It is.

[0327] In some embodiments, the compound of formula I is [ka] Examples include:

[0328] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; Q 7 is N or CH; Q 8 But N or CR 1 and Q 9 is N or CH; Q 9 If N, then Q 7 and Q 8 is also N; R 1 H, F, Cl, Br, C 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl)2 and R 2 is a 9-membered bicyclic heteroaryl comprising a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E, and E is an electrophilic moiety that can react with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety, or a pharma- ceutically acceptable salt thereof.

[0329] In some embodiments of the compound of Formula (II), Q 7 is N.

[0330] In some embodiments of the compound of Formula (II), Q 7 is CH.

[0331] In some embodiments of the compound of Formula (II), Q 8 is N.

[0332] In some embodiments of the compound of Formula (II), Q 8 CR 1 It is.

[0333] In some embodiments of the compound of Formula (II), Q 9 is N.

[0334] In some embodiments of the compound of Formula (II), Q 9 is CH.

[0335] In some embodiments of the present disclosure, the compound of formula II is a compound of formula IIA: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 and E have the definitions given above for formula I.

[0336] In some embodiments, the compound of formula IIA is a compound of formula IIA-2: [ka] where R 7b , R 7c , R 1 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 and E have the definitions given above for formula I.

[0337] In some embodiments of the compound of formula IIA-2, each R 7b are independently H or -CH 3 and R 7c is H or -CH 3 And Q 1 , Q 3 , Q 4 , and Q 5 are CH and Q 2 is C-CH 3 and E is -NHC(O)CH=CH 2 It is.

[0338] In some embodiments of the present disclosure, the compound of formula II is a compound of formula IB: [ka] or a pharma- ceutically acceptable salt thereof, 1 , Q 1 , R 4 , Q 3 , Q 4 , Q 5 and E have the definitions given above for formula I.

[0339] In some embodiments, compounds of formula (II) include: [ka]

[0340] Any reference herein to Formula (I) or Formula (II), or any subgenus thereof, is intended to encompass that particular formula and any subgenus of those formulas disclosed herein.

[0341] Stereoisomers of the compounds of Formula (I) or Formula (II) are also contemplated by the present disclosure. Accordingly, the present disclosure encompasses all stereoisomers and structural isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers, or mixtures thereof.

[0342] Pharmaceutically acceptable salts and solvates of the compounds of Formula (I) or Formula (II) are also within the scope of the present disclosure.

[0343] Isotopic variants of the compounds of Formula (I) or Formula (II) are also contemplated by the present disclosure.

[0344] For clarity, it should be understood that certain features of the invention described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless expressly incompatible or specifically excluded, each individual embodiment is considered combinable with any other embodiment, and such combination is considered to be another embodiment. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any subcombination. Although an embodiment may be described as part of a series of steps or as part of a more general structure, each such step may also be considered to be an independent embodiment in itself and combinable with others.

[0345] In some embodiments, compounds of the present disclosure include those illustrated in the Examples below.

[0346] The FGFR receptors (FGFRl, FGFR2, FGFR3, and FGFR4) share several common structural features, including three extracellular immunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain, and a kinase insert domain followed by an intracellular tyrosine kinase domain separated by a cytoplasmic c-terminal tail (Johnson et al., Adv. Cancer Res. 60:1-40, 1993, and Wilkie et al., Curr. Biol. 5:500-507, 1995). In FGFRl, the kinase insert domain spans positions 582-595 of the alpha Al isoform of FGFRl. In FGFR2, the kinase insert domain spans positions 585-598 of the FGFR2 Ille isoform. In FGFR3, the kinase insert domain spans positions 576-589 of the FGFR3 Ille isoform. In FGFR4, the kinase insert domain spans positions 571-584 of FGFR4 isoform 1. The c-terminal tail of FGFR begins after the end of the tyrosine kinase domain and extends to the c-terminus of the protein. Several isoforms of each FGFR have been identified and are the result of alternative splicing of their mRNAs (Johnson et al., Mol. Cell. Biol. 11:4627-4634, 1995, and Chellaiah et al., J. Biol. Chem. 269:11620-11627, 1994).

[0347] Some of the receptor variants resulting from this alternative splicing have different ligand binding specificities and affinities (Zimmer et al., J. Biol. Chem. 268:7899-7903, 1993; Cheon et al., Proc. Natl. Acad. Sci. USA 91:989-993, 1994; and Miki et al., Proc. Natl. Acad. Sci. USA 89:246-250, 1992). Protein sequences for FGFR proteins and nucleic acids encoding FGFR proteins are known in the art. Signaling by FGFRs regulates important biological processes including cell proliferation, survival, migration, and differentiation. Dysregulation of FGFR genes, FGFR proteins, or their expression or activity, or levels, is associated with many types of cancer. For example, dysregulation of FGFRs can occur by multiple mechanisms, such as overexpression of FGFR genes, amplification of FGFR genes, activating mutations (e.g., point mutations or truncations), and chromosomal rearrangements leading to FGFR fusion proteins. Dysregulation of FGFR genes, FGFR proteins, or their expression or activity, or levels, can result in (or partially cause) the development of a variety of different FGFR-associated cancers.

[0348] FGFR fusion proteins are known in the art, see, for example, Baroy et al., PloS One, 11(9):e0163859.doi:10.1371 / journal.pone.0163859, 2016; Ren et al., Int. J. Cancer, 139(4):836-40, 2016; Marchwicka et al., Cell Biosci.,6:7.doi:10.1186 / s13578-016-0075-9,2016, PCT Patent Application Publication No. 2014 / 071419A2, U.S. Patent Application Publication No. 2015 / 0366866Al, PCT Patent Application Publication No. 2016 / 084883Al, PCT Patent Application Publication No. 2016 / 030509Al, PCT Patent Application Publication No. 2015 / 150900A2, PCT Patent Application Publication No. 2015 / 120094A2, Kasaian et al.,BMC Cancer.,15:984,2015, Vakil et al.,Neuro-Oncology,18:Supp.Supplement 3,pp.iii93.Abstract Number:LG-64,17 thInternational Symposium on Pediatric Neuro-Oncology,Liverpool,United Kingdom,2016、Astsaturov et al.,Journal of Clinical Oncology,34:Supp.Supplement 15,Abstract Number:11504,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL、Heinrich et al.,Journal of Clinical Oncology,34:Supp.Supplement 15,Abstract Number:11012,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL、Hall et al.,Molecular Cancer Therapeutics,Vol.14,No.12,Supp.2,Abstract Number:B151,AACR-NCI-EORTC International Conference:Molecular Targets and Cancer Therapeutics,2015、Reuther et al.,Journal of Molecular Diagnostics,Vol.17,No.6,pp.813,Abstract Number:ST02,2015 Annual Meeting of the Association for Molecular Pathology,Austin,TX、Moeini et al.,Clin.Cancer.Res.,22(2):291-300,2016、Schrock et al,J Thorac.Oneal.pii S1556-0864(18)30674-9,2018.doi:10.1016 / j.jtho.2018.05.027、Pekmezci et al,Acta Nurotapho / .Commun.6(1):47.doi:10.1186 / s40478-018-0551-z、Lowery et al.Clin Cancer Res.pii:clincanres.0078.2018.doi:10.1158 / 1078-0432.CCR-18-0078, Ryland et al.J Clin Patho / pii:jclinpath-2018-205195,2018.doi:10.1136 / jclinpath-2018-205195, Ferguson et al.J Neuropatho / Exp Neural 77(6):437-442,2018.doi:10.1093 / jnen / nly022, Wu et al, BMC Cancer 18(1):343,2018.doi:10.1186 / s12885-018-4236-6、Shibata et al,Cancer Sci 109(5):1282-1291,2018.doi:10.1111 / cas.13582, Papdopoulos et al,Br J Cancer,1117(11):1592-1599,2017.doi:10.1038 / bjc.2017.330, Hall et al,PLoS One,11(9):e1062594,2016.doi:10.1371 / journal.pone.0162594, Johnson et al,Oncologist,22(12):1478-1490,2017.doi:10.1634 / theoncologist.2017-0242, Yang et al,Am J Hum Genet, 98(5):843-856, 2016.doi:10.1016 / j.ajhg.2016.03.017, U.S. Patent Application Publication No. 2013 / 009621, Babina and Turner, Nat Rev Cancer 17(5):318-332, 2017.doi:10.1038 / nrc.2017.8, Ryland et al, J Clin Patho / ., 2018 May 14.pii:jclinpath-2018-205195.doi:10.1136 / jclinpath-2018-205195, Kumar et al, Am J Clin Patho / .143(5):738-748, 2015.doi:10.See 1309 / AJCPUD6W1JLQQMNA, Grand et al, Genes Chromosomes Cancer 40(1):78-83, 2004. doi:10.1002 / gcc.20023; Reeser, et al, J Mo / Diagn, 19(5):682-696, 2017. doi:10.1016 / j.jmoldx.2017.05.006; Basturk, et al, Mod Patho / , 30(12):1760-1772, 2017. doi:10.1038 / modpathol.2017.60; Wang, et al, Cancer 123(20):3916-3924, 2017. doi:10.1002 / cncr.30837; Kim, et al, Oncotarget, 8(9):15014-15022, 2017. doi:10.18632 / oncotarget.14788; Busse, et al, Genes Chromosomes Cancer, 56(10):730-749, 2017. doi:10.1002 / gcc.22477; Shi, et al, J Transl Med., 14(1):339, 2016. doi:10.1186 / s12967-016-1075-6.

[0349] FGFR point mutations are known in the art. See, for example, UniParc entry UPI00000534B8, UniParc entry UPI000000lCOF, UniParc entry UPI000002A99A, UniParc entry UPI000012A72A, UniParc entry UPI000059D1C2, UniParc entry UPI000002A9AC, Uniparc entry UPI000012A72C, Uniparc entry UPI000012A72D, Uniparc entry UPI000013EOB8, Uniparc entry UPI0001CE06A3, Gen bank entry BAD92868.l, Ang et al., Diagn. Mo / .Patho / .Feb 24, 2014, U.S. Patent Application Publication No. 2011 / 0008347, Gallo et al. al., Cytokine Growth Factor Rev.26:425-449,2015, Davies et al., J. Cancer Res.65:7591,2005, Kelleher et al., Carcinogenesis 34:2198,2013, Cazier et al., Nat.Commun.5:3756,2014, Liu et al. al.,Genet.Mo / .Res.13:1109,2014, Trudel et al.,Blood 107:4039,2006, Gallo et al.,Cytokine Growth Factor Rev.26:425,2015, Liao et al.,Cancer Res.73:5195-5205,2013, Martincorena et al.,Science 348:880(2015), U.S. Patent Application Publication No. 2016 / 0235744Al, U.S. Patent Application Publication No. 9254288B2, U.S. Patent Application Publication No. 9267176B2, U.S. Patent Application Publication No. 2016 / 0215350Al, European Patent Application Publication No. 3023101Al, PCT Patent Application Publication No. 2016 / 105503Al, Rivera et al., Acta. Neuropatho / ., 131(6):847-63,2016, Lo Iacono et al., Oncotarget.,7(12):14394-404,2016, Deeken et al.,Journal of Clinical Oncology,34:Supp.Supplement 15,pp.iii93.Abstract Number:el 7520,2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, Sullivan et al.,Journal of Clinical Oncology Oncology,34:Supp.Supplement15,pp.iii93.Abstract Number:11596,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL,Nguyen et al.,Molecular Cancer Therapeutics,Vol.14,No.12,Supp.2,Abstract Number:C199,AACR-NCI-EORTC International Conference:Molecular Targets and Cancer Therapeutics,2015, Li et al. al., Hum. Patho / ., 55: 143-50, 2016, European Patent No. 2203449B1, Yoza et al., Genes Cells., (10): 1049-1058, 2016, U.S. Patent No. 9,254,288B2, European Patent Application Publication No. 3023101A1, PCT Application Publication No. 2015 / 099127A1, European Patent No. 2203449B1, Yoza et al., Genes Cells., (10): 1049-1058, 2016, Bunney et al., EbioMedicine, 2(3): 194-204, 2015, Byron et al. al., Neop / asia, 15(8):975-88, 2013, European Patent Application No. 3023101Al, PCT Application No. 2015 / 099127Al, Thussbas et al., J. Clin. Oneal., 24(23): 3747-55, 2006, Chell et al.,Oncogene,32(25):3059-70,2013、Tanizaki et al,Cancer Res.75(15):3149-3146 doi:10.1158 / 0008-5472.CAN-14-3771、Yang et al,EBioMedicine S2352-3964(18)30218-4.doi:10.1016 / j.ebiom.2018.06.011、Jakobsen,et al Oncotarget 9(40):26195-26208,2018.doi:10.18632 / oncotarget,2015、Stoneget et al. Acta Neuropatho / 135(1):115-129,2017.doi:10.1007 / s00401-017-1773-z、Pekmezci et al,Acta Nurotaphol.Commun.6(1):47.doi:10.1186 / s40478-01-51-z、z Mattos-Arruda et al,Oncotarget 9(29):20617-20630,2018.doi:10.18632 / oncotarget.25041、Oliveira et al,J Exp Clin Cancer Res 37(1):84,2018.doi:10.1186 / s13046-018-0746-y、Cha et al,Mo / Oneal 12(7):993-1003,2018.doi:10.1002 / 1878-0261.1941、Ikeda et al. al,Oncologist,23(5):586-593,2018.doi:10.1634 / theoncologist.2017-0479、Pelaez-Garda et al,PLoS One,8(5):e63695,2013.doi:10.1371 / journal.Shimada et al. al,Oncotarget,8(55):93567-93579,2017.doi:10.18632 / oncotarget.20510、Welander et al,World J Surg,42(2):482-489,2018.doi:10.1007 / s00268-0l 7-4320-0、Chandrani et al,Ann Oneal,28(3):597-603,2017.doi:10.1093 / annonc / mdw636、Dalin et al,Nat Commun,8(1):1197,2017.doi:10.1038 / s41467-017-01178-z、Taurin et al,Intl Gyneco / Cancer,28(1):152-160,2018.doi:10.1097 / IGC.0000000000001129、Haugh et al,J Invest Dermatol 138(2):384-393,2018.doi:10.1016 / j.jid.2017.08.022、Babina and Turner,Nat Rev Cancer 17(5):318-332,2017.doi:10.1038 / nrc.2017.8、Greenman et al,Nature 446(7132):153-158,2007.doi:10.1038 / nature05610、Helsten et al,Clin Cancer Res,22(1):259-267,2016.doi:10.1158 / 1078-0432.CCR-14-3212、Kim et al,BMC Urol,18:68,2018.doi:10.1186 / s12894-018-0380-1、Goyal et al,Cancer Discov,7(3):252-263,2017.doi:10.1158 / 2159-8290.CD-16-1000、Premov et al,Oncogene,36(22):3168-3177,2017.doi:10.1038 / onc.2016.464、Geelvink et al,Int J Mo / Sci.19(9):pii:E2548,2018.doi:10.3390 / ijms19092548、Lee et al,Exp Ther Med.16(2):1343-1349,2018.doi:10.3892 / etm.2018.6323、Kas et al,Cancer Res,78(19):5668-5679,2018.doi:10.1158 / 0008-5472.CAN-18-0757、Chesi et al,Blood,97(3):729-736,2001.PMID:11157491.Ge,et al,Am J Cancer Res.7(7):1540-1553,2017.PMID:2874Natia403 Genet,45(12):1470-1473,2013.doi:10.1038 / ng.2813、Jusakul et al,Cancer Discov.7(10):1116-1135,2017.doi:10.1158 / 2153.Gurd-8290 al,Respir Res.,18(1):120,2018.doi:10.1186 / s12931-017-0605-y、Paik et al,Clin Cancer Res.,23(18):5366-5373,2017.doi:10.1158 / 1078-0432.CCR-17-0645、Roy et al,Mod Patho / .,30(8):1133-1143,2017.doi:10.1038 / modpathol.2017.33、Chakrabarty et al,Br J Cancer,117(1):136-143,2017.doi:10.1048 et Transl Med.,5(197):197ra102.doi:10.1126 / scitranslmed.3006200、Kim et al,Ann Oneal.,28(6):1250-1259.doi:10.1093 / annonc / mdx098.

[0350] The compounds of the present disclosure have been found to inhibit FGFRl, FGFR2, and / or FGFR3, and are therefore believed to be useful for treating diseases and disorders that can be treated by inhibitors of FGFRl, FGFR2, FGFR3, and / or FGFR4. For example, the compounds of the present disclosure may be useful for treating FGFR-related diseases and disorders, such as proliferative disorders, including hematological cancers and solid tumors, and angiogenesis-related disorders. The compounds of the present disclosure may also be useful for treating disorders resulting from autosomal dominant mutations in FGFR, such as FGFR3, including developmental disorders. Developmental disorders that may be treated by the compounds of the present disclosure include achondroplasia (Ach) and related chondrodysplastic syndromes, including hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD).

[0351] Non-limiting examples of diseases and disorders associated with FGFR include acanthosis nigricans, achondroplasia, Apert syndrome, Beare-Stevenson syndrome (BSS), camptodactyly, tall stature, and hearing loss syndrome (CATSHL) syndrome, cleft lip and palate, congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, Crouzon syndrome, ectrodactyly, cerebrocranial dermatolipomatosis, Hartsfield syndrome, hypochondroplasia, hypogonadotropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 with or without anosmia, Kallman syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, and / or pulmonary dysplasia. dysplasia, microphthalmia, Muenke coronal craniosynostosis, cavitary dysplasia, Pfeiffer syndrome, seborrheic keratosis, syndactyly, thanatophoric dysplasia (e.g., types I or II), trigonocephaly 1 (also called metopic craniosynostosis), and tumor-induced osteomalacia. Non-limiting examples of diseases and disorders associated with FGFRl include congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, cerebrocranial lipomatosis, Hartsfield syndrome, hypogonadotropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 with or without anosmia, Kallmann syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, cavitary dysplasia, Pfeiffer syndrome, trigonocephaly 1 (also called frontal craniosynostosis), and tumor-induced osteomalacia.

[0352] Non-limiting examples of diseases and disorders associated with FGFR2 include Apert syndrome, Beare-Stevenson syndrome (BSS), Crouzon syndrome, ectrodactyly, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, Pfeiffer syndrome, and syndactyly. Non-limiting examples of diseases and disorders associated with FGFR3 include acanthosis nigricans, achondroplasia, camptodactyly, tall stature, and hearing loss syndrome (CATSHL) syndrome, cleft lip and palate, craniosynostosis, hypochondroplasia, microphthalmia, Muenke coronal suture synostosis, seborrheic keratosis, and thanatophoric dysplasia (e.g., type I or type II).

