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KR-20260062959-A - A combination comprising a BCR:ABL-1 inhibitor and a 2nd tyrosine kinase inhibitor for use in cancer treatment

KR20260062959AKR 20260062959 AKR20260062959 AKR 20260062959AKR-20260062959-A

Abstract

Combinations for inhibiting the tyrosine kinase activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or chimeric protein BCR-ABL1, compositions thereof, methods for inhibiting the tyrosine kinase enzyme activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or chimeric protein BCR-ABL1, and methods for treating a disease are provided herein, wherein the regulation of BCR-ABL1 activity prevents, inhibits, or improves the pathology and/or symptoms of the disease.

Inventors

  • 파슨스, 벤자민, 엠.
  • 존스, 크리스토퍼, 티.
  • 재스퍼, 제프리, 아르.

Assignees

  • 테른스 파마슈티칼스, 인크.

Dates

Publication Date
20260507
Application Date
20240830
Priority Date
20230831

Claims (20)

  1. A method for treating cancer in a subject requiring cancer treatment, comprising the step of administering a BCR:ABL1 inhibitor in combination with a second tyrosine kinase inhibitor [TKI], wherein the BCR:ABL1 inhibitor is a compound of the following formula (I), a tautomer or N-oxide, or a pharmaceutically acceptable salt of any of the previously mentioned. During the meal, L is -NH-CO-, -CO-NH-, -NH- SO2- , or -SO2 -NH-; R1 is an optionally substituted C6 - C10 aryl, an optionally substituted 5 to 10-membered heteroaryl, an optionally substituted 4 to 10-membered heterocycle, C (O) NR6R7 , S( O )2NR6R7 , NR6COR7 , NR6SO2R7 , or C(O) OR6 ; R2 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C2 - C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R3 is H, optionally substituted C1 - C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 or NR 6 R 7 ; R2 and R3 form an optionally substituted C3 - C8 cycloalkyl or an optionally substituted 4 to 10 heterocycloalkyl with an intervening atom; R4 is an optionally substituted C1 - C6 alkyl, an optionally substituted C2 - C6 alkenyl, or an optionally substituted C2 - C6 alkynyl; X is O or S and; Y is CH, C-( C1 - C2 alkyl) or C-halo or N; Z is CR 5 or N and; R 5 is H or a halogen; R6 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R7 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R6 and R7 form a 4 to 7-membered heterocycle that is selectively substituted with the nitrogen to which they are attached, and However, the above compounds exclude (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.
  2. A method for inhibiting the tyrosine kinase enzyme activity of BCR:ABL1, comprising the step of contacting a protein with an effective amount of a BCR:ABL-1 inhibitor of the following formula (I), or a tautomer or N-oxide or any pharmaceutically acceptable salt of the aforementioned, in combination with an effective amount of a tyrosine kinase inhibitor. During the meal, L is -NH-CO-, -CO-NH-, -NH- SO2- , or -SO2 -NH-; R1 is an optionally substituted C6 - C10 aryl, an optionally substituted 5 to 10-membered heteroaryl, an optionally substituted 4 to 10-membered heterocycle, C (O) NR6R7 , S( O )2NR6R7 , NR6COR7 , NR6SO2R7 , or C(O) OR6 ; R2 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C2 - C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R3 is H, optionally substituted C1 - C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 or NR 6 R 7 ; R2 and R3 form an optionally substituted C3 - C8 cycloalkyl or an optionally substituted 4 to 10 heterocycloalkyl with an intervening atom; R4 is an optionally substituted C1 - C6 alkyl, an optionally substituted C2 - C6 alkenyl, or an optionally substituted C2 - C6 alkynyl; X is O or S and; Y is CH, C-( C1 - C2 alkyl) or C-halo or N; Z is CR 5 or N and; R 5 is H or a halogen; R6 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R7 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R6 and R7 form a 4 to 7-membered heterocycle that is selectively substituted with the nitrogen to which they are attached, and However, the above compounds exclude (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.
  3. A method for treating a disease in a subject requiring treatment of the disease, comprising the step of administering to the subject a therapeutically effective amount of a BCR:ABL-1 inhibitor of the following formula (I), or a tautomer or N-oxide or any pharmaceutically acceptable salt of the aforementioned, in combination with a therapeutically effective amount of a tyrosine kinase inhibitor, wherein the modulation of BCR-ABL1 activity prevents, inhibits, or improves the pathology and/or symptoms of the patient's disease: During the meal, L is -NH-CO-, -CO-NH-, -NH- SO2- , or -SO2 -NH-; R1 is an optionally substituted C6 - C10 aryl, an optionally substituted 5 to 10-membered heteroaryl, an optionally substituted 4 to 10-membered heterocycle, C (O) NR6R7 , S( O )2NR6R7 , NR6COR7 , NR6SO2R7 , or C(O) OR6 ; R2 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C2 - C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R3 is H, optionally substituted C1 - C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 or NR 6 R 7 ; R2 and R3 form an optionally substituted C3 - C8 cycloalkyl or an optionally substituted 4 to 10 heterocycloalkyl with an intervening atom; R4 is an optionally substituted C1 - C6 alkyl, an optionally substituted C2 - C6 alkenyl, or an optionally substituted C2 - C6 alkynyl; X is O or S and; Y is CH, C-( C1 - C2 alkyl) or C-halo or N; Z is CR 5 or N and; R 5 is H or a halogen; R6 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R7 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R6 and R7 form a 4 to 7-membered heterocycle that is selectively substituted with the nitrogen to which they are attached, and However, the above compounds exclude (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.
