IP Library › Granted Patent US 7,026,484

Granted Patent B2

US 7,026,484 · App. 10/080,926 · Granted Apr 11, 2006

Tricyclic androgen receptor modulator compounds and methods

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Patent No.: US 7,026,484
App. No.: 10/080,926
Granted: Apr 11, 2006
Kind: B2

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Abstract

This invention relates to non-steroidal tricyclic compounds that are modulators of androgen receptors and to methods for making and using such compounds.

Claims (261)

1. A compound of the formula:

wherein:

R 1 is selected from among hydrogen, F, Cl, Br, I, NO 2 , OR 12 , SR 12 , SOR 12 , SO 2 R 12 , NR 12 R 12 , C 1 –C 8 alkyl, C 1 –C 8 haloalkyl and C 1 –C 8 heteroalkyl, wherein the haloalkyl and heteroalkyl groups are optionally substituted;

R 2 is selected from among hydrogen, F, Cl, Br, I, CF 3 , CHF 2 , CH 2 F, CF 2 Cl, CN, CF 2 OR 12 , CH 2 OR, OR 12 , SR 12 , SOR 12 , SO 2 R 12 , NR 12 R 13 , substituted C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, C 2 –C 8 alkenyl and C 2 –C 8 alkynyl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl and alkynyl groups are optionally substituted;

R 3 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 4 is selected from among hydrogen, F, Cl, Br, I, OR 12 , NR 12 R 13 , SR 12 , SOR 12 , SO 2 R 12 , C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, C 2 –C 8 alkynyl, C 2 –C 8 alkenyl, aryl, heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl, aryl, heteroaryl and arylalkyl groups are optionally substituted;

R 5 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 6 is selected from among hydrogen, F, Cl, Br, I, OR 12 , NR 12 R 13 , SR 12 , SOR 12 , SO 2 R 12 , C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, C 2 –C 8 alkynyl, C 2 –C 8 alkenyl, aryl, heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl, aryl, heteroaryl and arylalkyl groups are optionally substituted;

R 7 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 8 is selected from among hydrogen, F, Cl, Br, I, OR 12 , NR 12 R 13 , SR 12 , SOR 12 , SO 2 R 12 , C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, C 2 –C 8 alkynyl, C 2 –C 8 alkenyl, aryl, heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl, aryl, heteroaryl and arylalkyl groups are optionally substituted; or

R 3 and R 5 taken together form a bond; or

R 5 and R 7 taken together form a bond; or

R 4 and R 6 taken together form a three- to eight-membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted; or

R 6 and R 8 taken together form a three- to eight-membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted;

R 9 and R 10 each independently is selected from among hydrogen, F, Cl, Br, I, CN, OR 12 , NR 12 R 13 , C m (R 12 ) 2m OR 13 , SR 12 , SOR 12 , SO 2 R 12 , NR 12 C(O)R 13 , C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl and arylalkyl groups are optionally substituted;

R 11 is selected from among hydrogen, F, Br, Cl, I, CN, OR 14 , NR 14 R 13 , and SR 14 ;

R 12 and R 13 each independently is selected from the group of hydrogen, C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted;

R 14 is selected from among hydrogen, C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, aryl, heteroaryl, C(O)R 15 , CO 2 R 15 and C(O)NR 15 R 16 , wherein the alkyl, haloalkyl, heteroalkyl, aryl and heteroaryl groups are optionally substituted;

R 15 and R 16 each independently is selected from among hydrogen, C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

W is O or S;

X is N{R 14 };

Y is selected from among O, S, N{R 12 } and NO{R 12 };

Z is N{R 12 };

n is 0; and

m is 0 or 1;

or a pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 , wherein R 2 is selected from among F, Cl, Br, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , substituted C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the haloalkyl and heteroalkyl groups are optionally substituted.

3. A compound according to claim 1 , wherein R 2 is selected from among CF 2 OR 12 , CH 2 OR 12 , OR 12 , SR 12 , SOR 12 , SO 2 R 12 and NR 12 R 13 .

4. A compound according to claim 1 , wherein R 2 is selected from among hydrogen, F, Cl, Br, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , substituted C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, C 1 –C 4 heteroalkyl, C 2 –C 4 alkenyl and C 2 –C 4 alkynyl, wherein the haloalkyl, heteroalkyl, alkenyl and alkynyl groups are optionally substituted.

5. A compound according to claim 4 , wherein R 2 is selected from among F, Cl, CF 3 , CF 2 Cl, CF 2 H, CFH 2 and substituted C 1 –C 4 alkyl.

