RU2020138184A - QUINOLINE DERIVATIVES AS AXL/MER AND CSF1R RECEPTOR TYROSINE KINASE INHIBITORS - Google Patents

Claims (83)

1. A compound having the general formula I:

where X ¹ is independently in each case selected from CR ³ and N; X ² is independently selected from CR ⁴ and N at each occurrence; n is independently at each occurrence selected from 0, 1, and 2; A is independently at each occurrence selected from any of the structures shown in the following group W;

R ¹ is independently at each occurrence selected from the group consisting of hydrogen; C1-C6 alkyl, C1-C6 alkyl substituted with one or two of OR ⁵ and NR ⁵ R ⁶ ; C3-C10 cycloalkyl; C1-C4 haloalkyl; -(C=O)R ⁵ , any of which is optionally substituted; R ² is independently at each occurrence selected from the group consisting of C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; -NR ⁷ R ⁸ ; -OR ⁸ ; any of which is optionally substituted; R ³ and R ⁴ are each independently selected from the group consisting of hydrogen; halogen; for example, Cl or F; C1-C3 alkyl; OR ⁵ ; C1-C4 haloalkyl; any of which is optionally substituted; R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen; C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; any of which is optionally substituted; R ⁷ is independently at each occurrence selected from the group consisting of hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with one or two of OR ⁵ and NR ⁵ R ⁶ ; C3-C10 cycloalkyl, C1-C4 haloalkyl; any of which is optionally substituted; R ⁸ is independently in each occurrence selected from the group consisting of hydrogen; -CH(CH ₃ ) ₂ ; -C(CH ₃ ) ₃ ; C3-C10 cycloalkyl; C3-C10 heterocycloalkyl; C1-C4 haloalkyl; C1-C6 alkyl substituted with one or two of OR ⁵ and NR ⁵ R ⁶ ; and C1-C6 alkyl substituted with one or two of C3-C10 cycloacyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; any of which is optionally substituted; Z ¹ at each occurrence is independently selected from the group consisting of hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with one or two of (=O), CN, OR ⁵ and NR ⁵ R ⁶ ; C3-C10 cycloalkyl; C3-C10 cycloalkyl substituted with one or more of halo, OR ⁷ and NR ⁹ R ¹⁰ ; C3-C10 heterocycloalkyl; C3-C10 heterocycloalkyl substituted with one or more of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, and C1-C4 haloalkyl; C1-C4 haloalkyl; R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; any of which is optionally substituted; R ¹¹ and R ¹² are each independently selected from the group consisting of C1-C6 alkyl; C3-C10 cycloalkyl; C3-C10 heterocycloalkyl; C1-C4 haloalkyl; any of which is optionally substituted; and their pharmacologically acceptable salts. 2. The compound according to claim 1, having the general formula II:

where R ¹ , R ² , R ³ , R ⁴ , R ¹¹ , R ¹² , Z ¹ , X ¹ , X ² and n have the meanings defined in paragraph 1; and their pharmaceutically acceptable salts. 3. Connection according to any one of paragraphs. 1 and 2 having the general formula III:

where R ¹ , R ² , R ³ , R ⁴ , Z ¹ , X ¹ , X ² and n have the meanings defined in paragraph 1; and their pharmaceutically acceptable salts, where, preferably R ³ and R ⁴ are each independently selected from the group consisting of hydrogen; halogen, for example, Cl or F; C1-C3 alkyl which is optionally substituted; R ⁸ is independently in each occurrence selected from the group consisting of hydrogen; -CH(CH ₃ ) ₂ ; -C(CH ₃ ) ₃ ; C3-C10 cycloalkyl; C1-C4 haloalkyl; C1-C6 alkyl substituted with one or two of OR ⁵ and NR ⁵ R ⁶ ; or C1-C6 alkyl substituted with one or two of C3-C10 cycloacyl and C1-C4 haloalkyl; any of which is optionally substituted; and Z ¹ at each occurrence is independently selected from the group consisting of hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with one or two of OR ⁵ and NR ⁵ R ⁶ ; C3-C10 cycloalkyl; C3-C10 cycloalkyl substituted with one or more of halo, OR ⁷ and NR ⁹ R ¹⁰ ; C3-C10 heterocycloalkyl; C3-C10 heterocycloalkyl substituted with one or more of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, and C1-C4 haloalkyl; C1-C4 haloalkyl; and their pharmaceutically acceptable salts. 4. The connection according to any one of paragraphs. 1-3 having the general formula IV:

