IP Library › Granted Patent US 8,466,143

Granted Patent B2

US 8,466,143 · App. 10/565,702 · Granted Jun 18, 2013

Azepine derivatives as pharmaceutical agents

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Quick Facts

Patent No.: US 8,466,143
App. No.: 10/565,702
Granted: Jun 18, 2013
Kind: B2

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Abstract

Compounds, compositions and methods are provided for modulating the activity of receptors and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder related to the activity of the receptors.

Claims (227)

1. A compound having the formula (I):

wherein:

X is NR 9 , or S;

Y is CR 30 ;

Z is CR 31 or N;

R 30 and R 31 are each independently selected from the group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, —OR 32 , —SR 32 , —N(R 33 )R 34 , —N(R 33 )S(O) 2 R 23 ; —N(R 35 )N(R 33 )R 34 , —N(R 35 )N(R 33 )S(O) 2 R 23 , —C(O)R 36 , —C(O)OR 32 , —C(S)OR 32 , —C(O)SR 32 , —C(O)N(R 33 )R 34 , —C(S)N(R 33 )R 34 , —C(O)N(R 33 )S(O) 2 R 23 , —C(S)N(R 33 )S(O) 2 R 23 , —C(O)N(R 35 )N(R 33 )R 34 , —C(S)N(R 35 )N(R 33 )R 34 and —C(O)N(R 35 )N(R 33 )S(O) 2 R 23 ; or

R 30 and R 31 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring, or optionally substituted nonaromatic cycloalkenyl ring;

R 32 , R 33 , R 34 , R 35 and R 36 are selected as in (a) or (b) as follows: (a) R 32 , R 33 , R 34 , R 35 and R 36 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R 33 and R 34 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and R 32 , R 35 and R 36 are selected as in (a) above,

R 1 is selected from a group consisting of —OR 41 , —SR 14 , —N(R 15 )R 16 , —N(R 15 )S(O) 2 R 23 ; —N(R 17 )N(R 15 )R 16 , —N(R 17 )N(R 15 )S(O) 2 R 23 , —C(O)R 18 , —C(O)R 14 , —C(S)OR 14 , —C(O)SR 14 , —C(O)N(R 15 )R 16 , —C(O)N(R 15 )S(O) 2 R 23 , —C(O)N(R 15 )N═R 16 , —C(O)N(R 17 )N(R 15 )R 16 and —C(O)N(R 17 )N(R 15 )S(O) 2 R 23 ;

R 2 is hydrogen;

R 3 is hydrogen, —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 , —C(O)N(R 11 )R 12 , —C(O)N(R 11 )S(O) 2 R 23 , —C(O)N(R 13 )N(R 11 )R 12 , —C(O)N(R 11 )S(O) 2 R 23 , —N(R 13 )C(O)R 10 , —N(R 13 )C(O)N(R 11 )R 12 , —N(R 13 )C(O)N(R 11 )S(O) 2 R 23) , —N(R 10 C(O)N(R 13 )N(R 11 )R 12 , —N(R 10 )C(O)N(R 13 )N(R 11 )S(O) 2 R 23 , —N(R 13 )C(O)OR 10 , —P(O)OR 10 , or —P(O)(OR 19 )OR 12 ;

R 4 , R 5 , R 6 and R 7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;

R 9 is hydrogen, or optionally substituted alkyl;

R 10 , R 11 , R 12 , R 13 and R 19 are selected as in (a) or (b) as follows: (a) R 10 , R 11 , R 12 , R 13 and R 19 each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R 11 and R 12 or R 12 and R 19 , together with the atoms to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; and the others of R 10 , R 11 , R 12 , R 13 and R 19 are selected as in (a), above;

R 14 , R 15 , R 16 , R 17 and R 18 are selected as in (a) or (b) as follows: (a) R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R 15 and R 16 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and R 14 , R 17 and R 18 are selected as in (a) above;

R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 30 , R 31 , R 32 , R 33 , R 34 , R 35 and R 36 , when substituted, are substituted with one or more substituents, each independently selected from Q 1 ;

each Q 1 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkylthio, halosulfonyl, —OR 70 , —SR 70 , —R 60 —C(J)R 71 , —R 60 —N(R 70 )C(J)R 71 , —OC(O)R 71 , —R 60 —N(R 75 )(R 76 ), —P(R 78 ) 2 , —P(O)(R 78 ) 2 , —OP(O)(R 78 ) 2 , —N(R 70 )S(O) 2 R 71 , —S(O) 2 R 71 , —S(O)R 82 , —OS(O)R 83 , —OS(O) 2 R 83 or —Si(R 83 ) 3 ;

two Q 1 groups, which substitute atoms in a 1,2 or 1,3 arrangement, together with the carbon atoms to which they are attached form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; or