  4. A method for treating leukemia in a subject requiring treatment for leukemia, comprising the step of administering to the patient a therapeutically effective amount of a BCR:ABL-1 inhibitor of the following formula (I), or a tautomer or N-oxide or any pharmaceutically acceptable salt of the aforementioned, in combination with a second tyrosine kinase inhibitor, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL): During the meal, L is -NH-CO-, -CO-NH-, -NH- SO2- , or -SO2 -NH-; R1 is an optionally substituted C6 - C10 aryl, an optionally substituted 5 to 10-membered heteroaryl, an optionally substituted 4 to 10-membered heterocycle, C (O) NR6R7 , S( O )2NR6R7 , NR6COR7 , NR6SO2R7 , or C(O) OR6 ; R2 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C2 - C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R3 is H, optionally substituted C1 - C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 or NR 6 R 7 ; R2 and R3 form an optionally substituted C3 - C8 cycloalkyl or an optionally substituted 4 to 10 heterocycloalkyl with an intervening atom; R4 is an optionally substituted C1 - C6 alkyl, an optionally substituted C2 - C6 alkenyl, or an optionally substituted C2 - C6 alkynyl; X is O or S and; Y is CH, C-( C1 - C2 alkyl) or C-halo or N; Z is CR 5 or N and; R 5 is H or a halogen; R6 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R7 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R6 and R7 form a 4 to 7-membered heterocycle that is selectively substituted with the nitrogen to which they are attached, and However, the compounds exclude (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.
  5. Use of a compound of the following formula (I) or its tautomer or N-oxide or any pharmaceutically acceptable salt of the aforementioned in combination with a tyrosine kinase inhibitor for the manufacture of a medicine for the treatment of cancer in subjects requiring cancer treatment: During the meal, L is -NH-CO-, -CO-NH-, -NH- SO2- , or -SO2 -NH-; R1 is an optionally substituted C6 - C10 aryl, an optionally substituted 5 to 10-membered heteroaryl, an optionally substituted 4 to 10-membered heterocycle, C (O) NR6R7 , S( O )2NR6R7 , NR6COR7 , NR6SO2R7 , or C(O) OR6 ; R2 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C2 - C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R3 is H, optionally substituted C1 - C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 or NR 6 R 7 ; R2 and R3 form an optionally substituted C3 - C8 cycloalkyl or an optionally substituted 4 to 10 heterocycloalkyl with an intervening atom; R4 is an optionally substituted C1 - C6 alkyl, an optionally substituted C2 - C6 alkenyl, or an optionally substituted C2 - C6 alkynyl; X is O or S and; Y is CH, C-( C1 - C2 alkyl) or C-halo or N; Z is CR 5 or N and; R 5 is H or a halogen; R6 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R7 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R6 and R7 form a 4 to 7-membered heterocycle that is selectively substituted with the nitrogen to which they are attached, and However, the above compounds exclude (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.
  6. A method according to any one of claims 1 to 5, wherein the method comprises the step of administering the BCR:ABL1 inhibitor of formula (I) and the second TKI to a subject in a ratio of about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 2:1, about 2:3, about 2:5, about 3:1, about 3:2, about 3:4, about 3:5, about 4:1, about 4:3, or about 4:5.
  7. Method according to any one of claims 1 to 6, wherein the BCR:ABL1 inhibitor of formula (I) is ( R ) -N- (4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropane-2-yl)-7-(pyrimidine-5-yl) -1H -benzo[ d ]imidazole-5-carboxamide (compound A) or a pharmaceutically acceptable salt thereof: .
  8. A method according to any one of claims 1 to 7, wherein the subject has previously been treated with asiminib.
  9. A method according to any one of claims 1 to 8, wherein the subject has previously been treated with a combination of asiminib and a second TKI.
  10. A method according to any one of claims 1 to 9, wherein the second TKI binds to the active site of the BCR:ABL-1.
  11. A method according to any one of claims 1 to 10, wherein the second TKI is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.
  12. A method according to any one of claims 1 to 11, wherein the second TKI is selected from ponatinib and dasatinib.
  13. A method according to any one of claims 1 to 12, wherein the cancer is lymphoma or leukemia.
  14. A method according to any one of claims 1 to 13, wherein the lymphoma or leukemia is chronic myeloid leukemia (CML) or chronic lymphocytic leukemia (CLL).
  15. In any one of paragraphs 1 to 14, the method A step of determining the DNA sequence of the BCR:ABL1 gene expressed by the subject; and/or Step of determining the amino acid sequence of the BCR:ABL1 protein expressed by the above subject A method that additionally includes
  16. A method according to any one of claims 1 to 15, wherein the subject expresses wild-type BCR:ABL-1.
  17. A method according to any one of claims 1 to 16, wherein the wild-type form of BCR:ABL-1 has the amino acid sequence of SEQ ID NO. 1.
  18. A method for expressing a mutant form of BCR:ABL-1 in any one of claims 1 to 17, wherein the subject is said to express a mutant form of BCR:ABL-1.
  19. A method according to any one of claims 1 to 18, wherein the mutant form of BCR:ABL-1 comprises a single amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, and V468F.
  20. A method according to any one of claims 1 to 19, wherein the mutant forms of BCR:ABL-1 comprise several amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T315I, (iii) E255V and T315I, (iv) H396R and T315I, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viii) A344P and T315I, (ix) P465S and T315I and (x) V468F and T315I.