where R ¹ , R ² , R ³ , R ⁴ , Z ¹ , X ² and n have the meanings defined in any of paragraphs. 1-3; and their pharmaceutically acceptable salts. 5. Connection according to any one of paragraphs. 1-4 having the general formula V:

where R ¹ , R ² , R ³ , R ⁴ , Z ¹ and n have the meanings defined in any of paragraphs. 1-4; and their pharmaceutically acceptable salts; where, preferably, R ³ and R ⁴ are hydrogen; and their pharmaceutically acceptable salts. 6. The connection according to any one of paragraphs. 1-5, in which n = 0 or 1 and Z ¹ is selected from C1-C6 alkyl, in particular methyl, ethyl, propyl or isopropyl; C3-C10 cycloalkyl, in particular C3 cycloalkyl; C3-C10 heterocycloalkyl; C1-C6 alkyl substituted with one or two of OR ⁵ and NR ⁵ R ⁶ ; and their pharmaceutically acceptable salts. 7. Connection according to any one of paragraphs. 1-6, in which R ² represents OR ⁸ where R ⁸ is selected from -CH(CH ₃ ) ₂ ; -C(CH ₃ ) ₃ ; C1-C4 haloalkyl; C1-C6 alkyl substituted with one or two of C3-C10 cycloalkyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; or C1-C6 alkyl substituted with C1-C4 haloalkyl, in particular one of the following: trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl, and their pharmaceutically acceptable salts. 8. Connection according to any one of paragraphs. 6 and 7, in which n = 0 or 1 and Z ¹ is selected from C1-C6 alkyl, in particular methyl, ethyl, propyl or isopropyl; C3-C10 cycloalkyl, in particular C3 cycloalkyl; C3-C10 heterocycloalkyl; C1-C6 alkyl substituted with one or two of OR ⁵ and NR ⁵ R ⁶ ; where R ⁵ and R ⁶ in each case are independently selected from the group consisting of hydrogen; C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; any of which is optionally substituted; and R ² is OR ⁸ where R ⁸ is selected from -CH(CH ₃ ) ₂ ; -C(CH ₃ ) ₃ ; C1-C4 haloalkyl; C1-C6 alkyl substituted with one or two of C3-C10 cycloalkyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; or C1-C6 alkyl substituted with C1-C4 haloalkyl, in particular one of the following: trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl and their pharmaceutically acceptable salts. 9. A compound according to any one of the preceding claims, wherein R ² is OR ⁸ where R ⁸ is selected from C1-C4 haloalkyl, in particular one of the following: trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; or C1-C6 alkyl substituted with C1-C4 haloalkyl, in particular one of the following: trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl. 10. A compound according to any one of the preceding claims, wherein n = 0 or 1; and Z1 is selected from methyl; ethyl; propyl; isopropyl; C3 cycloalkyl; C4 cycloalkyl; and C5 cycloalkyl. 11. The connection according to any one of paragraphs. 9 and 10, in which n = 0 or 1; Z1 is selected from methyl; ethyl; propyl; isopropyl; C3 cycloalkyl; C4 cycloalkyl; and C5 cycloalkyl; and R ² is OR ⁸ where R ⁸ is selected from C1-C4 haloalkyl, in particular one of the following: trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; or C1-C6 alkyl substituted with C1-C4 haloalkyl, in particular one of the following: trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl. 12. A compound according to any one of the preceding claims, having one of the structures below:

