Acyclic Hydrazides as Cannabinoid Receptor Modulators

1 . A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein;

R 1 is selected from:

(1) hydrogen,

(2) C 1-4 alkyl,

(3) C 3-6 cycloalkyl,

(4) C 2-4 alkenyl, and

(5) C 2-4 alkynyl;

R 2 is selected from:

(1) C 1-10 alkyl,

(2) C 2-10 alkenyl,

(3) C 2-10 alkynyl,

(4) C 3-10 cycloalkyl,

(5) C 3-10 cycloalkyl C 1-4 alkyl,

(6) cycloheteroalkyl,

(7) cycloheteroalkyl C14alkyl

(8) aryl,

(9) aryl C 1-10 alkyl,

(10) aryl C 2-8 alkenyl,

(11) diaryl C 1-4 alkyl,

(12) heteroaryl,

(13) heteroaryl C 1-10 alkyl,

(14) NR c R d ,

wherein each alkyl, alkenyl, and alkynyl is straight or branched chain and unsubstituted or substituted with one to four substituents independently selected from R a and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R b ;

Ar 1 and Ar 2 are independently selected from:

(1) aryl, and

(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with one to four substituents independently selected from R b ;

each R a is independently selected from:

(1) —OR d ,

(2) —NR c S(O) m R d ,

(3) halogen,

(4) —SR d ,

(5) —S(O) m R d ,

(6) —S(O) m NR c R d ,

(7) —NR c R d ,

(8) —C(O)R d ,

(9) —CO 2 R d ,

(10) —CN,

(11) —C(O)NR c R d ,

(12) —NR c C(O)R d ,

(13) —NR c C(O)OR d ,

(14) —NR c C(O)NR c R d ,

(15) —CF 3 , and

(16) —OCF 3 ;

each R b is independently selected from:

(1) R a ,

(2) C 1-10 alkyl,

(3) oxo,

(4) aryl,

(5) arylC 1-4 alkyl,

(6) heteroaryl, and

(7) heteroarylC 1-4 alkyl;

each R c and R d is independently selected from:

(1) hydrogen,

(2) C 1-10 alkyl,

(3) C 2-10 alkenyl,

(4) cycloalkyl,

(5) cycloalkyl-C 1-10 alkyl,

(6) cycloheteroalkyl,

(7) cycloheteroalkyl-C 1-10 alkyl,

(8) aryl,

(9) heteroaryl,

(10) pyridyl,

(11) pyrimidyl,

(12) aryl-C 1-10 alkyl, and

(13) heteroaryl-C 1-10 alkyl, or

R c and R d together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g ,

each R c and R d may be unsubstituted or substituted with one to three substituents selected from R h ;

each R g is independently selected from:

(1) hydrogen,

(2) C 1-4 alkyl,

(3) —C(O)C 1-4 alkyl,

(4) —C(O)OR d ,

(5) —C(O)NR c R d ,

(6) —S(O) m R d , and

(7) —S(O) m NR c R d ;

each R h is independently selected from:

(1) halogen,

(2) C 1-10 alkyl,

(3) —O—C 1-4 alkyl,

(4) —S—C 1-4 alkyl,

(5) —S(O) m —C 1-4 alkyl,

(6) —CN,

(7) —NO 2 ,

(8) —CF 3 ,

(9) —CHF 2 and

(10) —OCF 3 ; and

m is selected from 1 and 2.

2 . The compound according to claim 1 , wherein:

Ar 1 is selected from: phenyl, and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with one to three R b substituents; and

Ar 2 is selected from: phenyl, and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with one to three R b substituents,

or a pharmaceutically acceptable salt thereof.

3 . The compound according to claim 2 , wherein:

Ar 1 is para-chlorophenyl and Ar 2 is selected from: m-chlorophenyl, m-bromophenyl, and m-cyanophenyl,

or a pharmaceutically acceptable salt thereof.

4 . The compound according to claim 1 , wherein:

R 1 is selected from:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) propyl, and

(5) allyl,

or a pharmaceutically acceptable salt thereof.

