Small molecule inhibitors of BCR-ABL

Abstract

Provided are compounds of formula (I) for use as inhibitors of native BCR-ABL kinase protein and clinically important BCR-ABL mutations such as T315I, F317L, E255K, and Y253F for the treatment of diseases including chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML), wherein X is selected from the group of ethanyl, ethenyl, ethynyl, and triazinyl; R is selected from the group of alkyl, alkoxy, cycloalkyl, -CH-cycloalkyl, -O-cycloalkyl, halogen, haloalkyl, OH, and CN; and R is a ring moiety selected from the group of imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, phenyl, and pyridinyl, each of which may be substituted. TIFF2025529126000111.tif89128

Description

[Technical Field]

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

[0002] Background of the Invention The development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene offers an effective approach for treating chronic myeloid leukemia (CML) and / or acute lymphoblastic leukemia (ALL). Currently available inhibitors are limited by drug resistance and toxicity. Ponatinib, a third-generation inhibitor, has demonstrated excellent efficacy against both wild-type and mutant BCR-ABL kinases, including the "gatekeeper" T315I mutation, which is resistant to all other currently available TKIs. However, it is one of the most cardiotoxic TKIs approved by the FDA. Therefore, an ideal inhibitor would need to be effective against both native and clinically relevant BCR-ABL mutations, while also being more cardiac- and immune-safe than ponatinib. Summary of the Invention

[0003] A first aspect provides 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: TIFF2025529126000002.tif40128In formula, X is Selected from the group TIFF2025529126000003.tif23128; 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 H, -NH-S(=O)2H, -NH-S(=O)2-C1-C6 alkyl, Selected from the group TIFF2025529126000004.tif52128; 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; However, if X is TIFF2025529126000005.tif10128, and R1 is CH3 or Cl, and the variable CF3 group is attached to either the 3- or 5-position of the phenyl ring B, then R2 is Not TIFF2025529126000006.tif32128. [Brief explanation of the drawings]

[0004] [Figure 1] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-109, CET-110, CET-111, and CET-84 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 2] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-067, CET-084, CET-105, and CET-104 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 3] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-001, CET-104, CET-105, and CET-106 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 4]1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-84, CET-99, and CET-100 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 5] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-100, CET-101, CET-102, and CET-103 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 6] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-67, CET-84, CET-85, CET-90, and CET-91 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 7] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-99, CET-100, CET-101, CET-102, and CET-103 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 8] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-84, CET-99, and CET-100 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 9] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-84, CET-85, CET-99, and CET-100 against Ba / F3 cells expressing BCR-ABL T315I. [Figure 10] 1 shows dose-response curves for imatinib, ponatinib, and the CET analogs CET-84, CET-99, and CET-100 on the HL60 AML-derived cell line. [Figure 11] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-109, CET-110, CET-111, and CET-84 against Ba / F3 cells expressing BCR-ABL E255V. [Figure 12]1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-001, CET-004, CET-105, and CET-106 on the K562 CML-derived cell line. [Figure 13] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-99, CET-100, CET-101, CET-102, and CET-103 on AML2 AML-derived cell lines. [Figure 14] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-001, CET-004, CET-105, and CET-106 on AML1 AML-derived cell lines. [Figure 15] 1 shows dose-response curves for imatinib, ponatinib, and the CET analogs CET-84, CET-99, and CET-100 on AML1 AML-derived cell lines. [Figure 16] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-001, CET-004, CET-105, and CET-106 on the K562 CML-derived cell line. [Figure 17] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-84, CET-85, CET-90, and CET-100 against Ba / F3 cells expressing BCR-ABL E255V. [Figure 18] 1 shows dose-response curves for imatinib, ponatinib, and CET analogs CET-84, CET-99, and CET-100 against Ba / F3 cells expressing BCR-ABL E255V. [Figure 19] 13C NMR of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-084). [Figure 20]1H NMR of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-084). [Figure 21] 1H NMR 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). [Figure 22] 13C NMR 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). [Figure 23] 1H NMR 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). [Figure 24] 13C NMR 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). [Figure 25] 1H NMR of 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). [Figure 26] 13C NMR of 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). [Figure 27]1H NMR of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)benzamide (CET-10-106). [Figure 28] 13C NMR of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-106). [Figure 29] 1H NMR of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-104). [Figure 30] 13C NMR of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-104). [Figure 31] 1H NMR of N-(4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-105). [Figure 32] 13C NMR of N-(4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-105). [Figure 33] 1H NMR of N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-109). [Figure 34]13C NMR of N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-109). [Figure 35] 1H NMR of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)benzamide (CET-10-110). [Figure 36] 13C NMR of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)benzamide (CET-10-110). [Figure 37] 1H NMR of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methylthiazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-111). [Figure 38] 13C NMR of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methylthiazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-111). [Figure 39] 1H NMR of 3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-101). [Figure 40] 13C NMR of 3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-101). [Figure 41]1H NMR of 3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-102). [Figure 42] 13C NMR of 3-(2-(imidazo[1,2-b]pyridazin-3-yl)vinyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-102). [Figure 43] 1H NMR of 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). [Figure 44] 13C NMR of 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). [Figure 45] 1H NMR of 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). [Figure 46] 13C NMR of 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). DETAILED DESCRIPTION OF THE INVENTION