[0353] Also see UniParc entry UPI00000534B8, UniParc entry UPI000000lCOF, Uni Par entry UPI000002A99A, UniParc entry UPI000012A72A, Yong-Xing et al., Hum. Mol. Genet. 9(13):2001-2008, 2000, Eeva-Maria Laitinen et al., PLoS One 7(6):e39450, 2012, Hart et al., Oncogene 19(29):3309-3320, 2000, Shiang et al., Cell 76:335-342, 1994, Rosseau et al., Nature 371:252-254, 1994, Tavormina et al., Nature Genet.9:321-328,1995, Bellus et al.,Nature Genet.10:357-359,1995, Muenke et al.,Nature Genet.8:269-274,1994, Rutland et al.,Nature Genet.9:173-176,1995, Reardon et al.,Nature Genet.8:98-103,1994, Wilkie et al.,Nature Genet.9:165-172,1995, Jabs et al.,Nature Genet.8:275-279,1994, Japan Patent No. 05868992B2, Ye et al.,Plast.Reconstr.Surg.,137(3):952-61,2016, U.S. Patent No. 9447098B2, Bellus et al., Am.J.Med.Genet.85(1):53-65,1999, PCT Patent Application Publication No. 2016139227Al, Australian Patent Application Publication No. 2014362227Al, China Patent No. 102741256B, Ohishi et al., Am.J.Med.Genet.A.,doi:10.1002 / ajmg.a.37992,2016, Nagahara et al., Clin.Pediatr.Endocrinol.,25(3):103-106,2016, Hibberd et al., Am.J.Med.Genet.A.,doi:10.1002 / ajmg.a.37862,2016、Dias et al.,Exp.Mol.Pathol.,101(1):116-23,2016、Lin et al.,Mol.Med.Rep.,14(3):1941-6,2016、Barnett et al.,Hum.Mutat.,37(9):955-63,2016、Krstevska-Konstantinova et al.,Med.Arch.,70(2):148-50,2016、Kuentz et al.,Br.J.Dermatol.,doi:10.1111 / bjd.14681,2016、Ron et al.,Am.J.Case Rep.,15、17:254-8,2016、Fernandes et al.,Am.J.Med.Genet.A.,170(6):1532-7,2016、Lindy et al.,Am.J.Med.Genet.A.,170(6):1573-9,2016、Bennett et al.,Am.J.Hum.Genet.,98(3):579-87,2016、lchiyama et al.,J.Eur.Acad.Dermatol.Venereal.,30(3):442-5,2016、Zhao et al.,Int.J.Clin.Exp.Med.,8(10):19241-9,2015、Hasegawa et al.,Am.J.Med.Genet.A.,170A(5):1370-2,2016、Legeai-Mallet,Endocr.Dev.,30:98-105,2016、Takagi,Am.J.Med.Genet.A.,167A(ll):2851-4,2015、Goncalves,Fertil.Steril.,104(5):1261-7.el,2015、Miller et al.,Journal of Clinical Oncology,34:Supp.Supplement 15,pp.iii93.AbstractNumber:e22500,2016 Annual Meeting of the American Society of Clinical Oncology、Chicago,IL、Sarabipour et al.,J.Mol.Biol.,428(20):3903-3910,2016、Escobar et al.,Am.J.Med.Genet.A.,170(7):1908-11,2016、Mazen et al.,Sex Dev.,10(1):16-gyy C.,2016 et al.,Tayller、 lmmunol,136(2):507-9,2015.doi:10.1016 / j.jaci.2015.02.010、Kant et al,EuroJourn Endocrinol,172(6):763-770,2015.doi-10-El55 / E1530、 Angel et al,Am J med Genet A,176(1):161-166,2018.doi:10.1002 / ajmg.a.38526、Lei and Deng,Int J Biol Sci 13(9):1163:1171,2017.271et 0ijuni.10 al,Eur J Hum Genet,14(3):289-298,2006.doi:10.1038 / sj.ejhg.5201558、Karadimas et al,Prenat Diagn,26(3):258-261,2006.doiH39:10hip et.10. Mo / Genet 13(19):2313-2324,2004.doi:10.1093 / hmg / ddh235、Trarbach et al,J Clin Endocrinol Metab.,91(10):4006-4012,2006.doi:10.1210 / jc.2005-2793、Dode et al,Nat Genet,33(4):463-465,2003.doi:10.1038 / ng1122.

[0354] The term "angiogenesis-associated disorder" refers to a disease characterized in part by an increase in the number or size of blood vessels in a tissue in a subject or patient compared to a similar tissue from a subject without the disease. Non-limiting examples of angiogenesis-associated disorders include cancer (e.g., any of the exemplary cancers described herein, such as prostate cancer, lung cancer, breast cancer, bladder cancer, kidney cancer, colon cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, hepatocellular carcinoma, sarcoma, and lymphoma), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, iritis rubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.

[0355] The compounds of the present disclosure inhibit wild-type FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, the compounds of the present disclosure inhibit mutated FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, the compounds of the present disclosure inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4 that contain FGFR kinase inhibitor mutations.

[0356] In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is a lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrine carcinoma, smoking-related lung cancer), prostate cancer, colorectal cancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g., endometrioid endometrial cancer, endometrial adenocarcinoma), breast cancer (e.g., hormone receptor-positive breast cancer, triple negative breast cancer, neuroendocrine carcinoma of the breast), cutaneous cancer, or a combination thereof. Skin cancer (e.g., melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, large squamous cell carcinoma), gallbladder cancer, liposarcoma (e.g., dedifferentiated liposarcoma, myxoid liposarcoma), pheochromocytoma, myoepithelial carcinoma, urothelial carcinoma, spermatocytic seminoma, gastric cancer, head and neck cancer (e.g., head and neck (squamous cell) carcinoma, head and neck adenoid cystadenocarcinoma), brain cancer (e.g., glioneuronal tumor, glioma, neuroblastoma, glioblastoma, pilocytic astrocytoma, rosette-forming glioneuronal tumor, dysembryoplastic neuroepithelial tumor, anaplastic astrocytoma, medulloblastoma, ganglioglioma, oligodendroglioma), malignant peripheral nerve sheath tumor, sarcoma (e.g., soft tissue sarcoma (e.g., leiomyosarcoma), osteosarcoma), esophageal cancer (e.g., esophageal adenocarcinoma), lymphoma, bladder cancer (e.g., bladder urothelial (transitional cell) carcinoma), cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma), fallopian tube cancer (e.g., fallopian tube carcinoma), ovarian cancer (e.g., ovarian serous carcinoma, ovarian mucinous carcinoma), bile duct carcinoma, adenoid cystic carcinoma, pancreatic cancer (e.g., pancreatic exocrine carcinoma, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, intradermal tumor), salivary gland cancer (e.g., pleomorphic salivary gland adenocarcinoma, salivary adenoid cystic carcinoma), oral cancer (e.g., oral squamous cell carcinoma), uterine cancer, gastric or stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor, myeloma (e.g., multiple myeloma), lymphoepithelioma, anal cancer (e.g., anal squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), renal cell carcinoma, thymic carcinoma, gastroesophageal junction adenocarcinoma, testicular cancer, rhabdomyosarcoma (e.g.,alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma), papillary renal carcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), carcinoid, myeloproliferative disorder (also called myeloproliferative neoplasm (MPN), e.g., 8pll myeloproliferative syndrome (EMS, also called stem cell leukemia / lymphoma), acute myeloid leukemia (AML), chronic myeloid leukemia (CML)), lymphoma (e.g., T-cell lymphoma, T-lymphoblastic lymphoma, acute lymphoblastic leukemia (ALL), B-cell lymphoma), myeloid lymphoid neoplasm, chronic neutrophilic leukemia, phosphaturic mesenchymal tumor, thyroid cancer (e.g., anaplastic thyroid carcinoma), or cholangiocarcinoma.

[0357] In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adolescents, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid Tumor, Cancer of unknown primary, Cardiac tumor, Cervical cancer, Childhood cancer, Chordoma, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Chronic myeloproliferative neoplasm, Neoplasm by site, Neoplasm, Colon cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Cutaneous angiosarcoma, Bile duct carcinoma, Ductal carcinoma in situ, Embryonal tumor, Endometrial cancer, Ependymoma, Esophageal cancer, Neuroepithelioma, Ewing's sarcoma, Extracranial germ cell tumor, Extragonadal germ cell tumor, Extrahepatic bile duct cancer , eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, breast neoplasm, head and neck neoplasm, CNS tumor, primary CNS tumor, cardiac cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer, la Anglerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell cervical cancer, midline duct cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, site-specific neoplasm, neoplasm, myeloid leukemia leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasm, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, lung neoplasm, lung cancer, pulmonary neoplasm, airway neoplasm, bronchogenic carcinoma, bronchial neoplasm, oral cancer, oral cavity cancercancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromosytoma, pituitary cancer, plasma cell neoplasms, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon neoplasms, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, Spitz tumor tumor), small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell cervical cancer, gastric cancer, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, cancer of unknown primary site, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0358] In some embodiments, the hematological cancer (e.g., a hematological cancer that is an FGFR-associated cancer) is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, trilineage myelodysplasia (TCM), myeloma (MYELODYSOL ... The present invention relates to a method for treating leukemia, therapies, and methods ...

[0359] Additional examples of hematological cancers include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer (e.g., a hematological cancer that is an FGFR-associated cancer) is AML or CMML.

[0360] In some embodiments, the cancer (e.g., FGFR-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are FGFR-associated cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer), bladder cancer, colorectal cancer, brain cancer, testicular cancer, bile duct cancer, cervical cancer, prostate cancer, and spermatocytic seminoma. See, for example, Turner and Grose, Nat.Rev.Cancer, 10(2):116-129, 2010.

[0361] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer. In some embodiments, the FGFRl-related cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer. In some embodiments, the cancer is selected from the group consisting of breast cancer, uterine cancer, bile duct cancer, and lung cancer. In some embodiments, the FGFR2-related cancer is selected from the group consisting of breast cancer, uterine cancer, bile duct cancer, and lung cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer. In some embodiments, the FGFR3-related cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer. In some embodiments, the cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer. In some embodiments, the FGFR4-associated cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0362] In some embodiments, the compounds of the disclosure are useful in treating cancers associated with amplification or overexpression of FGFR1, such as breast cancer or carcinoma (e.g., hormone receptor positive breast cancer, ductal carcinoma in situ (breast)), pancreatic ductal adenocarcinoma, pancreatic exocrine cancer, smoking-related lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer or carcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, rhabdomyosarcoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), esophageal cancer (e.g., For example, it is useful to treat esophageal squamous cell carcinoma, sarcoma (e.g., osteosarcoma), hepatocellular carcinoma, renal cell carcinoma, colorectal carcinoma (e.g., colorectal adenocarcinoma), prostate carcinoma, salivary gland tumors, glioblastoma multiforme, bladder carcinoma, urothelial carcinoma, carcinoma of unknown primary site, squamous cell non-lung tumors, gastric carcinoma, gastroesophageal junction carcinoma, adenoid cystic carcinoma, anal squamous cell carcinoma, oral squamous cell carcinoma, cholangiocarcinoma, hemangioendothelioma, leiomyosarcoma, melanoma, neuroendocrine carcinoma, squamous cell carcinoma, and uterine carcinosarcoma.

[0363] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR2 amplification, such as gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer (e.g., triple-negative breast cancer), colon cancer, colorectal cancer (e.g., colorectal adenocarcinoma), urothelial cancer, bladder adenocarcinoma, cancer of unknown primary site, bile duct cancer, endometrial cancer, endometrial adenocarcinoma, esophageal adenocarcinoma, gallbladder cancer, ovarian cancer, fallopian tube cancer, exocrine pancreatic cancer, sarcoma, and squamous cell carcinoma. In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR2 overexpression, such as myxoid lipocarcinoma, rectal cancer, renal cell carcinoma, and breast cancer.

[0364] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with upregulation of FGFR3 activity, such as colorectal cancer, hepatocellular carcinoma, and exocrine pancreatic cancer. In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with overexpression of FGFR3 activity, such as multiple myeloma and thyroid cancer. In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with amplification of FGFR3 activity, such as bladder and salivary adenoid cystic carcinoma, urothelial carcinoma, breast cancer, carcinoid, cancer of unknown primary site, colorectal cancer (e.g., colorectal adenocarcinoma), gallbladder cancer, gastric cancer, gastroesophageal junction adenocarcinoma, glioma, mesothelioma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, and exocrine pancreatic cancer.

[0365] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR4 amplification, such as rhabdomyosarcoma, prostate cancer or carcinoma, breast cancer, urothelial cancer, carcinoid, cancer of unknown primary site, esophageal adenocarcinoma, head and neck cancer, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, and renal cell carcinoma.

[0366] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with upregulation of FGFR4 activity, such as colorectal cancer, hepatocellular carcinoma, adrenal cancer, and breast cancer.

[0367] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with overexpression of FGFR4 activity, such as pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.

[0368] In some embodiments, the compounds of the present disclosure are more selective for FGFR kinase than other kinases that are not FGFR kinases. For example, the compounds of the present disclosure are at least 3 times more selective for FGFR kinase than other kinases that are not FGFR kinases. In some embodiments, the compounds of the present disclosure are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 times more selective for FGFR kinase than other kinases that are not FGFR kinases. Kinases that are not FGFR kinases include, for example, KDR kinase and Aurora B kinase.

[0369] In some embodiments, the compounds disclosed herein exhibit brain and / or central nervous system (CNS) permeability. Such compounds can cross the blood-brain barrier and inhibit FGFR kinases in the brain and / or other CNS structures. In some embodiments, the compounds provided herein can cross the blood-brain barrier in therapeutically effective amounts. For example, treating a subject with cancer (e.g., an FGFR-associated cancer, such as an FGFR-associated brain or CNS cancer) can include administering (e.g., orally administering) a compound to the subject. In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors. For example, an FGFR-associated primary or metastatic brain tumors.

[0370] In some embodiments, compounds of the present disclosure exhibit one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.

[0371] In some aspects, the compounds of the present disclosure can be used to treat a subject diagnosed with (or identified as having) a disease or disorder associated with FGFR (e.g., FGFR-associated cancer), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. Also provided herein is a method for treating a subject identified or diagnosed as having a disease or disorder associated with FGFR (e.g., FGFR-associated cancer), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the subject is identified or diagnosed as having a disease or disorder associated with FGFR (e.g., FGFR-associated cancer) through the use of a regulatory agency approved, e.g., FDA approved, test or assay for identifying dysregulation of expression or activity or level of FGFR gene, FGFR kinase, or any of them in the subject or a biopsy sample from the subject, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the disease or disorder associated with FGFR is FGFR-associated cancer. For example, an FGFR-associated cancer can be a cancer that contains one or more FGFR inhibitor-resistant mutations.

[0372] Also provided are methods for treating a disease or disorder in a subject in need thereof, comprising: (a) detecting a disease or disorder associated with FGFR in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent, such as a second FGFR inhibitor, a second compound of the present disclosure, or an immunotherapy. In some embodiments, the subject has been previously treated with a first FGFR inhibitor or has been previously treated with another treatment. In some embodiments, the subject is determined to have a disease or disorder associated with FGFR through the use of a regulatory agency approved, e.g., FDA approved, test or assay to identify dysregulation of expression or activity or levels of an FGFR gene, an FGFR kinase, or any of them in the subject or a biopsy sample from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0373] Also provided are methods for treating cancer in a subject in need thereof, comprising: (a) detecting an FGFR-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or an immunotherapy). In some embodiments, the subject has been previously treated with a first FGFR inhibitor or has been previously treated with another anti-cancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is determined to have an FGFR-associated cancer through the use of a regulatory agency approved, e.g., FDA approved, test or assay to identify dysregulation of expression or activity or levels of an FGFR gene, an FGFR kinase, or any of them in the subject or a biopsy sample from the subject, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an FGFR-associated cancer. For example, FGFR-associated cancer can be a cancer that comprises one or more FGFR inhibitor-resistant mutations.In some embodiments, cancer is an FGFR-associated cancer.For example, FGFR-associated cancer can be a cancer that comprises one or more FGFR activating mutations.

[0374] Also provided are methods of treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulated expression or activity or level of an FGFR gene, an FGFR kinase, or any of them; and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof to the subject determined to have a dysregulated expression or activity or level of an FGFR gene, an FGFR kinase, or any of them. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or an immunotherapy). In some embodiments of these methods, the subject has been previously treated with a first FGFR inhibitor or has been previously treated with another anti-cancer therapy, such as at least partial tumor resection or radiation therapy. In some embodiments, the subject is a subject suspected of having an FGFR-associated disease or disorder (e.g., FGFR-associated cancer), a subject exhibiting one or more symptoms of an FGFR-associated disease or disorder (e.g., FGFR-associated cancer), or a subject at high risk of developing an FGFR-associated disease or disorder (e.g., FGFR-associated cancer). In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the dysregulation of the expression or activity or level of the FGFR gene, FGFR kinase, or any of them comprises one or more FGFR inhibitor-resistant mutations.

[0375] Also provided herein is a method of selecting a treatment for a subject, the method comprising: performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulated expression or activity or level of an FGFR gene, an FGFR kinase, or any of them (e.g., one or more FGFR inhibitor-resistant mutations); and identifying or diagnosing the subject determined to have a dysregulated expression or activity or level of an FGFR gene, an FGFR kinase, or any of them as having an FGFR-associated cancer. Some embodiments further comprise administering the selected treatment to the subject identified or diagnosed as having an FGFR-associated cancer. For example, in some embodiments, the selected treatment may comprise administering a therapeutically effective amount of a compound of the present disclosure to the subject identified or diagnosed as having an FGFR-associated cancer. In some embodiments, the assay is an in vitro assay, e.g., an assay utilizing next generation sequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a kit approved by a regulatory agency, e.g., approved by the FDA. In some embodiments, the assay is a liquid biopsy.

[0376] Also provided herein are methods of treating an FGFR-associated cancer in a subject, comprising: (a) administering one or more (e.g., two or more, three or more, four or more, five or more, or ten or more) doses of a first FGFR kinase inhibitor to a subject identified or diagnosed (e.g., identified or diagnosed as having an FGFR-associated cancer using any of the exemplary methods described herein or known in the art) with an FGFR-associated cancer (e.g., any of the types of FGFR-associated cancer described herein); (b) determining the level of circulating tumor DNA in a biological sample (e.g., a biological sample comprising blood, serum, or plasma) obtained from the subject after step (a); and (c) administering a therapeutically effective amount of a second FGFR inhibitor or compound of the disclosure, as a monotherapy or in combination with an additional therapy or therapeutic agent, to the subject identified as having about the same or elevated levels of circulating tumor DNA compared to a reference level of circulating tumor DNA (e.g., any of the reference levels of circulating tumor DNA described herein). In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from the subject prior to step (a). Some embodiments of these methods further include determining the level of circulating tumor DNA in a biological sample obtained from the subject prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of subjects with similar FGFR-associated cancer and similar stage of FGFR-associated cancer but receiving ineffective treatment or placebo or not yet receiving therapeutic treatment, or the level of circulating tumor DNA in subjects with similar FGFR-associated cancer and similar stage of FGFR-associated cancer but receiving ineffective treatment or placebo or not yet receiving therapeutic treatment).In some examples of these methods, the first FGFR inhibitor is ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio-1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, surufatinib, TAS-120, or RLY-4008.

[0377] The compounds of the present disclosure can also be administered with additional therapy or therapeutic agents. In some aspects, the additional therapy or therapeutic agents include one or more of radiation therapy, chemotherapy (e.g., any of the exemplary chemotherapy agents described herein or known in the art), checkpoint inhibitors (e.g., any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partial resection of the tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).

[0378] The compounds of the present disclosure may also be useful as adjuvants for cancer treatment, i.e., they may be used in combination with one or more additional therapies or therapeutic agents, e.g., chemotherapeutic agents acting by the same or different mechanisms of action. In some embodiments, the compounds of the present disclosure may be used prior to administration of the additional therapeutic agent or therapy. For example, a subject in need thereof may be administered one or more doses of the compounds of the present disclosure for a period of time and then undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of the compounds of the present disclosure reduces the size of the tumor (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, the subject has a cancer (e.g., locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent such as a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)). In some embodiments, the subject has cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to previous therapy (e.g., administration of a chemotherapeutic agent such as a first FGFR inhibitor or a multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)).

[0379] In some embodiments of any of the methods described herein, a compound of the present disclosure is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.

[0380] Non-limiting examples of additional therapeutic agents include other FGFR targeted therapies (i.e., a first or second FGFR kinase inhibitor), other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapies (e.g., Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways (e.g., obataclax), cytotoxic chemotherapeutic agents, angiogenesis targeted therapies, immune targeted agents including immunotherapies, and radiation therapy.

[0381] Also provided herein is a method of treating a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical combination for treating the disease or disorder, comprising (a) a compound of the present disclosure, (b) an additional therapeutic agent, and (c) optionally at least one pharma- ceutically acceptable carrier for simultaneous, separate, or sequential use for the treatment of the disease or disorder, wherein the amounts of the compound of the present disclosure and the additional therapeutic agent are effective together to treat the disease or disorder. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered sequentially in any order as separate dosages, for example, in daily or intermittent dosages, in a jointly therapeutically effective amount. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the disease or disorder is a disease or disorder associated with FGFR. In some embodiments, the subject has been administered one or more doses of a compound of the present disclosure prior to administration of the pharmaceutical composition.

[0382] In some embodiments, the treatment period is at least 7 days (e.g., at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or about 17 days, at least or about 18 days, at least or about 19 days, at least or about 20 days, at least or about 21 days, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, or at least or about 30 days).

[0383] In some embodiments, the treatment period is at least 21 days (e.g., at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or about 35 days, at least or about 36 days, at least or about 37 days, at least or about 38 days, at least or about 39 days, or at least or about 40 days).

[0384] Also provided herein is a pharmaceutical composition that contains the compound of the present disclosure as an active ingredient in combination with one or more pharma- ceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is formulated as a tablet or capsule.

[0385] Compositions containing the compounds of the present disclosure may be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units for human and other subjects, each unit containing a predetermined amount of the active material (i.e., a compound of the present disclosure) to produce the desired therapeutic effect, together with a suitable pharmaceutical excipient.

