SUBSTITUTED TRICYCLIC COMPOUNDS AND METHOD OF APPLICATION Russian patent published in 2021 - IPC C07D493/04 C07D405/12 C07D407/12 C07D519/00 A61K31/36 A61K31/404 A61K31/426 A61K31/433 A61K31/443 A61K31/4184 A61K31/501 A61K31/497 A61P11/00 

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein R¹ represents H; X is characterized by Formula (a) or Formula (b):

wherein each of R^2A, R^2B, R^2C and R^2D independently represents hydrogen or halogen; each of R³, R⁴, R⁶ and R⁷ independently represents hydrogen or halogen; R⁵, in each case, independently represents C₁-C₃alkyl; X^1A represents O or CH₂; X^1B represents O or CH₂; Y represents -G¹ or Y is characterized by Formula (c), (d), (e), (f) or (g):

wherein G¹ represents phenyl or 5-6 membered monocyclic heteroaryl, containing 1-3 heteroatoms selected from the group consisting of S and N, each of which is optionally substituted with 1, 2 or 3 independently selected R^p-groups; with each R^p independently representing C₁-C₆alkyl, halogen, C₁-C₆haloalkyl, G², -C(O)NR^AR^B or -NR^AR^B; and R^A, in each case, independently representing hydrogen; R^B, in each case, independently representing C₁-C₆alkyl, which is optionally substituted with 1 or 2 -OH; and G² representing phenyl, 4-8-memebered heterocycle containing 1-2 heteroatoms selected from the group consisting of N and O, or 5-membered monocyclic heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of S and N; each of which is optionally substituted with 1, 2 or 3 independently selected R^q-groups; X² represents O or N(R^2x), with R^2x representing hydrogen; X³ representing N or CH; X⁴-X⁵ repin each case, independently represents hydrogen; R⁸-groups represent optional substituents at the benzene ring and each group represents halogen, C₁-C₃alkoxy or C₁-C₃haloalkoxy; m equals to 0, 1 or 2; G³ represents -(C₁-C₃alkylenyl)-OR^g, -(C₁-C₃alkylenyl)-G^B, phenyl, cycloalkyl, 5-6--membered monocyclic heteroaryl, containing 1-4 N atoms, or 5-6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of S and N; wherein each of phenyl, cycloalkyl, 5-6 membered monocyclic heterocycle and monocyclic heteroaryl is optionally substituted with 1 or 2 independently selected R^s-groups; G^B is pyridazine optionally substituted with 1 independently selected R^s-group; R⁹ represents C₁-C₃alkyl or phenyl; n equals to 1; R¹⁰ represents C₁-C₆alkyl, substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH and 2,2-dimethyl-1,3-dioxolan-4-yl; or R¹⁰ represents phenyl, wherein phenyl is optionally substituted with 1 independently selected R^v-group; R¹¹ represents halogen, C₁-C₃alkyl or G⁴, while G⁴ represents C₃-C₆cycloalkyl or phenyl; and eavh G⁴ optionally substituted with 1 independently selected R^w-group; R¹² represents optional substituents of the benzene ring and each independently represents halogen; p equals to 0 or 1; R¹³ represents hydrogen or C₁-C₆alkyl, which is substituted by 1 or 2 substituents independently selected from the group consisting of -CN, 2,2-dimethyl-1,3-dioxolan-4-yl, -OR^13a and -O-benzyl, with R^13a, ineach case, independently representing hydrogen; each of R¹⁴ and R¹⁵ independently representing C₁-C₃alkyl or R¹⁴ and R¹⁵, taken together with the carbon atom to which they are attached, forming C₃-C₆cycloalkyl or 4-6-membered monocyclic heterocycle, containing one heteroatom, selected from the group, consisting of an oxygen atom; R¹⁶ representing -OH or C₁-C₆alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OR^j, -O-benzyl; R^q representing halogen, C₁-C₆haloalkyl, -CN, -OR^x, -OC(O)R^y, -S(O)₂R^x, -S(O)₂N(R^x)₂, -C(O)OR^x, -C(O)N(R^x)₂, -C(O)N(R^x)S(O)₂R^y, G^2A or C₁-C₆alkyl, which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of -CN, -OR^x и G^2A; R^x, in each case, independently representing hydrogen, C₁-C₆alkyl or G^2A; R^y, in each case, independently representing C₁-C₆alkyl; G^2A, in each case, independently representing phenyl or C₃-C₆cycloalkyl; each of which is optionally substituted by 1 R^z-group; R^s, ineach case, independently representing C₂-C₆alkenyl, halogen, oxo, -OR^h, -C(O)R^j, -C(O)OR^j, -C(O)O(benzyl), -C(O)N(R^j)₂, -C(O)N(R^m)(Rⁿ), -N(R^j)C(O)O(R^k), G^3A or C₁-C₆alkyl, which is optionally substituted with 1 or 2 substituents, independently selected from the group consisting of -OR^j, -S(O)₂R^j, -N(R^j)₂ and G^3A; G^3A, in each case, independently representing phenyl or 5-6-membered monocyclic heterocycle, containing 1 to 2 heteroatoms selected from the group consisting of O and N; while G^3A is optionally substituted by 1 or 2 R^c-groups; R^g represents hydrogen or benzyl or R^g represents C₂-C₆alkyl, which is substituted by 1 or 2 -OR^j; R^h represents benzyl or R^h represents C₂-C₆alkyl that is substituted by 1 or 2 -OR^j; R^m represents G^3B or C₁-C₆alkyl, is optionally substituted with 1 or 2 substituents, independently selected from the group consisting of -OR^j, -S(O)₂R^j, -C(O)N(R^j)₂ and G^3B; Rⁿ represents hydrogen, C₁-C₆alkyl, benzyl or -(C₂-C₆alkylenyl)-OR^j; or R^m and Rⁿ, taken together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic heterocycle containing 1-2 heteroatoms selected from the group consisting of O and N, with the 4-7 membered monocyclic heterocycle optionally substituted with 1 or 2 independently selected R^c-groups; G^3B, in each case, independently represents phenyl, 5-6-membered monocyclic heterocycle, containing one heteroatom selected from the group consisting of S and N, or 4-9-membered cycloalkyl, each of which is optionally substituted with 1 or 2 independently selected R^c-groups; each of R^c, R^u, R^v, R^w and R^z, in each case, independently represents halogen, oxo, -OR^j, -S(O)₂N(R^j)₂, -C(O)R^j, -C(O)OR^j or C₁-C₆alkyl, which is optionally substituted by 1 or 2 substituents, independently selected from the group consisting of -OR^j; R^j, in each case, independently represents hydrogen or C₁-C₆alkyl; and R^k, in each case, independently represents C₁-C₆alkyl. The invention also relates to a pharmaceutical composition useful in the treatment of diseases and conditions mediated and modulated by CFTR, based on said compounds of Formula (I).

EFFECT: technical result is that new compounds and a pharmaceutical composition based on them have been obtained, which can be used in medicine as agents in the treatment of cystic fibrosis, Sjogren's syndrome, pancreatic insufficiency, chronic obstructive pulmonary disease and chronic airway obstruction.

64 cl, 3 tbl, 293 ex