Small molecule inhibitors of BCR-ABL

Abstract

The present invention provides compounds of formula (I) wherein X is selected from the group consisting of ethyl, vinyl, ethynyl and triazinyl; r1 is selected from the group consisting of alkyl, alkoxy, cycloalkyl,-CH2-cycloalkyl,-O-cycloalkyl, halogen, haloalkyl, OH and CN; and R2 is a ring moiety selected from the group consisting of an imidazolyl group, a pyrazolyl group, a 1, 2, 3-triazolyl group, a thiazolyl group, a phenyl group and a pyridyl group, each optionally substituted; the compounds of formula (I) are useful as inhibitors against native BCR-ABL kinase proteins and clinically important BCR-ABL mutations such as T315I, F317L, E255K and Y253F for the treatment of diseases including chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to small molecule potent BCR-ABL inhibitors that are effective against native BCR-ABL kinase protein and clinically important BCR-ABL mutations such as T315I, F317L, E255K and Y253F. Background Art

[0002] The development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene constitutes an effective method for treating chronic myeloid leukemia (CML) and / or acute lymphoblastic leukemia (ALL). Currently available inhibitors are limited by drug resistance and toxicity. The third-generation inhibitor Ponatinib has shown excellent efficacy against wild-type and mutant BCR-ABL kinases (including the "gatekeeper" T315I mutation that is resistant to all other currently available TKIs). However, Ponatinib is one of the most cardiotoxic TKIs approved by the FDA. Therefore, the ideal inhibitor should be effective against both natural and clinically important BCR-ABL mutations, and have a high degree of cardiac safety and immune safety compared to Ponatinib. Summary of the invention

[0003] The first embodiment provides a compound of formula (I):

[0004]

[0005] in:

[0006] X is selected from the following group:

[0007] R1 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, OH and CN;

[0008] R2 is selected from H, -NH-S(=O)2H, -NH-S(=O)2-C1-C6 alkyl,

[0009]

[0010] Groups;

[0011] R3 and R4 are each independently selected from the group consisting of H, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 haloalkyl, halogen, -NH-S(=O)2H and -NH-S(=O)2-C1-C6 alkyl;

[0012] The condition is that when X is When R1 is CH3 or Cl, and the variable CF3 group is bonded to the 3-position or 5-position of the benzene ring B, then R2 is not

[0013] or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Dose response curves of imatinib, ponatinib and CET analogs CET-109, CET-110, CET-111 and CET-84 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0015] Figure 2 Dose response curves of imatinib, ponatinib, and CET analogs CET-067, CET-084, CET-105, and CET-104 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0016] Figure 3 Dose response curves of imatinib, ponatinib, and CET analogs CET-001, CET-104, CET-105, and CET-106 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0017] Figure 4 Dose response curves of imatinib, ponatinib and CET analogs CET-84, CET-99 and CET-100 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0018] Figure 5 Dose response curves of imatinib, ponatinib, and CET analogs CET-100, CET-101, CET-102, and CET-103 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0019] Figure 6 Dose response curves of imatinib, ponatinib and CET analogs CET-67, CET-84, CET-85, CET-90 and CET-91 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0020] Figure 7Dose response curves of imatinib, ponatinib, and CET analogs CET-99, CET-100, CET-101, CET-102, and CET-103 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0021] Figure 8 Dose response curves of imatinib, ponatinib and CET analogs CET-84, CET-99 and CET-100 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0022] Fig. 9 Dose response curves of imatinib, ponatinib, and CET analogs CET-84, CET-85, CET-99, and CET-100 against Ba / F3 cells expressing BCR-ABL T315I are presented.

[0023] Fig.10 Dose response curves of imatinib, ponatinib and CET analogs CET-84, CET-99 and CET-100 against HL60 AML-derived cell lines are presented.

[0024] Fig.11 Dose response curves of imatinib, ponatinib, and CET analogs CET-109, CET-110, CET-111, and CET-84 against Ba / F3 cells expressing BCR-ABL E255V are presented.

[0025] Fig.12 Dose response curves of imatinib, ponatinib and CET analogs CET-001, CET-004, CET-105 and CET-106 against the K562 CML-derived cell line are presented.

[0026] Fig.13 Dose response curves of imatinib, ponatinib, and CET analogs CET-99, CET-100, CET-101, CET-102, and CET-103 against AML2 AML-derived cell lines are presented.

[0027] Fig.14 Dose response curves of imatinib, ponatinib, and CET analogs CET-001, CET-004, CET-105, and CET-106 against AML1 AML-derived cell lines are presented.

[0028] Fig.15 Dose response curves of imatinib, ponatinib and CET analogs CET-84, CET-99 and CET-100 against AML1 AML-derived cell lines are presented.

[0029] Fig.16 Dose response curves of imatinib, ponatinib and CET analogs CET-001, CET-004, CET-105 and CET-106 against the K562 CML-derived cell line are presented.

[0030] Fig.17 Dose response curves of imatinib, ponatinib and CET analogs CET-84, CET-85, CET-90 and CET-100 against Ba / F3 cells expressing BCR-ABL E255V are presented.

[0031] Fig.18 Dose response curves of imatinib, ponatinib, and CET analogs CET-84, CET-99, and CET-100 against Ba / F3 cells expressing BCR-ABL E255V are presented.

[0032] Fig.19 N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-084) is presented. 13 C NMR.

[0033] Fig. 20 N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-084) is presented. 1 H NMR.

[0034] Fig.21 Presentation of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-067) 1 H NMR.

[0035] Fig. 22 Presentation of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-067) 13 C NMR.

[0036] Fig.23 The results of N-(3-(4-fluoro-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-100) are presented.1 H NMR.

[0037] Fig.24 The results of N-(3-(4-fluoro-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-100) are presented. 13 C NMR.

[0038] Fig.25 The present invention discloses 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(trifluoromethyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)benzamide (CET-10-103) 1 H NMR.

[0039] Fig.26 The present invention discloses 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(trifluoromethyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)benzamide (CET-10-103) 13 C NMR.

[0040] Fig. 27 The present invention discloses 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-106) 1 H NMR.

[0041] Fig.28 The present invention discloses 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-106) 13 C NMR.

[0042] Fig.29 3-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-104) is presented 1 H NMR.

[0043] Fig.30 3-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-104) is presented 13 C NMR.

[0044] Fig.31 The results of N-(4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-105) are presented. 1 H NMR.

[0045] Fig.32 The results of N-(4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-105) are presented. 13 C NMR.

[0046] Fig.33 N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-109) is presented. 1 H NMR.

[0047] Fig.34 N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-109) is presented. 13 C NMR.

