IP Library › Granted Patent US 8,519,158
Granted Patent B2
US 8,519,158 · App. 10/590,119 · Granted Aug 27, 2013

Androgen receptor modulator compounds and methods

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Quick Facts
Patent No.
US 8,519,158
App. No.
10/590,119
Granted
Aug 27, 2013
Kind
B2
Abstract

Provided herein are compounds having a structure selected from among Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) and Formula (VI) that are androgen receptor modulators and/or androgen receptor binding agents. Also disclosed are methods of making and using such compounds, including, but not limited to, using such compounds for treating various conditions.

Claims (186)

1. A compound of Formula II:

wherein:

R 1 is selected from among SR A , NO 2 , CN, CF 3 , COR A , CONR A R B , SOR A , and SO 2 R A ;

R 2 is selected from among F, Cl, Br, I, SR A , NO 2 , CF 3 , COR A , CO 2 R A , CONR A R B , SOR A , SO 2 R A , SO 2 NR A R B , NHCOR A , and NHCONR A R B ;

R 3 and R 4 each independently is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 3 is selected from among hydrogen, F, Cl and CF 3 ;

R 6a and R 7a each independently is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 9 is selected from an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, CF 3 , an optionally substituted C 2 -C 8 haloalkenyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 haloalkynyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted heteroaryl, CH(R D )OR A , CH(R D )NR A R B , COR A , and (CH 2 ) m R C ;

R 10 is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 12 and R 13 each independently is selected from among hydrogen, F, Cl, OR A , NR A R B , SR A , an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 2 -C 6 alkenyl, and (CH 2 ) m R C ;

R A is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl and CF 3 ;

R B is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R C is selected from among an optionally substituted aryl and an optionally substituted heteroaryl that is optionally substituted with a substituent selected from among F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R D is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

Z is CR A R B ;

n is 0; and

m is 1 or 2;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:

R 1 is selected from among NO 2 , CN and CONR A R B ;

R 2 is selected from among F, Cl, Br, I, OR A , SR A , NO 2 , CF 3 , COR A , CO 2 R A , CONR A R B , SOR A , SO 2 R A , SO 2 NR A R B , NHCOR A , and NHCONR A R B ;

R 3 and R 4 each independently is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 5 is selected from among hydrogen, F, Cl, an optionally substituted C 1 -C 4 alkyl and CF 3 ;

R 6a and R 7a each independently is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 heterohaloalkyl, an optionally substituted C 2 -C 6 heterohaloalkenyl, an optionally substituted C 2 -C 6 heterohaloalkynyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 9 is selected from among an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, CF 3 , an optionally substituted C 2 -C 8 haloalkenyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 haloalkynyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted C 2 -C 6 heterohaloalkenyl, an optionally substituted C 2 -C 6 heterohaloalkynyl, an optionally substituted heteroaryl, CH(R D )OR A , CH(R D )NR A R B , COR A , and (CH 2 ) m R C ;

R 10 each independently is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 heterohaloalkyl, an optionally substituted C 2 -C 6 heterohaloalkenyl, an optionally substituted C 2 -C 6 heterohaloalkynyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 12 and R 13 each independently is selected from among hydrogen, F, Cl, OR A , NR A R B , SR A , an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 heterohaloalkyl, an optionally substituted C 2 -C 6 heterohaloalkenyl, an optionally substituted C 2 -C 6 heterohaloalkynyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 2 -C 6 alkenyl, and (CH 2 ) m R C ;

R A is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl and CF 3 ;

R B is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R C is selected from among an optionally substituted aryl and an optionally substituted heteroaryl that is optionally substituted with a substituent selected from among F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R D is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

Z is CR A R B ;

n is 0; and

m is 1 or 2.

3. The compound of claim 1 , wherein R 1 is NO 2 or CN.

4. The compound of claim 1 , wherein R 1 is NO 2 .

5. A compound of Formula II:

wherein:

R 1 is CN;

R 2 is selected from among F, Cl, Br, I, SR A , NO 2 , CF 3 , COR A , CO 2 R A , CONR A R B , SOR A , SO 2 R A , SO 2 NR A R B , NHCOR A , and NHCONR A R B ;

R 3 and R 4 each independently is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 5 is selected from among hydrogen, F, Cl and CF 3 ;

R 6a and R 7a each independently is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 9 is selected from an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, CF 3 , an optionally substituted C 2 -C 8 haloalkenyl, C 1 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 haloalkynyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted heteroaryl, CH(R D )OR A , CH(R D )NR A R B , COR A , CO 2 R A , and (CH 2 ) m R C ;

R 10 is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 12 and R 13 each independently is selected from among hydrogen, F, Cl, OR A , NR A R B , SR A , an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 2 -C 6 alkenyl, and (CH 2 ) m R C ;

R A and R B each independently is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R C is selected from among an optionally substituted aryl and an optionally substituted heteroaryl that is optionally substituted with a substituent selected from among F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R D is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

Z is CR A R B ;

n is 0; and

m is 1 or 2;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 2 is CF 3 .

