Nrf2 REGULATORS

Abstract

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators.

What is claimed is: 
     
         1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein, 
         B is benzotriazolyl, phenyl or triazolopyridinyl, each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, —O—C 1-3 alkyl, CN, —(CH 2 ) 2 —O—(CH 2 ) 2 —OR 4  and halo; 
         D is —C(O)OH, —C(O)NHSO 2 CH 3 , —SO 2 NHC(O)CH 3 , 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl; 
         R 1  is independently hydrogen, C 1-3 alkyl, F, or the two R 1  groups together with the carbon to which they are attached form a cyclopropyl group; 
         R 2  is hydrogen, methyl, CF 3 , or halo; 
         R 4  is hydrogen or —C 1-3 alkyl; 
         Linker is —CH 2 —, —CH 2 —N(-cyclopropyl)-CH 2 —, —CH 2 —N(CH 3 )—CH 2 — or —N—(CH 3 )—CH 2 —; 
         A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl, oxazepane or morpholinyl; 
         each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, C 3-6 spirocycloalkyl, halo, CN, —O—C 1-3 alkyl, —CH 2 —O—CH 3 , and OH; 
         and the piperidinyl is unsubstituted or additionally substituted by one or two substituents independently selected from pyrazolyl, —CH 2 pyrazolyl, and oxadiazolyl, each of which is unsubstituted or further substituted by one or two —C 1-3 alkyl, or, when A is piperidinyl, it is unsubstituted or substituted by —SO 2 R, wherein R is —C 1-3 alkyl, phenyl or C 3-7 cycloalkyl; 
         and the oxazepane is unsubstituted or substituted by 1 or 2 substituents independently selected from —C 1-3 alkyl and —C 3-7 cycloalkyl; 
         and the morpholinyl is unsubstituted or substituted by a phenyl which itself is unsubstituted or substituted by one or two substituents independently selected from C 1-3  alkyl and —O—C 1-3 alkyl; 
         and the pyrrolidinyl is unsubstituted or substituted by a triazolyl group which itself is unsubstituted or substituted by —C 1-3 alkyl; 
         and the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups are each unsubstituted or substituted by one or two substituents independently selected from —CH 2 —C 4-7 cycloalkyl, —CH2-05_7 heterocycloalkyl, —CH 2 -azabicycloheptanyl, —CH 2 -oxepane and —CH 2 -azabicyclohexanyl, each of which, including the —CH 2 —, is unsubstituted or further substituted by 1 or 2 substituents independently selected from —C 1-3  alkyl and F; and 
         X is independently CH or N; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein, B is benzotriazolyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl and halo;
 D is —C(O)OH, —C(O)NHSO 2 CH 3 , or tetrazolyl; 
 R 1  is independently hydrogen or methyl or the two R 1  groups together with the carbon to which they are attached form a cyclopropyl group; 
 R 2  is methyl or halo; 
 Linker is —CH 2 —; 
 A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, or tetrahydrobenzodiazepinyl; 
 each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3  alkyl, halo, CN, and —OC 1-3 alkyl; 
 and the piperidinyl is unsubstituted or additionally substituted by pyrazolyl or oxadiazolyl each of which is unsubstituted or further substituted by —C 1-3 alkyl or, when A is piperidinyl, it is unsubstituted or substituted by —SO 2 R, wherein R is —C 1-3 alkyl, phenyl or C 3-7 cycloalkyl; 
 and each of the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups is independently unsubstituted or additionally substituted by one or two substituents independently selected from —CH 2 —C 4-7 cycloalkyl, —CH 2 -oxepane and —CH 2 —C 5-7 ; and 
 X is independently CH or N; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . The compound of  claim 1 , wherein,
 B is benzotriazolyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl and halo;   D is —C(O)OH;   R 1  is independently hydrogen or methyl or the two R 1  groups together with the carbon to which they are attached form a cyclopropyl group;   R 2  is methyl or halo;   Linker is —CH 2 —;   A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, or tetrahydrobenzodiazepinyl;   each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3  alkyl, halo, CN, and —OC 1-3 alkyl;   and the piperidinyl is unsubstituted or additionally substituted by pyrazolyl or oxadiazolyl each of which is unsubstituted or further substituted by —C 1-3 alkyl or, when A is piperidinyl, it is unsubstituted or substituted by —SO 2 R, wherein R is —C 1-3 alkyl, phenyl or C 3-7 cycloalkyl;   and each of the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups is unsubstituted or additionally substituted by one or two substituents independently selected from —CH 2 —C 4-7 cycloalkyl, —CH 2 -oxepane and —CH 2 —C 5-7 ; and   X is CH;   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound of  claim 1 , wherein,
 B is benzotriazolyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl and halo;   D is —C(O)OH;   R 1  is independently hydrogen or C 1-3 alkyl;   R 2  is methyl or chloro;   Linker is —CH 2 —;   A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, or tetrahydrobenzodiazepinyl;   each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3  alkyl, halo, CN, and —OC 1-3 alkyl;   and the piperidinyl is unsubstituted or additionally substituted by pyrazolyl or oxadiazolyl each of which is unsubstituted or further substituted by —C 1-3 alkyl or, when A is piperidinyl, it unsubstituted or substituted by —SO 2 R, wherein R is —C 1-3 alkyl, phenyl or C 3-7 cycloalkyl;   and the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups are each unsubstituted or additionally substituted by 1 or 2 substituents independently selected from —CH 2 —C 4-7 cycloalkyl, —CH 2 -oxepane and —CH 2 —C 5-7 ; and   X is CH;   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . A compound which is:
 (S)-Methyl 3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;   (2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;   (2R,3S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-f][1,4]oxazepin-4(51-)-yl)methyl)-4-methylphenyhpropionic acid;   rel-(R)-3-(1,4-dimethyl-1H-benzo[d]-[1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)-propanoic acid;   rel-(R)-3-(4-chloro-3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid;   (S)-3-(4-chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   (S)-3-(3-(((R)-8-Chloro-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic acid;   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic acid;   (S)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;   (R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;   3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;   (2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;   (2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;   (2S,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid;   (2R,3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid;   (R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   (2R,3S)-3-(7-Chloro-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid;   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;   3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)pronoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;   (2R,3S)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid;   (2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-N-(methylsulfonyl)propenamide;   (S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl) propanoic acid;   (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyhpropanoic acid; or (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid, or a pharmaceutically acceptable salt thereof.   
     
     
         6 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable excipients. 
     
     
         7 . A method of treating respiratory and non-respiratory disorders, including COPD, asthma, fibrosis, chronic asthma, acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, acute kidney injury (AKI), kidney disease or malfunction seen during kidney transplantation, Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodeling, cardiac arrhythmias, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diabetic cardiomyopathy, Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or other inflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topical effects of radiation, immunosuppression due to radiation exposure, Preeclampsia, and high altitude sickness, which comprises administering to a human in need thereof, a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, of  claim 1 . 
     
     
         8 . The method of  claim 7  wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally. 
     
     
         9 . The method of  claim 7  wherein the compound, or a pharmaceutically acceptable salt thereof, is administered intravenously. 
     
     
         10 . The method of  claim 7  wherein the disease is heart failure.