[0048] Fig.35 The present invention discloses 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)benzamide (CET-10-110) 1 H NMR.

[0049] Fig.36 The present invention discloses 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)benzamide (CET-10-110) 13 C NMR.

[0050] Fig.37 Presentation of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methylthiazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-111) 1 H NMR.

[0051] Fig.38Presentation of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methylthiazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-111) 13 C NMR.

[0052] Fig.39 3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-101) is presented 1 H NMR.

[0053] Fig.40 3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-101) is presented 13 C NMR.

[0054] Fig.41 3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-102) is presented 1 H NMR.

[0055] Fig.42 3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-102) is presented 13 C NMR.

[0056] Fig.43 The present invention discloses 3-(4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-108) 1 H NMR.

[0057] Fig.44 The present invention discloses 3-(4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-108) 13 C NMR.

[0058] Fig.45N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-4-methylbenzamide (CET-10-107) is presented. 1 H NMR.

[0059] Fig.46 N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-4-methylbenzamide (CET-10-107) is presented. 13 C NMR. DETAILED DESCRIPTION

[0060] It should be understood that the conditions in the first embodiment above do not include the following compounds:

[0061] a) 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide (CAS 1542265-39-3);

[0062] b) 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (CAS 1289555-64-1);

[0063] c) 4-chloro-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide (CAS 1542265-40-6); and

[0064] d) 4-Chloro-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (CAS 1542265-41-7).

[0065] Additional embodiments provide three separate compounds having Formula (Ia), Formula (Ib) and Formula (Ic), respectively:

[0066]

[0067] wherein, in each case, all variables including X, R1, R2, R3 and R4 are defined as above for the embodiments of Formula (I), including limitations, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0068] Three additional separate examples provide compounds of formula (IIa), compounds of formula (IIb), and compounds of formula (IIc), respectively:

[0069]

[0070] Wherein, in each individual embodiment:

[0071] X is selected from the following group:

[0072] R1 is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, OH and CN;

[0073] R2 is selected from H, -NH-S(=O)2H, -NH-S(=O)2-C1-C6 alkyl,

[0074]

[0075] Groups;

[0076] R3 and R4 are each independently selected from the group consisting of H, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, halogen, -NH-S(=O)2H and -NH-S(=O)2-C1-C6 alkyl;

[0077] The condition is that when X is When R1 is CH3 or Cl, and the variable CF3 group is bonded to the 3-position or 5-position of the benzene ring B, then R2 is not

[0078] or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0079] Three additional separate examples provide compounds of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), and (IIIi), respectively:

[0080]

[0081]

[0082] wherein, in each case, R1 and R2 are as defined above for one or more embodiments of a compound of formula (IIa), a compound of formula (IIb), and a compound of formula (IIc); or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

[0083] Separate examples provide compounds of each of Formulae (IVa) to (IVi):

[0084]

[0085]

[0086] wherein, in each case, R1 and R3 are as defined above for one or more embodiments of compounds of Formula (IIa)-(IIc); or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0087] Individual examples provide compounds of each of Formulae (Va) to (Vi):

[0088]

[0089]

[0090] wherein, in each case, R1 and R3 are as defined above for one or more embodiments of compounds of Formula (IIa) to (IIc); or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0091] Other embodiments provide compounds of each of formula (VIa) to (VIi), respectively:

[0092]

[0093]

[0094] wherein, in each case, R1 and R3 are as defined above for one or more embodiments of compounds of Formula (IIa) to (IIb); or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0095] More embodiments provide compounds of formula (VIIa) to (VIIi), respectively:

[0096]

[0097]

[0098] wherein, in each case, R1, R3 and R4 are as defined above for one or more embodiments of compounds of Formula (IIa) to (IIc); or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0099] Additional individual embodiments provide compounds of formula (VIIIa) to (VIIIi), respectively:

[0100]

[0101]

[0102] wherein, in each case, R1, R3 and R4 are as defined above for one or more embodiments of compounds of Formula (IIa) to (IIc); or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0103] It is to be understood that various additional embodiments provide those compounds corresponding to formula (VIIIh) to (VIIIi) wherein the pyridine ring substituted by R3 and R4 is 2-pyridyl, 3-pyridyl and 4-pyridyl, respectively, as shown below:

[0104] or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0105] definition

[0106] The term "alkyl" refers to a straight or branched chain hydrocarbon. For example, an alkyl group can have 1 to 6 carbon atoms (i.e., a C1-C6 alkyl group or a C 1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-C4 alkyl or C 1-4 alkyl) or 1 to 3 carbon atoms (i.e., C1-C3 alkyl or C 1-3 Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH (CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (- CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3.

[0107] The term "halogen" or "halo" refers to an element or substituent selected from the group of F, Cl, Br and I.

[0108] The term "haloalkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by a halogen atom. The alkyl moiety of a haloalkyl group can have, for example, 1 to 4 carbon atoms (that is, C1-C4 haloalkyl), 1 to 3 carbon atoms (that is, C1-C3 haloalkyl) or 1 to 2 carbon atoms (that is, C1-C2 haloalkyl). The non-limiting examples of suitable haloalkyl groups (which may also be referred to as halogenated fluorine groups) include, but are not limited to: trifluoromethyl (-CF3), difluoromethyl (-CHF2), fluoromethyl (-CFH2), 2-fluoroethyl (-CH2CH2F), 2-fluoropropyl (-CH2CHF2), 2,2,2-trifluoroethyl (-CH2CF3), 1,1-difluoroethyl (-CF2CH3), 2-fluoropropyl (-CH2CHFCH3), 1,1-difluoropropyl (-CF2CH2CH3), 2,2-difluoropropyl (-CH2CF2CH3), 3,3-difluoroethyl (-CF3CH3), 2-fluoropropyl (-CH2CHFCH3), 3,3-difluoropropyl (-CF3CH2CH3), 3,3-difluoropropyl (-CF3CH2CH3), 3,3-difluoropropyl (-CF3CH2CH3), 3,3-difluoropropyl (-CH2CF2 ... Fluoropropyl (-CH2CH2CHF2), 3,3,3-trifluoropropyl (-CH2CH2CHF3), 1,1-difluorobutyl (-CF2CH2CH2CH3), perfluoroethyl (-CF2CF3), perfluoropropyl (-CF2CF2CF3), perfluoroprop-2-yl (-CF(CF3)2), 1,1,2,2,3,3-hexafluorobutyl (-CF2-CF2CF2CH3), perfluorobutyl (-CF2CF2CF2CF3), 1,1,1,3,3,3-hexafluoroprop-2-yl (-CH2(CF3)2) groups, etc. Additional groups in which the halogen is replaced by a bromine, iodine or chlorine atom are also understood for use herein.