7. A compound of Formula II:

wherein:

R 1 is selected from among SR A , NO 2 , CN, CF 3 , COR A , CONR A R B , SOR A , and SO 2 R A ;

R 2 is trifluoromethyl;

R 3 and R 4 each independently is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 5 is selected from among hydrogen, F, Cl and CF 3 ;

R 6a and R 7a each independently is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 9 is selected from an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, CF 3 , an optionally substituted C 2 -C 8 haloalkenyl, C 1 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 haloalkynyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted heteroaryl, CH(R D )OR A , CH(R D )NR A R B , COR A , CO 2 R A , and (CH 2 ) m R C ;

R 10 is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 12 and R 13 each independently is selected from among hydrogen, F, Cl, OR A , NR A R B , SR A , an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 2 -C 6 alkenyl, and (CH 2 ) m R C ;

R A and R B each independently is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R C is selected from among an optionally substituted aryl and an optionally substituted heteroaryl that is optionally substituted with a substituent selected from among F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R D is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

Z is CR A R B ;

n is 0; and

m is 1 or 2;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R 3 , R 4 , and R 5 each independently is selected from among hydrogen, F, Cl, and an optionally substituted C 1 -C 4 alkyl.

9. The compound of claim 1 , wherein R 3 is hydrogen.

10. The compound of claim 1 , wherein R 4 is hydrogen.

11. The compound of claim 1 , wherein R 5 is hydrogen.

12. The compound of claim 1 , wherein R 6a and R 7a each independently is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heterohaloalkyl.

13. The compound of claim 1 , wherein R 6a is hydrogen.

14. The compound of claim 1 , wherein R 7a is hydrogen or an optionally substituted C 1 -C 6 alkyl.

15. The compound of claim 1 , wherein R 7a is hydrogen or methyl.

16. The compound of claim 1 , wherein R 7a is hydrogen.

17. The compound of claim 1 , wherein R 7a is methyl.

18. The compound of claim 1 , wherein R 12 is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heterohaloalkyl and (CH 2 ) m R C .

19. The compound of claim 1 , wherein R 10 is hydrogen.

20. The compound of claim 1 , wherein R 9 is selected from among an optionally substituted C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, CH(R D )OR A , and CH(R D )NR A R B .

21. A compound of Formula II:

wherein:

R 1 is selected from among SR A , NO 2 , CN, CF 3 , COR A , CONR A R B , SOR A , and SO 2 R A ;

R 2 is selected from among F, Cl, Br, I, SR A , NO 2 , CN, CF 3 , COR A , CO 2 R A , CONR A R B , SOR A , SO 2 R A , SO 2 NR A R B , NHCOR A , and NHCONR A R B ;

R 3 and R 4 each independently is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 5 is selected from among hydrogen, F, Cl and CF 3 ;

R 6a and R 7a each independently is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 1 -C 6 alkenyl;

R 9 is formyl, hydroxy C 1 -C 6 alkyl, hydroxyhalo C 1 -C 6 alkyl, C 1 -C 6 alkylsilyloxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, amino C 1 -C 6 alkyl, or C 1 -C 6 alkylcarbonyloxyC 1 -C 6 alkyl;

R 10 is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 12 and R 13 each independently is selected from among hydrogen, F, Cl, OR A , NR A R B , SR A , an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 2 -C 6 alkenyl, and (CH 2 ) m R C ;

R A is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl and CF 3 ;

R B is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R C is selected from among an optionally substituted aryl and an optionally substituted heteroaryl that is optionally substituted with a substituent selected from among F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

Z is CR A R B ;

n is 0; and

m is 1 or 2;

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21 , wherein R 9 is formyl, hydroxymethyl, 1-hydroxy-2,2,2-trifluoroethyl, tributylsilyloxymethyl, ethoxycarbonyl, aminomethyl, or acetyoxymethyl.

23. The compound of claim 1 , wherein R 12 and R 13 each independently is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 6 alkyl, CF 3 and (CH 2 ) m R C .

24. The compound of claim 1 , wherein R 13 is hydrogen, F, OH or benzyl.

25. The compound of claim 1 of formula IIB:

26. The compound of claim 1 , wherein:

R 1 is NO 2 or CN;

R 2 is CF 3 ;

R 3 , R 4 , and R 5 each independently is selected from among hydrogen, F, Cl, and an optionally substituted C 1 -C 4 alkyl;

R 6a and R 7a each independently is selected from among hydrogen and an optionally substituted C 1 -C 6 alkyl;

R 9 is selected from among F, Cl, Br, I, an optionally substituted C 1 -C 4 alkyl, COR A , CH(R D )OR A , and CH(R D )NR A R B ;

R 10 is hydrogen; and

R 12 and R 13 each independently is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heterohaloalkyl and (CH 2 ) m R C .

27. The compound of claim 1 , wherein:

R 1 is NO 2 or CN;

R 2 is trifluoromethyl;

R 3 , R 4 , and R 5 each is hydrogen;

R 7a is hydrogen or methyl and R 6a is hydrogen;

R 9 is selected from among formyl, hydroxymethyl and 1-hydroxy-2,2,2-trifluoroethyl;

R 10 is hydrogen;

R 12 is hydrogen; and

R 13 is selected from among hydrogen, F, OH and benzyl.

