Nrf2 activator

Abstract

Provided are compounds of Formula I, or pharmaceutically acceptable salts thereof, and methods for their use and production.

1 . (canceled) 
     
     
         2 . A compound represented by Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is —CN, —C(O)R a  or C 1-8 alkyl substituted with one or more fluorine atoms; 
         R a  is H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —OR 11 , —SR 14 , —N(R 12 ) 2 , —NR 13 OR 13 , —NR 13 S(O) 2 R 13 , —NR 13 C(O)R 13 , —N(R 13 )N(R 13 ) 2 , —N(R 13 )C(O)OR 13  or —N(R 13 )C(O)N(R 13 ) 2 , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl, and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; 
         R 2  is H, halo, —NO 2 , —CN, —N 3 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —C(O)R 13 , —C(S)R 13 , —C(O)OR 13 , —C(S)SR 13 , —C(O)SR 13 , —C(S)OR 13 , —SC(O)R 13 , —OC(S)R 13 , —SC(S)R 13 , —C(O)N(R 13 ) 2 , —OR 11 , —SR 14 , —N(R 12 ) 2 , —N(R 13 )OR 13 , —N(R 13 )S(O) 2 R 13 , —N(R 13 )C(O)R 13 , —N(R 13 )N(R 13 ) 2 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —S(O) 2 R 13 , —S(O)R 13 , —S(O)N(R 13 ) 2 , —S(O) 2 N(R 13 ) 2 , —N + (R 13 ) 3 , —S + (R 13 ) 2  or —Si(R 13 ) 3 , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; 
         R 3a  is H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —C(O)R 13 , —C(O)OR 13 , —C(O)N(R 13 ) 2 , —OR 11 , —N(R 12 ) 2 , —N(R 13 )OR 13 , —N(R 13 )S(O) 2 R 13 , —N(R 13 )C(O)R 13 , —N(R 13 )N(R 13 ) 2 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —S(O)R 13 , —S(O)N(R 13 ) 2  or —S(O) 2 N(R 13 ) 2 , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; and 
         R 3b  is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —C(O)R 13 , —C(O)OR 13 , —C(O)N(R 13 ) 2 , —OR 11 , —N(R 12 ) 2 , —N(R 13 )OR 13 , —N(R 13 )S(O) 2 R 13 , —N(R 13 )C(O)R 13 , —N(R 13 )N(R 13 ) 2 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —S(O)R 13 , —S(O)N(R 13 ) 2  or —S(O) 2 N(R 13 ) 2 , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; or 
         R 3a  and R 3b  are taken together and are C 2-12 alkylene, C 2-12 alkenylene or C 2-12 alkynylene; 
         R 4  is H, halo, —NO 2 , —CN, —N 3 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —C(O)R 13 , —C(S)R 13 , —C(O)OR 13 , —C(S)SR 13 , —C(O)SR 13 , —C(S)OR 13 , —SC(O)R 13 , —OC(S)R 13 , —SC(S)R 13 , —C(O)N(R 13 ) 2 , —OR 11 , —SR 14 , —N(R 12 ) 2 , —N(R 13 )OR 13 , —N(R 13 )S(O) 2 R 13 , —N(R 13 )C(O)R 13 , —N(R 13 )N(R 13 ) 2 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —S(O) 2 R 13 , —S(O)R 13 , —S(O)N(R 13 ) 2 , —S(O) 2 N(R 13 ) 2 , —N + (R 13 ) 3 , —S + (R 13 ) 2  or —Si(R 13 ) 3 , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; 
         “ ” is either a single bond or a double bond, wherein when “ ” is a double bond, then R 5  is absent; and when “ ” is a single bond, then 
         R 5  is H, halo, —NO 2 , —CN, —N 3 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —C(O)R 13 , —C(S)R 13 , —C(O)OR 13 , —C(S)SR 13 , —C(O)SR 13 , —C(S)OR 13 , —SC(O)R 13 , —OC(S)R 13 , —SC(S)R 13 , —C(O)N(R 13 ) 2 , —OR 11 , —SR 14 , —N(R 12 ) 2 , —N(R 13 )OR 13 , —N(R 13 )S(O) 2 R 13 , —N(R 13 )C(O)R 13 , —N(R 13 )N(R 13 ) 2 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —S(O) 2 R 13 , —S(O)R 13 , —S(O)N(R 13 ) 2 , —S(O) 2 N(R 13 ) 2 , —N + (R 13 ) 3 , —S + (R 13 ) 2  or —Si(R 13 ) 3 , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; 
         R 6 , in each occurrence, is independently halo, —NO 2 , —CN, —N 3 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —C(O)R 13 , —C(S)R 13 , —C(O)OR 13 , —C(S)SR 13 , —C(O)SR 13 , —C(S)OR 13 , —SC(O)R 13 , —OC(S)R 13 , —SC(S)R 13 , —C(O)N(R 13 ) 2 , —OR 11 , —SR 14 , —N(R 12 ) 2 , —N(R 13 )OR 13 , —N(R 13 )S(O) 2 R 13 , —N(R 13 )C(O)R 13 , —N(R 13 )N(R 13 ) 2 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —S(O) 2 R 13 , —S(O)R 13 , —S(O)N(R 13 ) 2 , —S(O) 2 N(R 13 ) 2 , —N + (R 13 ) 3 , —S + (R 13 ) 2  or —Si(R 13 ) 3 ; or two R 6  attached to the same ring carbon to form an oxo, ═NR 14  or C 1-12 alkylidene, wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl, 3 to 12-membered heterocyclyl and C 1-12 alkylidene are each optionally substituted with one or more R 21 ; 
         X is NR b  or O; 
         R b  is H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —C(O)R c , —C(O)OR c , —C(O) NR c R c , —S(O) 2 R c , —S(O) 2 OR c  or —S(O) 2 NR c R c , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; 
         R c , in each occurrence, is independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl and a 3 to 12-membered heterocyclyl, wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; 
         R 11 , in each occurrence, is independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, C 1-12 acyl and —Si(R 13 ) 3 , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl, 3 to 12-membered heterocyclyl and C 1-12 acyl are each optionally substituted with one or more R 21 ; 
         R 12 , in each occurrence, is independently selected from H, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl and —Si(R 13 ) 3 , wherein the C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 ; 
         R 13 , in each occurrence, is independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl and a 3 to 12-membered heterocyclyl, wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are optionally substituted with one or more R 21 ; 
         R 14 , in each occurrence, is independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl and C 1-12 acyl, wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl, 3 to 12-membered heterocyclyl and C 1-12 acyl are each optionally substituted with one or more R 21 ; 
         R 21 , in each occurrence, is independently selected from halo, —OH, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, a 3 to 12-membered carbocyclyl and a 3 to 12-membered heterocyclyl, wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from halo, —OH and C 1-4 alkoxy; 
         n is 0 or an integer from 1 to 8; 
         p is 1 or 2; and 
         q is 1 or 2, 
         provided that the sum of p and q is not 4. 
       
