Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes

Abstract

The present invention provides novel pyrazoles that are useful as cannabinoid receptor antagonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, and/or cardiometabolic disorders.

1 . A compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C 1-6  alkyl, halogen, CF 3 , O—C 1-6  alkyl, NO 2 , NR 2 , O(CH 2 ) n CO 2 R, OCH 2 CH═CHCO 2 R, CH 2 O(CH 2 ) n CO 2 R, CH 2 OCH 2 CH═CHCO 2 R, O(CH 2 ) n PO(OR) 2 , CH 2 O(CH 2 ) n PO(OR) 2 , NR a (CH 2 ) n CO 2 R, NR a (CH 2 ) n PO(OR) 2 , NR a CH 2 CH═CHCO 2 R, NR a SO 2 R, NR a CO(CH 2 ) n CO 2 R, NR a CO(CH 2 ) n CONR a   2 , O(CH 2 ) n C 6 H 4 CO 2 R, O(CH 2 ) n C 6 H 4 (CH 2 ) n CO 2 R, CH 2 O(CH 2 ) n C 6 H 4 CO 2 R, O(CH 2 ) n C 6 H 4 CONR a   2 , O(CH 2 ) n C 6 H 4 (CH 2 ) n CONR a   2 , O(CH 2 ) n C 6 H 4 -tetrazole, CH 2 O(CH 2 ) n C 6 H 4 CONR a   2 , CH 2 O(CH 2 ) n C 6 H 4 -tetrazole, O(CH 2 ) n C 6 H 4 (CH 2 ) n -tetrazole, NR a (CH 2 ) n C 6 H 4 CO 2 R, CH 2 NR a (CH 2 ) n C 6 H 4 CO 2 R, NR a (CH 2 ) n C 6 H 4 (CH 2 ) n CO 2 R, NR a (CH 2 ) n C 6 H 4 CONR a   2 , CH 2 NR a (CH 2 ) n C 6 H 4 CONR a   2 , NR a (CH 2 ) n C 6 H 4 (CH 2 ) n CONR a   2 , NR a (CH 2 ) n C 6 H 4 -tetrazole, CH 2 NR a (CH 2 ) n C 6 H 4 -tetrazole, NR a (CH 2 ) n C 6 H 4 (CH 2 ) n -tetrazole, C(NH)NR 2 , (CH 2 ) n C(NH)NR 2 , O(CH 2 ) n CONR 2 , O(CH 2 ) n C(NH)NR 2 , CH 2 O(CH 2 ) n CONR a   2 , NR a (CH 2 ) n CONR a   2 , OCH 2 CH═CHCONR a   2 , CH 2 OCH 2 CH═CHCONR a   2 , NR a CH 2 CH═CHCONR 2 , (CH 2 ) m -tetrazole, O(CH 2 ) n -tetrazole, O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and SO 2 NHCH 3 ; 
         Z is selected from: H, C 1-6  alkyl, OH, O—C 1-6  alkyl, O(CH 2 CH 2 O) p R, OC(O)—C 1-6  alkyl, O(CH 2 ) n CO 2 R, OCH 2 CH═CHCO 2 R, O(CH 2 ) n PO(OR) 2 , O(CH 2 ) n CONH 2 , O(CH 2 ) n C(NH)NH 2 , OCH 2 CH═CHCONH 2 , O(CH 2 ) n -phenyl-(CH 2 ) m CO 2 R, and O(CH 2 ) n -phenyl-(CH 2 ) m -tetrazole; 
         Q is selected from: H, C 1-6  alkyl, (CH 2 ) n -aryl, (CH 2 CH 2 O) p R, (CH 2 ) n -heteroaryl, (CH 2 ) n -tetrazole, —CHA(CH 2 ) m C(O)NR 2 , CHA(CH 2 ) m CO 2 R, (CH 2 ) n -phenyl-(CH 2 ) m CO 2 R, (CH 2 ) n -phenyl-(CH 2 ) m CONH 2 , and (CH 2 ) n -phenyl-(CH 2 ) m -tetrazole, wherein the heteroaryl, phenyl, and aryl are substituted with 0-3 groups selected from H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, and NO 2 ; 
         M is C═O or SO 2 ; 
         R is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         R a  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         A is selected from H, C 1-6  alkyl, (CH 2 ) m C 3-6 -cycloalkyl, CH 2 OH, CH(CH 3 )OH, and (CH 2 ) m -phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, and NO 2 ; 
         p is selected from 2-12; 
         m is selected from 0, 1, 2, and 3; and, 
         n is selected from 1, 2, and 3; 
         provided that at least one of the following is satisfied:
 (a) at least one of X, Y, X′, Y′, X″, and Y″ is other than H, C 1-6  alkyl, halogen, CF 3 , O—C 1-6  alkyl, NO 2 , and NR 2 ; 
 (b) Z is other than H, C 1-6  alkyl, OH, O—C 1-6  alkyl, acetyloxy, and propionyloxy; or, 
 (c) Q is other than H, C 1-6  alkyl, (CH 2 ) n -heteroaryl, and (CH 2 ) n -aryl. 
 