[0005] Detailed Description of the Invention It will be understood that the provisos of the first embodiment above exclude the following compounds: (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); (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); (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 (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).

[0006] An additional embodiment provides three separate compounds of formula (Ia), formula (Ib), and formula (Ic), respectively: TIFF2025529126000007.tif111128 In each example, all variables, including X, R1, R2, R3, and R4, are as defined above for 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 embodiment thereof, including the provisos.

[0007] Three additional separate embodiments provide compounds of formula (IIa), (IIb), and (IIc), respectively, 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: In each separate embodiment, X is Selected from the group TIFF2025529126000009.tif23128; 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 H, -NH-S(=O)2H, -NH-S(=O)2-C1-C6 alkyl, Selected from the group TIFF2025529126000010.tif51128; 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; However, if X is TIFF2025529126000011.tif11128, and when R1 is CH3 or Cl and the variable CF3 group is attached to either the 3- or 5-position of the phenyl ring B, R2 is Not TIFF2025529126000012.tif33128.

[0008] Three further separate embodiments provide compounds of formula (IIIa), compounds of formula (IIIb), compounds of formula (IIIc), compounds of formula (IIIe), compounds of formula (IIIf), compounds of formula (IIIg), compounds of formula (IIIh), and compounds of formula (IIIi), 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: TIFF2025529126000013.tif211153 In each example, R1 and R2 are as defined above for the embodiments relating to compounds of formula (IIa), compounds of formula (IIb), and compounds of formula (IIc).

[0009] Separate embodiments provide compounds of each of formulas (IVa) through (IVi), 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: TIFF2025529126000014.tif138161TIFF2025529126000015.tif63161In each example, R1 and R3 are as defined above for the embodiments relating to compounds of formulae (IIa)-(IIc).

[0010] A separate embodiment provides a compound of each of Formulas (Va) through (Vi), 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: TIFF2025529126000016.tif196162 In each example, R1 and R3 are as defined above for the embodiments relating to compounds of formulae (IIa) to (IIc).

[0011] Further embodiments provide compounds of each of Formulas (VIa) through (VIi), respectively, 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: TIFF2025529126000017.tif206163 In each example, R1 and R3 are as defined above for the embodiments relating to compounds of formulae (IIa) to (IIb).

[0012] More embodiments provide compounds of formula (VIIa) to (VIIi), respectively, 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: TIFF2025529126000018.tif207162 In each example, R1, R3, and R4 are as defined above for the embodiments relating to compounds of formulae (IIa) through (IIc).

[0013] Additional separate embodiments provide compounds of formula (VIIIa) through (VIIIi), respectively, or pharmaceutically acceptable salts, co-crystals, esters, solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, or pharmaceutically acceptable prodrugs thereof: TIFF2025529126000019.tif184146 In each example, R1, R3, and R4 are as defined above for the embodiments relating to compounds of formulae (IIa) to (IIc).

[0014] A different additional embodiment is where the pyridine ring substituted by R3 and R4 is a 2-pyridinyl group, a 3-pyridinyl group, and a 4-pyridinyl group, respectively, as shown below: TIFF2025529126000020.tif28128, 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.

[0015] definition The term "alkyl" refers to a straight-chain or branched hydrocarbon. For example, an alkyl group may have from 1 to 6 carbon atoms (i.e., C1-C6 alkyl or 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 1~3Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCH), 2-propyl (i-Pr, i-propyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu , s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-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 (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (- These include 2-methyl-3-pentyl (-CH(CH)CH(CH)CHCH), 4-methyl-2-pentyl (-CH(CH)CHCH(CH)), 3-methyl-3-pentyl (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), and 3,3-dimethyl-2-butyl (-CH(CH)C(CH)).

[0016] The term "halogen" or "halo" refers to an element or substituent selected from the group of F, Cl, Br, and I.