     
     
         3 . (canceled) 
     
     
         7 . The compound of  claim 2 , wherein the compound is represented by 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . (canceled) 
     
     
         12 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R b  is H, C 1-12 alkyl, a 6 to 12-membered aryl, a 3-12-membered heterocyclyl, —C(O)R c , —C(O)OR c , —C(O)NR c R c , —S(O) 2 R c , —S(O) 2 OR c  or —S(O) 2 NR c R c , wherein R c , in each occurrence, is independently H, C 1-6 alkyl, a 3 to 8-membered cycloalkyl, a 3 to 8-membered heterocyclyl or a 6 to 12-membered aryl, wherein the alkyl, cycloalkyl, heterocyclyl and aryl, in each occurrence, in R b  or R c  are optionally substituted with 1 to 3 groups selected from halo, —OH, C 1-4 alkoxy, a 6 to 12-membered aryl and a 5 to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl each comprise 1 to 3 heteroatoms, wherein the heteroatoms are selected from the group consisting of N, S and O. 
     
     
         13 . (canceled) 
     
     
         21 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —CN, —CF 3  or —C(O)R a . 
     
     
         22 . (canceled) 
     
     
         25 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2  is H, —OH, halo, C 1-12 alkyl or C 1-12 alkoxy, wherein the alkyl and alkoxy are each optionally substituted with 1 to 3 groups selected from halo, —OH, C 1-4 alkoxy, a 6 to 12-membered aryl and a 5 to 12-membered heteroaryl. 
     
     
         26 . (canceled) 
     
     
         30 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3a  is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, a 3 to 12-membered carbocyclyl, a 3 to 12-membered heterocyclyl, —C(O)R 13 , —C(O)OR 13 , —C(O)N(R 13 ) 2 , —OR 11 , —N(R 12 ) 2 , —N(R 13 )OR 13 , —N(R 13 )S(O) 2 R 13 , —N(R 13 )C(O)R 13 , —N(R 13 )N(R 13 ) 2 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —S(O)R 13 , —S(O)N(R 13 ) 2  or —S(O) 2 N(R 13 ) 2 , wherein the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3 to 12-membered carbocyclyl and 3 to 12-membered heterocyclyl are each optionally substituted with one or more R 21 . 
     
     
         31 . (canceled) 
     
     
         34 . The compound of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 3a  and R 3b  are each methyl. 
     
