Patent RU-2744766-C2 (RU)
Title: Substituted tricyclic compounds and method of application
Inventor: ALTENBACH ROBERT J
IPC: A61P11/00
Filed: 2016-07-14
Granted: 2021-03-15
Abstract: FIELD: pharmaceuticals. 
     SUBSTANCE: invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
     
     wherein R 1  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 R 3 , R 4 , R 6  and R 7  independently represents hydrogen or halogen; R 5 , in each case, independently represents C 1 -C 3 alkyl; X 1A  represents O or CH 2 ; X 1B  represents O or CH 2 ; Y represents -G 1  or Y is characterized by Formula (c), (d), (e), (f) or (g): 
     
       
     
     
       
     
     
       
     
     wherein G 1  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 C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, G 2 , -C(O)NR A R B  or -NR A R B ; and R A , in each case, independently representing hydrogen; R B , in each case, independently representing C 1 -C 6 alkyl, which is optionally substituted with 1 or 2 -OH; and G 2  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; X 2  represents O or N(R 2x ), with R 2x  representing hydrogen; X 3  representing N or CH; X 4 -X 5  repin each case, independently represents hydrogen; R 8 -groups represent optional substituents at the benzene ring and each group represents halogen, C 1 -C 3 alkoxy or C 1 -C 3 haloalkoxy; m equals to 0, 1 or 2; G 3  represents -(C 1 -C 3 alkylenyl)-OR g , -(C 1 -C 3 alkylenyl)-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; R 9  represents C 1 -C 3 alkyl or phenyl; n equals to 1; R 10  represents C 1 -C 6 alkyl, 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 R 10  represents phenyl, wherein phenyl is optionally substituted with 1 independently selected R v -group; R 11  represents halogen, C 1 -C 3 alkyl or G 4 , while G 4  represents C 3 -C 6 cycloalkyl or phenyl; and eavh G 4  optionally substituted with 1 independently selected R w -group; R 12  represents optional substituents of the benzene ring and each independently represents halogen; p equals to 0 or 1; R 13  represents hydrogen or C 1 -C 6 alkyl, 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 R 14  and R 15  independently representing C 1 -C 3 alkyl or R 14  and R 15 , taken together with the carbon atom to which they are attached, forming C 3 -C 6 cycloalkyl or 4-6-membered monocyclic heterocycle, containing one heteroatom, selected from the group, consisting of an oxygen atom; R 16  representing -OH or C 1 -C 6 alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OR j , -O-benzyl; R q  representing halogen, C 1 -C 6 haloalkyl, -CN, -OR x , -OC(O)R y , -S(O) 2 R x , -S(O) 2 N(R x ) 2 , -C(O)OR x , -C(O)N(R x ) 2 , -C(O)N(R x )S(O) 2 R y , G 2A  or C 1 -C 6 alkyl, 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, C 1 -C 6 alkyl or G 2A ; R y , in each case, independently representing C 1 -C 6 alkyl; G 2A , in each case, independently representing phenyl or C 3 -C 6 cycloalkyl; each of which is optionally substituted by 1 R z -group; R s , ineach case, independently representing C 2 -C 6 alkenyl, 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 )(R n ), -N(R j )C(O)O(R k ), G 3A  or C 1 -C 6 alkyl, which is optionally substituted with  1 or 2 substituents, independently selected from the group consisting of -OR j , -S(O) 2 R 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 C 2 -C 6 alkyl, which is substituted by 1 or 2 -OR j ; R h  represents benzyl or R h  represents C 2 -C 6 alkyl that is substituted by 1 or 2 -OR j ; R m  represents G 3B  or C 1 -C 6 alkyl, is optionally substituted with  1 or 2 substituents, independently selected from the group consisting of -OR j , -S(O) 2 R j , -C(O)N(R j ) 2  and G 3B ; R n  represents hydrogen, C 1 -C 6 alkyl, benzyl or -(C 2 -C 6 alkylenyl)-OR j ; or R m  and R n , 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) 2 N(R j ) 2 , -C(O)R j , -C(O)OR j  or C 1 -C 6 alkyl, 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 C 1 -C 6 alkyl; and R k , in each case, independently represents C 1 -C 6 alkyl. 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