[0386] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of active ingredient, i.e., the compound of the present disclosure. One of ordinary skill in the art will appreciate that this embodies a compound or composition containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of active ingredient. In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies compounds or compositions containing from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 350 mg to about 400 mg, or from about 450 mg to about 500 mg of active ingredient. In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies a compound or composition containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

[0387] The active compound can be effective over a wide dosage range and is generally administered in a pharmacologic effective amount.However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound to be administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0388] In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, such administration can be once daily or twice daily (BID).

[0389] In some embodiments, the compounds of the present disclosure can be used for treatment in patients with FGFR mutations (either point mutations or various fusions) to provide excellent benefits, but also in situations where these mutations are likely to occur (e.g., in erdafitinib and / or infigratinib (BGJ398), pemigatinib, or TAS-120 therapy), where patients have recurrent multiple activating and resistant mutations. In some embodiments, the compounds of the present disclosure can be used as therapeutic intervention in patients with these mutations, either in combination with a pan-FGFR inhibitor, or as a monotherapy where genomic testing supports the mutations for which the compounds of the present disclosure are active.

[0390] In some embodiments, a method of treating cancer is provided. In some embodiments, the method of treating cancer comprises administering one or more compounds of the present disclosure. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure in response to determining the presence of an FGFR mutant polypeptide or an FGFR mutant polynucleotide in a sample from the subject. This can treat cancer in the subject. In some embodiments, the FGFR mutant is one of those disclosed herein and / or an activating mutant (including a point mutation or an FGFR fusion).

[0391] In some embodiments, the methods of treating cancer include administering to a patient suspected of having or at risk of having cancer one or more compounds of the present disclosure. In some embodiments, the methods include administering to the subject an effective amount of a compound of the present disclosure, which can be done with or without diagnosis or analysis of the subject's kinase (including whether the kinase is wild type or mutant).

[0392] In some embodiments, FGFR variants are fusions that can be caused by chromosomal translocations in cancer. These translocations can lead to fusion proteins that exert their oncogenic effects through overexpression of otherwise normal genes or growth factor-independent activation, or through the creation of chimeric genes in which parts of two genes are fused together. Fusions of FGFR genes with other genes or parts of genes are most commonly found in FGFR2 and FGFR3. The most common fusion partner reported for FGFR3 is TACC3 (Transforming Acidic Coiled-Coil Containing Protein).

[0393] In some embodiments, the mutations in FGFR are polyclonal. Thus, when FGFR or FGFR fusion-driven cancers metastasize, each metastasis may have different mutation patterns in the FGFR kinase domain. For example, a patient with different liver metastases may have gatekeeper mutations in a subset of metastases, but not necessarily in all of them at the time of treatment or biopsy. The presence of a founding mutation from the primary tumor, i.e., FGFR fusion, is likely to remain in all patients. In some embodiments, it is that founding mutation that is targeted by any one or more of the methods provided herein. In some embodiments, both the founding mutation and the other mutation are targeted by any one or more of the methods provided herein. In some embodiments, only the later mutation is targeted by one or more of the methods provided herein. In some embodiments, any of the methods provided herein may be a method in which a compound of the present disclosure is administered in an amount sufficient to treat a tumor in a subject with metastasis, and the tumor being treated is a primary tumor. In some embodiments, any of the methods provided herein can use a sufficient amount of the disclosed compound to treat a subset of tumors in a subject. For example, the subset can include or focus on tumors with underlying mutations (primary tumors). Thus, in some embodiments, the therapy does not need to target or include the amount of the disclosure to treat all tumors, but only a subset of tumors (e.g., primary tumors with underlying mutations). In some embodiments, the treated tumor can be a metastasis that is not a primary tumor but has detectable resistance or activating mutations not found in the primary tumor. In some embodiments, the method includes administering the disclosed compound in an amount sufficient to treat a tumor in a subject that has metastasis, where the treated tumor is not a primary tumor and the treated tumor is a metastasis that has detectable resistance or activating mutations not found in the primary tumor.

[0394] In some embodiments, the compounds can be used to treat subjects with other types of mutations in FGFR, including allosteric mutations such as FGFR3 S249C.

[0395] In some embodiments, a method of treating cancer is provided, the method comprising administering to the subject an effective amount of a compound of the present disclosure in response to determining the presence of an FGFR activating mutation in the subject, thereby treating the cancer in the subject, wherein the FGFR activating mutation is a driver in non-fusion cancer. In some embodiments, an effective amount of a compound of the present disclosure is an amount that reduces the activity of the FGFR mutant to a level sufficient to provide some treatment to the subject, for example, by reducing one or more symptoms. In some embodiments, the activity of the mutant FGFR is reduced by the compound of the present disclosure to near or below wild-type activity. In some embodiments, when a compound of the present disclosure is administered, activity for the mutant FGFR is reduced to 500, 400, 300, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 105, 104, 103, 102, 101, 100, 95, 90, or less percent of activity of the wild-type FGFR.

[0396] In some embodiments, a method of treating cancer in a subject in need of cancer treatment is provided. The method includes administering an inhibitor of FGFR kinase activity to a subject determined to have a gene fusion of an FGFR and a second gene, wherein the inhibitor of FGFR is at least as effective against the gene fusion of FGFR as against wild-type FGFR kinase. In some embodiments, the inhibitor can be a compound of the present disclosure. In some embodiments, the inhibitor of FGFR kinase activity is at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 300, 400, 500, 1000, 5000, or 10,000% or more effective against the fusion FGFR than against the wild-type FGFR. In some embodiments, the compounds of the present disclosure are at least 1.1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times more potent against mutant FGFRs than against wild type. In some embodiments, the IC50 for the compounds of the present disclosure is 0.5, 0.1, 0.05, or 0.01% greater against mutant FGFRs than against wild type (i.e., the numerical value for IC50 is lower against mutants).

[0397] In some embodiments, the IC of the disclosed compounds against FGFR variants or mutations 50 is about 100 nM or less (e.g., it is at least as potent as 100 nM). In some embodiments, the IC 50 is about 10 nM or less (e.g., it is at least as potent as 10 nM). In some embodiments, the IC 50 is less than or equal to single digit nM (e.g., it is at least as potent as single digit nM). In some embodiments, the IC 50 is at least as effective against FGFR mutants or variants as it is against wild-type FGFR.

[0398] In some embodiments of the method, the subject is in (or still in) a state of a multi-targeted kinase inhibitor ("MKI") or a targeted FGFR inhibitor. While in the MKI or targeted FGFR inhibitor state, the subject's tumor becomes resistant to the previous MKI or targeted FGFR inhibitor. At this point, a compound of the present disclosure can be administered. Alternatively, it can be determined whether the subject currently has a tumor with an FGFR mutation therein (such as an amino acid change that results in resistance to the previous therapy). If the subject has a tumor with a mutation, then a compound of the present disclosure can be administered to the subject.

[0399] In some embodiments, the method of using the compounds of the present disclosure can be directed to treating various cancers or cancers in general.In some embodiments, the cancer is one or more of urothelial carcinoma, breast cancer, endometrial carcinoma, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, pancreatic exocrine carcinoma, oral cavity, prostate, bladder, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous cell), melanoma, leiomyosarcoma, and / or sarcoma.In some embodiments, the subject has intrahepatic cholangiocarcinoma.This list shows some, but not all, of the FGFR mutation-related cancers. In some embodiments, the cancer may include any of the previous options and / or any of the following: urothelial cancer, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, exocrine pancreatic cancer, oral cavity, prostate, bladder, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, and / or sarcoma. In some embodiments, the subject has intrahepatic cholangiocarcinoma. In some embodiments, the cancer may include any of the previous options and / or any of the following: urothelial cancer, breast cancer, endometrial cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, exocrine pancreatic cancer, oral cavity, prostate, bladder, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, and / or sarcoma. EXAMPLES

[0400] In some embodiments, the compounds of the disclosure are those described in the Examples below.

[0401] The use of the general methods for synthesizing embodiments of the present invention is illustrated by the following representative examples.

[0402] [ka] Example 8. N-[3-methyl-1-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide Step 1. 1-(2-Chloro-5-methyl-pyrimidin-4-yl)-3-methyl-5-nitro-indole. To a solution of 3-methyl-5-nitro-1H-indole (2.0 g, 11.4 mmol) in dry DMF (14 mL) cooled to 0 °C (ice bath) was added NaH (60.0%, 0.681 g, 17.0 mmol) in portions. The resulting dark red suspension was stirred at 0 °C for 30 min and then slowly transferred to a solution of 2,4-dichloro-5-methyl-pyrimidine (2.22 g, 13.6 mmol) in dry DMF (6 ml). The reaction mixture was stirred at room temperature for 2 h. Water (20 ml) was added and the resulting precipitate was collected by filtration, washed with water, MeOH and dried in vacuum to give a yellow solid (3.0 g, 75%). LCMS m / z=303 (M+1).

[0403] Step 2. 5-Methyl-4-(3-methyl-5-nitro-indol-1-yl)-N-(1-methylpyrazol-4-yl)pyrimidin-2-amine. A suspension of 1-(2-chloro-5-methyl-pyrimidin-4-yl)-3-methyl-5-nitro-indole (300 mg, 0.991 mmol) and 1-methylpyrazol-4-amine (115 mg, 1.19 mmol) in isopropanol (4.80 mL) was irradiated at 140° C. for 30 min in a microwave reactor. The reaction was irradiated at 140° C. for another 30 min. The precipitate that formed was collected to give a yellow solid (255 mg, 85%). LCMS m / z=364 (M+1).

[0404] Step 3. 3-Methyl-1-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-amine. To a solution of 5-methyl-4-(3-methyl-5-nitro-indol-1-yl)-N-(1-methylpyrazol-4-yl)pyrimidin-2-amine (250 mg, 0.605 mmol) in a mixture of ethanol (15 mL) and water (4 mL) was added ammonium chloride (64.8 mg, 1.21 mmol) and Fe (406 mg, 7.27 mmol). The resulting mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, diluted with DCM, filtered through Celite, and the residue was washed with DCM and methanol. The organic layers were combined and washed with saturated NaHCO 3 solution (20 mL) and Na 2 SO 4 It was dried over and concentrated to give a solid (212 mg). LCMS m / z=334 (M+1).

[0405] Step 4. N-[3-Methyl-1-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide. To a cooled solution of 3-methyl-1-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-amine (50 mg, 0.142 mmol) in dry THF (1.5 ml) was added diisopropylethylamine (0.0486 mL, 0.356 mmol) followed by acryloyl chloride (12.9 mg, 0.142 mmol). The resulting mixture was stirred at room temperature for 45 min. The reaction was diluted with saturated NaHCO 3 (10 ml) and extracted with DCM (3×10 ml). The organic layers were combined, dried over sodium sulfate and evaporated to give a brown solid. Trituration with MeOH and diethyl ether gave a white solid (20 mg, 36%). LCMS m / z=388 (M+1); 1 H NMR(500MHz,DMSO-d6) δ:10.14(s,1H),9.45(br s,1H),8.42(s,1H),8.06(d,J=1.5Hz,1H),7.88-7.68(m,2H),7.57-7.55(m,1H),7.48(s,1H),7.40(dd,J =9.0,2.0Hz,1H),6.48(dd,J=16.9,10.2Hz,1H),6.26(dd,J=16.9,2.0Hz,1H),5.76-5.72(m,1H),3.75(br s,3H),2.29(s,3H),2.21(s,3H).

[0406] [ka] Example 24. N-[3-methyl-1-[5-chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide Step 1. 1-(2,5-dichloropyrimidin-4-yl)-3-methyl-5-nitro-indole. To a solution of 3-methyl-5-nitro-1H-indole (467 mg, 2.7 mmol) in DMF (5 mL) at 0 °C (ice bath) was added NaH (60% dispersion in mineral oil, 127 mg, 1.2 equiv.) carefully in portions. The suspension was stirred at ice bath temperature for 30 min. The resulting slurry was then transferred to a cold (0 °C) solution of 2,4,5-trichloropyrimidine (583 mg, 3.2 mmol, 1.20 equiv.) in DMF (5 mL) and stirred for 30 min. Upon completion, water (10 mL) was carefully added with stirring. The precipitate was collected, washed with EtOAc (3 mL) and dried in vacuum to give a yellow powder (725 mg, 83%). LCMS m / z=323, 325 (M+1, 1 Cl).

[0407] Step 2. 5-Chloro-4-(3-methyl-5-nitro-indol-1-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine. A suspension of 1-(2,5-dichloropyrimidin-4-yl)-3-methyl-5-nitro-indole (300 mg, 0.928 mmol) and 4-morpholinoaniline (199 mg, 1.11 mmol) in 2-propanol (10 mL) was heated at 140 °C for 60 min in a MW. The precipitate formed during the reaction was filtered off, washed with a small amount of MeOH and dried in vacuum to give a yellow solid (371 mg, 86%). LCMS m / z=465 (M+1).

[0408] Step 3. 1-[5-Chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]-3-methyl-indol-5-amine. A suspension of 5-chloro-4-(3-methyl-5-nitro-indol-1-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine (371 mg, 0.798 mmol), iron (535 mg, 9.58 mmol), and ammonium chloride (171 mg, 3.19 mmol) in EtOH (30 mL) and water (5 mL) was stirred at 85 °C for 2 h. Upon complete conversion, the reaction mixture was filtered through Celite and concentrated to dryness. The remaining residue was suspended in DCM and washed with saturated NaHCO 3The organic layer was separated and washed with MgSO 4 Dry on ice and evaporate to dryness to give a yellow solid (325 mg, 94%). LCMS m / z=435 (M+1).

[0409] Step 4. N-[1-[5-chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. To a solution of 1-[5-chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]-3-methyl-indol-5-amine (325 mg, 0.590 mmol) in dry THF (10 mL) was added DIPEA (0.161 mL, 1.18 mmol) followed by acryloyl chloride (0.0528 mL, 0.649 mmol). The resulting mixture was stirred at room temperature for 30 min. The reaction was then concentrated in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO 3 solution and brine, then Na 2 SO 4 After evaporation of DCM, the crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give a yellow solid (152 mg, 53%). LCMS m / z=489 (M+1); 1 H NMR(500MHz,DMSO-d6) δ:10.17(s,1H),9.74(s,1H),8.60(s,1H),8.06(d,J=1.5Hz,1H),7.84(br s,1H),7.70(s,1H),7.55(d,J=9.2Hz,2H),7.41(d,J=8.9Hz,1H),6.88(br d,J=8.9Hz,2H),6.47(dd,J=17.1,10.1Hz,1H),6.27(dd,J=16.9,2.0Hz,1H), 5.73-5.77(m,1H),3.73(t,J=4.6Hz,4H),3.03(t,J=4.9Hz,4H),2.28(s,3H).

[0410] [ka] Example 30. N-[3-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide Step 1. 1-Methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole. A 100 ml reaction tube was charged with boron tribromide (1M in DCM, 45.4 mL, 45.4 mmol), DCM (20 ml), and 2,6-lutidine (5.29, 45.4 mmol) in that order. The solution was cooled in an ice bath for 10 min, then a solution of 1-methyl-6-nitro-indole (2.0 g, 11.4 mmol) in DCM (10 ml) was added dropwise over 10 min. The reaction mixture was allowed to reach room temperature. After stirring at room temperature for 1 h, the reaction was cooled to 0° C. and a solution of pinacol (5.37 g, 45.4 mmol) in N,N-diisopropylethylamine (29.7 ml, 170.3 mmol) was added dropwise over 35 min. The resulting mixture was allowed to reach room temperature and stirred for 1 h. The reaction was then diluted with DCM and NaHCO 3 The solution was washed with water and brine. The organic extract was concentrated in vacuo and the crude material was purified by silica gel chromatography (EtOAc / CyHex=1 / 3) to give a green solid (1.65 g, 49%). LCMS m / z=303 (M+1).

[0411] Step 2. 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-6-nitro-indole. A suspension of 1-methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole (530 mg, 1.75 mmol), 2,4,5-trichloropyrimidine (221 μL, 1.93 mmol, 1.1 equiv.), and sodium carbonate (0.37 g, 3.51 mmol, 2 equiv.) in acetonitrile (12 mL) and water (6 mL) was bubbled with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.10 mg, 0.09 mmol, 0.05 equiv.) was added and the resulting mixture was irradiated at 80 °C for 60 min in a MW reactor. The reaction mixture was poured into water and the precipitate was collected by filtration and dried in vacuo to give a yellow solid (250 mg, 44%). LCMS m / z=323 (M+1); 1 H NMR(500MHz,DMSO-d6) δ 9.06(s,1H) 8.83(s,1H) 8.63(d,J=9.1Hz,1H) 8.61(d,J=1.8Hz,1H) 8.18(dd,J=8.8,2.1Hz,1H) 4.09(s,3H).

[0412] Step 3. 5-Chloro-4-(1-methyl-6-nitro-indol-3-yl)-N-(1-methylpyrazol-4-yl)pyrimidin-2-amine. A suspension of 1-methylpyrazol-4-amine (25.0 mg, 0.26 mmol) and 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-6-nitro-indole (70.0 mg, 0.22 mmol) in isopropanol (1.0 mL) was heated at 140 °C for 90 min in a microwave reactor. After cooling to 25 °C, the product was collected by filtration, washed with MeOH, and dried in vacuum to give a yellow solid (70 mg, 55%). LCMS m / z=384 (M+1).

[0413] Step 4. 3-[5-Chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-amine. To a suspension of 5-chloro-4-(1-methyl-6-nitro-indol-3-yl)-N-(1-methylpyrazol-4-yl)pyrimidin-2-amine (70.0 mg, 0.182 mmol) in EtOH / water (3 mL / 1 mL) was added iron (122 mg, 2.19 mmol) followed by ammonium chloride (19.5 mg, 0.36 mmol). The mixture was stirred at reflux for 1 h. Upon complete conversion, the reaction mixture was diluted with DCM (30 mL), stirred at room temperature for 5 min, filtered through Celite and concentrated to dryness in vacuo to give a yellow solid (98 mg, 65%). LCMS m / z=354 (M+1).

[0414] Step 5. N-[3-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide. To a solution of 3-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-amine (98 mg, 0.21 mmol) in dry THF (5 mL) was added DIPEA (72 μL, 0.41 mmol) followed by acryloyl chloride (17 μL, 0.21 mmol). The resulting mixture was stirred at room temperature for 5 minutes. Upon completion, the reaction mixture was evaporated to dryness. The product was purified by preparative HPLC to give a yellow solid (21 mg, 25%). LCMS m / z=408 (M+1); 1 H NMR(500MHz,DMSO-d6) δ:9.97(br s,1H),9.09(br s,1H),8.46(br d,1H,J=8.5Hz),8.39(s,1H),8.35(s,1H),8.08(d,1H,J=0.9Hz),7.84(s,1H),7.53(s,1H),7.32(dd,1H,J=1.7,8.7Hz ),6.50(dd,1H,J=10.2,16.9Hz),6.29(dd,1H,J=2.0,16.9Hz),5.73(dd,1H,J=1.8,10.4Hz),3.87(s,3H),3.82(s,3H).

[0415] Example 32. N-[1-[5-cyano-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide [ka] Step 1. 4-(3-Methyl-5-nitro-indol-1-yl)-2-[(1-methylpyrazol-4-yl)amino]pyrimidine-5-carbonitrile. A suspension of 2-chloro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidine-5-carbonitrile (300 mg, 0.96 mmol) and 1-methylpyrazol-4-amine (111 mg, 1.15 mmol) in isopropanol (4.5 mL) was irradiated at 140 °C for 30 min in a microwave reactor. After cooling to room temperature, the precipitate was collected and washed with MeOH to give the title product as a mixture of regioisomers (316 mg). LCMS m / z=375 (M+1).

[0416] Step 2. 4-(5-amino-3-methyl-indol-1-yl)-2-[(1-methylpyrazol-4-yl)amino]pyrimidine-5-carbonitrile. A suspension of 4-(3-methyl-5-nitro-indol-1-yl)-2-[(1-methylpyrazol-4-yl)amino]pyrimidine-5-carbonitrile (310 mg, 0.83 mmol), iron (555 mg, 9.94 mmol), and ammonium chloride (88.6 mg, 1.66 mmol) in EtOH (12 mL) and water (4.5 mL) was heated at reflux for 1.5 h. The mixture was then cooled to room temperature, DCM (15 mL) was added, and the mixture was stirred for 5 min. The solution was filtered to remove the precipitate, which was washed with DCM (10 mL) and MeOH (10 mL). The filtrate layers were separated and the organic phase was washed with Na 2 SO 4 Drying on ice and evaporation of the solvent gave a brown solid (266 mg, 68%). LCMS m / z=345 (M+1).