[0109] Wavy lines in chemical structures Indicates the bond through which the displayed structure is bonded to another chemical moiety or group.

[0110] The term "treatment" or "treating" herein is a method for obtaining a beneficial or desired result, including a clinical result. A beneficial or desired clinical result may include one or more of the following: (i) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition (including ALL, CLL, CML, and other diseases or conditions described herein), and / or reducing the extent of a disease or condition); (ii) slowing or preventing the development of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the deterioration or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis); and / or (iii) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of a disease or condition, enhancing the effect of another drug, delaying disease progression, improving quality of life, and / or prolonging survival).

[0111] The term "inhibiting" or "inhibition" means a decrease in the baseline activity of a biological activity or process, such as a significant decrease. "Inhibition of BCR-ABL activity" refers to a decrease in BCR-ABL activity as a direct or indirect response to the presence of a compound of Formula I or a pharmaceutically acceptable salt or co-crystal thereof relative to the activity of BCR-ABL in the absence of such a compound or a pharmaceutically acceptable salt or co-crystal thereof. The decrease in activity may be due to a direct interaction of the compound with BCR-ABL, or due to an interaction of the compound described herein with one or more other factors that in turn affect BCR-ABL activity. For example, the presence of the compound may reduce BCR-ABL activity by directly binding to BCR-ABL, by (directly or indirectly) causing another factor to reduce BCR-ABL activity, or by (directly or indirectly) reducing the amount of BCR-ABL present in a cell or organism. In some embodiments, the inhibition of BCR-ABL activity in the same individual before treatment or in other individuals who have not received the treatment can be compared. The term "inhibitor" is understood to mean a compound or agent that provides the desired inhibitory activity after administration to a human in need thereof in a pharmaceutically or therapeutically effective dose.

[0112] "Delay" refers to the progression of a disease or condition, meaning relief, hindrance, slowing, delay, stabilization and / or the progression of a postoperative disease or condition. This delay can have different lengths of time, depending on the history of the disease or condition and / or the individual being treated. The method of "delaying" the progression of a disease or condition is a method that reduces the probability of disease or condition progression within a given time frame and / or alleviates the degree of disease or condition within a given time frame when compared to not using the method. This comparison is usually based on clinical studies, using a statistically significant number of individuals. Disease or condition progression can be detected using standard methods, such as routine physical examination, mammography, imaging or biopsy. Progress can also refer to a disease or condition progression that may not be detected initially, and includes occurrence, recurrence and onset.

[0113] The term "subject" or "patient" refers to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for both human therapy and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human; and in some embodiments, the subject is selected from cats and dogs. "Subject in need" or "human in need" refers to an individual, such as a human, who may have or is suspected of having a disease or condition that will benefit from certain treatments as described herein; for example, treatment with a compound of Formula I as described herein, or a pharmaceutically acceptable salt or co-crystal thereof. This includes individuals who may be determined to be at risk for or susceptible to such diseases or conditions, such that treatment will prevent the disease or condition from developing.

[0114] The modifier "about" used in conjunction with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). In some embodiments, the term "about" refers to the indicated amount plus or minus 10%. In some embodiments, the term "about" refers to the indicated amount plus or minus 5%.

[0115] As used herein, the terms "embodiment" and "aspect" each refer to an example, example, or illustration of the present disclosure, and may be used interchangeably. In some cases, as described, may further define, limit, or serve as a subset, subclass description, or specific instance of another. In other cases, an embodiment or aspect may provide a comparison with or distinction from another embodiment or aspect.

[0116] As used herein, the singular terms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Furthermore, as used herein, the term "comprising" means "including". Thus, "comprising A or B" means including A, B, or A and B.

[0117] Unless stated otherwise, variables such as X and R, including all subvariables thereof (eg, R1, R2, etc.) used throughout this disclosure are the same variables as previously defined.

[0118] All ranges disclosed and / or claimed herein are inclusive of the recited endpoints and are independently combinable. For example, ranges of "2 to 10" and "2-10" include the endpoints 2 and 10, as well as all intermediate values ​​between the context of the units considered. For example, unless described in the context of an average, reference to "claims 2 to 10" or "C2-C 10 References to "alkyl" include units 2, 3, 4, 5, 6, 7, 8, 9, and 10 because the claims and atoms are numbered as consecutive numbers without fractions or decimal points. On the other hand, the context of "a pH of 5-9" or "a temperature of 5°C to 9°C" includes the integers 5, 6, 7, 8, and 9, and all fractional and decimal units therebetween, such as 6.5 and 8.24.

[0119] The term "independently selected" refers to the situation when more than one variable or item can be selected from a list of options, regardless of which option is applicable to the other variable or item. For example, when the variables R3 and R4 can be independently selected from the group of H, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, halogen, -NH-S(=O)2H, and -NH-S(=O)2-C1-C6 alkyl in each case, R3 and R4 can each include the same option from the list (i.e., R1 is -CH3 and R2 is -CH3) or different options from the list (i.e., R3 is -CH3 and R4 is H).

[0120] The term "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount or dosage sufficient to achieve treatment as defined below when administered to an individual (e.g., a mammal, such as a human) in need of such treatment. The therapeutic or pharmaceutically effective amount will vary depending on the individual and disease condition being treated, the weight and age of the individual, the severity of the disease condition, the mode of administration, etc., all of which can be readily determined by one of ordinary skill in the art. For example, a "therapeutically effective amount" or "pharmaceutically effective amount" of a compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof is an amount sufficient to modulate BCR-ABL expression or activity, and thereby treat an individual (e.g., a human) suffering from an indication or improving or alleviating existing symptoms of the indication. For example, a therapeutically effective amount or pharmaceutically effective amount may be an amount sufficient to reduce the symptoms of a disease or condition in response to inhibition of BCR-ABL activity.

[0121] In some embodiments, each dosage unit contains 0.1 mg to 1 g, 0.1 mg to 500 mg, or 0.1 mg to 100 mg of a compound of Formula I or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some embodiments, a therapeutically effective amount or a pharmaceutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises about 0.1 mg to about 500 mg per dose, administered once or twice daily. In some embodiments, individual doses are selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, and 500 mg per dose. In some embodiments, an initial dose of about 10 mg to about 100 mg may be used, decreasing to lower doses after achieving ≤ 1% BCR-ABL(IS).

[0122] As used herein, a "pharmaceutically acceptable excipient" is a pharmaceutically acceptable vehicle, including, but not limited to, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the composition.