28. A compound that is selected from among:

wherein:

R 1 is selected from among SR A , NO 2 , CN, CF 3 , CONR A R B , SOR A , and SO 2 R A ;

R 2 is selected from F, Cl, Br, I, SR A , NO 2 , a substituted C 1 -C 4 alkyl, CF 3 , COR A , CO 2 R A , CONR A R B , SOR A , SO 2 R A , SO 2 NR A R B , NHCOR A , and NHCONR A R B ;

R 3 and R 4 each independently is selected from among hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 5 is selected from among hydrogen, F, Cl, an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 7a is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 9 is selected from an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, CF 3 , an optionally substituted C 2 -C 8 haloalkenyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 haloalkynyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted heteroaryl, CH(R D )OR A , CH(R D )NR A R B , COR A , and (CH 2 ) m R C ;

R 13 is selected from among hydrogen, F, Cl, OR A , NR A R B , SR A , an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 2 -C 6 alkenyl, and (CH 2 ) m R C ;

R A is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl and CF 3 ;

R B is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R C is selected from among an optionally substituted aryl and an optionally substituted heteroaryl that is optionally substituted with a substituent selected from among F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R D is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

Z is CR A R B ; and

m is 1 or 2;

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 28 , wherein R 7a is an optionally substituted C 1 -C 6 heterohaloalkyl.

30. The compound of claim 28 , wherein R 13 is an optionally substituted C 1 -C 6 heterohaloalkyl.

31. The compound of claim 28 , wherein the compound is:

32. The compound of claim 28 , wherein the compound is:

33. A compound of claim 1 , wherein the compound is selected from among:

(2R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine;

(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;

(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)-pyrrolidine;

cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

trans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile;

5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol; and

2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine;

and pharmaceutically acceptable salts thereof.

34. The compound of claim 1 , wherein the compound is a selective androgen receptor modulator.

35. The selective androgen receptor modulator of claim 34 , wherein the compound is an androgen receptor agonist.

36. The selective androgen receptor modulator of claim 34 , wherein the compound is an androgen receptor antagonist.

37. The selective androgen receptor modulator of claim 34 , wherein the compound is an androgen receptor partial agonist.

38. The selective androgen receptor modulator of claim 34 , wherein the compound is a tissue-specific modulator.

39. The compound of claim 1 , wherein the compound is a selective androgen binding compound.

40. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

41. A compound of Formula II:

wherein:

R 1 is COR A , NO 2 or CN;

R 2 is selected from among hydrogen, F, Cl, Br, I, OR A , SR A , NO 2 , an optionally substituted C 1 -C 4 alkyl, CF 3 , COR A , CO 2 R A , CONR A R B , SOR A , SO 2 R A , SO 2 NR A R B , NHCOR A , and NHCONR A R B ;

R 3 , R 4 , and R 5 each independently is selected from among hydrogen, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 6a and R 7a each independently is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl; or R 6a and R 7a together form a carbonyl;

R 9 is selected from among CH(R D )OR A and CH(R D )NR A R B ;

R 10 is selected from among hydrogen, an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 alkenyl;

R 12 and R 13 each independently is selected from among hydrogen, F, Cl, OR A , NR A R B , SR A , an optionally substituted C 1 -C 6 alkyl, CF 3 , an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 2 -C 6 alkenyl, and (CH 2 ) m R C ;

R A is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl and CF 3 ;

R B is selected from among hydrogen, an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R C is selected from among an optionally substituted aryl and an optionally substituted heteroaryl that is optionally substituted with a substituent selected from among F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R D is selected from among an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

Z is CR A R B ;

n is 0; and

m is 1 or 2;

or a pharmaceutically acceptable salt thereof.

42. A compound of claim 41 , wherein the compound is selected from among:

(2R)—N-(4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

(2R)—N-(4-nitrophenyl)-2-(R)-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

(2R)—N-(4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine; and

(2R)—N-(4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

and pharmaceutically acceptable salts thereof.

43. A pharmaceutical composition, comprising a compound of claim 41 and a pharmaceutically acceptable carrier.

44. A pharmaceutical composition, comprising a compound of claim 28 and a pharmaceutically acceptable carrier.

Assignments (2)
SECURITY INTEREST Recorded Oct 18, 2023
From: CYDEX PHARMACEUTICALS, INC.; LIGAND PHARMACEUTICALS INCORPORATED; METABASIS THERAPEUTICS, INC.; PFENEX INC.
To: CITIBANK, N.A., AS ADMINISTRATIVE AGENT
Reel/Frame 065271/0025 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 3, 2006
From: ZHI, LIN; HIGUCHI, ROBERT I.; KALLEL, E. ADAM; VAN OEVEREN, CORNELIS ARJAN; CHEN, JYUN-HUNG; RUPPAR, DANIEL; PEDRAM, BIJAN; LAU, THOMAS LOT STEVENS; MILLER, T.
To: LIGAND PHARMACEUTICALS INCORPORATED
Reel/Frame 018349/0948 →