[0417] Step 3. N-[1-[5-cyano-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. To a stirred solution of the product from step 2 (266 mg, 0.58 mmol) and DIPEA (202 μL, 1.16 mmol) in dry THF (15 mL) at 0° C., acryloyl chloride (46.8 μL, 0.58 mmol) was added. The reaction mixture was stirred at room temperature for 5 min, quenched with water (0.1 mL), and then concentrated to give the crude product. The product was purified by preparative HPLC to give a light brown solid (30 mg, 13%). LCMS m / z=399 (M+1); 1 H NMR(600MHz,DMSO-d6) δ:10.48-10.42(m,2H),10.24(d,J=7.3Hz,2H),8.89(s,1H),8.85(s,1H),8.48(d,J=9.0Hz,1H),8.09(d ,J=1.8Hz,1H),8.07(d,J=1.8Hz,1H),8.00(d,J=8.8Hz,1H),7.97(s,1H),7.92(d,J=1.1Hz,1H),7.85(s, 1H),7.80(d,J=1.3Hz,1H),7.58(d,J=3.7Hz,2H),7.55(dd,J=2.0,9.0Hz,1H),7.44(dd,J=2.1,8.9Hz,1H ),6.51-6.45(m,2H),6.30-6.26(m,2H),5.78-5.75(m,2H),3.85(s,3H),3.80(s,3H),2.31-2.28(m,6H).

[0418] [ka] Example 34. N-[1-[5-chloro-2-[[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide Step 1. tert-Butyl 4-[4-[[5-chloro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate. A suspension of 1-(2,5-dichloropyrimidin-4-yl)-3-methyl-5-nitro-indole (1 g, 3.09 mmol), tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (907 mg, 3.40 mmol, 1.1 equiv.), cesium carbonate (2 g, 6.19 mmol, 2 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (183 mg, 0.309 mmol, 0.1 equiv.) in dry dioxane (15 mL) was degassed with argon for 5 min, then palladium(II) acetate (56 mg, 0.248 mmol, 0.08 equiv.) was added. The reaction mixture was heated at 80° C. for 45 min in a MW. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with DCM. The solvent was concentrated to give a brown solid (1.95 g). This material was used directly in the next step. LCMS m / z=551 (M+1).

[0419] Step 2. 5-Chloro-4-(3-methyl-5-nitro-indol-1-yl)-N-[1-(4-piperidyl)pyrazol-4-yl]pyrimidin-2-amine. A solution of the product Step 1 (1.95 g, 3.53 mmol) in DCM (15 ml) was added with trifluoroacetic acid (5.40 ml, 70.52 mmol, 20 equiv). The resulting mixture was stirred at room temperature for 30 min and then placed on a conditioned SCX column (20 g). The column was washed with MeOH (5×30 ml) and then eluted with 2N NH 3 / MeOH (50 ml) to give a yellow foam (1.27 g, 80%). LCMS m / z=453 (M+1).

[0420] Step 3. 5-Chloro-4-(3-methyl-5-nitro-indol-1-yl)-N-[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]pyrimidin-2-amine. To a solution of 5-chloro-4-(3-methyl-5-nitro-indol-1-yl)-N-[1-(4-piperidyl)pyrazol-4-yl]pyrimidin-2-amine (250 mg, 0.552 mmol) and oxetan-3-one (35 μl, 0.552 mmol, 1 equiv.) in THF (5 mL) was added sodium cyanoborohydride (41.6 mg, 0.662 mmol, 1.2 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO 3 The mixture was diluted with ethyl acetate (15 ml) and extracted with EtOAc (3×15 ml). The organic layer was washed with water (1×30 ml) and brine (1×30 ml) to give a solid (236 mg, 51%) which was used directly in the next step. LCMS m / z=509 (M+1).

[0421] Step 4. 1-[5-Chloro-2-[[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-amine. A suspension of 5-chloro-4-(3-methyl-5-nitro-indol-1-yl)-N-[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]pyrimidin-2-amine (236 mg, 0.464 mmol), iron (310.7 mg, 5.56 mmol, 12 equiv.), and ammonium chloride (99.2 mg, 1.85 mmol, 4 equiv.) in EtOH (3 mL) and water (1.5 mL) was stirred at reflux overnight. Upon complete conversion, the reaction mixture was diluted with DCM (30 mL), stirred at room temperature for 5 min, filtered through Celite and concentrated to give a yellow solid (204 mg, 92%). LCMS m / z=479 (M+1).

[0422] Step 5. N-[1-[5-chloro-2-[[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. To a solution of the product from step 4 (204 mg, 0.426 mmol) in dry THF (1 ml) was added diisopropylethylamine (145 μl, 1.604 mmol, 2.5 equiv.) followed by prop-2-enoyl chloride (34 μl, 0.426 mmol, 1 equiv.). The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with water (0.1 mL) and concentrated. The product was purified by preparative HPLC to give a yellow solid (36 mg, 16%). LCMS m / z=533 (M+1); 1 H NMR(DMSO-d6,500MHz) δ:9.91(br s,1H),9.56(s,1H),8.56(s,1H),7.97(s,1H),7.87(s,1H),7.82(br d,J=8.8Hz,1H),7.67(s,1H),7.53(s,1H),7.51(d,J=9.3Hz,1H),6.48(dd,J=16.9,10.2Hz,1H),6.27(dd,J=16.9,1.6Hz,1H),5.72(dd,J=10.2 ,1.6Hz,1H),4.5(t,J=6.41Hz,2H),4.44(t,J=5.9Hz,2H),4.01-4.09(m,1H),3.47(quin,J=6.3Hz,1H),2.72-2.82(m,2H),2.31(s,3H),2.00(br t,J=10.3Hz,4H),1.81-1.94(m,2H).

[0423] [ka] Example 52. N-[1-methyl-3-[5-methyl-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-6-yl]prop-2-enamide Step 1. 3-(2-Chloro-5-methyl-pyrimidin-4-yl)-1-methyl-6-nitro-indole. This intermediate was synthesized with 1-methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole and 2,4-dichloro-5-methyl-pyrimidine using the procedure for step 2 of example 30 to give a solid. LCMS m / z=303 (M+1).

[0424] Step 2. 5-Methyl-4-(1-methyl-6-nitro-indol-3-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine. A suspension of 4-morpholinoaniline (162.0 mg, 0.908 mmol) and 3-(2-chloro-5-methyl-pyrimidin-4-yl)-1-methyl-6-nitro-indole (125.0 mg, 0.413 mmol) in isopropanol (16.0 mL) was heated at 150 °C for 7 h in a microwave reactor. After cooling to 25 °C, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (DCM:MeOH = 100:4) to give a yellow solid (25 mg, 14%). LCMS m / z = 445.20 (M + 1).

[0425] Step 3. 1-Methyl-3-[5-methyl-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-6-amine. To a suspension of 5-methyl-4-(1-methyl-6-nitro-indol-3-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine (25.0 mg, 0.0562 mmol) in EtOH / water (5.0 mL / 0.75 mL in a 25 mL flask) was added iron (37.7 mg, 0.675 mmol) followed by ammonium chloride (12.0 mg, 0.225 mmol). The resulting mixture was stirred at 85° C. for 30 min. The reaction mixture was cooled to 25° C., diluted with DCM (10.0 mL) and the organic layer was filtered off from the brown residue that had accumulated in the flask. The contents of the flask were rinsed with DCM (30 mL) and the organic layer was decanted. The combined organic layers were washed with Na 2 SO 4Dry over low heat, filter and concentrate the solvent to give a yellow solid (23 mg, 100%). LCMS m / z=415.24 (M+1).

[0426] Step 4. N-[1-Methyl-3-[5-methyl-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-6-yl]prop-2-enamide. To a solution of 1-methyl-3-[5-methyl-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-6-amine (23.2 mg, 0.0560 mmol) in dry THF (4.0 mL) was added N,N-diisopropylethylamine (29.2 μL, 0.168 mmol), followed by acryloyl chloride (4.5 μL, 0.056 mmol). The reaction mixture was stirred at 25° C. for 10 min. The reaction mixture was then transferred to a separatory funnel containing distilled water and the mixture was extracted with DCM. The combined DCM layers were washed with Na 2 SO 4 The solvent was concentrated and the residue was purified by preparative HPLC to give a white solid (4.6 mg, 20%). LCMS m / z=469.13 (M+1); 1 H NMR (DMSO-d6, 500MHz) δ:10.22(s,1H),9.03(s,1H),8.56(d,J=8.63Hz,1H),8.20(s,1H),8.15(s,1H) ,8.00(s,1H),7.67-7.63(m,2H),7.21(d,J=8.66Hz,1H),6.90-6.86(m,2H),6.5 0(dd,J=10.19,16.95Hz,1H),6.28(dd,J=1.72,16.99Hz,1H),5.76(dd,J=1.51 ,10.03Hz,1H),3.86(s,3H),3.76-3.73(m,4H),3.05-3.02(m,4H),2.36(s,3H).

[0427] [ka] Example 53. N-[1-methyl-3-[2-(4-morpholino-anilino)pyrimidin-4-yl]indol-6-yl]prop-2-enamide Step 1. 3-(2-Chloropyrimidin-4-yl)-1-methyl-6-nitro-indole. This intermediate was synthesized using the procedure for step 2 of example 30 using 1-methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole and 2,4-dichloropyrimidine to give a yellow solid. LCMS m / z=307 (M+1).

[0428] Step 2. 4-(1-Methyl-6-nitro-indol-3-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine. A suspension of 3-(2-chloropyrimidin-4-yl)-1-methyl-6-nitro-indole (356 mg, 1.23 mmol) and 4-morpholinoaniline, A20 (264 mg, 1.48 mmol) in isopropanol (12 mL) was irradiated at 150 °C for 60 min in a microwave reactor. After cooling to room temperature, the precipitate was collected by filtration and washed with iPrOH to give a brown solid (516 mg, 81%). LCMS m / z=431 (M+1).

[0429] Step 3. 1-Methyl-3-[2-(4-morpholinoanilino)pyrimidin-4-yl]indol-6-amine. A suspension of 4-(1-methyl-6-nitro-indol-3-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine (516 mg, 1.20 mmol), iron (536 mg, 9.59 mmol), and ammonium chloride (128 mg, 2.40 mmol) in EtOH (20 mL) and water (9 mL) was heated at reflux for 5 min. The mixture was cooled to room temperature, diluted with DCM (20 mL), and stirred for 5 min. The precipitate was removed by filtration and washed with DCM (15 mL). The organic phase was washed with water and brine, then with NaCl. 2 SO 4 The mixture was dried over ice. The solvent was concentrated to give a dark grey powder (425 mg, 83%). LCMS m / z=401 (M+1).

[0430] Step 4. N-[1-Methyl-3-[2-(4-morpholino-anilino)pyrimidin-4-yl]indol-6-yl]prop-2-enamide. To a solution of 1-methyl-3-[2-(4-morpholino-anilino)pyrimidin-4-yl]indol-6-amine (405 mg, 0.85 mmol) with 4 Å molecular sieves (1.2 g) in EtOAc / DMF (40 mL / 10 mL) at 0° C. was added TEA (947 μL, 6.80 mmol), acrylic acid (58.3 μL, 0.85 mmol), and T3P (50.0 wt % in ethyl acetate, 1.52 mL, 2.55 mmol). The mixture was stirred at room temperature for 10 min. An additional 50 μL of T3P was added and stirring was continued for 5 min. The mixture was then transferred to a separatory funnel containing 100 mL of water, extracted, and the layers were separated. The aqueous phase was extracted with a DCM / MeOH mixture (10:1, 5×70 mL). The organic layers were washed with 5% aqueous LiCl (3×50 mL), combined, and washed with Na 2 SO 4 It was dried over water and evaporated to dryness. The product was purified by preparative HPLC to give a yellow solid (31 mg). LCMS m / z=455 (M+1); 1 H NMR(DMSO-d6,600MHz) δ:10.23(s,1H),9.14(s,1H),8.52(br d,J=8.3Hz,1H),8.27(d,J=5.2Hz,1H),8.23(s,1H),8.15(d,J=1.5Hz,1H), 7.66(d,J=8.0Hz,2H),7.25(dd,J=8.6,1.5Hz,1H),7.10(d,J=5.3Hz,1H),6. 93(d,J=7.9Hz,2H),6.50(dd,J=16.9,10.1Hz,1H),6.28(dd,J=17.0,1.9Hz ,1H),5.74-5.78(m,1H),3.83(s,3H),3.72-3.79(m,4H),3.03-3.09(m,4H).

[0431] Example 54. N-[3-methyl-1-[2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide [ka] Step 1. 4-(3-Methyl-5-nitro-indol-1-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine. A suspension of 1-(2-chloropyrimidin-4-yl)-3-methyl-5-nitro-indole (200 mg, 0.48 mmol) and 4-morpholinoaniline (104 mg, 0.58 mmol, 1.2 equiv) in 2-propanol (4 mL) was heated at 150 °C for 60 min in a MW. The mixture was concentrated and the residue was purified by silica gel chromatography (DCM:MeOH = 100:4) to give a white solid (152 mg). LCMS m / z = 431 (M + 1).

[0432] Step 2. 3-Methyl-1-[2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-amine. A suspension of 4-(3-methyl-5-nitro-indol-1-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine (145 mg, 0.34 mmol), iron (226 mg, 4.04 mmol), and ammonium chloride (72 mg, 1.35 mmol) in EtOH (3 mL) and water (1.5 mL) was stirred at 85° C. for 2 h. The reaction mixture was diluted with DCM (15 ml), filtered, and the solvent was evaporated in vacuo. The residue was suspended in water (50 ml) and extracted with DCM (3×30 ml). The combined organic layers were washed with water, brine, and concentrated to give a solid (78 mg, 78%). LCMS m / z=401 (M+1).

[0433] Step 3. N-[3-Methyl-1-[2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide. To a solution of 3-methyl-1-[2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-amine (78 mg, 0.1916 mmol) in dry THF (1 mL) was added DIPEA (85 μl, 0.49 mmol) followed by acryloyl chloride (3 μl, 0.19 mmol). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO 3 and brine, and Na 2 SO4 After drying over low heat and concentrating the solvent, the product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give a yellow solid (35 mg, 45%). LCMS m / z=455 (M+1); 1 H NMR(500MHz,DMSO-d6) δ:10.17(s,1H),9.39(s,1H),8.69(br s,1H),8.36(d,J=5.8Hz,1H),8.05(d,J=1.8Hz,1H),7.91(s,1H),7.58(br d,J=8.5Hz,2H),7.42(br d,J=8.2Hz,1H),7.03(d,J=5.8Hz,1H),6.95(d,J=9.1Hz,2H),6.47(dd,J=16.9,10.2Hz,1H),6.2 7(dd,J=16.9,1.9Hz,1H),5.73-5.77(m,1H),3.72-3.79(m,4H),3.03-3.12(m,4H),2.27(s,3H).

[0434] [ka] Example 57. N-[3-[5-fluoro-2-(4-morpholinoanilino)pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide Step 1. 3-(2-Chloro-5-fluoro-pyrimidin-4-yl)-1-methyl-6-nitro-indole. This intermediate was synthesized from 1-methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole and 2,4-dichloro-5-fluoro-pyrimidine using the procedure for step 2 of example 30 to give a yellow solid. LCMS m / z=307 (M+1).

[0435] Step 2. 5-Fluoro-4-(1-methyl-6-nitro-indol-3-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine. A suspension of 3-(2-chloro-5-fluoro-pyrimidin-4-yl)-1-methyl-6-nitro-indole (240 mg, 0.783 mmol) and 4-morpholinoaniline (167 mg, 0.939 mmol) in isopropanol (5 mL) was heated in a microwave reactor at 150° C. for 1 h and then at 155° C. for 1 h. The reaction mixture was cooled to 25° C. The precipitate was collected by filtration, washed with isopropanol and dried to give a brown solid (321 mg, 92%). LCMS m / z=449.24 (M+1).

[0436] Step 3. 3-[5-Fluoro-2-(4-morpholinoanilino)pyrimidin-4-yl]-1-methyl-indol-6-amine. To a suspension of 5-fluoro-4-(1-methyl-6-nitro-indol-3-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine (321 mg, 0.716 mmol) in EtOH / water (30.0 mL / 7.0 mL) was added iron (480 mg, 8.59 mmol) followed by ammonium chloride (153 mg, 2.86 mmol). The resulting mixture was stirred at reflux (oil bath temperature of 85° C.) for 30 min. The reaction mixture was then cooled to 25° C., diluted with DCM, and the organic layer was filtered to remove brown solids. The contents of the flask were rinsed with DCM / MeOH, and the organic layer was filtered. The combined organic phase was washed with Na 2 SO 4 Dry over medium, filter and concentrate to give a brown solid (279 mg, 93%). LCMS m / z=419.20 (M+1).

[0437] Step 4. N-[3-[5-Fluoro-2-(4-morpholinoanilino)pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide. A solution of 3-[5-fluoro-2-(4-morpholinoanilino)pyrimidin-4-yl]-1-methyl-indol-6-amine (300 mg, 0.716 mmol) in dry THF (20.0 mL) was added N,N-diisopropylethylamine (374.0 μL, 2.15 mmol) followed by acryloyl chloride (57.9 μL, 0.716 mmol). The reaction mixture was stirred at 25° C. for 10 min. The reaction mixture was transferred to a separatory funnel containing distilled water and the mixture was extracted with DCM. The combined organic extracts were washed with Na 2 SO 4 It was dried over, filtered and concentrated to give a brown solid. The product was purified by preparative HPLC to give a white solid (125 mg, 37%). LCMS m / z=472.10 (M+1); 1 H NMR(DMSO-d6,500MHz) δ:10.26(s,1H),9.29(s,1H),8.65(d,J=8.50Hz,1H),8.36(d,J=3.93Hz,1H),8.19-8.17(m,2H),7.64-7.59(m,2H),7.30-7.26(m,1H),7.00(br s,2H),6.50(dd,J=10.06,16.90Hz,1H),6.28(dd,J=1.95,16.90Hz,1H),5.77 (dd,J=1.88,10.03Hz,1H),3.87(s,3H),3.80-3.76(m,4H),3.16-3.08(m,4H).

[0438] [ka] Example 67. N-[1-[5-fluoro-2-(4-morpholino-anilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide Step 1. 3-(2-Chloro-5-fluoro-pyrimidin-4-yl)-1-methyl-6-nitro-indole. This intermediate was synthesized with 3-methyl-5-nitro-1H-indole and 2,4-dichloro-5-fluoro-pyrimidine using the procedure for step 1 of example 8 to give a solid. LCMS m / z=307 (M+1).

[0439] Step 2. 5-Fluoro-4-(3-methyl-5-nitro-indol-1-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine. A suspension of 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-3-methyl-5-nitro-indole (300 mg, 0.978 mmol) and 4-morpholinoaniline (213 mg, 1.174 mmol, 1.2 equiv) in 2-propanol (10 mL) was heated at 150 °C for 3 h in a MW. The precipitate formed in the reaction was filtered off, washed with a small amount of MeOH and dried in vacuum to give a brown solid (400 mg, 91%). LCMS m / z=449 (M+1).

[0440] Step 3.1-[5-Fluoro-2-(4-morpholinoanilino)pyrimidin-4-yl]-3-methyl-indol-5-amine. A suspension of 5-fluoro-4-(3-methyl-5-nitro-indol-1-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine (400 mg, 0.892 mmol), iron (598 mg, 10.704 mmol), and ammonium chloride (191 mg, 3.568 mmol) in EtOH (7 mL) and water (3.5 mL) was stirred at 85 °C for 3 h. The reaction mixture was then filtered through Celite and concentrated to dryness in vacuo. The residue was suspended in DCM and washed with saturated NaHCO 3 The organic layer was separated and washed with MgSO 4 Dry on ice and concentrate to give a brown solid (193 mg, 52%). LCMS m / z=419 (M+1).