each Q 1 is independently substituted or unsubstituted with one or more substituents each independently selected from Q 2 ;

each Q 2 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkylthio, halosulfonyl, —OR 70 , —SR 70 , —R 60 —C(J)R 71 , —R 60 —N(R 70 )C(J)R 71 , —OC(O)R 71 , —R 60 —N(R 75 )(R 76 ), —P(R 78 ) 2 , —P(O)(R 78 ) 2 , —OP(O)(R 78 ) 2 , —N(R 70 )S(O) 2 R 71 , —S(O) 2 R 71 , —S(O)R 82 , —OS(O)R 83 , —OS(O) 2 R 83 or —Si(R 83 ) 3 ;

two Q 2 groups, which substitute atoms in a 1,2 or 1,3 arrangement, together with the carbon atoms to which they are attached form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring;

each J is independently O, S or —NR 70 ;

each R 60 is independently a direct bond or alkylene;

each R 70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or heteroaralkyl;

each R 71 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroaralkyl, —OR 72 or —N(R 73 )R 74 ;

R 72 , R 73 and R 74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or

R 73 and R 74 , together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring;

R 75 and R 76 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or

R 75 and R 76 , together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring;

R 78 is alkyl, heteroaryl, heterocyclyl, aryl, —OR 79 or —N(R 80 )R 81 ;

R 79 is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;

R 80 and R 81 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or

R 80 and R 81 , together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring;

R 82 is alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl or —OR 83 ; and

each R 83 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;

as a single isomer, a mixture of isomers, or as a racemic mixture of isomers; or as a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein:

R 1 is —C(O)OR 14 or —C(O)N(R 15 )R 16 .

3. The compound of claim 2 , wherein R 3 is —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 or —C(O)N(R 11 )R 12 .

4. The compound of claim 3 wherein R 4 , R 5 , R 6 and R 7 are selected from a), b), c), and d) below:

a) R 4 and R 5 are each independently hydrogen or halo and R 6 and R 7 are optionally substituted alkyl;

b) R 6 and R 7 are each independently hydrogen or halo and R 4 and R 5 are optionally substituted alkyl;

c) R 4 , R 5 , R 6 and R 7 are each optionally substituted alkyl; and

d) R 4 , R 5 , R 6 and R 7 are each independently hydrogen or halo.

5. A compound of claim 1 having the formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is —C(O)OR 14 , or —C(O)N(R 15 )R 16 ;

R 2 is hydrogen;

R 3 is —C(O)R 10 ;

R 4 and R 5 are each independently hydrogen or halo; or

R 4 and R 5 are each optionally substituted alkyl;

R 6 and R 7 are each independently hydrogen or halo; or

R 6 and R 7 are each optionally substituted alkyl; or

R 9 is hydrogen, or optionally substituted alkyl;

R 10 is an optionally substituted aryl or an optionally substituted heteroaryl;

R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

R 30 is halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —OR 32 , —SR 32 , —N(R 33 )R 34 , —N(R 33 )S(O) 2 R 23 ; —N(R 35 )N(R 33 )R 34 , —N(R 35 )N(R 33 )S(O) 2 R 23 , —C(O)R 36 , —C(O)OR 32 , —C(S)OR 32 , —C(O)SR 32 , —C(O)N(R 33 )R 34 , —C(S)N(R 33 )R 34 , —C(O)N(R 33 )S(O) 2 R 23 , —C(S)N(R 33 )S(O) 2 R 23 , —C(O)N(R 35 )N(R 33 )R 34 , —C(S)N(R 35 )N(R 33 )R 34 or —C(O)N(R 35 )N(R 33 )S(O) 2 R 23 .

6. The compound of claim 5 wherein:

R 4 , R 5 , R 6 and R 7 are each independently hydrogen or halo; and

R 30 is selected from the group consisting of hydrogen, halo, —C(O)R 36 , —C(O)OR 32 , —C(S)OR 32 , —C(O)SR 32 , —C(O)N(R 33 )R 34 , —C(S)N(R 33 )R 34 , —C(O)N(R 33 )S(O) 2 R 23 , —C(S)N(R 33 )S(O) 2 R 23 , —C(O)N(R 35 )N(R 33 )R 34 , —C(S)N(R 35 )N(R 33 )R 34 and —C(O)N(R 35 )N(R 33 )S(O) 2 R 23 ;

where R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and

where R 32 , R 33 , R 34 , R 35 and R 36 are selected as in (a) or (b) as follows: (a) R 32 , R 33 , R 34 , R 35 and R 36 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R 33 and R 34 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R 32 , R 35 and R 36 are selected as in (a) above.

