IP Library › Granted Patent US 8,138,216

Granted Patent B2

US 8,138,216 · App. 12/650,947 · Granted Mar 20, 2012

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

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Quick Facts

Patent No.: US 8,138,216
App. No.: 12/650,947
Granted: Mar 20, 2012
Kind: B2

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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, hepatic disorders, and/or cardiometabolic disorders.

Claims (465)

1. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is selected from obesity, diabetes, dyslipidemia, atherosclerosis, hypertension, stroke, heart attack, cirrhosis, fatty liver disease, and a combination 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, O(CH 2 ) n CN, 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, CONHOH, C(NH)NR a 2 , (CH 2 ) n C(NH)NR a 2 , O(CH 2 ) n CONR a 2 , O(CH 2 ) n C(NH)NR a 2 , O(CH 2 ) n C(NOH)NR a 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 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 ;

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 CONR a 2 , O(CH 2 ) n C(NH)NH 2 , O(CH 2 ) n C(NOH)NR a 2 , OCH 2 CH═CHCONR a 2 , O(CH 2 ) n -phenyl-(CH 2 ) m CO 2 R, and O(CH 2 ) n -phenyl-(CH 2 ) m -tetrazole;

Z′ is selected from H, CO 2 R, and CONR a 2 ;

Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) n CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 3 R, (CH 2 ) m CHA(CH 2 ) m C(NH)NH 2 , (CH 2 ) m CHA(CH 2 ) m C(NOH)NH 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;

provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

A is selected from H, C 1-6 alkyl, (CH 2 ) m C 3-6 -cycloalkyl, OH, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, (CH 2 ) n CO 2 R b , (CH 2 ) n C(O)NR b 2 , 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 ;

alternatively, Q is CHA(CH 2 ) m C(O)NR 2 or CHA(CH 2 ) m CO 2 R, and (a) A is selected from OH, (CH 2 ) n CO 2 R b , and (CH 2 ) n C(O)NR b 2 ; (b) R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ; or (c) both (a) and (b);

A″ is C 1-6 alkyl;

M is C═O or SO 2 ;

R is independently selected from H, (CH 2 ) m (CHR b ) n (CH 2 ) m OH, CH(CH 2 OH) 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R a is independently selected from H, (CH 2 ) m (CHR) n (CH 2 ) m OH, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, 3, and 4; and,

n is selected from 1, 2, 3, and 4.

2. The method of claim 1 , wherein: M is SO 2 .

3. The method of claim 1 , wherein the compound is of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof:

4. The method of claim 1 , wherein the compound is of formula Ib or a stereoisomer or pharmaceutically acceptable salt thereof:

5. The method of claim 1 , wherein the compound is of formula Ic or a stereoisomer or pharmaceutically acceptable salt thereof:

6. The method of claim 1 , wherein the compound is a compound of formula Ia 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 CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) n CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;

provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

A is selected from H, C 1-4 alkyl, (CH 2 ) m C 3-6 -cycloalkyl, OH, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, (CH 2 ) n CO 2 R b , (CH 2 ) n C(O)NR b 2 , 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 ;

alternatively, Q is CHA(CH 2 ) m C(O)NR 2 or CHA(CH 2 ) m CO 2 R, and A is OH or (CH 2 ) n CO 2 R b or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;

R is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, and 8;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

7. The method of claim 6 , wherein:

Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;

provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

alternatively, Q is CHA(CH 2 ) m C(O)NR 2 and A is OH or (CH 2 ) n CO 2 R b or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;

M is SO 2 ;

R is independently selected from H and C 1-4 alkyl;

R b is independently selected from H and C 1-4 alkyl;

m is independently selected from 0, 1, and 2; and,

n is independently selected from 1 and 2.