[0441] Step 4. N-[1-[5-Fluoro-2-(4-morpholinoanilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. To a solution of 1-[5-fluoro-2-(4-morpholinoanilino)pyrimidin-4-yl]-3-methyl-indol-5-amine (190 mg, 0.454 mmol) in dry THF (2 mL) was added DIPEA (198 μl, 1.135 mmol) and acryloyl chloride (37 μl, 0.454 mmol). The resulting mixture was stirred at room temperature for 30 min and then concentrated. The residue was dissolved in DCM and NaHCO 3 and brine, and Na 2 SO 4 It was dried over and evaporated. The product was purified by preparative HPLC to give a yellow solid (25 mg, 12%). LCMS m / z=472 (M+1); 1 H NMR(300MHz,DMSO-d6) δ:10.20(s,1H),9.50(s,1H),8.53(d,J=4.7Hz,1H),8.32-8.48(m,1H),8.06(d,J=1.7Hz,1H),7.68(s,1H),7.55(d,J=9.0Hz,2H),7.44(br d,J=8.8Hz,1H),6.94(br d,J=9.0Hz,2H),6.47(dd,J=16.9,10.0Hz,1H),6.26(dd,J=16.9,2.1Hz,1 H),5.72-5.78(m,1H),3.69-3.80(m,4H),2.96-3.18(m,4H),2.26(s,3H).

[0442] Example 146. N-[1-[2-[(1,5-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide [ka] Step 1. 3-(2-Chloro-5-fluoro-pyrimidin-4-yl)-1-methyl-6-nitro-indole. This intermediate was synthesized with 3-methyl-5-nitro-1H-indole and 2,4-dichloro-5-fluoro-pyrimidine using the procedure for step 1 of example 8 to give a solid. LCMS m / z=307 (M+1).

[0443] Step 2. N-(1,5-Dimethylpyrazol-4-yl)-5-fluoro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-amine. To a suspension of 1,5-dimethylpyrazol-4-amine (99.7 mg, 0.897 mmol), 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-3-methyl-5-nitro-indole (250 mg, 0.815 mmol) and potassium carbonate (225 mg, 1.63 mmol) in dry dioxane (6 mL) was bubbled with nitrogen for 10 min, followed by the addition of Xantphos (70.8 mg, 0.122 mmol) and palladium(II) acetate (18.3 mg, 0.0815 mmol). The resulting mixture was irradiated in a MW at 80 °C for 45 min. The reaction was filtered and evaporated to dryness. The residue was dissolved in DCM (50 mL) and saturated NaHCO 3 The organic layer was dried over sodium sulfate and concentrated to give a crude solid, which was purified by silica gel chromatography (DCM:MeOH:NH 4 Purification by HCl=90:5:0.5, 0-50%) gave a solid (181 mg, 58%). LCMS m / z=382 (M+1).

[0444] Step 3. 1-[2-[(1,5-Dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-amine. A suspension of N-(1,5-dimethylpyrazol-4-yl)-5-fluoro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-amine (181 mg, 0.475 mmol), iron (318 mg, 5.70 mmol), and ammonium chloride (102 mg, 1.90 mmol) in EtOH (8 mL) and water (4 mL) was stirred at reflux (80° C.) for 0.5 h. Upon complete conversion, the reaction mixture was diluted with DCM (50 ml), filtered, and the layers were separated. The aqueous layer was extracted with DCM (2×30 ml). The organic layers were combined and washed with anhydrous Na 2 SO 4 Dry over medium, filter and concentrate to give a yellow solid (165 mg, 99%). LCMS m / z=352 (M+1).

[0445] Step 4. N-[1-[2-[(1,5-Dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. To a solution of 1-[2-[(1,5-Dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-amine (280 mg, 0.797 mmol) in dry THF (12 ml) stirred at 0° C., DIPEA (0.272 mL, 1.99 mmol) was added, followed by acryloyl chloride (72.1 mg, 0.797 mmol). The resulting mixture was stirred at room temperature for 20 min. Water was added and the reaction mixture was concentrated. The residue was dissolved in DCM (100 mL) and washed with saturated NaHCO 3 solution and brine, then Na 2 SO 4 The crude solid was purified by silica gel chromatography (DCM / DCM:MeOH:NH 4 OH=90:9:0.5=10 / 1) to give a yellow solid (167 mg, 52%). LCMS m / z=406 (M+1); 1H NMR(500MHz,DMSO-d6) δ:9.88(br s,1H),8.45(s,1H),8.39(d,J=4.9Hz,1H),8.10(br d,J=8.5Hz,1H),7.98(s,1H),7.63(s,1H),7.42(s,1H),7.38(br d,J=8.9Hz,1H),6.47(dd,J=16.9,10.2Hz,1H),6.27(br d,J=17.1Hz,1H),5.72(br d,J=10.1Hz,1H),3.77(s,3H),2.28(s,3H),2.15(s,3H).

[0446] Example 167. N-[1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide [ka] Step 1. N-(1,3-Dimethylpyrazol-4-yl)-5-fluoro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-amine. A suspension of 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-3-methyl-5-nitro-indole (5.50 g, 17.9 mmol), 1,3-dimethylpyrazol-4-amine (2.99 g, 26.9 mmol), and potassium carbonate (6.196 g, 44.8 mmol) in dry 1,4-dioxane (80 mL) was degassed with nitrogen for 10 min. Then, rac-BINAP (1.675 g, 2.69 mmol) and palladium(II) acetate (403 mg, 1.79 mmol) were added, and the resulting mixture was heated at 100° C. for 90 min. After cooling to room temperature, the reaction mixture was filtered. The filtrate was evaporated and the residue was purified by Interchim520+ (40 g column, eluent 0-100% DCM:MeOH=9:1 / DCM) to give 6.9 g (99%). LCMS m / z=382 (M+1).

[0447] Step 2. 1-[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-amine. N-(1,3-Dimethylpyrazol-4-yl)-5-fluoro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-amine (2.0 g, 5.24 mmol), iron (2.343 g, 42.0 mmol), and ammonium chloride (561 mg, 10.5 mmol) were heated at reflux in EtOH (107 mL) and water (36 mL) for 2 h. After cooling to room temperature, DCM (50 mL) was added and the mixture was filtered. The filtrate was dissolved in saturated NaHCO 3 The organic phase was diluted with Na 2 SO 4 Drying on ice and evaporation gave 1.7 g (92%) which was used directly in the next step. LCMS m / z=352 (M+1).

[0448] Step 3. N-[1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. To a solution of 1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-amine (1.70 g, 4.84 mmol) in DMF (30 mL) was added acryloyl chloride (0.398 mL, 4.84 mmol) and N,N-diisopropylethylamine (2.53 mL, 14.5 mmol). The resulting mixture was stirred at room temperature for 1 h and then concentrated. The residue was purified by silica gel chromatography (0-50% DCM:MeOH:NH4OH=90:5:1.5 / DCM) to give 875 mg (45%) as a white solid. LCMS m / z=406(M+1); 1H NMR(500MHz,DMSO-d6) δ:9.91(s,1H),8.52(s,1H),8.43(d,J=4.6Hz,1H),8.18(d,J=9.2Hz,1H),8.00(s,1H),7.71(s,1H),7.64(s,1H),7.41(d,J=9. 2Hz,1H),6.47(dd,J=17.1,10.1Hz,1H),6.27(d,J=17.1Hz,1H),5.73(d,J=10.4Hz,1H),3.78(s,3H),2.29(s,3H),2.10(s,3H).

[0449] Example 181: N-[1-[5-fluoro-2-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. [ka] Step 1. 2-Methyl-1-(4-nitropyrazol-1-yl)propan-2-ol. A suspension of 4-nitro-1H-pyrazole (7.0 g, 62 mmol, 1 eq.), 1-chloro-2-methyl-propan-2-ol (7.6 mL, 74 mmol, 1.2 eq.), and potassium carbonate (17.1 g, 124 mmol, 2 eq.) in i-PrOH was heated at 80° C. for 6 h. After cooling to room temperature, the reaction mixture was concentrated to one-third of the volume. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with Na 2 SO 4 After drying and concentration, a yellow viscous oil (11 g, 97%) was obtained. LCMS m / z=185.96 (M+1); 1 H NMR(500MHz,DMSO-d6) δ:8.65(s,1H),8.25(s,1H),4.83(s,1H),4.09(s,2H),1.09(s,6H).

[0450] Step 2. 1-(4-aminopyrazol-1-yl)-2-methyl-propan-2-ol. A solution of 2-methyl-1-(4-nitropyrazol-1-yl)propan-2-ol (16.3 g, 87.8 mmol) in MeOH (200 mL) was added Pd / C (10%, 1.87 g, 1.76 mmol) and the reaction mixture was heated in a Parr apparatus at 3 bar H 2 Shake at room temperature under ambient for 2 hours. The reaction mixture was filtered through a pad of Celite to remove the catalyst. The Celite pad was washed with MeOH and the combined solvents were concentrated to give a purple oil (13.8 g, 96%). LCMS m / z=155.96 (M+1); 1 H NMR(500MHz,DMSO-d6) δ:7.02(s,1H),6.89(s,1H),4.60(s,1H),3.76-3.85(m,4H),1.00(s,6H).

[0451] Step 3. 1-(2-Chloro-5-fluoro-pyrimidin-4-yl)-3-methyl-5-nitro-indole. The general procedure described above was followed. 2,4-Dichloro-5-fluoro-pyrimidine (1.05 equiv.), 3-methyl-5-nitro-1H-indole (1 equiv.), and K 2 CO 3 (1.5 equiv.) was stirred at room temperature for 4 h. The reaction mixture was diluted with water and the precipitate formed was collected, washed with water and diethyl ether, then dried under vacuum overnight to give a yellow solid. LCMS m / z=307 (M+1); 1 H NMR (DMSO-d6,500MHz) δ:9.03(d,J=3.7Hz,1H),8.57(d,J=2.1Hz,1H),8.41(d,J=9.2Hz,1H),8.28(dd,J=9.2,2.1Hz,1H),7.91(s,1H),2.40(s,3H).

[0452] Step 4. 1-[4-[[5-Fluoro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-yl]amino]pyrazol-1-yl]-2-methyl-propan-2-ol. The following general procedure was used. A suspension of 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-3-methyl-5-nitro-indole (1 eq.), 1-(4-aminopyrazol-1-yl)-2-methyl-propan-2-ol (1.2 eq.), and 4-methylbenzenesulfonic acid (1 eq.) in 1,4-dioxane was heated at reflux (105 °C) for 48 h. The product precipitates during the reaction. The mixture was cooled to room temperature, diluted with water, and washed with saturated NaHCO 3 The solution was neutralized and stirred at room temperature for 30 minutes. The precipitate was collected, washed thoroughly with water and ethanol, and then dried under vacuum overnight to give a yellow solid. Yield 86%; LCMS m / z=426.08 (M+1); 1 H NMR(DMSO-d6,500MHz) δ:9.44(s,1H),8.63(d,J=3.7Hz,1H),8.54(d,J=2.1Hz,1H),8.37(br d,J=8.9Hz,1H),8.12(dd,J=9.0,2.0Hz,1H),7.87(s,1H),7.83(s,1H),7.56(s,1H),4.38(br s,1H),3.99(s,2H),2.42(s,3H),1.10(s,6H).

[0453] Step 5. 1-[4-[[4-(5-amino-3-methyl-indol-1-yl)-5-fluoro-pyrimidin-2-yl]amino]pyrazol-1-yl]-2-methyl-propan-2-ol. A suspension of 1-[4-[[5-fluoro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-yl]amino]pyrazol-1-yl]-2-methyl-propan-2-ol (1 equiv.), Pd / C (10.0%, 0.1 equiv.) in THF was heated in an autoclave with H 2Stirred overnight under atmosphere (6 bar at room temperature). The reaction mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The solvent was concentrated and the solid was suspended in MeOH, filtered and dried in a vacuum oven to give a beige solid. Yield 71%; LCMS m / z=396.29 (M+H); 1 H NMR(500MHz,DMSO-d6) δ:9.15(s,1H),8.40(d,J=4.9Hz,1H),8.12(br d,J=8.5Hz,1H),7.86(s,1H),7.55(s,1H),7.49(s,1H),6.73(d,J=1.8Hz,1H),6.64(d d,J=8.7,2.0Hz,1H),4.68(s,2H),4.41(s,1H),3.98(s,2H),2.21(s,3H),1.10(s,6H).

[0454] Step 6. N-[1-[5-fluoro-2-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. To a solution of 1-[4-[[4-(5-amino-3-methyl-indol-1-yl)-5-fluoro-pyrimidin-2-yl]amino]pyrazol-1-yl]-2-methyl-propan-2-ol (1 eq.) and N,N-diisopropylethylamine (2.5 eq.) in dry THF was added acryloyl chloride (1 eq.) in four portions at 15 min intervals. The mixture was then stirred at room temperature for 2 h. Water was added and the mixture was concentrated. The residue was diluted with ethanol, water was added slowly, and the product was precipitated as a yellow slurry after stirring for 30 min. The solvent was decanted and the product was collected by filtration and dried under vacuum to give a pale yellow solid. Yield 85%; LCMS m / z=450 (M+H); 1H NMR(500MHz,DMSO-d6) δ:9.94(s,1H),9.28(s,1H),8.50(d,J=4.6Hz,1H),8.31(d,J=8.2Hz,1H),8.01(s,1H),7.88(s,1H),7.64(s,1H),7.57(s,1H),7. 49(d,J=8.5Hz,1H),6.46-6.44(m,1H),6.32-6.24(m,1H),5.76-5.70(m,1H),4.41(s,1H),3.99(s,2H),2.30(s,3H),1.10(s,6H).

[0455] Example 185. N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide [ka] Step 1. (2R)-1-(4-nitropyrazol-1-yl)propan-2-ol. A suspension of 4-nitro-1H-pyrazole (2.0 g, 17.7 mmol), (2R)-2-methyloxirane (1.86 mL, 26.5 mmol), and cesium carbonate (11500 mg, 35.4 mmol) in dry DMF (25 mL) was heated at 100 °C for 30 min. Upon complete conversion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 5% aqueous LiCl and Na 2 SO 4 The residue was purified by silica gel chromatography (cyclohexane:EtOAc=2:1) ​​to give a yellow oil (1.7 g, 38%). LCMS m / z=172 (M+1).

[0456] Step 2. (2R)-1-(4-aminopyrazol-1-yl)propan-2-ol. To a solution of (2R)-1-(4-nitropyrazol-1-yl)propan-2-ol (674 mg, 3.94 mmol) in methanol (70 mL) was added Pd / C (10.0%, 169 mg, 0.158 mmol) and the reaction mixture was stirred at room temperature under hydrogen atmosphere (2 bar) for 3 h. The reaction mixture was filtered over Celite and rinsed thoroughly with MeOH. The filtrate was concentrated to dryness to give a purple oil (553 mg, 99%). LCMS m / z=142 (M+1); 1 H NMR(300MHz,DMSO-d6) δ:6.99(s,1H),6.87(s,1H),4.79(d,J=4.7Hz,1H),3.68-3.96(m,5H),0.95(d,J=6.1Hz,3H).

[0457] Step 3. (2R)-1-[4-[[5-fluoro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-yl]amino]pyrazol-1-yl]propan-2-ol. A suspension of 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-3-methyl-5-nitro-indole (400 mg, 1.30 mmol), (2R)-1-(4-aminopyrazol-1-yl)propan-2-ol (203 mg, 1.43 mmol), and potassium carbonate (361 mg, 2.61 mmol) in dry 1,4-dioxane (15 mL) was degassed with argon for 10 min. Xantphos (113 mg, 0.196 mmol) and palladium(II) acetate (29.3 mg, 0.130 mmol) were then added and the reaction mixture was irradiated in a MW at 80 °C for 45 min. After cooling to room temperature, the reaction mixture was concentrated and the residue was dissolved in DCM and saturated NaHCO 3 Wash with NaCl solution and brine. 2 SO 4 It was dried over and concentrated. The crude product was triturated with MeOH, collected and dried to give a yellowish solid (428 mg, 80%). LCMS m / z=412 (M+1).

[0458] Step 4. (2R)-1-[4-[[4-(5-amino-3-methyl-indol-1-yl)-5-fluoro-pyrimidin-2-yl]amino]pyrazol-1-yl]propan-2-ol. A suspension of (2R)-1-[4-[[5-fluoro-4-(3-methyl-5-nitro-indol-1-yl)pyrimidin-2-yl]amino]pyrazol-1-yl]propan-2-ol (92.0%, 428 mg, 0.957 mmol), iron (641 mg, 11.5 mmol), and ammonium chloride (205 mg, 3.83 mmol) in EtOH (15 mL) and water (3 mL) was stirred at reflux for 1 h. Upon complete conversion, the reaction mixture was diluted with DCM, filtered, and the solvent was concentrated in vacuo. The residue was dissolved in DCM (100 mL) and washed with saturated NaHCO 3 Wash with NaCl solution and brine. 2 SO 4 It was dried over water and concentrated to dryness to give a yellow solid (335 mg, 92%). LCMS m / z=382 (M+1).

[0459] Step 5. Preparation of N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. To a solution of (2R)-1-[4-[[4-(5-amino-3-methyl-indol-1-yl)-5-fluoro-pyrimidin-2-yl]amino]pyrazol-1-yl]propan-2-ol (335 mg, 0.826 mmol) in dry THF (10 ml) was added DIPEA (0.225 mL, 1.65 mmol) followed by acryloyl chloride (0.0671 mL, 0.826 mmol). The resulting mixture was stirred at room temperature for 30 min. Water was added, the reaction mixture was concentrated, and the residue was dissolved in DCM (100 mL) and saturated NaHCO 3 Wash with NaCl solution and brine. 2 SO 4 After drying and concentration, the product was purified by silica gel chromatography (DCM:MeOH=10:1) to give a white solid (155 mg, 43%). LCMS m / z=436 (M+1); 1H NMR(500MHz,DMSO-d6) δ:9.93(s,1H),9.27(s,1H),8.49(d,J=4.6Hz,1H),8.31(d,J=8.9Hz,1H),8.01(d,J= 1.5Hz,1H),7.86(s,1H),7.64(s,1H),7.55(s,1H),7.50(dd,J=8.9,1.8Hz,1H),6.48( dd,J=17.1,10.4Hz,1H),6.28(dd,J=16.9,2.0Hz,1H),5.73(dd,J=10.1,1.8Hz,1H),4 .60(d,J=4.0Hz,1H),3.94-4.03(m,3H),2.30(d,J=0.9Hz,3H),1.07(d,J=5.8Hz,3H).

[0460] Example 186. N-[1-[5-fluoro-2-[[1-[(2S)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide [ka] Step 1. (2S)-1-(4-aminopyrazol-1-yl)propan-2-ol was synthesized using the procedure for (2R)-1-(4-aminopyrazol-1-yl)propan-2-ol example 185 starting from 4-nitro-1H-pyrazole and (2S)-2-methyloxirane to give an oil. LCMS m / z=142 (M+1), 1 H NMR(300MHz,DMSO-d6) δ:6.99(s,1H),6.87(s,1H),4.79(d,J=4.7Hz,1H),3.71-3.84(m,5H),0.95(d,J=5.9Hz,3H).

[0461] Step 2. N-[1-[5-fluoro-2-[[1-[(2S)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide. This example was synthesized using the procedure for example 185 with 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-3-methyl-5-nitro-indole and (2S)-1-(4-aminopyrazol-1-yl)propan-2-ol to give a white solid. LCMS m / z=436 (M+1); 1 H NMR (500MHz, DMSO-d6, 353K) δ:9.94(s,1H),9.27(s,1H),8.50(d,J=4.9Hz,1H),8.31(d,J=8.9Hz,1H),8.01( s,1H),7.86(s,1H),7.64(s,1H),7.55(s,1H),7.49(dd,J=8.9,1.8Hz,1H),6.48( dd,J=16.9,10.2Hz,1H),6.28(dd,J=17.1,1.8Hz,1H),5.73(dd,J=10.4,1.8Hz,1 H),4.60(d,J=3.1Hz,1H),3.94-4.03(m,3H),2.30(s,3H),1.07(d,J=5.5Hz,3H).

[0462] The examples in Table 1 below, which were synthesized using the general methods described above, are embodiments of the present invention.

[0463] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

[0464] Kinase assay Kinase-tagged T7 phage stocks were prepared in E. coli host derived from the BL21 strain. E. coli were grown to log phase, infected with T7 phage, and incubated with shaking at 32°C until lysis. Lysates were centrifuged and filtered to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. Ligandized beads were blocked with excess biotin and washed with blocking buffer SeaBlock (Pierce), 1% BSA, 0.05% Tween20, 1 mM DTT to remove unbound ligand and reduce nonspecific binding. Binding reactions were assembled by combining kinase, liganded affinity beads, and test compounds in 1× binding buffer (20% SeaBlock, 0.17× PBS, 0.05% Tween20, 6 mM DTT).