6. A compound according to claim 1 , wherein R 9 and R 10 each independently is selected from among hydrogen, F, Cl, Br, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

7. A compound according to claim 6 , wherein R 9 and R 10 each independently is selected from among hydrogen, F, Cl, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl and C 1 –C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

8. A compound according to claim 7 , wherein R 9 and R 10 each independently is selected from among hydrogen, F and CH 3 .

9. A compound according to claim 1 , wherein R 1 is selected from among hydrogen, F, Cl, Br, I, substituted C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the haloalkyl and heteroalkyl groups are optionally substituted.

10. A compound according to claim 9 , wherein R 11 is selected from among hydrogen, F, Cl, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl and C 1 –C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

11. A compound according to claim 9 , wherein R 1 is hydrogen or F.

12. A compound according to claim 1 , wherein Y is O or S.

13. A compound according to claim 12 , wherein Y is O.

14. A compound according to claim 1 , wherein R 11 is selected from among F, Cl, CN, OR 14 , NR 14 R 13 and SR 14 .

15. A compound according to claim 14 , wherein R 11 is selected from among F, Cl, OR 14 , SR 14 and NR 14 R 13 .

16. A compound according to claim 15 , wherein R 11 is selected from among F, Cl, OR 14 and SR 14 .

17. A compound according to claim 16 , wherein R 11 is OR 14 .

18. A compound according to claim 1 , wherein R 12 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted.

19. A compound according to claim 18 , wherein R 12 is selected from among hydrogen, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl and C 1 –C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

20. A compound according to claim 1 , wherein R 13 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted.

21. A compound according to claim 20 , wherein R 13 is selected from among hydrogen, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl and C 1 –C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

22. A compound according to claim 1 , wherein:

R 3 and R 4 each independently is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; or

R 3 and R 5 taken together form a bond; or

R 4 and R 6 taken together form a four to six membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring are optionally substituted.

23. A compound according to claim 22 , wherein R 3 and R 4 each independently is selected from among hydrogen, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl and C 1 –C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

24. A compound according to claim 1 , wherein:

R 5 and R 7 each independently is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; or

R 5 and R 7 taken together form a bond.

25. A compound according to claim 24 , wherein R 5 and R 7 each independently is selected from among hydrogen, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl and C 1 –C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

26. A compound according to claim 1 , wherein:

R 6 and R 8 each independently is selected from are hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, heteroaryl and aryl groups are optionally substituted; or

R 6 and R 8 taken together form a three to eight membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted.

27. A compound according to claim 26 , wherein:

R 6 and R 8 each independently is selected from among hydrogen, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, C 1 –C 4 heteroalkyl, heteroaryl and aryl, wherein alkyl, haloalkyl, heteroaryl and aryl are optionally substituted; or

R 6 and R 8 taken together form a four to six membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted.

28. A compound according to claim 1 , wherein:

R 1 is selected from among hydrogen, F, Cl, Br, I, substituted C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the haloalkyl and heteroalkyl groups are optionally substituted;

R 2 is selected from among hydrogen, F, Cl, Br, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , substituted C 1 –C 6 alkyl; C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein haloalkyl and heteroalkyl groups are optionally substituted; and

29. A compound according to claim 28 , wherein:

R 5 through R 8 each independently is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; or

R 6 and R 8 taken together form a four to six membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring are optionally substituted.

30. A compound according to claim 29 , wherein:

R 9 and R 10 each independently is selected from among hydrogen, F, Cl, Br, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 12 is selected from among hydrogen, C 1 –C 6 alkyl C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted; and

R 14 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, C(O)R 15 , CO 2 R 15 and C(O)NR 15 R 16 , wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

31. A compound according to claim 30 , wherein Y is O or S.

32. A compound according to claim 1 , wherein said compound is selected from among:

6-Methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Isopropyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Allyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-(4-Methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

4-Trifluoromethyl-5,6,7,8-tetrahydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

4-Trifluoromethyl-5,6,7,8,9,10-hexahydrocyeloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4e,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;

(±)-4e,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]-quinolin-2(1H)-one;

(±)-5,6-Dihydro-5,6-cis-dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-furanylmethyl)-4trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-thiophenemethyl)-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2-methylpropyl)-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoro-ethyl)-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2-dimethoxyethyl)-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclohexano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,8,9,9a(cis),10-Octahydro-10-(2,2,2-trifluoroethyl)-4-trifluoromethylcycloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-(4-nitrophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-(4-dimethylaminophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-(3-trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-(4-fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-Dihydro-5-phenyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2-dimethoxyethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-isopropyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo-[3,2-f]quinolin-2(1H)-one;

(±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo-[3,2-f]quinolin-2(1H)-one;

(±)-5,6-Dihydro-5-(2-ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)one;

5,6,7,8-Tetrahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]-quinolin-2(1H)-one;

8-Trifluoroethyl-4-trifluoromethyl-6,8-dihydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