[0017] The term "haloalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group have been replaced with a halogen atom. The alkyl portion of a haloalkyl group can have, for example, 1 to 4 carbon atoms (i.e., a C1-C4 haloalkyl), 1 to 3 carbon atoms (i.e., a C1-C3 haloalkyl), or 1 to 2 carbon atoms (i.e., a C1-C2 haloalkyl). Non-limiting examples of suitable haloalkyl groups, which may also be referred to as halofluoro 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 (-CF2CH3), 4,4-difluoropropyl (-CF2CH2CH3), 5,5-difluoropropyl (-CF2CH2CH3), 6,6-difluoropropyl (-CF2CH2CH3), 7,7-difluoropropyl (-CF2CH2CH3), 8,8-difluoropropyl (-CF2CH2CH3), 9,9-difluoropropyl (-CF2CH2CH3), 10,10-difluoropropyl (-CF2CH2CH3), 11,1-difluoropropyl (-CF2CH2CH3), 12,12-difluoropropyl (-CF2CF2CH3), 13,14-difluoropropyl (-CF2CH2CH3), 15,16-difluoropropyl (-CF2CH2CH3), 16,17-difluoropropyl (-CF2CH2CH3), 17,18-difluoropropyl (-CF2CH2CH3), 18,19-difluoropropyl (-CF2CH2CH3), 19,10-difluoropropyl (-CF2CH2CH3), 20,21-difluoropropyl (-CF2CH2CH3), 21,22-difluoropropyl (-CF2CF2CH3), 22,23-difluoropropyl (-CF2CH2CH3), 23 Examples of halogen-substituted groups include perfluoropropyl (-CH2CH2CHF2), 3,3,3-trifluoropropyl (-CH2CH2CHF3), 1,1-difluorobutyl (-CF2CH2CH2CH3), perfluoroethyl (-CF2CF3), perfluoropropyl (-CF2CF2CF3), perfluoropropan-2-yl (-CF(CF3)2), 1,1,2,2,3,3-hexafluorobutyl (-CF2-CF2CF2CH3), perfluorobutyl (-CF2CF2CF2CF3), 1,1,1,3,3,3-hexafluoropropan-2-yl (-CH2(CF3)2) groups, and the like. Additional groups in which the halogen substitution is with a bromine, iodine, or chlorine atom are also understood for use herein.

[0018] Wavy lines in chemical structures TIFF2025529126000021.tif4128 shows the bond by which the depicted structure is attached to another chemical moiety or group.

[0019] The term "treatment" or "treating," as used herein, refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: (i) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition, including ALL, CLL, CML, and other diseases or disorders described herein, and / or reducing the severity of the disease or condition); (ii) slowing or arresting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or delaying the worsening or progression of a disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of a disease or condition); and / or (iii) palliating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating pathology, causing partial or total remission of a disease or condition, enhancing the effectiveness of another drug therapy, delaying disease progression, improving quality of life, and / or prolonging survival).

[0020] The term "inhibit" or "inhibition" refers to a decrease, e.g., a significant decrease, in the baseline activity of a biological activity or process. "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 cocrystal thereof, compared to the activity of BCR-ABL in the absence of such a compound or a pharmaceutically acceptable salt or cocrystal thereof. The decrease in activity can be due to the direct interaction of the compound with BCR-ABL, or due to the interaction of the compound described herein with one or more other factors that affect BCR-ABL activity. For example, the presence of a compound can decrease BCR-ABL activity by directly binding to BCR-ABL, by allowing another factor to decrease BCR-ABL activity (directly or indirectly), or by reducing the amount of BCR-ABL present in a cell or organism (directly or indirectly). In some embodiments, the inhibition of BCR-ABL activity can be compared to the same subject prior to treatment or to another subject not receiving treatment. The term "inhibitor" is understood to refer to a compound or agent that, when administered in a pharmaceutically or therapeutically effective amount to a human in need thereof, brings about the desired inhibitory activity.

[0021] " Delaying " when referring to the occurrence of disease or condition means to prolong, prevent, slow, delay, stabilize, and / or postpone the occurrence of disease or condition. This delay can be of various lengths of time depending on the history of disease or condition and / or the subject undergoing treatment. A method of " delaying " the occurrence of disease or condition is a method of reducing the probability of disease or condition occurring in a given time frame and / or reducing the severity of disease or condition in a given time frame compared with the case where the method is not used. Such comparisons are typically based on clinical studies using a statistically significant number of subjects. The occurrence of disease or condition can be detectable using standard methods, such as routine physical examination, mammography, diagnostic imaging, or biopsy. Occurrence can also refer to the progression of disease or condition, which may be undetectable at the beginning, and includes appearance, recurrence, and onset.