       
     
     
         2 . A compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 at least one of X, Y, X′, Y′, X″, and Y″ is independently selected from: O(CH 2 ) n CO 2 R, OCH 2 CH═CHCO 2 R, CH 2 O(CH 2 ) n CO 2 R, CH 2 OCH 2 CH═CHCO 2 R, O(CH 2 ) n PO(OR) 2 , CH 2 O(CH 2 ) n PO(OR) 2 , NR a (CH 2 ) n CO 2 R, NR a (CH 2 ) n PO(OR) 2 , NR a CH 2 CH═CHCO 2 R, NR a CO(CH 2 ) n CONR a   2 , NR a SO 2 CH 3 , NR a CO(CH 2 ) n CO 2 R, O(CH 2 ) n C 6 H 4 CO 2 R, O(CH 2 ) n C 6 H 4 (CH 2 ) n CO 2 R, CH 2 O(CH 2 ) n C 6 H 4 CO 2 R, O(CH 2 ) n C 6 H 4 CONH 2 , O(CH 2 ) n C 6 H 4 (CH 2 ) n CONR a   2 , O(CH 2 ) n C 6 H 4 -tetrazole, CH 2 O(CH 2 ) n C 6 H 4 CONH 2 , CH 2 O(CH 2 ) n C 6 H 4 -tetrazole, O(CH 2 ) n C 6 H 4 (CH 2 ) n -tetrazole, NR a (CH 2 ) n C 6 H 4 CO 2 R, CH 2 NR a (CH 2 ) n C 6 H 4 CO 2 R, NR a (CH 2 ) n C 6 H 4 (CH 2 ) n CO 2 R, NR a (CH 2 ) n C 6 H 4 CONR a   2 , CH 2 NR a (CH 2 ) n C 6 H 4 CONR a   2 , NR a (CH 2 ) n C 6 H 4 (CH 2 ) n CONR a   2 , NR a (CH 2 ) n C 6 H 4 -tetrazole, CH 2 NR a (CH 2 ) n C 6 H 4 -tetrazole, NR a (CH 2 ) n C 6 H 4 (CH 2 ) n -tetrazole, C(NH)NR 2 , (CH 2 ) n C(NH)NR 2 , O(CH 2 ) n CONR a   2 , O(CH 2 ) n C(NH)NH 2 , CH 2 O(CH 2 ) n CONR a   2 , NR a (CH 2 ) n CONH 2 , OCH 2 CH═CHCONR a   2 , CH 2 OCH 2 CH═CHCONR a   2 , NR a CH 2 CH═CHCONR a   2 , (CH 2 ) m -tetrazole, O(CH 2 ) n -tetrazole, O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and SO 2 NHCH 3 ;   the other of X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, NO 2 , and NR 2 ;   R is independently selected from H, C 1-4  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl;   R a  is independently selected from H, C 1-4  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl;   Z is selected from: H, C 1-4  alkyl, OH, O—C 1-4  alkyl, acetyloxy, and propionyloxy;   Q is selected from: is selected from H, C 1-4  alkyl, (CH 2 CH 2 O) p R, (CH 2 ) n -heteroaryl, and (CH 2 ) m -aryl, wherein the heteroaryl and aryl are substituted with 0-3 groups selected from H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, and NO 2 ;   M is C═O or SO 2 ;   p is selected from 2-12;   m is independently selected from 0, 1, 2, and 3; and,   n is independently selected from 1, 2, and 3.   
     