13. Composition containing at least one compound according to any one of paragraphs. 1-12 together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. 14. The composition according to claim 13, additionally containing at least one other pharmaceutically active agent. 15. The use of a compound according to any one of paragraphs. 1-12 as a pharmaceutically active agent, preferably for the treatment of a disorder. 16. The use of a compound according to any one of paragraphs. 1-12 in the treatment of a disorder associated with, accompanied by, caused or induced by Axl/Mer and CSF1R receptor tyrosine kinase, in particular associated with, accompanied by or caused by Axl/Mer and CSF1R (colony stimulating factor receptor-1), preferably associated with, accompanied by or caused by hyperfunction said Axl/Mer and hyperfunction of said CSF1R. 17. The use of the composition according to any one of paragraphs. 13-14 as a pharmaceutically active agent, preferably for the treatment of a disorder. 18. The use of a composition according to any one of paragraphs. 13-14 in the treatment of a disorder associated with, accompanied by, caused or induced by Axl/Mer and CSF1R receptor tyrosine kinase, in particular associated with, accompanied by or caused by Axl/Mer and CSF1R (colony stimulating factor receptor-1), preferably associated with, accompanied by or caused by hyperfunction said Axl/Mer and hyperfunction of said CSF1R. 19. Application according to any one of paragraphs. 15-18 wherein said disorder is selected from hyperproliferative disorders, inflammatory disorders, and neurodegenerative disorders. 20. Use according to claim 19, wherein said hyperproliferative disorder is a cancer, preferably a cancer selected from the following: adenocarcinoma, acoustic neuroma, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-associated cancer types, AIDS-associated lymphoma , anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, ampullary colon carcinoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brainstem glioma, brain tumor , atypical teratoid / rhabdoid tumor of the central nervous system, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, parenchymal tumors of the pineal gland of intermediate differentiation, supratentorial primitive neuroectodermal tumors and pineoblastoma, tumors of the brain and spinal cord, breast cancer, urinary duct tumors, Burkitt's lymphoma, carcinoid tumor, choroidal melanoma, gastrointestinal tract cancer, central nervous system lymphoma, cervical cancer, uterine body cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative diseases, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, desmoid tumor, fungoid granuloma, endometrial cancer, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma tumor family, extracranial embryonic cell tumor, extragonadal embryonic cell tumor, extrahepatic bile duct cancer, tumors ear, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, carcinoid tumor of the gastrointestinal tract, stromal tumor of the gastrointestinal tract, stromal cell tumor of the gastrointestinal tract, gynecological tumors, embryonic cell tumor of the ovary, gestational trophoblastic tumor , glioma, gallbladder carcinomas, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, subesophageal cancer, hematopoietic neoplasia, insulomas (tumors of the pancreas of internal secretion), renal cell carcinoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and mouth cancer, liver cancer, lung cancer, non-small cell lung cancer, tumors of the small intestine, small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, and osteosarcoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary site, squamous cell carcinomas, multiple endocrine neoplasia syndromes, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, myeloid leukemia, multiple myeloma, myeloproliferative disorders, cancer nasal cavity and paranasal sinuses, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous bone histiocytoma, ovarian cancer, epithelial ovarian cancer, borderline ovarian tumor, oligodendroglioma, plasmacytoma, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell carcinoma, transitional cell carcinoma, respiratory tract cancer, rhabdomyosarcoma, salivary gland cancer, sarcoma, cancer testicular, Ewing's sarcoma, Kaposi's sarcoma, uterine sarcoma, non-melanoma skin cancer, melanoma skin cancer, skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, neck squamous cell carcinoma, gastric cancer, soft tissue tumors, testicular cancer, throat cancer, thymoma and carcinoma of the thymus, thyroid cancer, transitional cell carcinoma of the kidney ohanka and ureter, trophoblastic tumor, testicular cancer, gestational cancer, urological tumors, cancer of the ureter and renal pelvis, urethra cancer, urothelial carcinoma, uterine cancer, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia and Wilms tumor, tumors that cause effusions in potential cavities body, pleural effusions, pericardial effusions, peritoneal effusion also called ascites, giant cell tumor (GCT), giant cell tumor of bone, pigmented villonesonodular synovitis (PVNS), tenosynovial giant cell tumor (TGCT), tendon sheath tenosynovial giant cell tumor (TGCT-TS). 21. Use according to claim 19, wherein said inflammatory disorder is selected from the following: osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki syndrome, hemophagocytic syndrome (syndrome macrophage activation), multicentric reticulohistiocytosis, atherosclerosis, primary progressive multiple sclerosis, type I diabetes mellitus, type II diabetes mellitus, insulin resistance, hyperglycemia, obesity, lipolysis, hypereosinophilia, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis ( osteomyelitis) located near the prostate or mediated by wear products, osteolysis, endometriosis, inflammatory pain, chronic pain, and bone pain. 22. Use according to claim 19, wherein said neurodegenerative disorder is selected from the following: Binswanger's dementia, prosencephaly, microcephaly, cerebral palsy, congenital hydrocephalus, hydrocephalus, progressive supranuclear palsy, glaucoma, Wilson's disease, Alzheimer's disease and other dementias, disease Parkinson's disease (PD) and diseases associated with PD, multi-infarct dementia, frontotemporal dementia, pseudodementia, prion disease, motor neuron diseases, Huntington's disease, spinal cerebellar ataxia, and spinal muscular atrophy. 23. Application according to any one of paragraphs. 15-22, wherein said use is combined with another pharmaceutically active drug or therapy, in particular radiation therapy, chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor drugs. 24. A method of treating a disease selected from hyperproliferative disorders, inflammatory disorders and/or neurodegenerative disorders, comprising administering a compound according to any one of paragraphs. 1-12 or compositions according to any one of paragraphs. 13-14 to a patient in need of such treatment.