RU2021109317A - COMPOUND WITH AGONISTIC ACTIVITY AGAINST STING - Google Patents

Claims (100)

1. The compound represented by the general formula (I-1),

, where X and Y represent -CH= or a nitrogen atom (provided that X and Y do not simultaneously represent -CH=), respectively, Z represents an oxygen atom or a sulfur atom, T represents a carbon atom or a nitrogen atom, a ring A is a 5-7-membered monocycle, ring B is a 5-7-membered monocycle or an 8-10-membered bicycle, L ¹ is a bond, -O-, -CONH-, -CO-, -CO ₂ - , -S-, -SO ₂ - or -SO-, L ² represents a bond, a C1-3 alkylene group, a C3-7 cycloalkylene group or a phenylene group, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, N(R ^1a ) ₂ (wherein the two R ^1a are each independently a hydrogen atom or a C1-4 alkyl group), a C1-4 alkyl group, a carboxyl group, a C1-4 alkoxycarbonyl group, a C1-4 haloalkyl group, a methyl-d ₃ group, C3-7 cycloalkyl group, phenyl group or 3-7 membered monocyclic non-aromatic heterocycle, R ^2c is a hydrogen atom, a hydroxyl group, a halogen atom, an oxo group, a nitro group, a cyano group, a C1-4 alkoxy group, or -CH ₂ NR ^2d R ^2e or NR ^2d R ^2e (wherein R ^2d is a hydrogen atom, a C1-4 alkyl group, or R ^FR , R ^2e is a hydrogen atom), m is an integer 0 or 1, R ³ is a hydrogen atom, a halogen atom, a hydroxyl group, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 a haloalkoxy group or an amino group, n is an integer from 1 to 16 (wherein when n is two or more, the groups represented by R ³ may be the same or different), R ^4a is a hydrogen atom, a C1-4 alkyl group, a carboxyl group or R ^FR , R ⁵ is a C1-4 alkyl group, p is an integer from 0 to 5 (wherein when p is 2 or more, the groups represented by R ⁵ may be the same or different), R ^6a is an atom hydrogen, C1-4 alkyl group or R ^FR , R ⁷ pr is a hydrogen atom, b is the attachment position of ring B, R ^FR is -(CR ^Fb ₂ ) _q OP(=O)(OR ^Fa ) ₂ [wherein each R ^Fa is independently a hydrogen atom, a C1-4 alkyl group , a C3-6 cycloalkyl group, -(CH ₂ ) ₂ OH, or -CH ₂ OCO ₂ CH(CH ₃ ) ₂ , R ^Fb is a hydrogen atom or a methyl group, q is the integer 1 or 2 (wherein the groups represented R ^Fb may be the same or different)], provided that two or more of R ^2d , R ^4a and R ^6a do not simultaneously represent R ^FR , a pharmaceutically acceptable salt or solvate thereof. 2. A compound, pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein ring A is (a) a C5-6 monocyclic carbocycle or (b) a 5-6 membered monocyclic heterocycle containing 1-4 heteroatoms selected from an oxygen atom , a nitrogen atom and a sulfur atom. 3. A compound, pharmaceutically acceptable salt or solvate thereof according to claim 1 or 2, wherein ring B is (a) a C5-6 monocyclic carbocycle or (b) a 5-6 membered monocyclic heterocycle containing 1-4 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom. 4. A compound, pharmaceutically acceptable salt or solvate thereof according to claim 1 or 3, wherein ring A is (a) a benzene ring or (b) a 5-6 membered monocyclic aromatic heterocycle containing 1-4 heteroatoms selected from an oxygen atom , a nitrogen atom and a sulfur atom. 5. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1, 2 and 4, wherein ring B is (a) a benzene ring or (b) a 5-6 membered monocyclic aromatic heterocycle containing 1-4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. 6. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1, 3 and 5, where ring A is a 5-6 membered monocyclic aromatic nitrogen-containing heterocycle containing 1-4 nitrogen atoms without any other heteroatoms. 7. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-6, where Z is an oxygen atom. 8. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-7, where X is a nitrogen atom, Y is -CH=. 9. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-8 where the group

, where the arrow represents the bond to the carbon atom represented by b in the general formula (I-1) and the other symbols have the meanings defined in paragraph 1, in the general formula (I-1) represents the group represented by the formula (Ib-1 ),

, where U is a nitrogen atom or a carbon atom (wherein when U is a nitrogen atom, m is 0, and when U is a carbon atom, m is 1), W is -CR ³ = or a nitrogen atom, V is - CH= or a nitrogen atom, and when the formula (Ib-1) includes several R ³ groups, they may be the same or different, and other symbols have the meanings defined in paragraph 1. 10. A compound, a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the compound represented by the general formula (I-1) is a compound of the general formula (II-1),