     
         3 . A compound of  claim 2 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, NO 2 , O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and NR 2 ;   Z is selected from: O(CH 2 CH 2 O) p R, O(CH 2 ) n CO 2 R, OCH 2 CH═CHCO 2 R, O(CH 2 ) n PO(OR) 2 , O(CH 2 ) n CONH 2 , O(CH 2 ) n C(NH)NH 2 , OCH 2 CH═CHCONH 2 , O(CH 2 ) n -phenyl-(CH 2 ) m CO 2 R, and O(CH 2 ) n -phenyl-(CH 2 ) m -tetrazole;   Q is selected from: H, C 1-4  alkyl, (CH 2 CH 2 O) p R, (CH 2 ) n -heteroaryl, and (CH 2 ) n -aryl, wherein the heteroaryl and aryl are substituted with 0-3 groups selected from H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, and NO 2 ;   M is C═O or SO 2 ;   R is independently selected from H, C 1-4  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl;   p is selected from 2-12;   m is independently selected from 0, 1, 2, and 3; and,   n is independently selected from 1, 2, and 3.   
     
     
         4 . A compound of  claim 3 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 X, Y, X′, Y′, X″, and Y″ are individually selected from the following: H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, NO 2 , O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and NR 2 ;   Z is selected from: H, C 1-4  alkyl, OH, O—C 1-4  alkyl, acetyloxy, and propionyloxy;   Q is selected from: —(CH 2 ) n -tetrazole, —CHA(CH 2 ) m C(O)NHR, CHA(CH 2 ) m CO 2 R, (CH 2 ) n -phenyl-(CH 2 ) m CO 2 R, (CH 2 ) n -phenyl-(CH 2 ) m CONH 2 , (CH 2 ) n -phenyl-(CH 2 ) m -tetrazole, and (CH 2 CH 2 O) p R;   M is C═O or SO 2 ;   A is selected from H, C 1-4  alkyl, (CH 2 ) m —C 3-6 -cycloalkyl, CH 2 OH, CH(CH 3 )OH, (CH 2 ) m -phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, and NO 2 ;   R is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl;   p is selected from 2-12;   m is independently selected from 0, 1, 2, and 3; and,   n is independently selected from 1, 2, and 3.   
     
     
         5 . A compound of  claim 1 , wherein the compound is selected from the compounds of Table 1a, 1b, 1c, 1d, 2, and 3 or a stereoisomer or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A pharmaceutical composition, comprising: a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         7 . A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of according to  claim 1 , wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof. 
     
     
         8 . The method of  claim 7 , wherein the cardiometabolic disorder is selected from hypertension and dyslipidemia. 
     
     
         9 . The method of  claim 8 , wherein the dyslipidemia is selected from low levels of high-density lipoprotein, high levels of low-density lipoprotein, and high levels of triglycerides. 
     
     
         10 . A method of treating a co-morbidity of obesity, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         11 . The method of  claim 10 , wherein the co-morbidity is selected from diabetes, Metabolic Syndrome, dementia, and heart disease. 
     
     
         12 . The method of  claim 10 , wherein the co-morbidity is selected from hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; accident proneness; increased risks with surgeries; osteoarthritis; high cholesterol; and, increased incidence of malignancies of the ovaries, cervix, uterus, breasts, prostrate, and gallbladder. 
     
     
         13 . The method of  claim 7 , wherein the diabetes disorder is selected from: Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulin resistance. 
     
     
         14 . A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of
 a. a compound of according to  claim 1 , and   b. a second therapeutic agent;   wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof and the second therapeutic agent is useful for treating the disease.   
     
     
         15 . The method of  claim 14 , wherein the second component is selected from the appetite suppressant sibutramine and the gut lipase inhibitor orlistat. 
     
     
         16 . The method of  claim 15 , wherein the second component is useful for treating diabetes.