Description

A combination comprising a BCR:ABL-1 inhibitor and a 2nd tyrosine kinase inhibitor for use in cancer treatment Cross-reference regarding related applications This application claims priority and benefit to U.S. Patent Application No. 63/535,881 filed August 31, 2023, the entirety of which is incorporated herein by reference for all purposes. Reference to the electronic sequence list The contents of the electronic sequence list (TRPH_048_001WO_SeqList_ST26.xml; size: 44,747 bytes; and creation date: August 29, 2024) are incorporated herein by reference in their entirety. In chronic myeloid leukemia (CML), the Philadelphia chromosome (Ph) is formed in bone marrow progenitor cells through a reciprocal translocation between chromosome 9 and chromosome 22. This chromosome carries the BCR-ABL1 oncogene, which encodes the chimeric BCR-ABL1 protein. Drugs that inhibit the tyrosine kinase activity of BCR-ABL1 via an ATP competitive mechanism, such as Gleevec®/Glivec® (imatinib), Tasigna® (nilotinib), Iclusig® (ponatinib), and Sprycel® (dasatinib), may be effective in treating CML; however, some patients relapse due to the emergence of drug-resistant clones or drug intolerance. Therefore, there is a need to provide additional treatment options. The present disclosure relates to a method for treating cancer in a subject requiring cancer treatment, comprising the step of administering a BCR:ABL1 inhibitor in combination with a tyrosine kinase inhibitor, wherein the BCR:ABL1 inhibitor is a compound of the following formula (I), a tautomer or N-oxide, or a pharmaceutically acceptable salt of any of the aforementioned: During the meal, L is -NH-CO-, -CO-NH-, -NH- SO2- , or -SO2 -NH-; R1 is an optionally substituted C6 - C10 aryl, an optionally substituted 5 to 10-membered heteroaryl, an optionally substituted 4 to 10-membered heterocycle, C (O) NR6R7 , S( O )2NR6R7 , NR6COR7 , NR6SO2R7 , or C(O) OR6 ; R2 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C2 - C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R3 is H, optionally substituted C1 - C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 or NR 6 R 7 ; R2 and R3 form an optionally substituted C3 - C8 cycloalkyl or an optionally substituted 4 to 10 heterocycloalkyl with an intervening atom; R4 is an optionally substituted C1 - C6 alkyl, an optionally substituted C2 - C6 alkenyl, or an optionally substituted C2 - C6 alkynyl; X is O or S and; Y is CH, C-( C1 - C2 alkyl) or C-halo or N; Z is CR 5 or N and; R 5 is H or a halogen; R6 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R7 is H, optionally substituted C1 - C6 alkyl, optionally substituted C3 - C8 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted C6 - C10 aryl, or optionally substituted 5 to 10-membered heteroaryl; R6 and R7 form a 4 to 7-membered heterocycle that is selectively substituted with the nitrogen to which they are attached, and However, the compounds exclude (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-. In some embodiments, the BCR:ABL1 inhibitor is a compound of the following formula (IA-1) or a pharmaceutically acceptable salt thereof: . The present disclosure relates to the use of ( R ) -N- (4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropane-2-yl)-7-(pyrimidine-5-yl) -1H -benzo[ d ]imidazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof in combination with a tyrosine-kinase inhibitor to treat cancer in a subject requiring cancer treatment: . The present disclosure relates to the use of a pharmaceutically acceptable salt of compound A in combination with a tyrosine-kinase inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib to treat cancer in a subject requiring cancer treatment: . The present disclosure also relates to a method for treating cancer in a subject requiring cancer treatment, comprising the step of administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor. The present disclosure also relates to a method for treating cancer in a subject requiring cancer treatment, comprising the step of administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inh