[0465] Test compounds were prepared as 111X stocks in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series with three DMSO adjustment points. All compounds for Kd measurements were distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. Compounds were then directly diluted into the assay so that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plates. Each was in a final volume of 0.02 ml. The assay plate was incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. Kinase concentrations in the eluates were measured by qPCR.

[0466] Coupling constant (Kd) Binding constants were calculated using the Hill equation with standard dose-response curves.

number

[0467] The Hill slope was set to -1. Curves were fitted using a nonlinear least-squares fit with the Levenberg-Marquardt algorithm. [Table 2]

[0468] Cell viability assays for RT112 / 84, UM-UC-14, SNU-16, and KG-1 cancer cell lines Cell Titer-Glo® detects changes in intracellular ATP and assesses the in vitro IC 50 The inhibitory effect of the compound on the cancer cell line is evaluated by determining the .

[0469] Cell Titer-Glo® 2.0 Luminescent Cell Viability Assay Reagent was purchased from Promega (Madison, WI). RT112 / 84, SNU-16, and KG-1 cell lines were purchased from American Type Culture Collection (Manassas, VA). UM-UC-14 cell line was purchased from Sigma (St. Louis, MO). RT112 / 84, UM-UC-14, SNU-16, and KG-1 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0470] Cell viability assay procedure: Cells were seeded at 10,000 cells / well in 100 μl of medium in 96-well clear bottom / white plates (Corning #3903) and incubated overnight. The next day, DMSO stock solutions of test compounds were made at final concentrations of 10 mM and 2 μM. Compounds were then added to the cells in a 9-dose, 10-fold dilution series starting at 30 μM using an HP300e digital dispenser (each dose was applied in triplicate). DMSO was filled to each well up to a total volume of 301 nL of test compound+DMSO, and a total of 301 nL of DMSO was added to the control / non-test compound wells in triplicate. Cells in cell culture plates were incubated with compounds at 37°C and 5% CO 2 The cells were incubated at 4°C for 72 hours. 50 μl of Cell Titer Glo 2.0 reagent was then added to each well of the cell culture plate. The contents were covered from light and mixed for 10 minutes at room temperature on an orbital shaker. Luminescence was recorded by a Synergy H1 Microplate Reader (Biotek, Winooski, VT). Cells were assessed as a percentage of control cells treated with DMSO only. Curves were plotted and IC values ​​were calculated using the GraphPad Prism8 program based on a sigmoidal dose-response equation (4 parameters). 50 values ​​were calculated. The Kd values ​​are shown in Table 2. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0471] In some embodiments, the present disclosure is directed to the following aspects: Aspect 1. A compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 1 H, F, Cl, Br, C 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2, -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 and R 2 is a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E, and E is an electrophilic moiety that can react with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety, or a pharma- ceutically acceptable salt thereof. Aspect 2.R 2 but, [ka] where: Q 1 is N or CH; Q 2 But N or CR 3A and R 3A But, H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 is alkyl, Q 3 , Q 4 , Q 5 , and Q 6 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, C3 ~C 7 cycloalkyl, or E, where Q 3 , Q 4 , Q 5 , and Q 6 At least one of the following is CE: R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO 2 (C 1 ~C 6 2. The compound according to embodiment 1, wherein R is an alkyl group. Aspect 3.R 2 The compound according to aspect 2, wherein [ka] Aspect 4. The compound of formula I is a compound of formula IA: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Q 1 is N or CH; Q 2 But N or CR 3A and R 3A But, H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 is alkyl, Q 3 , Q 4, and Q 5 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, or C 3 ~C 7 The compound according to embodiment 1, wherein said compound is cycloalkyl. Aspect 5. Q 1 is CH, Q 2 But, CR 3A and Q 3 and Q 4 However, each 3B and Q 5 But N or CR 3B and R 3A is H or -CH 3 and Each R 3B are independently H or -CH 3 5. The compound according to embodiment 4, wherein Aspect 6. Q 1 is N, Q 2 But, CR 3A and Q 3 and Q 4 However, each 3B and Q 5 But N or CR 3B and R 3A is H or -CH 3 and Each R 3B are independently H or -CH 3 5. The compound according to embodiment 4, wherein Aspect 7. The compound of formula I is a compound of formula IB: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Q 1 is N or CH; Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, or C 3 ~C 7 is cycloalkyl, R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO 2 (C 1 ~C 6 2. The compound according to embodiment 1, wherein R is an alkyl group. Aspect 8. Q 1 is CH, R 4 But -CH 3 and Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B and Each R 3B are independently H or -CH 3 8. The compound of claim 7, Aspect 9. Q 1 is N, R 4 But -CH 3 and Q 3 , Q 4 , Q 5 But N or CR 3B and Each R 3B are independently H or -CH3 8. The compound of embodiment 7, wherein Aspect 10.R 1 -H, -Cl, -F, -CH 3 or -CN. Aspect 11.R 1 is -Cl. Aspect 12.R 1 But -CH 3 11. The compound according to embodiment 10, wherein Aspect 13.R 1 is -H. Aspect 14.R 1 The compound according to embodiment 10, wherein Aspect 15.R 1 is -CN. Embodiment 16. A compound according to any one of the preceding embodiments, wherein Ar is an optionally substituted 6-10 membered aryl group. Aspect 17. The compound according to aspect 16, wherein the optionally substituted 6-10 membered aryl group is an optionally substituted phenyl group. Embodiment 18. The phenyl group is one or more optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 6 Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl), -O(optionally substituted C 1 ~C 6 18. The compound according to embodiment 17, wherein the compound is substituted with -alkyl, -CN, or halogen. Embodiment 19. A compound according to any one of embodiments 1 to 15, wherein Ar is an optionally substituted 5-10 membered heteroaryl group. Aspect 20. A compound according to aspect 19, wherein the 5-10 membered heteroaryl group is pyridinyl, pyrazolyl, triazolyl, imidazolyl, pyrazolopyrimidine, or triazolopyridine. Embodiment 21. A 5-10 membered heteroaryl group is one or more optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 6 Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl), -O(optionally substituted C 1 ~C 6 21. The compound according to any one of embodiments 19 to 20, wherein the compound is substituted with -alkyl), -CN, or halogen. 22. Optionally substituted C 1 ~C 6 Alkyl is -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl), or -CH 2 CH 2 The compound according to embodiment 18 or embodiment 21, wherein R is OH. Aspect 23.-CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl) is [ka] 23. The compound according to embodiment 22, wherein 24. Optionally substituted C 3 ~C 6 The compound according to embodiment 18 or embodiment 21, wherein cycloalkyl is cyclopropyl or cyclobutyl. 25. An optionally substituted 4-6 membered heterocycloalkyl is [ka] 22. The compound according to embodiment 18 or embodiment 21, Aspect 26.-N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl) is [ka] 2. A compound according to claim 18 or claim 21, wherein 27. -O(optionally substituted C 1 ~C 6 alkyl) is -OCH 3 , -OCH 2 CH 3 or [ka] 22. The compound according to embodiment 18 or embodiment 21, Aspect 28. The compound according to aspect 18 or aspect 21, wherein the halogen is -F. Aspect 29. The compound according to aspect 16, wherein Ar is: [ka] Aspect 30. The compound according to aspect 19, wherein Ar is: [ka] Aspect 31. The compound according to aspect 19, wherein Ar is: [ka] Aspect 32. The compound according to aspect 19, wherein Ar is: [ka] Aspect 33. The compound according to aspect 19, wherein Ar is: [ka] Aspect 34. The compound according to aspect 19, wherein Ar is: [ka] Aspect 35. The compound according to aspect 19, wherein Ar is: [ka] Aspect 36. The compound of formula IA is a compound of formula IA-1: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] The compound according to embodiment 4, wherein the compound is -CN or -F. Aspect 37. The compound of formula IA is a compound of formula IA-2: [ka] where each R7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 5. The compound according to embodiment 4, wherein Embodiment 38. The compound of formula IA is a compound of formula IA-3: [ka] where each R 7bare independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 5. The compound according to embodiment 4, wherein Aspect 39. The compound of formula IA is a compound of formula IA-4: [ka] where each R 7b are independently H, -CH3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 5. The compound according to embodiment 4, wherein Aspect 40. The compound of formula IA is a compound of formula IA-5: [ka] where each R 7a are independently H, -CH 3 , -CH2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] The compound according to embodiment 4, wherein the compound is -CN or -F. Embodiment 41. The compound of formula IA is a compound of formula IA-6: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 5. The compound according to embodiment 4, wherein Aspect 42.Q 1 is CH and Q 2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 The compound according to any one of aspects 36 to 41, wherein Aspect 43.Q 1 is CH and Q 2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But, CR 3B and R 3A -CH 3 , each R 3B is H. Aspect 44.Q 1 is N and Q2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 The compound according to any one of aspects 36 to 41, wherein Embodiment 45. The compound of formula IB is a compound of formula IB-1: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] The compound according to embodiment 7, wherein the compound is -CN or -F. Aspect 46. The compound of formula IB is a compound of formula IB-2: [ka] where each R 7b are independently H, -CH 3 , -CH2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] or -F, R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 8. The compound of embodiment 7, wherein Aspect 47. The compound of formula IB is a compound of formula IB-3: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3, isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 8. The compound of embodiment 7, wherein Embodiment 48. The compound of formula IB is a compound of formula IB-4: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 8. The compound of embodiment 7, wherein Embodiment 49. The compound of formula IB is a compound of formula IB-5: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] The compound according to embodiment 7, wherein the compound is -CN or -F. Embodiment 50. The compound of formula IB is a compound of formula IB-6: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 8. The compound of embodiment 7, wherein Aspect 51.Q 1 is CH and R 4 But -CH 3 And Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B And each R 3B are independently H or -CH 3 The compound according to any one of aspects 45 to 50, Aspect 52.Q 1 is N and R 4 But -CH 3 And each Q 3 , Q 4 , and Q 5 But N or CR 3B And each R 3B are independently H or -CH 3 The compound according to any one of aspects 45 to 50, In embodiment 53.E, [ka] In the formula, each R 5 and each R 6 is independently H, optionally substituted C 1 ~C 6 alkyl or halogen; R8 But H or C 1 ~C 6 The compound according to any one of the preceding embodiments, wherein R is alkyl and X is halogen. Embodiment 54. A compound according to embodiment 53, wherein E is: [ka] Aspect 55.R 5 , R 6 , and R 8 and each is H. Embodiment 56. A compound according to embodiment 53, wherein E is: [ka] Aspect 57.R 6 is H and R 8 is H. Aspect 58.R 6 But -CH 3 and R 8 is H. Embodiment 59. A pharma- ceutically acceptable salt of a compound according to any one of the preceding embodiments. Embodiment 60. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments and a pharma- ceutically acceptable excipient. Aspect 61. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of aspects 1 to 58, or a pharma- ceutically acceptable salt thereof. Aspect 62. The method of aspect 61, wherein the cancer is urothelial carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, pancreatic exocrine carcinoma, oral, prostate, bladder, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, or sarcoma. Embodiment 63. A compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 1 H, F, Cl, Br, C 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 and R 2 is a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E, and E is an electrophilic moiety that can react with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety, or a pharma- ceutically acceptable salt thereof. Aspect 64.R 2 but, [ka] where: Q 1 is N or CH; Q 2 But N or CR 3A and R 3A But, H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 is alkyl, Q 3 , Q 4 , Q5 , and Q 6 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, C 3 ~C 7 cycloalkyl, or E, where Q 3 , Q 4 , Q 5 , and Q 6 At least one of the following is CE: R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO 2 (C 1 ~C 6 64. The compound according to embodiment 63, wherein R is an alkyl group. Aspect 65.R 2

[0082] A compound according to embodiment 64, wherein [ka] Embodiment 66. The compound of formula I is a compound of formula IA: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Q 1 is N or CH; Q 2 But N or CR 3A and R 3A But, H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 is alkyl, Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, or C 3 ~C 7 64. The compound according to embodiment 63, wherein said compound is cycloalkyl. Aspect 67. Q 1 is CH, Q 2 But, CR 3A and Q 3 and Q 4 However, each 3B and Q 5 But N or CR 3B and R 3A H, -CH 3 , -CH 2 CH 3 and Each R 3B are independently H or -CH 3 67. The compound according to embodiment 66, wherein Aspect 68. Q 1 is N, Q 2 But, CR 3A and Q 3 and Q 4 However, each 3B and Q 5 But N or CR 3B and R 3A H, -CH 3 , -CH 2 CH 3 and Each R 3B are independently H or -CH 3 67. The compound according to embodiment 66, wherein Embodiment 69. The compound of formula I is a compound of formula IB: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Q 1 is N or CH; Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, or C 3 ~C 7 is cycloalkyl, R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO 2 (C 1 ~C 6 64. The compound according to embodiment 63, wherein R is an alkyl group. Aspect 70. Q 1 is CH, R 4 But -CH 3 and Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B and Each R 3B are independently H or -CH3 8. The compound of embodiment 7, wherein Aspect 71. Q 1 is N, R 4 But -CH 3 and Q 3 , Q 4 , Q 5 But N or CR 3B and Each R 3B are independently H or -CH 3 70. The compound according to embodiment 69, wherein Aspect 72.R 1 -H, -Cl, -F, -CH 3 or -CN. Aspect 73.R 1

[0082] 73. The compound according to embodiment 72, wherein Aspect 74.R 1 But -CH 3 73. The compound according to embodiment 72, wherein Aspect 75.R 1 is -H. Aspect 76.R 1 The compound according to embodiment 72, wherein Aspect 77.R 1 is -CN. Embodiment 78. A compound according to any one of embodiments 63 to 77, wherein Ar is an optionally substituted 6- to 10-membered aryl group. Embodiment 79. The compound according to embodiment 78, wherein the optionally substituted 6-10 membered aryl group is an optionally substituted phenyl group. Embodiment 80. The phenyl group is one or more optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 6 Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C6 alkyl), -O(optionally substituted C 1 ~C 6 80. The compound according to embodiment 79, wherein the compound is substituted with -alkyl), -CN, or halogen. Embodiment 81. A compound according to any one of embodiments 63 to 77, wherein Ar is an optionally substituted 5-10 membered heteroaryl group. Aspect 82. A compound according to aspect 81, wherein the 5-10 membered heteroaryl group is pyridinyl, pyrazolyl, triazolyl, imidazolyl, pyrazolopyrimidine, or triazolopyridine. Embodiment 83. A 5-10 membered heteroaryl group is one or more optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 6 Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl), -O(optionally substituted C 1 ~C 6 alkyl), -CN, halogen, or -C(O)-O(optionally substituted C 1 ~C 6 83. The compound according to any one of embodiments 81 to 82, wherein said compound is substituted with (alkyl). Optionally substituted C 1 ~C 6 Alkyl is -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl), -CH 2 CH 2 OH, -CH 2 CH(OH)CH 3 , -CH 2C(OH)(CH 3 ) 2 , -C(CN)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , C.H. 2 CH(OCH 3 )CH 3 , -CH 2 CHF 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl), or -CH 2 - optionally substituted cyclopropyl. Aspect 85.-CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl) is [ka] 85. The compound according to embodiment 84, wherein Optionally substituted C 3 ~C 6 The compound according to embodiment 18 or embodiment 21, wherein cycloalkyl is cyclopropyl or cyclobutyl. Embodiment 87. The compound according to embodiment 80 or embodiment 83, wherein the optionally substituted 4-6 membered heterocycloalkyl is: [ka] Aspect 88.-N(C 1 ~C 6Alkyl) (optionally substituted C 1 ~C 6 alkyl) is [ka] 22. The compound according to embodiment 18 or embodiment 21, 89. -O(optionally substituted C 1 ~C 6 alkyl) is -OCH 3 , -OCH 2 CH 3 or [ka] 84. The compound according to embodiment 80 or embodiment 83, wherein Aspect 90. A compound according to aspect 80 or aspect 83, wherein the halogen is -F. Embodiment 91. The compound according to embodiment 78, wherein Ar is: [ka] Embodiment 92. The compound according to embodiment 81, wherein Ar is: [ka] Embodiment 93. The compound according to embodiment 81, wherein Ar is: [ka] Embodiment 94. The compound according to embodiment 81, wherein Ar is: [ka] Embodiment 95. The compound according to embodiment 81, wherein Ar is: [ka] Embodiment 96. The compound according to embodiment 81, wherein Ar is: [ka] Embodiment 97. The compound according to embodiment 81, wherein Ar is: [ka] Embodiment 98. The compound of formula IA is a compound of formula IA-1: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] 67. The compound according to embodiment 66, wherein said compound is -CN or -F. Aspect 99. The compound of formula IA is a compound of formula IA-2: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH and -CH 2 CHF 2 , -CH 2 -CH(OH)-CH 3 , -CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OH, -C(CH 3 ) 2 -CN, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH 2 CH 2 O.C.H.F. 2 , -CH 2 CH 2 N(CH 3 )2 , [ka] Cyclopropyl, cyclobutyl, [ka] 67. The compound according to embodiment 66, wherein Aspect 100. The compound of formula IA is a compound of formula IA-3: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, -C(O)OC(CH 3 ) 3 , [ka] 67. The compound according to embodiment 66, wherein Embodiment 101. The compound of formula IA is a compound of formula IA-4: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 67. The compound according to embodiment 66, wherein Embodiment 102. The compound of formula IA is a compound of formula IA-5: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] 67. The compound according to embodiment 66, wherein said compound is -CN or -F. Embodiment 103. The compound of formula IA is a compound of formula IA-6: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 67. The compound according to embodiment 66, wherein Aspect 104.Q 1 is CH and Q 2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But N or CR 3B and R 3A is H or -CH 3 And each R 3Bare independently H or -CH 3 The compound according to any one of aspects 98 to 103, wherein Manner 105.Q 1 is CH and Q 2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But, CR 3B and R 3A -CH 3 , each R 3B is H. Manner 106.Q 1 is N and Q 2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 The compound according to any one of aspects 98 to 103, wherein Embodiment 107. The compound of formula IB is a compound of formula IB-1: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] 70. The compound according to embodiment 69, wherein said compound is -CN or -F. Embodiment 108. The compound of formula IB is a compound of formula IB-2: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] or -F, R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, -CH 2 CHF 2 , [ka] 70. The compound according to embodiment 69, wherein Embodiment 109. The compound of formula IB is a compound of formula IB-3: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 70. The compound according to embodiment 69, wherein Embodiment 110. The compound of formula IB is a compound of formula IB-4: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 70. The compound according to embodiment 69, wherein Embodiment 111. The compound of formula IB is a compound of formula IB-5: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] 70. The compound according to embodiment 69, wherein said compound is -CN or -F. Embodiment 112. The compound of formula IB is a compound of formula IB-6: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3, -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 70. The compound according to embodiment 69, wherein Manner 113.Q 1 is CH and R 4 But -CH 3 And Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B And each R 3B are independently H or -CH 3 113. The compound according to any one of aspects 107 to 112, wherein Aspect 114.Q 1 is N and R 4 But -CH 3 And each Q 3 , Q 4 , and Q 5 But N or CR 3B And each R 3B are independently H or -CH 3 113. The compound according to any one of aspects 107 to 112, wherein In one embodiment, the invention relates to a method for producing a compound according to the present invention. [ka] In the formula, each R 5 and each R 6 is independently H, optionally substituted C 1 ~C 6 alkyl or halogen; R 8 But H or C 1 ~C 6 The compound according to any one of the preceding embodiments, wherein R is alkyl and X is halogen. Embodiment 116. A compound according to embodiment 115, wherein E is: [ka] Aspect 117.R 5 H, -CH 3 or -Cl, and each R 6 is independently H or optionally substituted C 1 ~C 6 alkyl, and each R 8 are independently H or -CH 3 117. The compound according to embodiment 116, wherein Embodiment 118. A compound according to embodiment 115, wherein E is: [ka] Aspect 119.R 6 is H and R 8 is H. Manner 120.R 6 But -CH 3and R 8 is H or -CH 3 19. The compound according to embodiment 118, wherein Embodiment 121. A pharma- ceutically acceptable salt of a compound according to any one of embodiments 63 to 120. Embodiment 122. A pharmaceutical composition comprising a compound according to any one of embodiments 63 to 120 and a pharma- ceutically acceptable excipient. Aspect 123. A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of aspects 63 to 120, or a pharma- ceutically acceptable salt thereof. Aspect 124. The method of aspect 123, wherein the cancer is urothelial carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, pancreatic exocrine carcinoma, oral, prostate, bladder, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, or sarcoma. Embodiment 125. A compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, Ar is an optionally substituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 1 H, F, Cl, Br, C 1~6 Alkyl, CN, C 1~6 Haloalkyl, -C(O)NH 2 , -C(O)NH(C 1~6 alkyl), or -C(O)N(C 1~6 Alkyl) 2 and R 2 but, a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E; or a 13-membered tricyclic heteroaryl containing a 6-5-6 fused ring system in which the 5-membered ring contains at least one nitrogen atom and one of the 6-membered rings is substituted with at least one E; or a 12- or 13-membered tricyclic group containing a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted by at least one E; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein E is an electrophilic moiety capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety. Aspect 126.R 2 is a 9-membered bicyclic heteroaryl comprising a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E, and E is an electrophilic moiety that can react with a nucleophile such as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety. Manner 127.R 2 but, [ka] where: Q 1 But N or CR 3A and Q 2 But N or CR 3A and R 3A But, H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, each R is independently H or C. 1 ~C6 Is it an alkyl group? Or Q 1 CR 3A And Q 2 CR 3A If so, Q 1 R 3A and Q 2 R 3A together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring, or a phenyl ring; Q 3 , Q 4 , Q 5 , and Q 6 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, C 3 ~C 7 cycloalkyl, or E, where Q 3 , Q 4 , Q 5 , and Q 6 at least one of is CE, where E is an electrophilic moiety capable of reacting with a nucleophile to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety; R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO 2 (C 1 ~C 6 alkyl) or Or Q 1 CR 3A If so, Q 1 R 3A and R 4