8. The method of claim 1 , wherein the compound is a compound of formula Ib 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;

provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

alternatively, Q is CHA(CH 2 ) m C(O)NR 2 or CHA(CH 2 ) m CO 2 R, and A is OH or (CH 2 ) n CO 2 R b or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;

R is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, and 8;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

9. The method of claim 8 , wherein:

provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

alternatively, Q is CHA(CH 2 ) m C(O)NR 2 and A is OH or (CH 2 ) n CO 2 R b or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;

M is SO 2 ;

R is independently selected from H and C 1-4 alkyl;

R b is independently selected from H and C 1-4 alkyl;

m is independently selected from 0, 1, and 2; and,

n is independently selected from 1 and 2.

10. The method of claim 1 , wherein the compound is selected from Table B or a stereoisomer or a pharmaceutically acceptable salt thereof:

TABLE B

Number

Y″

X″

CH 2 CH 2 CH(OH)CO 2 Me

4-Cl

CH(CH 2 CO 2 tBu)CO 2 Me

4-Cl

C(CH 3 ) 2 CO 2 H

4-Cl

C(CH 3 ) 2 CONH—

4-Cl

CH(CH 3 )CO 2 Me

CH(CH(CH 3 ) 2 )—

4-OMe

CONHCH 2 CH 2 OH

CH 2 CH(OH)CH 2 CONH 2

4-Cl

CHCH(CH 3 ) 2 CONH—

4-Cl

CH(CH 2 OH) 2

CH 2 CH 2 CH(OH)CONH 2

4-Cl

CHCH(CH 3 ) 2 CONH—

4-OMe

CH(CH 2 OH) 2

CH(CH 2 CONH 2 )CONH 2

4-Cl

CH 2 CONHCH 2 CONH 2

4-Cl

CH 2 CONHCH 2 CONH 2

4-OMe

CH 2 CONH—

4-OMe

CH(CHCH 3 OH)CONH 2

CHCH 3 CONH—CH 2 CONH 2

4-Cl

CHCH 3 CONH—CH 2 CONH 2

4-OMe

CHCH(CH 3 ) 2 CONH—

4-Cl

CH 2 CONH 2

CHCH(CH 3 ) 2 CONH—

4-Cl

CHCH 3 CONH 2

CHCH 3 CONH—

4-Cl

CHCH 2 OHCONH 2

CHCH 3 CONH—CHCH 3 CONH 2

4-Cl

CH 2 CH 2 SO 2 NH 2

4-Cl

Cl.

11. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound selected from the compounds of Table A and C or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the disease is selected from obesity, diabetes, dyslipidemia, atherosclerosis, hypertension, stroke, heart attack, cirrhosis, fatty liver disease, and a combination thereof:

TABLE A

Number

Y″

X″

CH(CH 3 )CH 2 CO 2 Et

4-Cl

CH(CH 3 )CH 2 CO 2 H

4-Cl

CH 2 CO 2 Me

4-Cl

CH 2 CO 2 H

4-Cl

CH(CH 3 )CO 2 Me

4-Cl

CH(CHOHCH 3 )CO 2 Me

4-Cl

CH(C(CH 3 ) 3 )CO 2 Me

4-Cl

CH 2 CO 2 Me

4-OMe

3-OMe

CH 2 CO 2 Me

4-OMe

3-Cl

CH(CH 2 OH)CO 2 Me

4-Cl

CH 2 CONHCH 2 CO 2 Me

4-Cl

CH(CH 3 )CONH—

4-Cl

CH 2 CO 2 Me

CH(CH(CH 3 ) 2 )CONH—

4-Cl

CH 2 CO 2 Me

CH 2 CONHCH 2 CO 2 Me

4-OMe

CH 2 CONH 2

4-Cl

CH(CH 3 )CONH 2

4-Cl

CH 2 CH 2 CONH 2

4-Cl

CH(CH 3 )CH 2 CONH 2

4-Cl

CH(C(CH 3 ) 3 )CONH 2

4-Cl

CH(CH(CH 3 ) 2 )CONH 2

4-Cl

CHCH(CH 3 ) 2 )—

4-Cl

CONHCH 3

CH(CHOHCH 3 )CONH 2

4-Cl

CH 2 CONH 2

4-OMe

CH(CH 3 )CONH 2

4-OMe

CH(CH 3 )CONH 2

4-OCH 2 —

C(CH 3 ) 2 CONH 2

4-Cl

CH 2 CH(CH 3 )CONH 2

4-Cl

CH(CH 3 )CONH 2

4-OMe

CH(CH 3 )CONH 2

4-OMe

3-Cl

CH 2 CONH 2

4-Cl

OMe

CH(CH(CH 3 ) 2 )CONH 2

3-OMe

CH 2 CH 2 CONH 2

4-Cl

TABLE C

Number

Y″

X″

4-OCH 2 CO 2 Et

4-CONHOH

Cl.