     
         35 . (canceled) 
     
     
         37 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4  is H, —OH, halo, C 1-12 alkyl, C 1-12 alkoxy or 6 to 12-membered aryl, wherein the alkyl, alkoxy and aryl are each optionally substituted with 1 to 3 groups selected from halo, —OH, C 1-4 alkoxy, a 6 to 12-membered aryl and a 5 to 12-membered heteroaryl. 
     
     
         38 . (canceled) 
     
     
         39 . The compound of  claim 37 , or a pharmaceutically acceptable salt thereof, wherein R 4  is C 1-4 alkyl or phenyl. 
     
     
         40 . (canceled) 
     
     
         45 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein n is 2; and two R 6  are attached to the same ring carbon to form an oxo, ═NR 14  or C 1-12 alkylidene. 
     
     
         46 . (canceled) 
     
     
         56 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 1  is —CN, —CF 3  or —C(O)R a ;   R 2  is H, —OH, halo, C 1-12 alkyl or C 1-12 alkoxy, wherein the alkyl and alkoxy are each optionally substituted with 1 to 3 groups selected from halo, —OH, C 1-4 alkoxy, a 6 to 12-membered aryl and a 5 to 12-membered heteroaryl;   R 3a  is H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, —C(O)R 13 , —OR 11 , —N(R 12 ) 2  or —N(R 13 )C(O)R 13 ; and R 3b  is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, —C(O)R 13 , —OR 11 , —N(R 12 ) 2  or —N(R 13 )C(O)R 13 , wherein R 11  to R 13  are each independently H or C 1-4 alkyl; or R 3a  and R 3b  taken together with the carbon, to which they are both attached to, form a C 3-8  membered non-aromatic ring;   R 4  is H, —OH, halo, C 1-12 alkyl, C 1-12 alkoxy or 6 to 12-membered aryl, wherein the alkyl, alkoxy and aryl are each optionally substituted with 1 to 3 groups selected from halo, —OH, C 1-4 alkoxy, a 6 to 12-membered aryl and a 5 to 12-membered heteroaryl;   “ ” is a double bond;   R b  is H, C 1-12 alkyl, a 6 to 12-membered aryl, a 3-12-membered heterocyclyl, —C(O)R c , —C(O)OR c , —C(O)NR c R c , —S(O) 2 R c , —S(O) 2 OR c  or —S(O) 2 NR c R c , wherein R c , in each occurrence, is independently H, C 1-6 alkyl, a 3 to 8-membered cycloalkyl, a 3 to 8-membered heterocyclyl or a 6 to 12-membered aryl, wherein the alkyl, cycloalkyl, heterocyclyl and aryl, in each occurrence, in R b  or R c  are optionally substituted with 1 to 3 groups selected from halo, —OH, C 1-4 alkoxy, a 6 to 12-membered aryl and a 5 to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl each comprise 1 to 3 heteroatoms, wherein the heteroatoms are selected from the group consisting of N, S and O; and   n is 0.   
     
     
         57 . (canceled) 
     
     
         68 . The compound of claim  67 , wherein the compound is represented by Formula XIII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         69 . The compound of claim  61 , wherein the compound is represented by Formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         71 . A pharmaceutical composition comprising at least one compound of  claim 2 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         72 . (canceled) 
     
     
         73 . A method of treating a disease caused by oxidative stress in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, thereby treating the disease in the subject. 
     
     
         74 . A method for treating a disorder in a subject in need thereof, wherein the disorder is selected from the group consisting of a neurodegenerative disease, inflammation/an inflammatory disease, an autoimmune disease, an ischemic fibrotic disease, a cancer, premature aging, a cardiovascular disease, a liver disease, a hemoglobinopathy, thalassemia (e.g., beta-thalassemia) and a metabolic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, thereby treating the disorder in the subject. 
     
     
         75 . A method for treating sickle cell disease or thalassemia (e.g., beta-thalassemia) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, thereby treating sickle cell disease or thalassemia (e.g., beta-thalassemia). 
     
     
         77 . A method for treating a neurodegenerative disorder in a subject in need thereof, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis, diffuse Lewy body disease, chorea-acanthocytosis, primary lateral sclerosis, multiple sclerosis, frontotemporal dementia, Friedreich's ataxia and epilepsy, the method comprising administering to the subject a therapeutically effective amount of a compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, thereby treating the neurodegenerative disorder. 
     
     
         79 . A compound, which is (8aR)-2,5,5-trimethyl-1,6-dioxo-8a-phenyl-3H-isoquinoline-7-carbonitrile and is represented by the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         80 . A compound, which is (8aS)-2,5,5-trimethyl-1,6-dioxo-8a-phenyl-3H-isoquinoline-7-carbonitrile represented by the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.