RU2022129070A - TLR7/8 POLYCYCLIC ANTAGONISTS AND THEIR USE IN THE TREATMENT OF IMMUNE DISORDERS - Google Patents

Claims (47)

1. Compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: Ring A is aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; Ring B is aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; R ¹ is absent or represents -H, -CHF ₂ , -CF ₃ , -OMe or -CN; each R ² is independently -H, -R, halogen, haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, - C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; each R ³ is independently -H, -R, halogen, haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, - C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; X is C(R ⁴ ) ₂ , O, NR ⁴ , S, S(R ⁴ ) or S(R ⁴ ) ₂ ; each R ⁴ is independently -H, -R, halogen, haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, - C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; each R ⁵ is independently -H, -R, halogen, haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, - C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; each R is independently hydrogen, C _1-6 aliphatic, C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of these groups is optionally substituted; or two R groups on the same atom are taken together with the atom to which they are attached to form a C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocyclic ring containing 1- 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; k is 0 or 1; n is 0, 1, or 2; p is 0, 1, or 2; r is 0, 1, or 2; and t is 0, 1, or 2. 2. The compound according to claim 1, where ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl; each of which is optionally substituted. 3. A compound according to any one of the preceding claims, wherein ring A is

4. A compound according to any one of the preceding claims, wherein ring A is

5. The compound according to any one of the preceding paragraphs, where ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole or thiazole; each of which is optionally substituted. 6. A compound according to any one of the preceding claims, wherein Ring B is

7. A compound according to any one of the preceding claims, wherein Ring B is

8. A compound according to any one of the preceding claims, wherein X is CH ₂ . 9. A compound according to any one of the preceding claims, wherein X is O. 10. A compound according to any one of the preceding claims, wherein each R ⁴ is independently -H, C _1-6 aliphatic, -OR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; each of these groups is optionally substituted. 11. A compound according to any one of the preceding claims, wherein each R ⁴ is independently -H, C _1-6 aliphatic, -C(O)N(R) ₂ , -NRC(O)R or -N(R) ₂ ; each of these groups is optionally substituted. 12. Compound according to claim 1, formulas I-h

or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 1, formulas I-J

or a pharmaceutically acceptable salt thereof. 14. Compound according to claim 1, formulas I-m

or a pharmaceutically acceptable salt thereof. 15. A compound according to any one of the preceding claims, selected from Table 1. 16. Pharmaceutical composition comprising a compound according to any one of paragraphs. 1-15 and a pharmaceutically acceptable adjuvant, carrier or excipient. 17. A method of inhibiting the activity of TLR7/8 or its mutant in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound according to any one of paragraphs. 1-15 or its physiologically acceptable salt. 18. A method of treating a TLR7/8-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to any one of paragraphs. 1-15 or its physiologically acceptable salt. 19. The method of claim 18 wherein the disorder is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory disease bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke , atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease and cancer. 20. A method of treating cancer in a subject, comprising the step of administering to said subject a compound of claim 1 or a physiologically acceptable salt thereof.