[0022] The term "subject" or "patient" refers to an animal, e.g., a mammal, that has been or is likely to be the subject of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human; in some embodiments, the subject is selected from cats and dogs. A "subject in need thereof" or a "human in need thereof" refers to a subject, e.g., a human, that may have or is suspected of having a disease or condition that would benefit from a particular treatment; for example, treatment with a compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof described herein. This includes subjects that may be determined to be at risk of or susceptible to such a disease or condition, and therefore, treatment would prevent the disease or condition from occurring.

[0023] The modifier "about" used in connection 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 stated amount plus or minus 10%. In some embodiments, the term "about" refers to the stated amount plus or minus 5%.

[0024] As used herein, the terms "embodiment" and "aspect" refer to an example, instance, or illustration of the present disclosure, respectively, and may be used interchangeably. In some instances, one may further define, limit, or serve as a subset, subgeneric description, or particular example of the other, as described. In other instances, one embodiment or aspect may provide a comparison with, or distinction from, another embodiment or aspect.

[0025] As used herein, the singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. Also, as used herein, the term "comprises" means "includes." Thus, "comprising A or B" means including A, B, or A and B.

[0026] As used throughout this disclosure, variables such as X and R, including all their subvariables (e.g., R, R, etc.), are the same variables as previously defined unless otherwise stated.

[0027] All ranges disclosed and / or claimed herein are inclusive of the recited endpoints and are independently combinable. For example, the ranges "2 to 10" and "2-10" include the endpoints 2 and 10, and all intermediate values ​​therebetween in the context of the units considered. For example, "Claim 2-10" or "C2-C 10 References to "alkyl" include the units 2, 3, 4, 5, 6, 7, 8, 9, and 10, unless stated in the context of an average number, as claims and atoms are numbered consecutively, without fractions or decimal points, whereas the context of "a pH of 5 to 9" or "a temperature of 5°C to 9°C" includes the integers 5, 6, 7, 8, and 9, and all fractions or decimals therebetween, e.g., 6.5 and 8.24.

[0028] The term "independently selected" refers to a situation in which more than one variable or item can be selected from a list of alternatives, regardless of which of the alternatives applies to another variable or item. For example, if the variables R3 and R4 can, in each instance, be independently selected from the group: H, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, halogen, -NH-S(=O)2H, and -NH-S(=O)2-C1-C6 alkyl, then 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).

[0029] The term "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount or dose sufficient to achieve treatment, as defined below, when administered to a subject (e.g., a mammal, e.g., a human) in need of such treatment. The therapeutically or pharmaceutically effective amount will vary depending on the subject and disease state being treated, the subject's weight and age, the severity of the disease state, the mode of administration, etc., and can be easily determined by one skilled 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 the expression or activity of BCR-ABL, thereby treating a subject (e.g., a human) suffering from an indication, or improving or alleviating existing symptoms of the indication. For example, a therapeutically or pharmaceutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition responsive to inhibition of BCR-ABL activity.

[0030] 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, co-crystal, 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 or 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 given 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 administration. In some embodiments, an initial dose of about 10 mg to about 100 mg can be used, reduced to a lower dose upon achievement of ≦1% BCR-ABL(IS).

[0031] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable vehicle, including, but not limited to, any and all carriers, solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the composition.

[0032] The term "pharmaceutically acceptable carrier" refers to an excipient or vehicle, including, but not limited to, diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, etc., with which a compound is administered. Carriers are generally described herein and also in "Remington's Pharmaceutical Sciences" by E.W. 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, hydroxyoctacosanyl hydroxystearate, 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, silicone, silicone adhesive 4102, and silicone emulsion. However, it should be understood that the carrier selected for a pharmaceutical composition and the amount of such carrier in the composition may vary depending on the method of formulation (e.g., dry granulation formulation, solid dispersion formulation).

[0033] The term "pharmaceutically acceptable salt" or "therapeutically acceptable salt" refers to a salt form of a compound of Formula (I) that, within the bounds of sound medical evaluation, is suitable for use in contact with the tissues and organs of humans and / or animals, and therefore 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 include hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate salts (e.g., acetate, HOOC-(CH2) where n is 0-4). n -COOH). Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0034] Physiologically acceptable salts (e.g., pharmaceutically acceptable salts) of the compounds of the present invention can be prepared by the addition of a suitable base, such as an alkali metal or alkaline earth base (e.g., Na + , Li + , K+, Ca +2 , and Mg +2Physiologically 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) 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-acetamidobenzoic acid, caproic acid, caprylic acid, adipic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, glutamic acid, etc. and (c) salts formed with elemental anions such as chlorine, bromine, methyl ... Physiologically acceptable salts of hydroxy compounds include Na + and the anion of the compound in combination with a suitable cation, such as NR4+. Each R is independently selected from H and (C1-C8) alkyl.

