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 R2A, R2B, R2C and R2D 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; X1A represents O or CH2; X1B 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 Rp-groups; with each Rp independently representing C1-C6alkyl, halogen, C1-C6haloalkyl, G2, -C(O)NRARB or -NRARB; and RA, in each case, independently representing hydrogen; RB, 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 Rq-groups; X2 represents O or N(R2x), with R2x 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)-ORg, -(C1-C3alkylenyl)-GB, 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 Rs-groups; GB is pyridazine optionally substituted with 1 independently selected Rs-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 Rv-group; R11 represents halogen, C1-C3alkyl or G4, while G4 represents C3-C6cycloalkyl or phenyl; and eavh G4 optionally substituted with 1 independently selected Rw-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, -OR13a and -O-benzyl, with R13a, 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 -ORj, -O-benzyl; Rq representing halogen, C1-C6haloalkyl, -CN, -ORx, -OC(O)Ry, -S(O)2Rx, -S(O)2N(Rx)2, -C(O)ORx, -C(O)N(Rx)2, -C(O)N(Rx)S(O)2Ry, G2A or C1-C6alkyl, which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of -CN, -ORx и G2A; Rx, in each case, independently representing hydrogen, C1-C6alkyl or G2A; Ry, in each case, independently representing C1-C6alkyl; G2A, in each case, independently representing phenyl or C3-C6cycloalkyl; each of which is optionally substituted by 1 Rz-group; Rs, ineach case, independently representing C2-C6alkenyl, halogen, oxo, -ORh, -C(O)Rj, -C(O)ORj, -C(O)O(benzyl), -C(O)N(Rj)2, -C(O)N(Rm)(Rn), -N(Rj)C(O)O(Rk), G3A or C1-C6alkyl, which is optionally substituted with 1 or 2 substituents, independently selected from the group consisting of -ORj, -S(O)2Rj, -N(Rj)2 and G3A; G3A, 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 G3A is optionally substituted by 1 or 2 Rc-groups; Rg represents hydrogen or benzyl or Rg represents C2-C6alkyl, which is substituted by 1 or 2 -ORj; Rh represents benzyl or Rh represents C2-C6alkyl that is substituted by 1 or 2 -ORj; Rm represents G3B or C1-C6alkyl, is optionally substituted with 1 or 2 substituents, independently selected from the group consisting of -ORj, -S(O)2Rj, -C(O)N(Rj)2 and G3B; Rn represents hydrogen, C1-C6alkyl, benzyl or -(C2-C6alkylenyl)-ORj; or Rm 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 Rc-groups; G3B, 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 Rc-groups; each of Rc, Ru, Rv, Rw and Rz, in each case, independently represents halogen, oxo, -ORj, -S(O)2N(Rj)2, -C(O)Rj, -C(O)ORj or C1-C6alkyl, which is optionally substituted by 1 or 2 substituents, independently selected from the group consisting of -ORj; Rj, in each case, independently represents hydrogen or C1-C6alkyl; and Rk, 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
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Authors
Dates
2021-03-15—Published
2016-07-14—Filed