[0123] The term "pharmaceutically acceptable carrier" refers to excipients or vehicles with which the compound is administered, including but not limited to diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, etc. Carriers are generally described herein and also described in "Remington's Pharmaceutical Sciences" by EW Martin. Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxydioctadecylhydroxystearate, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, siloxane, silicone binder 4102, and silicone emulsion. However, it should be understood that the carrier selected for the pharmaceutical composition and the amount of such carrier in the composition may vary depending on the formulation method (e.g., dry granulation formulation, solid dispersion formulation).

[0124] The term "pharmaceutically acceptable salt" or "therapeutically acceptable salt" refers to a salt form of a compound of formula (I) that is suitable for contact with human and / or animal tissues and organs within a reasonable medical assessment, such that any resulting toxicity, irritation, allergic reaction, etc. is commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Examples of salts may include hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, malates, maleates, fumarates, tartrates, succinates, citrates, acetates, lactates, methanesulfonates (methanesulfonate / mesylate), benzenesulfonates (benzenesuflonate / besylate), p-toluenesulfonates (toluenesulfonates), 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and alkanoates (such as acetates, HOOC-(CH2) n-COOH, wherein n is 0-4). In addition, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. In contrast, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared according to conventional procedures for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0125] Physiologically acceptable salts (e.g., pharmaceutically acceptable salts) of the compounds of the invention include salts derived from appropriate bases, such as alkali metals or alkaline earth metals (e.g., Na + , Li + , K+, Ca +2 and Mg +2 ), ammonium and NR4. Physiologically acceptable salts of nitrogen atoms or amino groups include (a) acid addition salts formed with inorganic acids such as aspartic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; (b) salts formed with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, 4-acetamido-benzoic acid, caproic acid, caprylic acid, adipic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, glutamic acid, polyglutamic acid, formic acid, naphthalenesulfonic acid, naphthalene-2- (c) salts formed by elemental anions such as chloride, bromide and iodide. Physiologically acceptable salts of hydroxy compounds include salts of the anion of the compound and a suitable cation such as Na + Each R is independently selected from H and (C1-C8) alkyl.

[0126] The term "expression amount" herein refers to the rate at which information from a gene (e.g., BCR-ABL with or without T315I, F317L, E255K, and Y253F mutations) is processed in the synthesis of a gene product, particularly a functional gene product. In various embodiments, gene expression can be indicated by the transcriptional expression amount of mRNA or the transcriptional expression amount of protein.

[0127] As used herein, "co-crystal" or "co-crystal salt" means a crystalline material composed of two or more unique solids at room temperature, each of which has unique physical characteristics, such as structure, melting point, heat of fusion, hygroscopicity, solubility and stability. Co-crystals or co-crystal salts can be produced according to co-crystal methods known per se. The term co-crystal (or co-crystal) or co-crystal salt is also referred to as a multi-component system in which there are one or more host API (active pharmaceutical ingredient) molecules (such as compounds of formula I) and one or more guest (or co-former) molecules. In a particular embodiment, a pharmaceutically acceptable co-crystal of a compound of formula I or a compound of formula II with a co-former molecule is in a crystalline form selected from malonic acid co-crystals, succinic acid co-crystals, capric acid co-crystals, salicylic acid co-crystals, vanillic acid co-crystals, maltol co-crystals or glycolic acid co-crystals. Co-crystals may have improved properties compared to the parent form (i.e., free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties may include increased solubility, increased dissolution rate, increased bioavailability, increased dose response, reduced hygroscopicity, crystalline form of a normally amorphous compound, crystalline form of a compound that is difficult or unsaltable, reduced form diversity, a more desirable morphology, and the like.

[0128] The term "co-crystal" refers to a physical association of two or more molecules that have stability through non-covalent interactions. One or more components of this molecular complex provide a stable framework in the form of a lattice. In some cases, the guest molecule is incorporated into the lattice as an anhydrate or solvate, see, for example, "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O. et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0129] Treatment

[0130] Provided is a method for inhibiting the proliferation of cancer cells in an individual, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0131] Provided herein is a method of inhibiting the proliferation of cells expressing BCR-ABL in an individual, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0132] Provided herein is a method for treating chronic myeloid leukemia (CML) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0133] Provided herein is a method for treating chronic phase chronic myeloid leukemia (CML) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0134] Provided herein is a method for treating accelerated phase chronic myeloid leukemia in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0135] Provided herein is a method for treating blast crisis chronic myeloid leukemia (CML) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0136] For each type or stage of CML listed above, there is a separate method of treating the CML in question, comprising administering to the individual in need thereof:

[0137] a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof; and

[0138] b) a therapeutically effective amount of a tyrosine kinase inhibitor selected from imatinib Nilotinib ), dasatinib, ), Ponatinib and bosutinib ( ) group.

[0139] Also provided herein is a method of treating acute lymphoblastic leukemia (ALL) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0140] Also provided herein is a method for treating acute lymphoblastic leukemia in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0141] Also provided herein is a method for treating lymphoma in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0142] Also provided herein is a method for treating a solid tumor in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0143] Additionally provided herein is a method of treating Ph-positive acute lymphoblastic leukemia (Ph+ALL or Philadelphia chromosome-positive ALL) in a human subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0144] Further provided herein is a method of treating Ph-positive acute lymphoblastic leukemia (Ph+ALL or Philadelphia chromosome-positive ALL) in a human subject, the method comprising administering to a subject in need thereof:

[0145] a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof; and

[0146] b) a therapeutically effective amount of at least one tyrosine kinase inhibitor selected from the group consisting of: imatinib Dasatinib Ponatinib Bosutinib Asciminid ) and nilotinib or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug of one or more tyrosine kinase inhibitors.

[0147] Also provided herein is a method of treating Ph-positive acute lymphoblastic leukemia (Ph+ALL or Philadelphia chromosome-positive ALL) in a human subject, the method comprising administering to a subject in need thereof:

[0148] a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof; and

[0149] b) a therapeutically effective amount of blinatumomab.

[0150] Also provided herein is a method for treating acute myeloid leukemia (AML) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0151] Also provided herein is a method of treating myelodysplastic syndrome in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0152] Also provided herein is a method for treating gastric cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0153] Also provided herein is a method for treating endometrial cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0154] Also provided herein is a method of treating bladder cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0155] Also provided herein is a method of treating multiple myeloma in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0156] Also provided herein is a method for treating breast cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0157] Also provided herein is a method for treating prostate cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0158] Also provided herein is a method for treating lung cancer in a human individual, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including its optical isomers, racemates or other mixtures), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof. Another embodiment provides such a method for treating lung cancer, wherein the lung cancer is non-small cell lung cancer.