[0073] The compound according to embodiment 125 or embodiment 126, wherein, together with the atom to which they are attached, form a 5- or 6-membered heterocycloalkyl ring. Manner 128.R 2 but, [ka] where: Q 1 is N or CH; Q 2 But N or CR 3A and R 3A But, H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 is alkyl, Q 3 , Q 4 , Q 5 , and Q 6 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, C 3 ~C 7 cycloalkyl, or E, where Q 3 , Q 4 , Q 5 , and Q 6 At least one of the following is CE: R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO2 (C 1 ~C 6 128. The compound according to any one of embodiments 125 to 127, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 2 Manner 129.R 2 The compound according to any one of aspects 125 to 128, wherein [ka] Embodiment 130. The compound of formula I is a compound of formula IA: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Q 1 But N or CR 3A and Q 2 But N or CR 3A and R 3A But, H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 is alkyl, Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, or C 3 ~C 7130. The compound according to any one of embodiments 125-129, which is cycloalkyl. Aspect 131.Q 1 is N or CH. Aspect 132. Q 1 is CH, Q 2 But, CR 3A and Q 3 and Q 4 However, each 3B and Q 5 But N or CR 3B and R 3A H, -CH 3 , -CH 2 CH 3 and Each R 3B are independently H or -CH 3 132. The compound according to embodiment 131, wherein Aspect 133. Q 1 is N, Q 2 But, CR 3A and Q 3 and Q 4 However, each 3B and Q 5 But N or CR 3B and R 3A H, -CH 3 , -CH 2 CH 3 and Each R 3B are independently H or -CH 3 132. The compound according to embodiment 131, wherein Embodiment 134. The compound of formula I is a compound of formula IB: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Q 1But N or CR 3A and R 3A But, H, C 1 ~C 6 Alkyl, -CN, -C 1 ~C 6 Haloalkyl, halo, -CON(R) 2 , -NR 2 , cycloalkyl, -CH 2 Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO 2 R, Each R is independently H or C 1 ~C 6 is alkyl, Q 3 , Q 4 , and Q 5 each independently represents N or CR 3B and Each R 3B However, independently, H, -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -CN, or C 3 ~C 7 is cycloalkyl, R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 7 Cycloalkyl or SO 2 (C 1 ~C 6 130. The compound according to any one of embodiments 125 to 129, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 2 Aspect 135.Q 1 is N or CH. Aspect 136. Q 1 is CH, R 4 But -CH 3 and Q 3 , Q 4, and Q 5 each independently represents N or CR 3B and Each R 3B are independently H or -CH 3 136. The compound according to embodiment 135, wherein Aspect 137. Q 1 is N, R 4 But -CH 3 and Q 3 , Q 4 , Q 5 But N or CR 3B and Each R 3B are independently H or -CH 3 136. The compound according to embodiment 135, wherein Aspect 138.R 1 -H, -Cl, -F, -CH 3 or -CN. Aspect 139.R 1 The compound according to embodiment 138, wherein is -Cl. Aspect 140.R 1 But -CH 3 19. The compound according to embodiment 138, wherein Aspect 141.R 1 is -H. Aspect 142.R 1 The compound according to embodiment 138, wherein Aspect 143.R 1 is -CN. Embodiment 144. A compound according to any one of embodiments 125 to 143, wherein Ar is an optionally substituted 6- to 10-membered heteroaryl group. Embodiment 145. The compound according to embodiment 144, wherein the optionally substituted 6-10 membered aryl group is an optionally substituted phenyl group. Embodiment 146. The phenyl group is one or more optionally substituted C 1 ~C 6 Alkyl, optionally substituted C3 ~C 6 Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl), -O(optionally substituted C 1 ~C 6 146. The compound according to embodiment 145, wherein the compound is substituted with -alkyl), -CN, or halogen. Embodiment 147. A compound according to any one of embodiments 125 to 143, wherein Ar is an optionally substituted 5-10 membered heteroaryl group. Aspect 148. A compound according to aspect 147, wherein the 5-10 membered heteroaryl group is pyridinyl, pyrazolyl, triazolyl, imidazolyl, pyrazolopyrimidine, or triazolopyridine. Embodiment 149. A 5-10 membered heteroaryl group is one or more optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 6 Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl), -O(optionally substituted C 1 ~C 6 alkyl), -CN, halogen, or -C(O)-O(optionally substituted C 1 ~C 6 149. The compound according to any one of embodiments 147 to 148, wherein said compound is substituted with (alkyl). Optionally substituted C 1 ~C 6 Alkyl is -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2-Cyclopropyl, -CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl), -CH 2 CH 2 OH, -CH 2 CH(OH)CH 3 , -CH 2 C(OH)(CH 3 ) 2 , -C(CN)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , C.H. 2 CH(OCH 3 )CH 3 , -CH 2 CHF 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl), or -CH 2 - an optionally substituted cyclopropyl. Aspect 151.-CH 2 -(optionally substituted 5- or 6-membered heterocycloalkyl) is [ka] 151. The compound according to embodiment 150, wherein Optionally substituted C 3 ~C 6 A compound according to embodiment 146 or embodiment 149, wherein cycloalkyl is cyclopropyl or cyclobutyl. Embodiment 153. The compound according to embodiment 146 or embodiment 149, wherein the optionally substituted 4-6 membered heterocycloalkyl is: [ka] Aspect 154.-N(C 1 ~C 6 Alkyl) (optionally substituted C 1 ~C 6 alkyl) is [ka] 150. The compound according to embodiment 146 or embodiment 149, wherein Embodiment 155. -O (optionally substituted C 1 ~C 6 alkyl) is -OCH 3 , -OCH 2 CH 3 or [ka] 150. The compound according to embodiment 146 or embodiment 149, wherein Aspect 156. A compound according to aspect 146 or aspect 149, wherein the halogen is -F. Embodiment 157. The compound according to embodiment 144, wherein Ar is: [ka] Embodiment 158. The compound according to embodiment 147, wherein Ar is: [ka] Embodiment 159. The compound according to embodiment 147, wherein Ar is: [ka] Embodiment 160. The compound according to embodiment 147, wherein Ar is: [ka] Embodiment 161. The compound according to embodiment 147, wherein Ar is: [ka] Embodiment 162. The compound according to embodiment 147, wherein Ar is: [ka] Embodiment 163. The compound according to embodiment 147, wherein Ar is: [ka] Embodiment 164. The compound of formula IA is a compound of formula IA-1: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] 132. The compound according to any one of embodiments 125-131, wherein the compound is -CN, or -F. Embodiment 165. The compound of formula IA is a compound of formula IA-2: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH and -CH 2 CHF 2 , -CH 2 -CH(OH)-CH 3 , -CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OH, -C(CH 3 ) 2 -CN, -CH 2 CH 2 OCH 3 , -CH 2 CH2 OCH 2 CH 3 , -CH 2 CH 2 OCH(CH 3 ) 2 , -CH 2 CH 2 O.C.H.F. 2 , -CH 2 CH 2 N(CH 3 ) 2 , [ka] Cyclopropyl, cyclobutyl, [ka] 132. The compound according to any one of embodiments 125 to 131, wherein Embodiment 166. The compound of formula IA is a compound of formula IA-3: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, -C(O)OC(CH 3 ) 3 , [ka] 132. The compound according to any one of embodiments 125 to 131, wherein Embodiment 167. The compound of formula IA is a compound of formula IA-4: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 132. The compound according to any one of embodiments 125 to 131, wherein Embodiment 168. The compound of formula IA is a compound of formula IA-5: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] 132. The compound according to any one of embodiments 125-131, wherein the compound is -CN, or -F. Embodiment 169. The compound of formula IA is a compound of formula IA-6: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 132. The compound according to any one of embodiments 125 to 131, wherein Manner 170.Q 1 is CH and Q 2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 169. The compound according to any one of embodiments 164 to 169, Manner 171.Q 1 is CH and Q 2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But, CR 3B and R 3A -CH 3 , each R 3B is H. Manner 172.Q 1 is N and Q 2 But, CR 3A And Q 3 and Q 4 However, each 3B And Q 5 But N or CR 3B and R 3A is H or -CH 3 And each R 3B are independently H or -CH 3 169. The compound according to any one of embodiments 164 to 169, Manner 173.Q 1 But, CR 3A And Q 2 But, CR 3A And Q 3 But, CR 3B And Q 4But, CR 3B And Q 5 But, CR 3B And each R 3A are independently H or -CH 3 And each R 3B are independently H or -CH 3 169. The compound according to any one of embodiments 164 to 169, Manner 174.Q 1 But, CR 3A And Q 2 But, CR 3A And Q 3 But, CR 3B And Q 4 But, CR 3B And Q 5 But, CR 3B And each R 3B are independently H or -CH 3 And Q 1 R 3A and Q 2 R 3A together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring, or a phenyl ring. Embodiment 175. The compound of formula IB is a compound of formula IB-1: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] The compound according to any one of aspects 125-129 or 134-135, which is -CN, or -F. Embodiment 176. The compound of formula IB is a compound of formula IB-2: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] or -F, R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH2 OH, [ka] Cyclopropyl, cyclobutyl, -CH 2 CHF 2 , [ka] 136. The compound according to any one of aspects 125-129 or 134-135, Embodiment 177. The compound of formula IB is a compound of formula IB-3: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 136. The compound according to any one of aspects 125-129 or 134-135, Embodiment 178. The compound of formula IB is a compound of formula IB-4: [ka] where each R 7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 136. The compound according to any one of aspects 125-129 or 134-135, Embodiment 179. The compound of formula IB is a compound of formula IB-5: [ka] where each R 7a are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] The compound according to any one of aspects 125-129 or 134-135, which is -CN, or -F. Embodiment 180. The compound of formula IB is a compound of formula IB-6: [ka] where each R7b are independently H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] -OCH 3 , -OCH 2 CH 3 , [ka] -CN or -F; R 7c H, -CH 3 , -CH 2 CH 3 , isopropyl, -CH 2 CF 3 , -CHF 2 , -CF 3 , -CH 2 -Cyclopropyl, -CH 2 CH 2 OH, [ka] Cyclopropyl, cyclobutyl, [ka] 136. The compound according to any one of aspects 125-129 or 134-135, Manner 181.Q 1 is CH and R 4 But -CH 3 And Q 3 , Q 4 , and Q5 each independently represents N or CR 3B And each R 3B are independently H or -CH 3 181. The compound according to any one of embodiments 175 to 180, Manner 182.Q 1 is N and R 4 But -CH 3 And each Q 3 , Q 4 , and Q 5 But N or CR 3B And each R 3B are independently H or -CH 3 181. The compound according to any one of embodiments 175 to 180, In one embodiment, the invention relates to a method for producing a compound according to the present invention. [ka] In the formula, each R 5 and each R 6 is independently H, optionally substituted C 1 ~C 6 alkyl or halogen; R 8 But H or C 1 ~C 6 The compound according to any one of embodiments 125 to 182, wherein R is alkyl and X is halogen. Embodiment 184. A compound according to embodiment 183, wherein E is: [ka] Aspect 185.R 5 H, -CH 3 or -Cl, and each R 6 is independently H or optionally substituted C 1 ~C 6 alkyl, and each R 8 are independently H or -CH 3 185. The compound according to embodiment 184, wherein Embodiment 186. A compound according to embodiment 183, wherein E is: [ka] Aspect 187.R 6 is H and R 8 is H. Aspect 188.R 6 But -CH 3 and R 8 is H or -CH 3 187. The compound according to embodiment 186, wherein Embodiment 189. A pharma- ceutically acceptable salt of a compound according to any one of embodiments 125 to 188. Embodiment 190. A pharmaceutical composition comprising a compound according to any one of embodiments 125 to 188, and a pharma- ceutically acceptable excipient. Embodiment 191. A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 125 to 188, or a pharma- ceutically acceptable salt thereof. Aspect 192. The method of aspect 191, wherein the cancer is urothelial carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, pancreatic exocrine carcinoma, oral, prostate, bladder, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, or sarcoma. Aspect 193. The method of aspect 191, wherein the cancer is urothelial carcinoma, breast cancer, endometrial carcinoma, endometrial adenocarcinoma, ovarian carcinoma, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung carcinoma, pancreatic exocrine carcinoma, oral cavity, prostate, bladder, colorectal carcinoma, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, or sarcoma.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, Ar is an optionally substituted 6- to 10-membered aryl or 5- to 10-membered heteroaryl group; R １ H, F, Cl, Br, C １～６ Alkyl, C, N １～６ Haloalkyl, —C(O)NH ２ , -C(O)NH(C １～６ alkyl), or -C(O)N(C １～６ Alkyl) ２ and R ２ but, a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted with at least one E; or a 13-membered tricyclic heteroaryl containing a 6-5-6 fused ring system in which the 5-membered ring contains at least one nitrogen atom and one of the 6-membered rings is substituted with at least one E; or a 12- or 13-membered tricyclic group containing a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted by at least one E; E. 【Chemistry 2】 and A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein each R5 and each R6 is independently H, optionally substituted C1-C6 alkyl, or halogen; R8 is H or C1-C6 alkyl; and X is halogen.

2. R ２ is a 9-membered bicyclic heteroaryl containing a 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom and the 6-membered ring is substituted by at least one E; Optionally, R ２ but, 【Chemistry 3】 where: Q １ But N or C-R ３Ａ and Q ２ But N or C-R ３Ａ and R ３Ａ But, H, C １ ~C ６ Alkyl, -CN, -C １ ~C ６ Haloalkyl, halo, -CON(R) ２ , -NR ２ , cycloalkyl, -CH ２ Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO ２ R, each R is independently H or C １ ~C ６ Is it an alkyl group? Or Q １ is C-R ３Ａ And Q ２ is C-R ３Ａ If Q １ The R ３Ａ and Q. ２ The R ３Ａ together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring, or a phenyl ring; Q ３ , Q ４ , Q ５ , and Q ６ each independently represents N or C-R ３Ｂ and Each R ３Ｂ are independently H, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -CN, C ３ ~C ７ cycloalkyl, or E, where Q ３ , Q ４ , Q ５ , and Q ６ At least one of is C-E; R ４ But, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl or SO ２ (C １ ~C ６ alkyl) or Or Q １ is C-R ３Ａ If Q １ The R ３Ａ and R ４ together with the atom to which they are attached form a 5- or 6-membered heterocycloalkyl ring; Optionally, R ２ but, 【Chemistry 4】 where: Q １ is N or C—H, Q ２ But N or C-R ３Ａ and R ３Ａ But, H, C １ ~C ６ Alkyl, -CN, -C １ ~C ６ Haloalkyl, halo, -CON(R) ２ , -NR ２ , cycloalkyl, -CH ２ Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO ２ R, Each R is independently H or C １ ~C ６ is alkyl, Q ３ , Q ４ , Q ５ , and Q ６ each independently represents N or C-R ３Ｂ and Each R ３Ｂ are independently H, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -CN, C ３ ~C ７ cycloalkyl, or E, where Q ３ , Q ４ , Q ５ , and Q ６ At least one of is C-E; R ４ But, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, or SO ２ (C １ ~C ６ alkyl), Optionally, R ２ but, 【Chemistry 5】 2. The compound of claim 1,

3. The compound of formula I is a compound of formula IA: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof, wherein: Q １ But N or C-R ３Ａ and Q ２ But N or C-R ３Ａ and R ３Ａ But, H, C １ ~C ６ Alkyl, -CN, -C １ ~C ６ Haloalkyl, halo, -CON(R) ２ , -NR ２ , cycloalkyl, -CH ２ Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO ２ R, Each R is independently H or C １ ~C ６ is alkyl, Q ３ , Q ４ , and Q ５ each independently represents N or C-R ３Ｂ and Each R ３Ｂ are independently H, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -CN, or C ３ ~C ７ is cycloalkyl, Optionally, Q １ is N or C—H, Optionally, The compound according to claim 6 . Q １ is C—H, Q ２ But, C-R ３Ａ and Q ３ and Q. ４ are C-R, respectively. ３Ｂ and Q ５ But N or C-R ３Ｂ and R ３Ａ is H, -CH ３ , -CH ２ CH ３ and Each R ３Ｂ are independently H or -CH ３ is, or Q １ is N, Q ２ But, C-R ３Ａ and Q ３ and Q. ４ are C-R, respectively. ３Ｂ and Q ５ But N or C-R ３Ｂ and R ３Ａ is H, -CH ３ , -CH ２ CH ３ and Each R ３Ｂ are independently H or -CH ３ That is, The compound of claim 1.

4. The compound of formula I is a compound of formula IB: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, wherein: Q １ But N or C-R ３Ａ and R ３Ａ But, H, C １ ~C ６ Alkyl, -CN, -C １ ~C ６ Haloalkyl, halo, -CON(R) ２ , -NR ２ , cycloalkyl, -CH ２ Cycloalkyl, -COR, -CH(OH)R, -CO-cycloalkyl, -CH(OH)cycloalkyl, -SR, or -SO ２ R, Each R is independently H or C １ ~C ６ is alkyl, Q ３ , Q ４ , and Q ５ each independently represents N or C-R ３Ｂ and Each R ３Ｂ are independently H, -C １ ~C ６ Alkyl, -C １ ~C ６ Haloalkyl, -CN, or C ３ ~C ７ is cycloalkyl, R ４ But, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, or SO ２ (C １ ~C ６ alkyl), Optionally, Q １ is N or C—H, Optionally, Q １ is C—H, R ４ But -CH ３ and Q ３ , Q ４ , and Q ５ each independently represents N or C-R ３Ｂ and Each R ３Ｂ are independently H or -CH ３ is, or Q １ is N, R ４ But -CH ３ and Q ３ , Q ４ , Q ５ But N or C-R ３Ｂ and Each R ３Ｂ are independently H or -CH ３ That is, The compound of claim 1.

5. R １ is H, -Cl, -F, -CH ３ or -CN.

6. Ar is an optionally substituted 6-10 membered aryl group; Optionally, the optionally substituted 6- to 10-membered aryl group is an optionally substituted phenyl group; Optionally, The phenyl group is one or more optionally substituted C １ ~C ６ Alkyl, optionally substituted C ３ ~C ６ Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C １ ~C ６ alkyl) (optionally substituted C １ ~C ６ alkyl), -O(optionally substituted C １ ~C ６ alkyl), -CN, or halogen; Ar is an optionally substituted 5-10 membered heteroaryl group; Optionally, the 5-10 membered heteroaryl group is pyridinyl, pyrazolyl, triazolyl, imidazolyl, pyrazolopyrimidine, or triazolopyridine; or The 5- to 10-membered heteroaryl group is selected from the group consisting of one or more optionally substituted C １ ~C ６ Alkyl, optionally substituted C ３ ~C ６ Cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -N(C １ ~C ６ alkyl) (optionally substituted C １ ~C ６ alkyl), -O(optionally substituted C １ ~C ６ alkyl), -CN, halogen, or -C(O)-O (optionally substituted C １ ~C ６ alkyl), The compound of claim 1.