7. The compound of claim 6 wherein said compound is

6-(4-fluoro-benzoyl)-3,6,7,8-tetrahydro-imidazo[4,5-d]azepine-4-carboxylic acid ethyl ester.

8. The compound of claim 5 wherein:

R 4 and R 5 are each independently hydrogen or halo; and

R 6 and R 7 are optionally substituted alkyl.

9. The compound of claim 8 wherein

R 9 is hydrogen.

10. The compound of claim 9 wherein R 30 is selected from the group consisting of —C(O)R 36 , —C(O)OR 32 , —C(S)OR 32 , —C(O)SR 32 , —C(O)N(R 33 )R 34 , —C(S)N(R 33 )R 34 , —C(O)N(R 33 )S(O) 2 R 23 , —C(S)N(R 33 )S(O) 2 R 23 , —C(O)N(R 35 )N(R 33 )R 34 , —C(S)N(R 35 )N(R 33 )R 34 and —C(O)N(R 35 )N(R 33 )S(O) 2 R 23 ;

11. The compound of claim 10 wherein R 1 is —C(O)OCH 2 CH 3 , —C(O)OCH 3 , —C(O)OCH(CH 3 ) 2 , —C(O)OH, —C(O)OCH 2 CH 2 CH 3 , —C(O)NHCH 3 , —C(O)NHCH 2 CH 3 , —C(O)NHCH (CH 3 ) 2 , —C(O)NH(cyclopropyl), —C(O)NH(cyclopentyl), —C(O)NHCH(CH 3 )(CH 2 CH 3 ) or —C(O)N(CH 3 )(cyclopropyl).

12. The compound of claim 4 wherein:

Z is CR 31 ; and

R 31 is independently selected from a group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —OR 32 , —SR 32 , —N(R 33 )R 34 , —N(R 33 )S(O) 2 R 23 ; —N(R 35 )N(R 33 )R 34 , —N(R 35 )N(R 33 )S(O) 2 R 23 , —C(O)R 36 , —C(O)OR 32 , —C(S)OR 32 , —C(O)SR 32 , —C(O)N(R 33 )R 34 , —C(S)N(R 33 )R 34 , —C(O)N(R 33 )S(O) 2 R 23 , —C(S)N(R 33 )S(O) 2 R 23 , —C(O)N(R 35 )N(R 33 )R 34 , —C(S)N(R 35 )N(R 33 )R 34 and —C(O)N(R 35 )N(R 33 )S(O) 2 R 23 ;

13. The compound of claim 12 wherein:

Z is CR 31 ; and

R 31 is independently selected from a group consisting of optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, —C(O)R 36 , —C(O)OR 32 , —C(S)OR 32 , —C(O)SR 32 , —C(O)N(R 33 )R 34 , —C(S)N(R 33 )R 34 , —C(O)N(R 33 )S(O) 2 R 23 , —C(S)N(R 33 )S(O) 2 R 23 , —C(O)N(R 35 )N(R 33 )R 34 , —C(S)N(R 35 )N(R 33 )R 34 and —C(O)N(R 35 )N(R 33 )S(O) 2 R 23 ;

14. The compound of claim 12 wherein X is S.

15. The compound of claim 14 wherein R 4 , R 5 , R 6 and R 7 are each independently hydrogen or halo; and

16. The compound of claim 1 wherein said compound is

6-(3,4-difluoro-benzoyl)-5,6-dihydro-4H-thieno[2,3-d]azepine-8-carboxylic acid ethyl ester.

17. The compound of claim 14 wherein:

R 4 and R 5 are each independently hydrogen or halo; and

R 6 and R 7 are optionally substituted alkyl.

18. The compound of claim 17 wherein:

R 9 is hydrogen.

19. The compound of claim 18 wherein R 30 is selected from the group consisting of —C(O)R 36 , —C(O)OR 32 , —C(S)OR 32 , —C(O)SR 32 , —C(O)N(R 33 )R 34 , —C(S)N(R 33 )R 34 , —C(O)N(R 33 )S(O) 2 R 23 , —C(S)N(R 33 )S(O) 2 R 23 , —C(O)N(R 35 )N(R 33 )R 34 , —C(S)N(R 35 )N(R 33 )R 34 and —C(O)N(R 35 )N(R 33 )S(O) 2 R 23 ;

20. The compound of claim 19 wherein R 1 is —C(O)OCH 2 CH 3 , —C(O)OCH 3 , —C(O)OCH(CH 3 ) 2 , —C(O)OH, —C(O)OCH 2 CH 2 CH 3 , —C(O)NHCH 3 , —C(O)NHCH 2 CH 3 , —C(O)NHCH (CH 3 ) 2 , —C(O)NH(cyclopropyl), —C(O)NH(cyclopentyl), —C(O)NHCH(CH 3 )(CH 2 CH 3 ) or —C(O)N(CH 3 )(cyclopropyl); and

R 3 is —C(O)R 10 wherein R 10 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl or optionally substituted aralkyl.