5 . The compound according to claim 1 , wherein:

R 2 is selected from:

(1) C 1-8 alkyl,

(2) C 3-6 cycloalkyl,

(3) cycloheteroalkyl,

(4) phenyl,

(5) phenyl C 1-3 alkyl,

(6) pyridyl,

(7) pyrimidyl,

(8) pyridyl C 1-3 alkyl, and

(9) pyrimidyl C 1-3 alkyl,

wherein each alkyl moiety is straight or branched chain and unsubstituted or substituted with one, two or three substituents independently selected from R a , and each cycloalkyl, cycloheteroalkyl, phenyl, and heteroaryl moiety is unsubstituted or substituted with one, two or three substituents independently selected from R b ;

each R b is independently selected from:

(1) —OR d ,

(2) halogen,

(3) —CN,

(4) —CF 3 ,

(5) —OCF 3 ,

(6) cycloheteroalkyl;

(7) C 1-4 alkyl,

(8) oxo,

(9) phenyl,

(10) benzyl, and

(11) heteroaryl;

each R d is independently selected from:

(1) hydrogen,

(2) C 1-5 alkyl,

(3) —CH 2 CH═CH 2 ,

(4) cyclohexyl,

(5) cyclopentyl,

(6) cyclopropyl,

(7) cyclobutylmethyl,

(8) cyclopentylmethyl,

(9) cyclohexylmethyl,

(10) pyrrolidinyl,

(11) phenyl,

(12) thiazolyl,

(13) pyridyl,

(14) pyrimidyl,

(15) benzothiazolyl,

(16) benzoxazolyl,

(17) triazolyl,

(18) benzyl, and

(19) pyridyl-methyl-,

wherein each R d may be unsubstituted or substituted with one to three substituents selected from R h ;

each R h is independently selected from:

(1) halogen,

(2) methyl,

(3) methoxy,

(4) —S(O) m —C 1-4 alkyl,

(5) —CN,

(6) —CF 3 ,

(7) —CHF 2 , and

(8) —OCF 3 ;

or a pharmaceutically acceptable salt thereof.

6 . The compound according to claim 1 , wherein:

R 2 is selected from:

each R d is independently selected from:

(1) hydrogen,

(2) phenyl,

(3) pyridyl, and

(4) pyrimidyl,

wherein phenyl, pyridyl and pyrimidyl are unsubstituted or substituted with one or two R h substituents; and

each R g is independently selected from:

(1) hydrogen,

(2) C 1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

7 . The compound according to claim 1 , selected from the group consisting of:

(1) N′-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-{2-methyl-2-[5-(trifluoromethylpyridin-2-yl)oxy]propanoyl}hydrazide;

(2) N′-[1-(3-bromophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-{2-methyl-2-[5-trifluoromethypyridin-2-yl)oxy]propanoyl}hydrazide;

(3) N′-[1-(3-bromophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-(1-phenylcyclopentanecarboxyl)hydrazide;

(4) N′-[1-(3-bromophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-[(2S)-phenylbutanoyl]hydrazide;

(5) N′-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-[(2S)-phenylbutanoyl]hydrazide;

(6) N′-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-{2-[5-trifluoromethypyridin-2-yl)oxy]butanoyl}hydrazide;

(7) N′-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N′-allyl-N-{2-methyl-2-[5-trifluoromethypyridin-2-yl)oxy]propanoyl}hydrazide;

(8) N′-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-(2-methyl-2-hydroxypropanoyl)hydrazide;

(9) N′-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-(2-methyl-2-hydroxypropanoyl)hydrazide;

(10) N′-[1-(3-cyanophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-{2-methyl-2-[(5-trifluoromethylpyridin-2-yl)oxy]propanoyl}hydrazide;

(11) N′-[1-(3-cyanophenyl)-2-(4-chlorophenyl)ethyl]-N′-methyl-N-[(2S)-phenylbutanoyl]hydrazide;

(12) N′-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N′-propyl-N-{2-methyl-2-[5-trifluoromethypyridin-2-yl)oxy]propanoyl}hydrazide; and

(13) N′-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N-{2-methyl-2-[5-trifluoromethypyridin-2-yl)oxy]propanoyl}hydrazide;

or a pharmaceutically acceptable salt thereof.

8 - 14 . (canceled)

15 . A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

16 . The composition according to claim 15 additionally comprising an HMG-CoA reductase inhibitor.

17 . The composition according to claim 15 additional comprising 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine, or a pharmaceutically acceptable salt thereof.

18 . A method of treating a disease mediated by the Cannabinoid-1 receptor in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

19 . The method according to claim 18 , wherein the disease mediated by the Cannabinoid-1 receptor is selected from: psychosis, memory deficit, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders, cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, schizophrenia, substance abuse disorders relating to opiates, alcohol, marijuana, and nicotine; constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, asthma, and obesity or other eating disorders associated with excessive food intake.

20 . A method of treating obesity in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

21 . A method of reducing body weight in a subject in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

22 . A method of maintaining the weight of an obese subject comprising administration of an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

23 . A method of reducing the body weight of a subject at risk for obesity comprising administration of an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

24 . A method of treating obesity in a subject in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 7 , or a pharmaceutically acceptable salt thereof.