[0159] Also provided herein is a method for treating colorectal cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0160] Also provided herein is a method for treating renal cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0161] Also provided herein is a method of treating glioblastoma in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0162] Further provided is a method for treating gastrointestinal stromal tumors in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0163] Also provided is a use of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof for preparing a medicament for use as a pan-BCR-ABL inhibitor.

[0164] Reference herein to a disease or condition associated with a BCR-ABL mutation indicates that a BCR-ABL mutation in the kinase domain has been identified or can be identified in a human individual of interest, including those human individuals in need of treatment for the disease or condition in question. Such a mutation may be associated with a disease or condition described herein, including but not limited to CML, AML, and / or ALL. In some embodiments, individuals experiencing a BCR-ABL mutation have been shown to be refractory or resistant to treatment with one or more agents, such as tyrosine kinase inhibitors (ponatinib, imatinib, dasatinib, nilotinib, etc.). It should be understood that such a mutation may be referred to as an individual experiencing such a mutation, an individual having such a mutation, or a disease or condition associated with such a mutation, or a specific tumor having or expressing a product of such a mutation.

[0165] The BCR-ABL inhibitory compounds described herein can be produced by methods known in the art, including those described in the following: U.S. Pat. No. 8,859,553 (Yu et al.); US2021 / 0393628 A1 (Mackall et al.); US2015 / 0105377 (Gozgit et al.); Designing Novel BCR-ABL Inhibitors for Chronic Myeloid Leukemia with Improved Cardiac Safety, Pandrala et al., Journal of Medicinal Chemistry, 2022, 65, 10898-10919; Rapid Discovery of a Novel Series of Abl Kinase Inhibitors by Application of an Integrated Microfluidic Synthesis and Screening, Desai et al., Journal of Medicinal Chemistry, 2013, 56, 3033-3047; Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)-methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL)7 Kinase, Including the T315I Gatekeeper Mutant BreakpointCluster Region-Abelson (BCR-ABL) 7 Kinase Including the T315I Gatekeeper Mutant), Huang et al., Journal of Medicinal Chemistry, 2010, 53, 4701-4719;Design, synthesis, and biological evaluation of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives as potent pan-Bcr-Abl inhibitors, including threonine; 315 →Isoleucine 315 Mutants (Design,Synthesis,and Biological Evaluation of3-(1H-1,2,3-Triazol-1-yl)benzamide Derivatives as Potent Pan Bcr-Abl Inhibitors Including the Threonine 315 →Isoleucine 315 Mutant, Li et al., Journal of Medicinal Chemistry, 2012, 55, 10033-10046; and Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2-a]pyrazin-3-ylethynyl)-4-isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1and2, Wang et al., Journal of Medicinal Chemistry, 2018, 61, 7977-7990.

[0166] As a non-limiting example using the method from Pandela et al., Journal of Medicinal Chemistry, 2022, 65, 10898-10919, 3-iodo-4-methylbenzoic acid (A) is reacted with 3-bromo-5-(trifluoromethyl)aniline (B) (SOCl2, diisopropylethylamine, DMAP, THF, reflux, 5 hours, THF) to produce N-(3-bromo-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (C). C is then reacted with 3-ethynylimidazo[1,2-b]pyridazine (D) in the presence of CuI, [Pd(Ph3P)4] and DMF in a sealed tube at 100°C for 5 hours to produce N-(3-bromo-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (E). Copper-catalyzed N-arylation can then be used to introduce the R2 group, including, inter alia, 1-H-imidazole (CET-10-084), 2-methyl-1H-imidazole (CET-10-067), 4-fluoro-1H-imidazole (CET-10-100), 4-(trifluoromethyl)-1H-imidazole (CET-10-103), and 4-methyl-1H-imidazole (CET-10-108).

[0167]

[0168] General synthesis of BCR-ABL inhibitors / compounds

[0169] Synthesis of coupled aryl aniline

[0170]

[0171] Synthesis of HIT compounds

[0172]

[0173] General procedure for the synthesis of coupled aryl amines.

[0174] The desired arylamines were prepared by the reported procedure. 1Synthesis. 3-Bromo-5-(trifluoromethyl)aniline 1 (1 mmol, 1 eq.) was combined with the corresponding arylboronic acid 2a-d (2 mmol, 2 eq.), tetrakis(triphenylphosphine)palladium(0) (0.025 mmol, 0.025 eq.) and Na2CO3 (7 mmol, 7 eq.) in 30 mL of deoxygenated DMF / H2O (7:2) and heated to reflux overnight. The reaction was then cooled to room temperature and diluted with DCM / hexanes (1:1). The combined organic layers were washed with saturated aqueous NaHCO3 (2×25 mL), water (2×25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2, 30%→80% EtOAc / hexanes) to give the desired coupled arylanilines 3a-d.

[0175] Synthesis of compounds 5a-d.

[0176] Under nitrogen atmosphere, 3-iodo-4-methylbenzoic acid 4 (20mmol, 1 equivalent) is added to SOCl2 (100mmol, 5 equivalents), and two drops of DMF are then added at room temperature. The reaction mixture is stirred at reflux for 5 hours, then cooled to room temperature, and the excess SOCl2 is carefully removed. The crude material is co-evaporated with benzene and dried under vacuum to obtain the desired acyl chloride. The acyl chloride is dissolved in anhydrous THF (20mL), and then added dropwise at 0°C to a stirred mixture of 3-bromo-5-(trifluoromethyl)aniline 3a-d (20mmol, 1 equivalent), diisopropylethylamine (24mmol, 1.2 equivalents) and DMAP (2.0mmol, 0.1 equivalent) in THF. After addition is complete, the reaction mixture is warmed to room temperature and stirred overnight. The reactant is quenched with water, and the product is extracted into EtOAc (3×50mL). The combined organic extracts were washed with brine solution (25 mL), dried over Na2SO4, filtered and evaporated to dryness to give the crude material which was purified on a silica gel column using a gradient of 0% to 50% EtOAc in hexanes as eluent to afford the desired products 5a-d as off-white solids.

[0177] Synthesis of alkyne 7:

[0178] Compound 7 was prepared according to a previously reported method. 2Several modifications were made. CuI (0.5 g, 2.63 mmol), Pd (PPh 3 ) 2 Cl 2 (1.8 g, 2.63 mmol) and TEA (21.0 mL, 150.6 mmol) were added to a solution of 3-bromoimidazo [1,2-b] pyridazine 6 (10.0 g, 50.5 mmol) in acetonitrile. The solution was purged with a stream of nitrogen for 10 minutes, and then ethynyltrimethylsilane (21.0 mL, 151.8 mmol) was added. The mixture was heated to reflux and kept overnight. After cooling to room temperature, the reaction mixture was filtered to remove undissolved solids. The solids were washed with a large amount of acetonitrile. The filtrate was evaporated to dryness and then placed in methanol (300 mL). K2CO3 (14.3 g, 103.5 mmol) was added to this mixture at room temperature, and the mixture was then stirred for 4 hours. The reaction progress was monitored by TLC. The reaction mixture was filtered to remove excess K2CO3. The solids were washed with a minimum amount of methanol. The filtrate was concentrated to dryness, dissolved in excess EtOAc, and subsequently washed with water and then with brine solution. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to give a crude product which was purified on a silica gel column using a gradient of 0% to 50% EtOAc in hexanes to obtain the desired product as a light brown solid (5.0 g, 69%).

[0179] Synthesis of compounds 8a-d:

[0180] Compounds 8a-d were prepared according to literature procedures. 3 Minimal modifications were made. 3-iodo-4-methylbenzoate derivatives 5a-d (6.71 mmol, 1.2 eq) were added to a stirred solution of 3-ethynyl imidazole [1,2-b] pyridazine 7 (5.59 mmol, 1 eq) in DMF (10 mL). The mixture was subjected to three vacuum / nitrogen filling cycles, and then CuI (1.11 mmol, 0.2 eq), Pd (PPh3) 4 (0.55 mmol, 0.1 eq) and diisopropylethylamine (11.17 mmol, 2 eq) were added. The reaction mixture was stirred at 80 ° C for 2 hours and then cooled to room temperature. Water (25 mL) was added and the product was extracted into EtOAc (3×25 mL). The organic layers were combined and washed with water (20 mL) and then with brine solution (20 mL). The organic phase was dried over Na2SO4, filtered and then evaporated to dryness to give a gummy solid which was then triturated with minimal acetonitrile to give a solid. The solid was collected by filtration, washed with minimal acetonitrile and dried under vacuum for 2 hours to give the desired compounds 8a-d as off-white solids.

[0181] References:

[0182] 1.VLGunderson,ALSmeigh,CHKim,DTCo,MRWasielewski,J.Am.Chem.Soc.2012,134,4363-4372.

[0183] 2.WSHuang,CAMetcalf,R.Sundaramoorthi,Y.Wang,D.Zou,RMThomas,X.Zhu,L.Cai,D.Wen,S.Liu,J.Romero,J.Qi,I.Chen,G.Banda,SPLentini,S.Das,Q.Xu,J.Keats,F.Wang,S.Wardwell,Y.Ning,J TSnodgrass,MIBroudy,K.Russian,T.Zhou,L.Commodore,NINarasimhan,QKMohemmad,J.Iuliucci,VMRivera,DCDalgarno,TKSawyer,T.Clackson,WCShakespeare,J.Med.Chem.2010,53,4701-4719.

[0184] 3. M. Najjar, C. Suebsuwong, SSRay, RJ Thapa, JLMaki, S. Nogusa, S. Shah, D. Saleh, PJ Gough, J. Bertin, et al. Cell Rep. 2015, 10, 1850-1860.

[0185] The following specific compounds have been prepared and tested and provide a non-limiting group of materials that fall within Formula (I) and other formulae provided herein.

[0186] Example No. 1 -N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-084).

[0187]

[0188] Example No. 2-3-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-067)

[0189]

[0190] HRMS (ESI-TOF) m / z of compound CET-10-067: C 27 H 19 [M+Na] of F3N6ONa + The calculated value is 523.1470.

[0191] Example No. 3-N-(3-(4-fluoro-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-100).

[0192]

[0193] HRMS (ESI-TOF) m / z of compound CET-10-100: C 26 H 16 [M+Na] of F4N6ONa + The calculated value is 523.1470;

[0194] Example No. 4-3-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(trifluoromethyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)benzamide (CET-10-103).

[0195]

[0196] HRMS (ESI-TOF) m / z of compound CET-10-103: C 27 H 16 [M+Na] of F6N6ONa + The calculated value is 577.1187;

[0197] Example No. 5-3-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-106).

[0198]

[0199] HRMS (ESI-TOF) m / z of compound CET-10-106: C 29 H 19 [M+Na] of F3N4ONa + The calculated value is 519.1408;

[0200] Example No. 6-3-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-104)

[0201]

[0202] HRMS (ESI-TOF) m / z of compound CET-10-104: C 28 H 18 [M+Na] of F3N5ONa + The calculated value is 520.1361;

[0203] Example No. 7-N-(4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-105).

[0204]

[0205] HRMS (ESI-TOF) m / z of compound CET-10-105: C 26 H 17 [M+Na] of F3N6ONa + The calculated value is 509.1313;

[0206] Example No. 8 - N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-109).

[0207]

[0208] HRMS (ESI-TOF) m / z of compound CET-10-109: C 27 H 17 [M+Na] of F5N6ONa + The calculated value is 559.1281;

[0209] Example No. 9-3-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)benzamide (CET-10-110).

[0210]

[0211] HRMS (ESI-TOF) m / z of compound CET-10-110: C 24H 18 [M+Na] of F3N5O3SNa + The calculated value is 536.0980;

[0212] Example No. 10-3-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methylthiazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-111).

[0213]

[0214] HRMS (ESI-TOF) m / z of compound CET-10-111: C 27 H 18 [M+Na] of F3N5OSNa + The calculated value is 540.1081;

[0215] Example No. 11-3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-101).

[0216]

[0217] HRMS (ESI-TOF) m / z of compound CET-10-101: C 29 H 21 [M+Na] of F3N4ONa + The calculated value is 521.1565;

[0218] Example No. 12-3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-102).

[0219]

[0220] HRMS (ESI-TOF) m / z of compound CET-10-102: C 28 H 20 [M+Na] of F3N5ONa + The calculated value is 522.1517;

[0221] Example No. 13-3-(4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-108).

[0222]

[0223] HRMS (ESI-TOF) m / z of compound CET-10-108: C 27 H 20 [M+Na] of F3N9ONa + The calculated value is 566.1640;

[0224] Example No. 14-N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(4-(imidazo[1,2-b]pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-4-methylbenzamide (CET-10-107)

[0225]

[0226] HRMS (ESI-TOF) m / z of compound CET-10-107: C 26 H 18 [M+Na] of F3N9ONa + The calculated value is 552.1484;

[0227] , or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0228] Cell proliferation assay

[0229] Cell proliferation assays were performed using a murine pro-B cell line (Ba / F3) that stably expresses native or mutant BCR-ABL. Ba / F3 cells are interleukin-3 (IL3) dependent. However, expression of BCR-ABL renders them independent of IL3 and able to grow in the absence of IL3 signaling. Therefore, using a tetrazolium salt (MTS) assay, it was found that BCR-ABL inhibition resulted in a detectable decrease in cell proliferation and revealed the pharmacodynamic efficacy of the candidate TKI.

[0230] For this project, we wanted a TKI with similar pharmacodynamics profile to ponatinib when achieving efficacy in the assay. We also used cells that do not express BCR-ABL, showing lower toxicity by being potentially specific only to the target. Imatinib was our negative drug control and ponatinib was our positive drug control.

[0231] K562 cells and Ba / F3 parental cells or those transduced with empty vectors or vectors expressing BCR-ABL WT or a series of point mutations known to confer resistance to ABL tyrosine kinase inhibitors were seeded into 384-well plates at 750 cells / well in RPMI medium containing 10% FBS and supplemented with L-glutamine, penicillin / streptomycin and amphotericin B (amphotericin B). Cells were cultivated in triplicate with vehicle or graded concentrations of designated inhibitors for 72 hours, at which time the relative number of viable cells was quantified using a tetrazolium-based MTS assay. After the cells were cultivated with the MTS reagent for 1-4 hours, the absorbance values ​​were read at 490nm using a Synergy 2 plate reader. The absorbance values ​​from the blank wells containing only the medium were subtracted from all other wells, and then the absorbance values ​​from all wells were normalized relative to the mean of the duplicate vehicle controls to produce normalized survival percentage values. These normalized values ​​were curve fit to generate dose response metrics for each inhibitor.

Claims

1. A compound of formula (I): in: X is selected from the group consisting of: R1 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, OH and CN; R2 is selected from H, -NH-S(=O)2H, -NH-S(=O)2-C1-C6 alkyl, Groups; R3 and R4 are each independently selected from the group consisting of H, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, halogen, -NH-S(=O)2H and -NH-S(=O)2-C1-C6 alkyl; The condition is that when X is When R1 is CH3 or Cl, and the variable CF3 group is bonded to the 3-position or 5-position of the benzene ring B, then R2 is not or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

2. The compound according to claim 1, which has formula (Ia): wherein X, R1 and R2 are as defined in claim 1, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

3. The compound according to claim 1, which has formula (Ib): wherein X, R1 and R2 are as defined in claim 1, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

4. The compound according to claim 1, which has formula (Ic): wherein X, R1 and R2 are as defined in claim 1, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

5. The compound according to claim 1, which has formula (IIa): in: X is selected from the group consisting of: R1 is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, OH and CN; R2 is selected from H, -NH-S(=O)2H, -NH-S(=O)2-C1-C6 alkyl, Groups; R3 and R4 are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -NH-S(=O)2H and -NH-S(=O)2-C1-C6 alkyl; The condition is that when X is When R1 is CH3 or Cl, and the variable CF3 group is bonded to the 3-position or 5-position of the benzene ring B, then R2 is not or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

6. The compound according to claim 1, which has formula (IIb): wherein X, R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

7. The compound according to claim 1, which has the formula (IIc): wherein X, R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

8. The compound according to claim 1, which has formula (IIIa): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

9. The compound according to claim 1, which has the formula (IIIb): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

10. The compound according to claim 1, which has the formula (IIIc): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

11. The compound according to claim 1, which has the formula (IIId): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

12. The compound according to claim 1, which has the formula (IIIe): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

13. The compound according to claim 1, which has the formula (IIIf): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

14. The compound according to claim 1, which has the formula (IIIg): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

15. The compound according to claim 1, which has the formula (IIIh): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

16. The compound according to claim 1, which has the formula (IIIi): wherein R1 and R2 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

17. The compound according to claim 1, which has the formula (IVa): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

18. The compound according to claim 1, which has the formula (IVb): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

19. The compound according to claim 1, which has the formula (IVc): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

20. The compound according to claim 1, which has the formula (IVd): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

21. The compound according to claim 1, which has the formula (IVe): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

22. The compound according to claim 1, which has the formula (IVf): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

23. The compound according to claim 1, which has the formula (IVg): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

24. The compound according to claim 1, which has the formula (IVh): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

25. The compound according to claim 1, which has the formula (IVi): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

26. The compound according to claim 1, which has formula (Va): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

27. The compound according to claim 1, having formula (Vb): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

28. The compound according to claim 1, having the formula (Vc): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

29. The compound according to claim 1, which has the formula (Vd): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

30. The compound according to claim 1, having formula (Ve): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

31. The compound according to claim 1, which has the formula (Vf): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

32. The compound according to claim 1, having the formula (Vg): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

33. The compound according to claim 1, which has the formula (Vh): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

34. The compound according to claim 1, which has formula (Vi): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

35. The compound according to claim 1, which has formula (VIa): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

36. The compound according to claim 1, which has the formula (VIb): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

37. The compound according to claim 1, which has the formula (VIc): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

38. The compound according to claim 1, having the formula (VId): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

39. The compound according to claim 1, which has the formula (VIe): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

40. The compound of claim 1 having formula (VIf): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

41. The compound of claim 1 having formula (VIg): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

42. The compound according to claim 1, which has the formula (VIh): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

43. The compound according to claim 1, which has the formula (VIi): wherein R1 and R3 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

44. The compound according to claim 1, which has the formula (VIIa): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

45. The compound according to claim 1, which has the formula (VIIb): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

46. ​​The compound according to claim 1, which has the formula (VIIc): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

47. The compound according to claim 1, which has the formula (VIId): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

48. The compound according to claim 1, which has the formula (VIIe): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

49. The compound according to claim 1, which has the formula (VIIf): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

50. The compound according to claim 1, which has the formula (VIIg): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

51. The compound according to claim 1, which has the formula (VIIh): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

52. The compound according to claim 1, which has the formula (VIIi): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

53. The compound according to claim 1, which has the formula (VIIIa): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

54. The compound of claim 1, having formula (VIIIb): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

55. The compound according to claim 1, which has the formula (VIIIc): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

56. The compound according to claim 1, which has the formula (VIIId): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

57. The compound according to claim 1, which has the formula (VIIIe): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

58. The compound according to claim 1, which has the formula (VIIIf): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

59. The compound according to claim 1, which has the formula (VIIIg): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

60. The compound of claim 1 having the formula (VIIIh): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

61. The compound of claim 1, having formula (VIIIi): wherein R1, R3 and R4 are as defined in claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

62. A compound according to any one of claims 59, 60 and 61, wherein the pyridine ring substituted by R3 and R4 is bonded in the form of a 4-pyridyl ring; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

63. A compound according to any one of claims 59, 60 and 61, wherein the pyridine ring substituted by R3 and R4 is bonded in the form of a 3-pyridyl ring; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

64. A compound according to any one of claims 59, 60 and 61, wherein the pyridine ring substituted by R3 and R4 is bonded in the form of a 2-pyridyl ring; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

65. The compound of any one of claims 1 to 64, wherein R1 is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, OH and CN; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

66. The compound of any one of claims 1 to 65, wherein R1 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, OH and CN; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

67. The compound of any one of claims 1 to 65, wherein R1 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, halogen, and C1-C3 haloalkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

68. The compound of any one of claims 1 to 66, wherein R1 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen, and C1-C3 haloalkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

69. The compound of any one of claims 1 to 66, wherein R1 is selected from the group consisting of C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, and -O-C3-C6 cycloalkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

70. The compound of any one of claims 1 to 67, wherein R1 is selected from the group of halogen and C1-C3 haloalkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

71. The compound of any one of claims 1 to 67, wherein R1 is selected from the group of halogen and C1-C3 fluoroalkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

72. The compound of any one of claims 1 to 67, wherein R1 is selected from the group of C1-C3 alkyl and C1-C3 alkoxy; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

73. A compound according to any one of claims 1 to 67, wherein R1 is C1-C3 alkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

74. A compound according to any one of claims 1 to 67 and 72, wherein R1 is -CH3; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

75. A compound according to any one of claims 1 to 67 and 72, wherein R1 is ethyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

76. The compound of any one of claims 1 to 67 and 72, wherein R1 is selected from the group of n-propyl and isopropyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

77. The compound of any one of claims 1 to 74, wherein R3 is selected from the group consisting of H, C1-C4 alkyl, -O-C1-C4 alkyl, C1-C4 haloalkyl, halogen, -NH-S(=O)2H, and -NH-S(=O)2-C1-C4 alkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

78. The compound of any one of claims 1 to 75, wherein R3 is selected from the group consisting of H, C1-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, halogen, -NH-S(=O)2H, and -NH-S(=O)2-C1-C3 alkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

79. The compound of any one of claims 1 to 76, wherein R3 is selected from the group of H, C1-C3 alkyl and -O-C1-C3 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

80. The compound of any one of claims 1 to 76, wherein R3 is selected from the group of C1-C3 haloalkyl and halogen; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

81. The compound of any one of claims 1 to 76 and 78, wherein R3 is selected from the group of C1-C3 fluoroalkyl and F; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

82. The compound of any one of claims 1 to 76, wherein R3 is selected from the group consisting of -NH-S(=O)2H and -NH-S(=O)2-C1-C3 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

83. The compound of any one of claims 1 to 76, wherein R3 is H; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

84. The compound of any one of claims 1 to 16 and 44 to 81, wherein R4 is selected from the group consisting of H, C1-C4 alkyl, -O-C1-C4 alkyl, C1-C4 haloalkyl, halogen, -NH-S(=O)2H, and -NH-S(=O)2-C1-C4 alkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

85. The compound of any one of claims 1 to 16 and 44 to 81, wherein R4 is selected from the group consisting of H, C1-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, halogen, -NH-S(=O)2H, and -NH-S(=O)2-C1-C3 alkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

86. The compound of any one of claims 1 to 16 and 44 to 81, wherein R4 is selected from the group of H, C1-C3 alkyl and -O-C1-C3 alkyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

87. The compound of any one of claims 1 to 16 and 44 to 81, wherein R4 is selected from the group of C1-C3 haloalkyl and halogen; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

88. The compound of any one of claims 1 to 16 and 44 to 81, wherein R4 is selected from the group of C1-C3 fluoroalkyl and F; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

89. The compound of any one of claims 1 to 16 and 44 to 81, wherein R4 is selected from the group consisting of -NH-S(=O)2H and -NH-S(=O)2-C1-C3 alkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

90. The compound of any one of claims 1 to 16 and 44 to 81, wherein R4 is H; or Its pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including its optical isomer, racemate or other mixture), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug.

91. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

92. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

93. Use of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof, for the preparation of a medicament.

94. A method of inhibiting the proliferation of cancer cells in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

95. A method of inhibiting proliferation of cells expressing BCR-ABL in an individual, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

96. A method of treating chronic myeloid leukemia (CML) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

97. A method of treating chronic phase chronic myeloid leukemia (CML) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

98. A method of treating accelerated phase chronic myeloid leukemia in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

99. A method for treating blast crisis chronic myeloid leukemia (CML) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

100. A method of treating acute lymphoblastic leukemia (ALL) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

101. A method of treating acute lymphoblastic leukemia in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

102. A method of treating lymphoma in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

103. A method of treating a solid tumor in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

104. A method of treating Ph-positive acute lymphoblastic leukemia (Ph+ALL or Philadelphia chromosome-positive ALL) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

105. A method of treating Ph-positive acute lymphoblastic leukemia (Ph+ ALL or Philadelphia chromosome-positive ALL) in a human subject, the method comprising administering to a subject in need thereof: a) a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof; and b) a therapeutically effective amount of at least one tyrosine kinase inhibitor selected from the group consisting of imatinib, ), dasatinib, ), ponatinib, ), bosutinib, ), Asciminid ) and nilotinib ( ), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug of one or more tyrosine kinase inhibitors.

106. A method of treating Ph-positive acute lymphoblastic leukemia (Ph+ ALL or Philadelphia chromosome-positive ALL) in a human subject, the method comprising administering to a subject in need thereof: a) a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof; and b) a therapeutically effective amount of blinatumomab.

107. A method of treating acute myeloid leukemia (AML) in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

108. A method of treating myelodysplastic syndrome in a human subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

109. A method for treating gastric cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

110. A method of treating endometrial cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

111. A method of treating bladder cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

112. A method of treating multiple myeloma in a human subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

113. A method of treating breast cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

114. A method of treating prostate cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

115. A method of treating lung cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof. Another embodiment provides such a method of treating lung cancer, wherein the lung cancer is non-small cell lung cancer.

116. A method of treating colorectal cancer in a human subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

117. A method of treating renal cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

118. A method of treating glioblastoma in a human subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

119. A method for treating gastrointestinal stromal tumors in a human subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

120. The method of any one of claims 92-117, wherein the individual in need thereof has a point mutation in the kinase domain.

121. The method of any one of claims 92-118, wherein the individual in need thereof has a BCR-ABL mutation.

122. The method of any one of claims 92-119, wherein the individual in need thereof has a T315I mutation.

123. The method of any one of claims 92-119, wherein the individual in need thereof has a F317L mutation.

124. The method of any one of claims 92-119, wherein the individual in need thereof has an E255K mutation.

125. The method of any one of claims 92-119, wherein the individual in need thereof has a Y253F mutation.

126. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof, for use in the preparation of a medicament for use as a pan-BCR-ABL inhibitor.

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