Glp-1r agonists and uses thereof

Abstract

The present disclosure provides compounds of Formula (I) and pharmaceutical compositions thereof, for use in, e.g. treating type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease.

1 . (canceled) 
     
     
         2 . A compound represented by structural formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
 X 1 , X 2 , X 3 , X 4 , and X 5  are each independently selected from N and CH; wherein no more than three of X 1 , X 2 , X 3 , X 4 , and X 5  are N and wherein ring A does not contain 3 nitrogen ring atoms at 3 contiguous positions; 
 W is selected from O, S, CR 5 R 6 , and NR 5′ ; 
 ring B is 6 membered heteroaryl or phenyl, wherein Y 1 , Y 3 , Y 4 , and Y 5  are each independently selected from N or CH; wherein there are no more than 3 nitrogen ring atoms in ring B and ring B does not contain 3 nitrogen ring atoms at 3 contiguous positions; 
 T 2  is selected from N and C; 
 T 4  is selected from N, NR 4 , O, S, and CR 4 ; 
 T 6 , T 7 , and T 8  are each independently selected from N and CR 4 ; 
 wherein no more than 4 of T 2 , T 4 , T 6 , T 7 , and T 8  are selected from N, O, and S; 
 EE is —COOH or a carboxylic group surrogate, optionally, the carboxylic group surrogate is: 
 
       
         
           
           
               
               
           
         
         each R a  and R b  are independently selected from hydrogen, deuterium, halogen, —CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NR 5′ R 6′ , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1 -C 6  alkyl or C 1 -C 6  alkoxy represented by R a /R b  is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C 3 -C 6  saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R a /R b  or in the group represented by R a /R b  is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C 1 -C 3  alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and C 1 -C 3  alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and NR 5′ R 6′ ; 
         each R c  and R d  are independently selected from hydrogen, deuterium, halogen, —CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NR 5′ R 6′ , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1 -C 6  alkyl or C 1 -C 6 alkoxy represented by R c /R d  is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C 3 -C 6  saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R c /R d  or in the group represented by R c /R d  is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, and NR 5′ R 6′ ; 
         each R 1  is independently selected from H, halogen, —CN, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, NR 5′ R 6′ , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl represented by R 1  is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , and saturated or partially saturated C 3 -C 6  cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R 1  or in the group represented by R 1  is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C 1 -C 3  alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and C 1 -C 3  alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and NR 5′ R 6′ . 
         each R 2  is independently selected from H, halogen, —CN, OH, oxo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NR 5′ R 6′ , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1 -C 6  alkyl, C 1 -C 6  alkoxy represented by R 2  is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , and saturated or partially saturated C 3 -C 6  cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R 2  or in the group represented by R 2  is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C 1 -C 3  alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and C 1 -C 3  alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and NR 5′ R 6′ ; 
         each R 3  is independently selected from H, halogen, —CN, OH, oxo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NR 5′ R 6′ , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1 -C 6  alkyl or C 1 -C 6  alkoxy represented by R 3  is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , and saturated or partially saturated C 3 -C 6  cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , and OCH 2 CH 3 ); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R 3  or in the group represented by R 3  is optionally substituted with one or more groups selected from halogen, oxo (as appropriate), CN, OH, C 1 -C 3  alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and C 1 -C 3  alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and NR 5′ R 6′ ; 
         each R 4  is H, deuterium, halogen, OH, —CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or NR 5′ R 6′ , wherein the C 1 -C 6  alkyl and C 1 -C 6  alkoxy represented by R 4  is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , and saturated or partially saturated C 3 -C 6  cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , and OCH 2 CH 3 ); 
         R 5′  and R 6′  are each independently selected from hydrogen and C 1 -C 6  alkyl; 
         m is an integer selected from 0, 1, 2, 3, and 4, 
         n is an integer selected from 0, 1, 2, 3, and 4, and 
         o is an integer selected from 0, 1, 2, 3, 4, and 5. 
       