7. The optionally substituted C １ ~C ６ The alkyl is -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ -(optionally substituted 5- or 6-membered heterocycloalkyl), -CH ２ CH ２ OH, -CH ２ CH(OH)CH ３ , -CH ２ C(OH)(CH ３ ) ２ , -C(CN)(CH ３ ) ２ , -CH ２ CH ２ CH ２ OH, -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH (CH ３ ) ２ , C.H. ２ CH (OCH ３ ) CH ３ , -CH ２ CHF ２ , -CH ２ CH ２ N (CH ３ ) ２ , -CH ２ CH ２ -(optionally substituted 5- or 6-membered heterocycloalkyl), or -CH ２ - optionally substituted cyclopropyl, Optionally, The -CH ２ -(optionally substituted 5- or 6-membered heterocycloalkyl) is 【Chemistry 8】 is, or The optionally substituted C ３ ~C ６ cycloalkyl is cyclopropyl or cyclobutyl; or said optionally substituted 4-6 membered heterocycloalkyl being 【Chemistry 9】 is, or -N(C １ ~C ６ alkyl) (optionally substituted C １ ~C ６ alkyl), 【Chemistry 10】 is, or The -O(optionally substituted C １ ~C ６ alkyl) is -OCH ３ , -OCH ２ CH ３ or 【Chemistry 11】 is, or the halogen is -F; The compound according to claim 6 .

8. Ar is 【Chemistry 12】 is, or Ar is 【Chemistry 13】 is, or Ar is 【Chemistry 14】 is, or Ar is 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 is, or Ar is 【Chemistry 16】 is, or Ar is 【Chemistry 17】 is, or Ar is 【Chemistry 18】 That is, The compound according to claim 6.

9. The compound of formula IA is a compound of formula IA-1: 【Chemistry 19】 wherein each R ７ａ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 20】 Cyclopropyl, cyclobutyl, 【Chemistry 21】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemical 22】 -CN or -F, or The compound of formula IA is a compound of formula IA-2: 【Chemistry 23】 wherein each R ７ｂ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 24】 Cyclopropyl, cyclobutyl, 【Chemistry 25】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemistry 26】 -CN or -F, R ７ｃ is H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ OH and -CH ２ CHF ２ , -CH ２ -CH(OH)-CH ３ , -CH ２ C(OH)(CH ３ ) ２ , -CH ２ CH ２ CH ２ OH, -C(CH ３ ) ２ -CN, -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH (CH ３ ) ２ , -CH ２ CH ２ O.C.F. ２ , -CH ２ CH ２ N (CH ３ ) ２ , 【Chemical 27】 Cyclopropyl, cyclobutyl, 【Chemistry 28】 is, or The compound of formula IA is a compound of formula IA-3: 【Chemical Formula 29】 wherein each R ７ｂ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 30】 Cyclopropyl, cyclobutyl, 【Chemistry 31】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemistry 32】 -CN or -F, R ７ｃ is H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemical 33】 Cyclopropyl, cyclobutyl, -C(O)OC(CH ３ ) ３ , 【Chemical Formula 34】 is, or The compound of formula IA is a compound of formula IA-4: 【Chemistry 35】 wherein each R ７ｂ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemical 36】 Cyclopropyl, cyclobutyl, 【Chemical 37】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemical Formula 38】 -CN or -F, R ７ｃ is H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemical 39】 Cyclopropyl, cyclobutyl, 【Chemistry 40】 is, or The compound of formula IA is a compound of formula IA-5: 【Chemistry 41】 wherein each R ７ａ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 42】 Cyclopropyl, cyclobutyl, 【Chemistry 43】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemistry 44】 -CN or -F, or The compound of formula IA is a compound of formula IA-6: 【Chemistry 45】 wherein each R ７ｂ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 46】 Cyclopropyl, cyclobutyl, 【Chemistry 47】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemistry 48】 -CN or -F, R ７ｃ is H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 49】 Cyclopropyl, cyclobutyl, 【Chemistry 50】 That is, The compound according to claim 3.

10. Q １ is C—H, and Q ２ But, C-R ３Ａ And Q ３ and Q. ４ are C-R, respectively. ３Ｂ And Q ５ But N or C-R ３Ｂ and R ３Ａ is H or -CH ３ and each R ３Ｂ are independently H or -CH ３ is, or Q １ is C—H, and Q ２ But, C-R ３Ａ And Q ３ and Q. ４ are C-R, respectively. ３Ｂ And Q ５ But, C-R ３Ｂ and R ３Ａ -CH ３ , each R ３Ｂ is H, or Q １ is N and Q ２ But, C-R ３Ａ And Q ３ and Q. ４ are C-R, respectively. ３Ｂ And Q ５ But N or C-R ３Ｂ and R ３Ａ is H or -CH ３ and each R ３Ｂ are independently H or -CH ３ is, or Q １ But, C-R ３Ａ And Q ２ But, C-R ３Ａ And Q ３ But, C-R ３Ｂ And Q ４ But, C-R ３Ｂ And Q ５ But, C-R ３Ｂ and each R ３Ａ are independently H or -CH ３ and each R ３Ｂ are independently H or -CH ３ is, or Q １ But, C-R ３Ａ And Q ２ But, C-R ３Ａ And Q ３ But, C-R ３Ｂ And Q ４ But, C-R ３Ｂ And Q ５ But, C-R ３Ｂ and each R ３Ｂ are independently H or -CH ３ And Q １ R ３Ａ and Q. ２ R ３Ａ together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring, or a phenyl ring; The compound according to claim 9.

11. The compound of formula IB is a compound of formula IB-1: 【Chemistry 51】 wherein each R ７ａ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 52】 Cyclopropyl, cyclobutyl, 【Chemistry 53】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemical 54】 -CN or -F, or The compound of formula IB is a compound of formula IB-2: 【Chemistry 55】 wherein each R ７ｂ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 56】 Cyclopropyl, cyclobutyl, 【Chemistry 57】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemistry 58】 or -F, R ７ｃ is H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 59】 Cyclopropyl, cyclobutyl, -CH ２ CHF ２ , 【Chemistry 60】 is, or The compound of formula IB is a compound of formula IB-3: 【Chemistry 61】 wherein each R ７ｂ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 62】 Cyclopropyl, cyclobutyl, 【Chemistry 63】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemistry 64】 -CN or -F, R ７ｃ is H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 65】 Cyclopropyl, cyclobutyl, 【Chemistry 66】 is, or The compound of formula IB is a compound of formula IB-4: 【Chemistry 67】 wherein each R ７ｂ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 68】 Cyclopropyl, cyclobutyl, 【Chemistry 69】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemistry 70】 -CN or -F, R ７ｃ is H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 71】 Cyclopropyl, cyclobutyl, 【Chemical 72】 is, or The compound of formula IB is a compound of formula IB-5: 【Chemical Formula 73】 wherein each R ７ａ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemical Formula 74】 Cyclopropyl, cyclobutyl, 【Chemistry 75】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemical 76】 -CN or -F, or The compound of formula IB is a compound of formula IB-6: 【Chemical 77】 wherein each R ７ｂ are independently H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemical 78】 Cyclopropyl, cyclobutyl, 【Chemical Formula 79】 -OCH ３ ,-OCH ２ CH ３ 、 【Chemistry 80】 -CN or -F, R ７ｃ is H, -CH ３ , -CH ２ CH ３ , isopropyl, -CH ２ CF ３ , -CHF ２ , -CF ３ , -CH ２ -Cyclopropyl, -CH ２ CH ２ O.H. 【Chemistry 81】 Cyclopropyl, cyclobutyl, 【Chemistry 82】 That is, The compound according to claim 4.

12. Q １ is C—H, and R ４ But -CH ３ And Q ３ , Q ４ , and Q ５ each independently represents N or C-R ３Ｂ and each R ３Ｂ are independently H or -CH ３ is, or Q １ is N and R ４ But -CH ３ And each Q ３ , Q ４ , and Q ５ But N or C-R ３Ｂ and each R ３Ｂ are independently H or -CH ３ That is, The compound according to claim 11.

13. E. 【Chemistry 83】 is, or R ５ is H, -CH ３ or -Cl, and each R ６ is independently H or optionally substituted C １ ~C ６ alkyl, R ８ is H or -CH ３ is, or E. 【Chemistry 84】 and Optionally, R ６ is H, and R ８ is H, or R ６ But -CH ３ and R ８ is H or -CH ３ That is, A compound according to any one of claims 1 to 12.

14. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is N-[3-methyl-1-[5-chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[3-[5-fluoro-2-(4-morpholinoanilino)pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[4-[2-(dimethylamino)ethyl-methyl-amino]anilino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]indol-5-yl]propanamide; N-[4-methyl-1-[5-methyl-2-[3-(2-morpholinoethoxy)anilino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[3-(2-morpholinoethoxy)anilino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[3-(2-morpholinoethoxy)anilino]pyrimidin-4-yl]-4-methyl-indol-5-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[3-(2-morpholinoethoxy)anilino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[4-(2-morpholinoethoxy)anilino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(2-ethoxy-4-morpholino-anilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]-pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[2-(2-morpholinoethoxy)anilino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(3-ethoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(3-fluoro-4-morpholino-anilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(3-fluoro-4-morpholino-anilino)pyrimidin-4-yl]-4-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-4-methyl-indol-5-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[4-(2-morpholinoethoxy)anilino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(2-ethoxyanilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[4-(2-morpholinoethoxy)anilino]pyrimidin-4-yl]-4-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(3-fluoro-4-morpholino-anilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(3,4-dimethoxyanilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[5-chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1-methylimidazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(2-ethoxy-6-methyl-anilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[5-chloro-2-(3,4-dimethoxyanilino)pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[5-cyano-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-cyano-2-(2-ethoxy-6-methyl-anilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1,3-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[(1-methylimidazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-cyano-2-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-cyano-2-(4-morpholinoanilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-cyano-2-(2-ethoxyanilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1,5-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1,3,5-trimethylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[[1-(1-ethyl-4-piperidyl)pyrazol-4-yl]amino]-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[5-chloro-2-(pyrazolo[1,5-a]pyrimidin-6-ylamino)pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[3-[5-chloro-2-[(6-morpholino-3-pyridyl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[2-(3-methoxy-4-morpholino-anilino)-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-([1,2,4]triazolo[1,5-a]pyridin-6-ylamino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[5-chloro-2-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]-pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]-pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[3-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]-pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[5-chloro-2-(3-methoxy-4-morpholino-anilino)pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-methyl-3-[5-methyl-2-(4-morpholinoanilino)pyrimidin-4-yl]indol-6-yl]prop-2-enamide; N-[1-methyl-3-[2-(4-morpholino-anilino)pyrimidin-4-yl]indol-6-yl]prop-2-enamide; N-[3-methyl-1-[2-(4-morpholinoanilino)pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(2,5-dimethylpyrazol-3-yl)amino]-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[5-fluoro-2-(4-morpholino-anilino)pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[5-chloro-2-[4-[2-(dimethylamino)ethyl-methyl-amino]-3-methoxy-anilino]-pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[5-chloro-2-[[6-(4-methylpiperazin-1-yl)-3-pyridyl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[5-chloro-2-(4-morpholinoanilino)-pyrimidin-4-yl]-3,6-dimethyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[5-chloro-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[5-chloro-2-[(2,5-dimethylpyrazol-3-yl)amino]-pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[2-[(2,5-dimethylpyrazol-3-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[4-[(4-methylpiperazin-1-yl)methyl]-anilino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[3-methyl-4-(morpholinomethyl)anilino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-(4-morpholino-anilino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[3-fluoro-4-(morpholinomethyl)anilino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(3-cyano-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,7-dimethyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(3-methyltriazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[3-(4-methylpiperazin-1-yl)anilino]-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-(4-morpholinoanilino)pyrimidin-4-yl]-3,7-dimethyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[4-(morpholinomethyl)anilino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3-methyl-indazol-5-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indazol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[3-(morpholinomethyl)anilino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-methyl-1-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[(1-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[3-methyl-1-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[3-methyl-1-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,7-dimethyl-indol-5-yl]prop-2-enamide; Example 85: N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[3-fluoro-4-[(4-methylpiperazin-1-yl)methyl]-anilino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-methyl-1-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indazol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[3-[4-(2-hydroxyethyl)piperazin-1-yl]anilino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-chloro-2-[(6-morpholino-3-pyridyl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-methyl-3-[2-[(1-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-6-yl]prop-2-enamide; N-[1-[2-[(1-ethylpyrazol-3-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methylindol-5-yl]prop-2-enamide; N-[3-[2-[(1-ethylpyrazol-3-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[2-[(1-isopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[(1-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[3-methyl-1-[2-[(1-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[1-[2-[(1-cyclopropylpyrazol-3-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[[1-(2-hydroxyethyl)pyrazol-3-yl]amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[2-[[1-(2-hydroxyethyl)pyrazol-3-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[2-[(1,5-dimethylpyrazol-3-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[2-[(1,5-dimethylpyrazol-3-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; 2-methyl-N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[3-[2-[[1-(cyclopropylmethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; (E)-4-(dimethylamino)-N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]but-2-enamide; N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-ynamide; N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]ethenesulfonamide; 2-fluoro-N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-methyl-3-[2-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]indol-6-yl]prop-2-enamide; N-[3-[2-[(1-cyclopropylpyrazol-3-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[[1-(oxetan-3-yl)pyrazol-3-yl]amino]-pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[1-[2-[(1-ethylpyrazol-3-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; (E)-4-(dimethylamino)-N-[1-[2-[(1-ethylpyrazol-3-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]but-2-enamide; 2-chloro-N-[3-methyl-1-[5-methyl-2-[(1-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; 2-fluoro-N-[3-methyl-1-[5-methyl-2-[(1-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; 2-methyl-N-[3-methyl-1-[5-methyl-2-[(1-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[1-[2-[[1-(2-hydroxyethyl)pyrazol-3-yl]amino]-5-methyl-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[[1-(oxetan-3-yl)pyrazol-3-yl]amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; (E)-4-(dimethylamino)-N-[1-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]but-2-enamide; N-[3-methyl-1-[5-methyl-2-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; tert-butyl 5-methyl-3-[[5-methyl-4-[3-methyl-5-(prop-2-noylamino)pyrrolo[2,3-b]pyridin-1-yl]pyrimidin-2-yl]amino]pyrazole-1-carboxylate; N-[1-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]-5-methyl-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]prop-2-enamide; N-[3-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]-5-methyl-pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[5-chloro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[5-fluoro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-ynamide; N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]but-2-ynamide; N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]but-2-ynamide; N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyrrolo[2,3-b]pyridin-5-yl]prop-2-ynamide; N-[1-[5-fluoro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]prop-2-ynamide; N-[1-[5-fluoro-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]but-2-ynamide; N-[3-[5-chloro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]but-2-ynamide; N-[3-ethyl-1-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-ynamide; N-[1-[5-fluoro-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]but-2-ynamide; N-[1-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]but-2-ynamide; N-[1-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]-5-methyl-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]prop-2-ynamide; N-[3-[5-fluoro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-ynamide; N-[3-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-ynamide; (E)-4-(dimethylamino)-N-[1-[5-fluoro-2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]but-2-enamide; N-[3-[2-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]but-2-ynamide; Example 146: N-[1-[2-[(1,5-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[(1,5-dimethylpyrazol-4-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-(isothiazolo-4-ylamino)pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[[1-(difluoromethyl)-3-methyl-pyrazol-4-yl]amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[(2,4-dimethylpyrimidin-5-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-methyl-N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-methyl-N-[3-methyl-1-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]indol-5-yl]but-2-ynamide; N-[1-[5-fluoro-2-[(2-methyl-3-pyridyl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(3-methylisoxazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[(1-ethyl-3-methyl-pyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(2-fluoro-3-pyridyl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxypropyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(3-hydroxypropyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(5-methylisothiazolo-3-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxyethyl)-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxyethyl)-5-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[[1-[2-(dimethylamino)ethyl]-3-methyl-pyrazol-4-yl]amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[[1-[2-(dimethylamino)ethyl]-5-methyl-pyrazol-4-yl]amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-methyl-3-[2-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]indol-6-yl]prop-2-enamide; N-[3-[2-[[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]amino]-5-fluoro-pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[2-[[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; (E)-4-(dimethylamino)-N-[1-[2-[(1-ethyl-3-methyl-pyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]but-2-enamide; N-[3-[2-[(1,3-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[2-[(1-ethyl-3-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[3-methyl-1-(2-morpholinoethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[5-methyl-1-(2-morpholinoethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(1-hydroxycyclopropyl)methyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxyethyl)-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[2-[(1-ethyl-3-methyl-pyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[2-[(1-cyclopropylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; (E)-4-(dimethylamino)-N-[1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]but-2-enamide; (E)-N-[1-[5-chloro-2-[(1,3-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]-4-(dimethylamino)but-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxy-2-methyl-propyl)-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxy-2-methyl-propyl)-5-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-methyl-3-[2-[[1-(trifluoromethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]indol-6-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2S)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-[2-[[1-(difluoromethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[3-[2-[(1-cyclobutylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-methyl-3-[2-[[1-(oxetan-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]indol-6-yl]prop-2-enamide; (E)-4-(dimethylamino)-N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]but-2-enamide; N-[1-[5-fluoro-2-[[1-(2-hydroxyethyl)-5-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-[[1-(2-ethoxyethyl)pyrazol-4-yl]amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]-5-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2S)-2-hydroxypropyl]-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2S)-2-hydroxypropyl]-5-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; (E)-4-(dimethylamino)-N-[1-[5-fluoro-2-[[1-[(2S)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]but-2-enamide; (E)-N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]-4-morpholino-but-2-enamide; (E)-N-[1-[5-fluoro-2-[[1-[(2S)-2-hydroxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]-4-morpholino-but-2-enamide; (E)-4-(dimethylamino)-N-[1-[2-[(1,5-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]but-2-enamide; (E)-4-(dimethylamino)-N-[1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-methyl-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]but-2-enamide; N-[3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-isopropoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-methoxypropyl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2S)-2-methoxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(1-hydroxycyclopropyl)methyl]-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(1-hydroxycyclopropyl)methyl]-5-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ylamino)-5-fluoro-pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(1-tetrahydropyran-4-ylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[6-[(1,3-dimethylpyrazol-4-yl)amino]-3-methyl-pyridazin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2R)-2-methoxypropyl]pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-isopropoxyethyl)-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-(2-isopropoxyethyl)-5-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; (E)-N-[1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-fluoro-pyrimidin-4-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]-4-morpholino-but-2-enamide; N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]-3-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(1-tetrahydrofuran-3-ylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[[1-[(2R)-2-hydroxypropyl]-5-methyl-pyrazol-4-yl]amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[6-[(1,3-dimethylpyrazol-4-yl)amino]-3-methyl-pyridazin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-methyl-1-[4-[(1-methylpyrazol-4-yl)amino]-1,3,5-triazin-2-yl]indol-5-yl]prop-2-enamide; N-[3-methyl-1-[6-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[4-[(1,3-dimethylpyrazol-4-yl)amino]-1,3,5-triazin-2-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-methyl-1-[3-methyl-6-[(1-methylpyrazol-4-yl)amino]pyridazin-4-yl]indol-5-yl]prop-2-enamide; N-[1-[6-[(1,3-dimethylpyrazol-4-yl)amino]pyrimidin-4-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[3-methyl-1-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl]indol-5-yl]prop-2-enamide; N-[1-[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-methyl-4-pyridyl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[6-chloro-3-[(1,3-dimethylpyrazol-4-yl)amino]-1,2,4-triazin-5-yl]-3-methyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2,3-dimethyl-indol-5-yl]prop-2-enamide; N-[1-[5-fluoro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-methyl-indol-5-yl]prop-2-enamide; N-[9-[5-fluoro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]carbazol-3-yl]prop-2-enamide; N-[4-[5-fluoro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2,3-dihydro-1H-cyclopenta[b]indol-7-yl]prop-2-enamide; or N-[9-[5-fluoro-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-5,6,7,8-tetrahydrocarbazol-3-yl]prop-2-enamide or a pharma- ceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharma- ceutically acceptable excipient.

16. 15. A method comprising administering a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, for use in treating cancer in a subject.

17. 17. The compound for use according to claim 16, wherein the cancer is urothelial carcinoma, breast cancer, endometrial carcinoma, endometrial adenocarcinoma, ovarian carcinoma, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung carcinoma, pancreatic exocrine carcinoma, oral cavity, prostate, bladder, colorectal carcinoma, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, or sarcoma.

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