, where all symbols take on the meanings defined in paragraphs. 1 and 9. 11. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-10, where T is a nitrogen atom. 12. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 9-11, where U represents a carbon atom. 13. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1, 3, 5 and 7-12, where ring A is pyrazole, triazole, tetrazole, oxazole, isoxazole, imidazole, thiazole or isothiazole. 14. A compound, a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the compound represented by the general formula (I-1) is a compound represented by the general formula (III-1),

, where pa is an integer from 0 to 2, and the other characters take on the values defined in paragraphs. 1 and 9. 15. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-14, where L ² is a bond or a C1-3 alkylene group. 16. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-15, L ¹ is -CONH- (assuming the left side of the group is attached to ring B), -CO-, -CO ₂ -, -S-, -SO ₂ - or -SO-. 17. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-16, where R ¹ represents a hydrogen atom or a C1-4 alkyl group. 18. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-17, where R ^2c is a nitro group or NR ^2d R ^2e . 19. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-18, where R ³ represents a hydrogen atom, a halogen atom or a hydroxyl group. 20. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-19, where R ^4a represents a hydrogen atom or R ^FR , and R ^2d and R ^6a represent hydrogen atoms. 21. A compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-20, wherein the group is -(CR^fb ₂)_qOP(=O)(OR^Fa)₂, represented by R^FR, represents -CH₂OP(=O)(OH)₂, -CH(CH₃)OP(=O)(OH)₂ or -CH₂OP(=O)(OH)(OCH₂OCO₂CH(CH₃)₂). 22. Connection, its pharmaceutically acceptable salt or solvate according to any one of paragraphs. 1-21 where p and pa are zero or 1. 23. The compound, pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the compound represented by the general formula (I-1) is a compound selected from the group consisting of the following compounds: (1) 4-(4-amino-2-fluoro-5-methoxyphenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[5,4-c]pyridine-3-amine, (2) 4-(4-amino-2-fluoro-5-methoxyphenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (3) 4-(4-amino-3-methoxyphenyl)-7-(1 H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (4) 4-(4-Amino-2-fluoro-5-(methylthio)phenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (5) 4-(4-Amino-2-fluoro-5-(methoxy-d ₃ )phenyl)-7-(1 H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine , (6) 4-(4-Amino-2-fluoro-5-(methylsulfonyl)phenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (7) 4-(4-amino-5-(ethylthio)-2-fluorophenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (8) 4-(4-amino-2-fluoro-5-(methylsulfinyl)phenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (9) 4-(4-amino-2-fluoro-3-methoxyphenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (10) methyl 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluorobenzoate, (11) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluorobenoic acid, (12) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluorobenzamide, (13) 4-(4-Amino-2-fluoro-5-methoxyphenyl)-7-(3-methyl- 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (14) methyl-2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H- pyrazol -4-yl)isoxazolo[4,5- c ]pyridin-4-yl )-4-fluorobenzoate, (15) 1-(2-amino-5-(3-amino-7-(1 H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluorophenyl)ethane- 1-he, (16) 4-(4-Amino-2-chloro-5-(methylthio)phenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (17) ethyl 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluorobenzoate, (18) (4-(4-(5-Acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1-yl)methyldihydrophosphate , (19) ethyl-2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl) -4-fluorobenzoate, (20) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluoro- N -methylbenzamide, (21) 1-(2-Amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluorophenyl)propan- 1-he, (22) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl) -N -ethyl-4-fluorobenzamide, (23) 1-(2-Amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)phenyl)ethan-1-one , (24) methyl 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)benzoate, (25) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl) -N -propylbenzamide, (26) 1-(2-Amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluorophenyl)butan- 1-he, (27) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluoro- N -propylbenzamide, (28) 1-(2-Amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)phenyl)butan-1-one , (29) 2-hydroxyethyl-2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-fluorobenzoate, (30) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)benzamide, (31) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl) -N -methylbenzamide, (32) (4-(3-amino-4-(4-amino-5-(ethylcarbamoyl)-2-fluorophenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1 H -pyrazol-1- yl) methyl dihydrogen phosphate, (33) 1-(2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-hydroxyphenyl)ethane- 1-he, (34) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl) -N -ethylbenzamide, (35) 1-(2-Amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)phenyl)propan-1-one , (36) 2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridin-4-yl)-4-chloro- N -ethylbenzamide, (37) (4-(3-amino-4-(4-amino-2-fluoro-5-(methylthio)phenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1 H -pyrazol-1 -yl)methyl dihydrophosphate, (38) (4-(3-amino-4-(4-amino-2-fluoro-5-propionylphenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1-yl) methyl dihydrogen phosphate, (39) (4-(4-(3-acetyl-4-aminophenyl)-3-aminoisoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1-yl)methyl dihydrogen phosphate, (40) 4-(2-fluoro-5-methoxy-4-nitrophenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine, (41) (4-(3-amino-4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1 -yl)methyl dihydrophosphate, (42) (4-(3-Amino-4-(4-amino-5-(ethylcarbamoyl)-2-chlorophenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1 H -pyrazol-1- yl) methyl dihydrogen phosphate, (43) 1-(2-amino-5-(3-amino-7-( 1H -pyrazol-4-yl)isothiazolo[4,5- c ]pyridin-4-yl)-4-fluorophenyl)ethane- 1-he and (44) 4-(4-Amino-2-fluoro-5-(trifluoromethyl)phenyl)-7-( 1H -pyrazol-4-yl)isoxazolo[4,5- c ]pyridine-3-amine. 24. The compound, pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the compound represented by the general formula (I-1) is a compound selected from the group consisting of the following compounds: (1) methyl-2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H- pyrazol -4-yl)isoxazolo[4,5- c ]pyridin-4-yl )-4-fluorobenzoate, (2) (4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1-yl)methyl dihydrogen phosphate , (3) ethyl-2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H- pyrazol -4-yl)isoxazolo[4,5- c ]pyridin-4-yl )-4-fluorobenzoate, (4) (4-(3-amino-4-(4-amino-5-(ethylcarbamoyl)-2-fluorophenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1- yl) methyl dihydrogen phosphate, (5) (4-(3-amino-4-(4-amino-2-fluoro-5-(methylthio)phenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1 H -pyrazol-1 -yl)methyl dihydrophosphate, (6) (4-(3-amino-4-(4-amino-2-fluoro-5-propionylphenyl)-isoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1-yl )methyl dihydrophosphate, (7) (4-(4-(3-acetyl-4-aminophenyl)-3-aminoisoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1-yl)methyl dihydrogen phosphate, (8) (4-(3-amino-4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1 -yl)methyl dihydrophosphate and (9) (4-(3-amino-4-(4-amino-5-(ethylcarbamoyl)-2-chlorophenyl)isoxazolo[4,5- c ]pyridin-7-yl)-1H- pyrazol -1- yl) methyl dihydrogen phosphate. 25. A pharmaceutically acceptable salt of a compound or a solvate thereof according to any one of paragraphs. 1-24, where a pharmaceutically acceptable salt of the compound according to any one of paragraphs. 1-24 is an alkali metal salt. 26. Solvate compounds or pharmaceutically acceptable salts according to any one of paragraphs. 1-25, where the solvate of the compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-25 is a hydrate. 27. A pharmaceutical composition comprising a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 28. A drug for suppressing development, suppressing recurrence and/or treating cancer or an infectious disease, comprising a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof as an active ingredient. 29. The drug according to claim 28, where the cancer is a solid cancer or a malignant disease of the blood. 30. The drug according to claim 29, wherein the solid cancer is one or more cancers selected from malignant melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, renal cell cancer, breast cancer, ovarian cancer, clear cell adenocarcinoma of the ovary, nasopharyngeal cancer, uterine cancer, anal cancer, colorectal cancer, rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastrointestinal cancer, esophagogastric junction cancer, pancreatic cancer, urothelial cancer, cancer prostate cancer, fallopian tube cancer, primary peritoneal cancer, pleural malignant mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer, testicular cancer (embryo cell tumour), vaginal cancer, vulvar cancer, penile cancer, cancer small intestine, endocrine system cancer, thyroid cancer, parathyroid cancer cancer, adrenal cancer, spinal cord tumor, neuroblastoma, medulloblastoma, retinoblastoma of the eye, neuroendocrine tumor, brain tumor and squamous cell carcinoma. 31. The medicament of claim 29 wherein the solid cancer is bone/soft tissue sarcoma or Kaposi's sarcoma. 32. The medicament of claim 29, wherein the blood cancer is one or more cancers selected from multiple myeloma, malignant lymphoma, leukemia, malignant lymphoma of the central nervous system, myeloplastic syndromes, and myeloproliferative syndromes. 33. The drug according to any one of paragraphs. 28-32, which is administered in combination with one or more types of other anti-cancer drugs. 34. The medicament of claim 33, wherein the other anti-cancer drug is an immunotherapeutic anti-cancer drug. 35. The medicament of claim 34, wherein the immunotherapeutic anti-cancer drug is an anti-PD-1 antibody or an anti-PD-L1 antibody. 36. A drug having STING agonist activity, comprising a compound represented by the general formula (I-1), a pharmaceutically acceptable salt or solvate thereof as an active ingredient. 37. A compound, a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the compound represented by the general formula (I-1) is (4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3 -aminoisoxazolo[4,5- c ]pyridin-7-yl)-1 H -pyrazol-1-yl)methyl dihydrogen phosphate.