     
     
         3 . The compound according to according to  claim 2 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
 W is O, NH or CH 2 ;   R a  is H, CH 3 , or CF 3 ;   R b  is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NR 5′ R 6′ , 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated or partially saturated cycloalkyl and 3-7 membered saturated or partially saturated heterocyclyl, wherein the C 1 -C 6  alkyl or C 1 -C 6  alkoxy represented by R b  is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C 3 -C 6  saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R b  or in the group represented by R b  is optionally substituted with one or more groups selected from halogen, oxo (when R b  is non-aromatic), CN, OH, C 1 -C 3  alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and C 1 -C 3  alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and NR 5′ R 6′ ;   R c  is selected from hydrogen, halogen, and C 1 -C 4  alkyl optionally substituted with one or more groups selected from halogen and hydroxy;   R is H, F, CH 3 , or CF 3 ; and   each R 2  and R 3  are independently selected from H, halogen, —CN, OH, oxo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NR 5′ R 6′ , wherein the C 1 -C 6  alkyl or C 1 -C 6  alkoxy represented by R 2  and/or R 3  is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , and saturated or partially saturated C 3 -C 6  cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , and OCH 2 CH 3 );   each R 4  is independently selected from H, deuterium, halogen, OH, —CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and NR 5′ R 6′ , wherein the C 1 -C 6  alkyl and C 1 -C 6  alkoxy represented by R 4  is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , and saturated or partially saturated C 3 -C 6  cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , and OCH 2 CH 3 ); and   o is an integer selected from 0, 1, 2, 3, and 4.   
     
     
         4 . The compound according to  claim 3 , wherein the compound is represented by structural formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
 EE is —COOH; 
 each R 2  is independently selected from halogen, —CN, OH, C 1 -C 2  alkyl, C 1 -C 2  haloalkyl, and C 1 -C 2  alkoxy; 
 each R 3  is independently selected from halogen, CN, OH, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy, and NR 5′ R 6′ ; 
 each R 4  is independently selected from H, F, Cl, methyl, and methoxy. 
 
     
     
         5 . The compound according to  claim 4 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein n is an integer selected from 0, 1, 2, 3, and 4, as appropriate. 
     
     
         6 . The compound according to  claim 5 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is 
       
         
           
           
               
               
           
         
       
       each R 1  is independently selected from halogen, OH, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  hydroxyalkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkoxy, C 1 -C 4  hydroxyalkoxy, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, —NH 2 , —NHC 1 -C 4  alkyl, —N(C 1 -C 4  alkyl) 2 ; and m is an integer selected from 0, 1, and 2. 
     
     
         7 . (canceled) 
     
     
         8 . The compound according to  claim 6 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein R b  is 
       
         
           
           
               
               
           
         
       
       each of which is optionally substituted with 1 or 2 groups selected from halogen, oxo (when R b  is non-aromatic), CN, NR 5′ R 6′ , C 1 -C 4  alkyl, and C 1 -C 4  alkoxy, wherein the C 1 -C 4  alkyl or C 1 -C 4  alkoxy in the group represented by R b  is optionally substituted with 1 or 2 groups selected from F, OH, and OCH 3 . 
     
     
         9 . The compound according to  claim 8 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein 
       
         
           
           
               
               
           
         
       
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The compound according to  claim 9 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is 
       
         
           
           
               
               
           
         
       
       each R 1  is independently selected from halogen, OH, CN, C 1 -C 2  alkyl, C 1 -C 2  haloalkyl, C 1 -C 2  hydroxyalkyl, C 1 -C 2  alkoxy, C 1 -C 2 haloalkoxy, C 1 -C 2  hydroxyalkoxy, and C 2 -C 4  alkynyl; and m is an integer selected from 0, 1, and 2. 
     
     
         13 . The compound according to  claim 12 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound according to  claim 13 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 14 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 2  is independently selected from halogen; and n is an integer selected from 0, 1, and 2. 
     
     
         16 . The compound according to  claim 15 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 3  is F, Cl or CH 3 ; and o is 0, 1, or 2. 
     
     
         17 . The compound according to  claim 16 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound according to  claim 17 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound according to  claim 18 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         20 . (canceled) 
     
     
         21 . A pharmaceutical composition comprising the compound of  claim 2 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, and a pharmaceutically acceptable excipient. 
     
     
         22 . A method of treating cardiometabolic and associated diseases comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 2  or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the disease is T1D, T2DM, pre-diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity, eating disorders, weight gain from use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's Disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome Crohn's disease, colitis, irritable bowel syndrome, prevention or treatment of Polycystic Ovary Syndrome and treatment of addiction. 
     
     
         23 . (canceled)