[0035] The term "level of expression" as used 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 different embodiments, gene expression can be indicated by transcriptional expression at the mRNA level or protein level.

[0036] As used herein, the term "co-crystal" or "co-crystal salt" refers to a crystalline substance composed of two or more unique solids at room temperature, each of which has unique physical characteristics, such as structure, melting point and heat of fusion, hygroscopicity, solubility, and stability. Co-crystals or co-crystal salts can be produced according to per se known co-crystallization methods. The term co-crystal (or co-crystal) or co-crystal salt also refers to a multi-component system in which one or more host API (active pharmaceutical ingredient) molecules, such as a compound of Formula I, and one or more guest (or co-former) molecules are present. In certain embodiments, the 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, decanoic acid co-crystals, salicylic acid co-crystals, vanillic acid co-crystals, maltol co-crystals, or glycolic acid co-crystals. Cocrystals may have improved properties compared to the parent form (i.e., the free molecule, zwitterion, etc.) or salt of the parent compound. Improved properties may include increased solubility, increased melting, increased bioavailability, increased dose response, reduced hygroscopicity, crystalline forms of normally non-crystalline compounds, crystalline forms of compounds that are difficult or impossible to salt, reduced form diversity, more desirable morphology, etc.

[0037] The term "cocrystal" refers to a physical association of two or more molecules that derives its stability through non-covalent interactions. One or more components of this molecular complex provide a stable framework in the crystal lattice. In certain cases, the guest molecule is incorporated into the crystal lattice as a hydrate 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. An example of a cocrystal is p-toluenesulfonic acid and benzenesulfonic acid.

[0038] Treatment method Provided is a method of inhibiting the growth of cancer cells in a subject, 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 isomer, racemate, or other mixture thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

[0039] Provided herein are methods of inhibiting proliferation of BCR-ABL-expressing cells in a 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.

[0040] Provided herein is 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 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.

[0041] Provided herein is 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 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.

[0042] 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, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

[0043] Provided herein is a method of treating blast crisis 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.

[0044] For each of the types or stages of CML listed above, subjects in need of treatment are: (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 (b) a therapeutically effective amount of a tyrosine kinase inhibitor selected from the group consisting of imatinib (GLEEVEC®), nilotinib (TASIGNA®), dasatinib (SPRYCEL®), ponatinib (ICLUSIG®), and bosutinib (BOSULIF®). There are separate treatment methods for CML in question, which involve administering

[0045] 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.

[0046] Also provided herein is a method of treating acute lymphocytic 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.

[0047] Also provided herein is 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 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.

[0048] Also provided herein is 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 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.

[0049] 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 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.

[0050] A method for treating Ph-positive acute lymphoblastic leukemia (Ph+ALL or Philadelphia chromosome-positive ALL) in a human subject, comprising administering to a subject in need thereof (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 (b) a therapeutically effective amount of at least one tyrosine kinase inhibitor selected from the group consisting of imatinib (GLEEVEC®), dasatinib (SPRYCEL®), ponatinib (ICLUSIG®), bosutinib (BOSULIF®), asciminib (SCEMBLIX®), and nilotinib (TASIGNA®), 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. Further provided herein is a method comprising administering

[0051] 1. A method for treating Ph-positive acute lymphoblastic leukemia (Ph+ ALL or Philadelphia chromosome-positive ALL) in a human subject, comprising: (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 (b) a therapeutically effective amount of blinatumomab to a subject in need thereof. Also provided herein is a method comprising:

[0052] Also provided herein is 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 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.

[0053] 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.

[0054] Also provided herein is a method of 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.

[0055] Also provided herein is 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 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.

[0056] 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.

[0057] 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.

[0058] Also provided herein is 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 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.

[0059] Also provided herein is 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 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.

[0060] Also provided herein is a method for treating lung cancer in a human subject, comprising administering a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomer, racemate, or other mixture thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug to a subject in need thereof.A further aspect provides such a method for treating lung cancer that is non-small cell lung cancer.

[0061] Also provided herein is a method of 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.

[0062] Also provided herein is a method of treating kidney 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.

[0063] 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.

[0064] Further provided is a method of treating gastrointestinal stromal tumors in a human subject, 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.

[0065] Also provided is the use 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, in the preparation of a medicament for use as a pan-BCR-ABL inhibitor.