12. The method of claim 1 , wherein the disorder is dyslipidemia.

13. The method of claim 12 , wherein the dyslipidemia is selected from low levels of high-density lipoprotein, high levels of low-density lipoprotein, high levels of triglycerides, and a combination thereof.

14. 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 formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the co-morbidity is selected from diabetes, dementia, and heart disease:

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, O(CH 2 ) n CN, 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, CONHOH, C(NH)NR a 2 , (CH 2 ) n C(NH)NR a 2 , O(CH 2 ) n CONR a 2 , O(CH 2 ) n C(NH)NR a 2 , O(CH 2 ) n C(NOH)NR a 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 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 ;

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 CONR a 2 , O(CH 2 ) n C(NH)NH 2 , O(CH 2 ) n C(NOH)NR a 2 , OCH 2 CH═CHCONR a 2 , O(CH 2 ) n -phenyl-(CH 2 ) m CO 2 R, and O(CH 2 ) n -phenyl-(CH 2 ) m -tetrazole;

Z′ is selected from H, CO 2 R, and CONR a 2 ;

Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) n CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 3 R, (CH 2 ) m CHA(CH 2 ) m C(NH)NH 2 , CH 2 ) m CHA(CH 2 ) m C(NOH)NH 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;

provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

A″ is C 1-6 alkyl;

M is C═O or SO 2 ;

R is independently selected from H, (CH 2 ) m (CHR b ) n (CH 2 ) m OH, CH(CH 2 OH) 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R a is independently selected from H, (CH 2 ) m (CHR) n (CH 2 ) m OH, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, 3, and 4; and,

n is selected from 1, 2, 3, and 4.

15. 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 formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the co-morbidity is selected from hypertension; gallbladder disease; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; osteoarthritis; and, high cholesterol:

wherein:

Z′ is selected from H, CO 2 R, and CONR a 2;

provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

A″ is C 1-6 alkyl;

M is C═O or SO 2 ;

R is independently selected from H, (CH 2 ) m (CHR b ) n (CH 2 ) m OH, CH(CH 2 OH) 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R a is independently selected from H, (CH 2 ) m (CHR) n (CH 2 ) m OH, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, 3, and 4; and,

n is selected from 1, 2, 3, and 4.

16. The method of claim 14 , wherein the diabetes disorder is selected from: Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulin resistance.

17. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of

a. a first therapeutic agent that is a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, and

b. a second therapeutic agent;

wherein the disease is selected from obesity, diabetes, cirrhosis, fatty liver disease, dyslipidemia, atherosclerosis, hypertension, stroke, heart attack, and a combination thereof and the second therapeutic agent is useful for treating the disease:

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, O(CH 2 ) n CN, 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, CONHOH, C(NH)NR a 2 , (CH 2 ) n C(NH)NR a 2 , O(CH 2 ) n CONR a 2 , O(CH 2 ) n C(NH)NR a 2 , O(CH 2 ) n C(NOH)NR a 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 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 ;

Z′ is selected from H, CO 2 R, and CONR a 2 ;

provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

A″ is C 1-6 alkyl;

M is C═O or SO 2 ;

R is independently selected from H, (CH 2 ) m (CHR b ) n (CH 2 ) m OH, CH(CH 2 OH) 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R a is independently selected from H, (CH 2 ) m (CHR) n (CH 2 ) m OH, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, 3, and 4; and,

n is selected from 1, 2, 3, and 4.

18. The method of claim 1 , wherein the hepatic disorder is fatty liver disease.

19. The method of claim 1 , wherein the compound is: