US 12,552,770 B2 · Compounds for treating respiratory disease

Abstract

Compounds of general formula (I) and their tautomeric forms all enantiomers and isotopic variants and salts and solvates thereof: wherein represents a single or a double bond and R1, R2, X1, X2, X3, X4, X5, Y and Z are as defined herein; are useful for treating respiratory disease and other diseases and conditions modulated by TMEM16A.

A compound selected from:

2-(1-Adamantyl)-N-[2-(tetrahydropyran-2-ylmethyl)-1H-benzimidazol-5-yl] acetamide (Compound 1.1);
2-(2-Adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl) (Compound 2);
2-(2-Adamantyl)-N-[2-(2-phenylethyl)-1H-benzimidazol-5-yl]acetamide (Compound 2.1);
2-(2-Adamantyl)-N-[2-[methoxy (phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 2.2);
2-(2-Adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 2.3);
2-(2-Adamantyl)-N-[2-[(R)-methylamino (phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 3);
2-(1-Adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 4);
2-(2-Adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 5);
2-(2-Adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 5.1);
2-(2-Adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 5.2);
2,2,2-Trifluoroethyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl] methyl]carbamate (Compound 6);
2-(1-Adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide (Compound 7);
tert-Butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate (Compound 8);
2-(2-Adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide (Compound 9);
N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide (Compound 10);
2-(1-Adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide (Compound 11);
2-Cyclohexyl-N-(2-isopropyl-1,3-benzoxazol-5-yl)acetamide (Compound 12);
N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide (Compound 13);
2-(1-Adamantyl)-N-(2-benzyl-3H-imidazo[4,5-c]pyridin-6-yl)acetamide (Compound 14);
2-Benzyl-N-(cycloheptylmethyl) imidazo[1,2-a]pyridine-7-carboxamide (Compound 15);
2-(1-Adamantyl)-N-(2-benzylindazol-6-yl)acetamide (Compound 16);
2-(1-Adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide (Compound 17);
N-(2-tert-Butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide (Compound 18);
tert-Butyl N-[3-[(2-benzyl-1H-benzimidazole-5-carbonyl)amino]-2,2-dimethyl-propyl]carbamate (Compound 19);
2-tert-Butyl-N-(cycloheptylmethyl)-3H-benzimidazole-5-carboxamide (Compound 20);
2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl) cyclopropyl]-1H-benzimidazole-5-carboxamide (Compound 21);
2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl) cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (Compound 21.1);
2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Compound 21.2);
2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl) cyclopropyl]-1,3-benzoxazole-5-carboxamide (Compound 21.3);
2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl) cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide (Compound 21.4);
2-[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl) phenyl]-N-[2-[1-(trifluoromethyl) cyclopropyl]-1H-benzimidazol-5-yl]acetamide (Compound 22);
2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl) cyclopropyl]-1H-benzimidazol-5-yl]acetamide (Compound 23);
2-Benzyl-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Compound 24);
2-Benzyl-N-(cycloheptylmethyl)-1H-benzimidazole-5-carboxamide (Compound 24.2);
N-(Cycloheptylmethyl)-2-[(2-fluoro-6-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25);
N-(Cycloheptylmethyl)-2-[(5-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.1);
N-(Cycloheptylmethyl)-2-[(3-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.2);
N-(Cycloheptylmethyl)-2-[(2-hydroxy phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.3);
N-(Cycloheptylmethyl)-2-[(4-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.4);
N-(Cycloheptylmethyl)-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.5);
2-(5-Chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide (Compound 26);
N-(2-tert-Butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide (Compound 27);
N-(Cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide (Compound 28);
2-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (Compound 29);
2-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Compound 29.1);
N-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Compound 30);
2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Compound 31);
2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Compound 31.1);
2-[[5-Fluoro-2-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (Compound 32);
2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl] imidazo[1,2-a]pyridine-7-carboxamide (Compound 33);
and salts and solvates of the above.

48 more elements

Compounds for treating respiratory disease

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Compounds for treating respiratory disease

Life of this patent

Abstract

Claims8