[0066] Reference herein to the disease or condition associated with BCR-ABL mutation indicates that the BCR-ABL mutation in the kinase domain has been identified or can be identified in the human subject of interest, including the subject who needs treatment for the disease or condition in question.Such mutation can be associated with the diseases or conditions described herein, including but not limited to CML, AML, and / or ALL.In some embodiments, the subject who has experienced BCR-ABL mutation has proven refractory or resistant to treatment with one or more pharmaceutical agents, for example, tyrosine kinase inhibitors (ponatinib, imatinib, dasatinib, nilotinib, etc.).It will be understood that such mutation can be referred to as the subject who has experienced such mutation, the subject who has the mutation, or the disease or condition associated with such mutation, or the specific tumor that has or expresses the product of such mutation.

[0067] The BCR-ABL inhibitory compounds described in this specification are disclosed in U.S. Patent No. 8,859,553 (Yu et al.); US 2021 / 0393628 A1 (Mackall et al.); US 2015 / 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, 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 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 1 and 2, Wang et al., Journal of Medicinal Chemistry, 2018, 61, 7977-7990.

[0068] As a non-limiting example, using the method of Pandrala 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) (SOCl, 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 at 100 °C for 5 h in a sealed tube to produce N-(3-bromo-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (E). Copper-catalyzed N-aryl can then be used to introduce the R2 group, particularly, for example, 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). TIFF2025529126000022.tif107128

[0069] General synthesis of BCR-ABL inhibitors / compounds Synthesis of linked arylamines TIFF2025529126000023.tif44130Synthesis of HIT compounds TIFF2025529126000024.tif55165

[0070] General procedure for the synthesis of linked arylamines Reported Procedures 1The desired arylamines were synthesized by the following procedure. 3-Bromo-5-(trifluoromethyl)aniline 1 (1 mmol, 1 equiv.) and the corresponding arylboronic acids 2a–d (2 mmol, 2 equiv.), tetrakis(triphenylphosphine)palladium(0) (0.025 mmol, 0.025 equiv.), and NaCO (7 mmol, 7 equiv.) were combined in 30 mL of deoxygenated DMF / HO (7:2) and heated to reflux overnight. The reaction was then cooled to room temperature and diluted with DCM / hexane (1:1). The combined organic layer was washed with saturated aqueous NaHCO (2 × 25 mL), water (2 × 25 mL), and brine (25 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO, 30% to 80% EtOAc / hexane) to afford the desired coupled arylanilines 3a–d.

[0071] Synthesis of compounds 5a-d Under a nitrogen atmosphere, 3-iodo-4-methylbenzoic acid 4 (20 mmol, 1 equiv.) was taken up in SOCl (100 mmol, 5 equiv.) and then two drops of DMF were added at room temperature. The reaction mixture was refluxed and stirred for 5 h, then cooled to room temperature, and excess SOCl was carefully removed. The crude material was coevaporated with benzene and dried under vacuum to give the desired acid chloride. The acid chloride was dissolved in anhydrous THF (20 mL) and then added dropwise to a stirred mixture of 3-bromo-5-(trifluoromethyl)aniline 3a-d (20 mmol, 1 equiv.), diisopropylethylamine (24 mmol, 1.2 equiv.), and DMAP (2.0 mmol, 0.1 equiv.) in THF at 0 °C. Upon completion of the addition, the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water, and the product was extracted into EtOAc (3 × 50 mL). 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 the eluent to give the desired products 5a-d as off-white solids.

[0072] Synthesis of alkyne 7: Previously reported method with some modifications 2 Compound 7 was prepared according to the method described in Example 1. To a solution of 3-bromoimidazo[1,2-b]pyridazine 6 (10.0 g, 50.5 mmol) in acetonitrile, CuI (0.5 g, 2.63 mmol), Pd(PPh3)2Cl2 (1.8 g, 2.63 mmol), and TEA (21.0 mL, 150.6 mmol) were added. 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 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 taken up in methanol (300 mL). To this mixture, K2CO3 (14.3 g, 103.5 mmol) was added at room temperature, and the mixture was stirred for 4 hours. The progress of the reaction was monitored by TLC. The reaction mixture was filtered to remove excess K2CO3. The solid was washed with a minimal amount of methanol. The filtrate was concentrated to dryness, dissolved in excess EtOAc, and then washed with water, followed by brine solution. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give the crude product, which was purified on a silica gel column using a gradient of 0% to 50% EtOAc in hexanes to give the desired product as a light brown solid (5.0 g, 69%).