21. The compound of claim 1 wherein said compound is

6-(3,4-difluoro-benzoyl)-4,4-dimethyl-5,6-dihydro-4H-thieno[2,3-d]azepine-8-carboxylic acid ethyl ester.

22. The compound of claim 12 wherein

X is NR 9 ;

R 9 is hydrogen, or optionally substituted alkyl; and

R 18 and R 23 each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.

23. The compound of claim 22 wherein:

R 4 and R 5 are each independently hydrogen or halo; and

R 6 and R 7 are optionally substituted alkyl.

24. The compound of claim 23 wherein:

R 9 is hydrogen.

25. The compound of claim 24 wherein R 30 is selected from the group consisting of —C(O)R 36 , —C(O)OR 32 , —C(S)OR 32 , —C(O)SR 32 , —C(O)N(R 33 )R 34 , —C(S)N(R 33 )R 34 , —C(O)N(R 33 )S(O) 2 R 23 , —C(S)N(R 33 )S(O) 2 R 23 , —C(O)N(R 35 )N(R 33 )R 34 , —C(S)N(R 35 )N(R 33 )R 34 and —C(O)N(R 35 )N(R 33 )S(O) 2 R 23 ;

26. The compound of claim 25 wherein R 1 is —C(O)OCH 2 CH 3 , —C(O)OCH 3 , —C(O)OCH(CH 3 ) 2 , —C(O)OH, —C(O)OCH 2 CH 2 CH 3 , —C(O)NHCH 3 , —C(O)NHCH 2 CH 3 , —C(O)NHCH(CH 3 ) 2 , —C(O)NH(cyclopropyl), —C(O)NH(cyclopentyl), —C(O)NHCH(CH 3 )(CH 2 CH 3 ) or —C(O)N(CH 3 )(cyclopropyl); and

R 3 is —C(O)R 10 wherein R 10 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl or optionally substituted aralkyl.

27. The compound of claim 26 wherein said compound is selected from the group consisting of:

6-(3,4-difluoro-benzoyl)-4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid diethyl ester; and

6-(3,4-difluoro-benzoyl)-4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid 2-ethyl ester 8-isopropyl ester.

28. The compound of claim 4 wherein:

R 4 , R 5 , R 6 and R 7 are each independently hydrogen or halo; and

29. The compound of claim 1 wherein said compound is

6-(3,4-difluoro-benzoyl)-1,4,4-trimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid 2-ethyl ester 8-isopropyl ester.

30. The compound of claim 4 wherein:

Y is CR 30 ;

Z is CR 31 ; and

R 30 and R 31 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring, or optionally substituted nonaromatic cycloalkenyl ring.

31. The compound of claim 30 wherein said optionally substituted cycloalkyl ring is optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cycloheptyl or optionally substituted cyclooctyl.

32. A compound having the formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

n is 0 to 8;

R 1 is selected from a group consisting of —OR 14 , —SR 14 , —N(R 15 )R 16 , —N(R 15 )S(O) 2 R 23 ; —N(R 17 )N(R 15 )R 16 , —N(R 17 )N(R 15 )S(O) 2 R 23 , —C(O)R 18 , —C(O)OR 14 , —C(S)OR 14 , —C(O)SR 14 , —C(O)N(R 15 )R 16 , —C(O)N(R 15 )S(O) 2 R 23 , —C(O)N(R 15 )N═R 16 , —C(O)N(R 17 )N(R 15 )R 16 , and —C(O)N(R 17 )N(R 15 )S(O) 2 R 23 ;

R 2 is hydrogen;

R 3 is hydrogen, —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 , —C(O)N(R 11 )R 12 , —C(O)N(R 11 )S(O) 2 R 23 , —C(O)N(R 13 )N(R 11 )R 12 , —C(O)N(R 13 )N(R 11 )S(O) 2 R 23 , —N(R 13 )C(O)R 10 , —N(R 13 )C(O)N(R 11 )R 12 , —N(R 13 )C(O)N(R 11 )S(O) 2 R 23 , —N(R 10 C(O)N(R 13 )N(R 11 )R 12 , —N(R 10 )C(O)N(R 13 )N(R 11 )S(O) 2 R 23 , —N(R 13 )C(O)OR 10 , —P(O)OR 10 , or —P(O)(OR 19 )OR 12 ;

R 4 , R 5 , R 6 and R 7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;

R 9 is hydrogen, or optionally substituted alkyl;

each of R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 , when substituted, are substituted with one or more substituents, each independently selected from Q 1 ;