[0073] Synthesis of compounds 8a-d: Procedures from the literature with few modifications 3Compounds 8a-d were prepared according to the procedure described above. 3-Iodo-4-methylbenzoic acid derivatives 5a-d (6.71 mmol, 1.2 equiv.) were added to a stirred solution of 3-ethynylimidazo[1,2-b]pyridazine 7 (5.59 mmol, 1 equiv.) in DMF (10 mL). The mixture was subjected to three vacuum / nitrogen-fill cycles, followed by the addition of CuI (1.11 mmol, 0.2 equiv.), Pd(PPh3)4 (0.55 mmol, 0.1 equiv.), and diisopropylethylamine (11.17 mmol, 2 equiv.). The reaction mixture was stirred at 80 °C for 2 h and then cooled to room temperature. Water (25 mL) was added and extracted into EtOAc (3 × 25 mL). The organic layers were combined and washed with water (20 mL) followed by brine solution (20 mL). The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give a sticky solid, which was then triturated with a minimum of acetonitrile to give a solid, which was collected by filtration, washed with a minimum of acetonitrile, and dried under vacuum for 2 hours to give the desired compounds 8a-d as off-white solids.

[0074] References: TIFF2025529126000025.tif68155 [Example]

[0075] The following specific compounds have been made and tested, and provide a non-limiting set of chemical species that fall within the scope of Formula (I) and other formulas provided herein. Example 1 - N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-084) TIFF2025529126000026.tif32128; Example 2 - 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) TIFF2025529126000027.tif32128; HRMS (ESI-TOF) m / z:C of compound CET-10-067 27 H 19 F3N6ONa [M+Na] + The calculated value is 523.1470. Example 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) TIFF2025529126000028.tif40128 HRMS (ESI-TOF) m / z: C of compound CET-10-100 26 H 16 F4N6ONa [M+Na] + The calculated value is 523.1470; Example 4 - 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) TIFF2025529126000029.tif40128 HRMS (ESI-TOF) m / z: C of compound CET-10-103 27 H 16 F6N6ONa [M+Na] + The calculated value is 577.1187; Example 5 - 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)benzamide (CET-10-106) TIFF2025529126000030.tif32128 HRMS (ESI-TOF) m / z: C of compound CET-10-106 29 H 19 F3N4ONa [M+Na] + The calculated value is 519.1408; Example 6 - 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-104) TIFF2025529126000031.tif32128 HRMS (ESI-TOF) m / z: C of compound CET-10-104 28 H 18 F3N5ONa [M+Na] + The calculated value is 520.1361; Example 7 - N-(4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide (CET-10-105) TIFF2025529126000032.tif28128 HRMS (ESI-TOF) m / z: C of compound CET-10-105 26 H 17 F3N6ONa [M+Na] + The calculated value is 509.1313; Example 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) TIFF2025529126000033.tif30128 HRMS (ESI-TOF) m / z: C of compound CET-10-109 27 H 17 F5N6ONa [M+Na] + The calculated value is 559.1281; Example 9 -3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)benzamide (CET-10-110) TIFF2025529126000034.tif27128 HRMS (ESI-TOF) m / z: C of compound CET-10-110 24 H 18 [M+Na] in F3N5O3SNa +The calculated value is 536.0980; Example 10 - 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(3-(2-methylthiazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide (CET-10-111) TIFF2025529126000035.tif27128 HRMS (ESI-TOF) m / z: C of compound CET-10-111 27 H 18 F3N5OSNa [M+Na] + The calculated value is 540.1081; Example 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) TIFF2025529126000036.tif29128 HRMS (ESI-TOF) m / z: C of compound CET-10-101 29 H 21 F3N4ONa [M+Na] + The calculated value is 521.1565; Example 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) TIFF2025529126000037.tif30128 HRMS (ESI-TOF) m / z: C of compound CET-10-102 28 H 20 F3N5ONa [M+Na] + The calculated value is 522.1517; Example 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) TIFF2025529126000038.tif34128 HRMS of compound CET-10-108 (ESI-TOF) m / z:C 27 H 20 F3N9ONa [M+Na] + The calculated value is 566.1640; Example 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) TIFF2025529126000039.tif30128 HRMS (ESI-TOF) m / z: C of compound CET-10-107 26 H 18 F3N9ONa [M+Na] + The calculated value is 552.1484; or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomer, racemate, or other mixture thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

[0076] Cell proliferation assay This cell proliferation assay uses a murine pro-B cell line (Ba / F3) stably expressing native or mutant BCR-ABL. Ba / F3 cells are interleukin-3 (IL3) dependent. However, expression of BCR-ABL renders Ba / F3 cells IL3 independent and capable of proliferation without IL3 signaling. Therefore, BCR-ABL inhibition, using tetrazolium salt (MTS), results in a detectable reduction in cell proliferation, revealing the pharmacodynamic efficacy of candidate TKIs.

[0077] For this project, we sought a TKI with a pharmacodynamic profile similar to ponatinib in terms of efficacy in this assay. We also used cells that do not express BCR-ABL to demonstrate potential low toxicity by being specific for this target. Imatinib was the negative drug control, and ponatinib was the positive drug control.

[0078] K562 cells and Ba / F3 parental cells, or cells transduced with an empty vector or vectors expressing BCR-ABL WT or a series of point mutations known to confer resistance to ABL tyrosine kinase inhibitors, were seeded at 750 cells per well in 384-well plates in RPMI medium containing 10% FBS and supplemented with L-glutamine, penicillin / streptomycin, and fungizone (amphotericin B). Cells were incubated in triplicate with vehicle or graded concentrations of the indicated inhibitors for 72 hours. At 72 hours, the relative number of viable cells was quantified using a tetrazolium-based MTS assay. After incubating cells with the MTS reagent for 1–4 hours, absorbance values ​​were read at 490 nm using a Synergy 2 plate reader. The absorbance value of blank wells containing medium alone was subtracted from all other wells, and then all wells' absorbance values ​​were normalized to the average of replicate vehicle controls to generate normalized percent viability values. These normalized values ​​were curve-fitted to generate dose-response metrics for each inhibitor.

Claims

1. Compounds of formula (I), or their pharmaceutically acceptable salts, cocrystals, esters, solvates, hydrates, isomers, tautomers, isotopes, polymorphs, or pharmaceutically acceptable prodrugs: During the ceremony, X is Selected from the group; R 1 is C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 3 to C 6 cycloalkyl, -CH 2 -C 3 to C 6 cycloalkyl, -O-C 3 to C 6 cycloalkyl, halogen, C[[ID=2D]] 1 to C 3 selected from the group of haloalkyl, OH, and CN; R 2 teeth, H, -NH-S (=O) 2 H and -NH-S (=O) 2 -C 1 ~C 6 Alkyl, Selected from the group; R 3 and R 4 H, C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, halogen, -NH-S(=O) 2 H and -NH-S (=O) 2 -C 1 ~C 6 Each is independently selected from the alkyl group; However, X And R 1 CH 3 or Cl and variable CF 3 If the group is attached to either the 3rd or 5th position of the phenyl ring B, then R 2 teeth isn't it.

2. A compound according to claim 1 having formula (Ia), optionally having formula (IIIa), or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof: In the formula, X, R 1 , and R 2 This is as defined in claim 1.

3. A compound according to claim 1 having formula (Ib), optionally having formula (IIId), or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof: In the formula, X, R 1 , and R 2 This is as defined in claim 1.

4. A compound according to claim 1 having formula (IVa), optionally having formula (IVd), or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof: In the formula, R 1 and R 3 This is as defined in claim 1.

5. A compound according to claim 1 having formula (Va), optionally having formula (VIa), or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof: In the formula, R 1 and R 3 This is as defined in claim 1.

6. A compound according to claim 1 having formula (VIIa), or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof: In the formula, R 1 , R 3 , and R 4 This is as defined in claim 1.

7. A compound according to claim 1 having formula (VIIIa), or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof: In the formula, R 1 , R 3 , and R 4 This is as defined in claim 1.

8. R 1 C 1 ~C 3 A compound according to any one of claims 1 to 7, which is alkyl; or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

9. R 3 However, H, C 1 ~C 3 Alkyl and -OC 1 ~C 3 A compound according to any one of claims 1 to 7, selected from the group of alkyls; or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

10. R 3 However, C 1 ~C 3 Compounds according to any one of claims 1 to 7, selected from the group consisting of fluoroalkyl and F; or pharmaceutically acceptable salts, cocrystals, esters, solvated compounds, hydrates, isomers, tautomers, isotopes, polymorphs, or pharmaceutically acceptable prodrugs thereof.

11. R 4 A compound according to any one of claims 1 to 3, 6, and 7, wherein is H; or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

12. A compound according to Claim 1, or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof, selected from the group.

13. A therapeutically effective amount of any one of claims 1 to 7 of the compound, or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof, and pharmaceutically acceptable carrier or excipient A pharmaceutical composition containing [the specified substance].

14. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof for use in a therapeutic method.

15. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, cocrystal, ester, solvated compound, hydrate, isomer, tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof, for use as a pan-BCR-ABL inhibitor.

Images