9-Trifluoroethyl-4-trifluoromethyl-9H-benzo[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

5-(3-Trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-(4-Fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

5-(2-Ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

5-Methyl-6-(1-hydroxyethyl)-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

5-Methyl-6-acetyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Formyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Acetyloxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

2-Acetyloxy-5-hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinoline;

6-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Ethoxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

(+)-6-(1-Methoxyethyl)-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

7-Allyl-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one;

6-Ethyl-7-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one;

7-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one;

7-(2-Hydroxyethyl)-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one;

(+)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;

(−)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-Dihydro-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-Dihydro-7-ethyl-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one;

5-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one;

6-Formyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one; and

5,6-Dimethyl-7-(2,2-difluorovinyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one.

33. A compound according to claim 1 , wherein said compound is selected from the group consisting of:

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]-quinolin-2(1H)-one;

(±)-5,6-Dihydro-5,6-cis-dimethyl-7-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-trifluoromethylcyclopentano-[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethyl-cyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclohexano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(±)-5,6-cis-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;

5,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

5,6,7,8-Tetrahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]-quinolin-2(1H)-one;

6-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;

(+)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]-pyrrolo[3,2-f]quinolin-2(1H)-one; and

(−)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one.

34. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and

a compound of formula:

wherein:

R 1 is selected from among hydrogen, F, Cl, Br, I, NO 2 , OR 12 , SR 12 , SOR 12 , SO 2 R 12 , NR 12 R 13 , C 1 –C 8 alkyl, C 1 –C 8 haloalkyl and C 1 –C 8 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 2 is selected from among F, Cl, Br, I, CF 3 , CHF 2 , CH 2 F, CF 2 Cl, CN, CF 2 OR 12 , CH 2 OR 12 , OR 12 , SR 12 , SOR 12 , SO 2 R 12, NR 12 R 13 , substituted C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, C 2 –C 8 alkenyl and C 2 –C 8 alkynyl, wherein the haloalkyl, heteroalkyl, alkenyl and alkynyl groups are optionally substituted;

R 3 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 5 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloroalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 7 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloroalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 3 and R 5 taken together form a bond; or

R 5 and R 7 taken together form a bond; or

R 4 and R 6 taken together form a three- to eight-membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted; or

R 6 and R 8 taken together form a three- to eight-membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted;

R 11 is selected from among hydrogen, F, Br, Cl, I, CN, OR 14 , NR 14 R 13 and SR 14 ;

R 12 and R 13 each independently is selected from among hydrogen, C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted;

R 14 is selected from among hydrogen, C 1 –C 8 alkyl, C 1 –C 8 haloalkyl, C 1 –C 8 heteroalkyl, aryl, heteroaryl, C(O)R 15 , CO2R 15 and C(O)NR 15 R 16 , wherein the alkyl, haloalkyl, heteroalkyl, aryl and heteroaryl groups are optionally substituted;

W is O or S;

X is N{R 14 };

Y is selected from among O, S, N{R 12 } and N{OR 12 };

Z is N{R 12 };

n is 0; and

m is 0 or 1;

or a pharmaceutically acceptable salts thereof.

35. A pharmaceutical composition according to claim 34 , wherein the carrier is suitable for enteral, parenteral, suppository, or topical administration.

36. A pharmaceutical composition according to claim 34 , wherein R 1 is selected from among hydrogen, F, Cl, Br, I, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

37. A pharmaceutical composition according to claim 36 , wherein R 1 is selected from among hydrogen, F, Cl, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl and C 1 –C 4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

38. A pharmaceutical composition according to claim 34 , wherein R 2 is selected from among F, Cl, Br, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , substituted C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the haloalkyl and heteroalkyl groups are optionally substituted.

39. A pharmaceutical composition according to claim 38 , wherein R 2 is selected from among F, Cl, Br, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , substituted C 1 –C 4 alkyl, C 1 –C 4 haloalkyl and C 1 –C 4 heteroalkyl, wherein the haloalkyl and heteroalkyl groups are optionally substituted.

40. A pharmaceutical composition according to claim 34 , wherein R 9 and R 10 each independently is selected from among hydrogen, F, Cl, Br, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

41. A pharmaceutical composition according to claim 40 , wherein R 9 and R 10 each independently is selected from among hydrogen, F and CH 3 .

42. A pharmaceutical composition according to claim 34 , wherein R 11 is selected from among hydrogen, F, Cl, CN, OR 14 , NR 14 R 13 and SR 14 .

43. A pharmaceutical composition according to claim 42 , wherein R 11 is selected from among hydrogen, F, Cl, OR 14 , SR and NR 14 R 13 .

44. A pharmaceutical composition according to claim 34 , wherein Y is O or S.

45. A pharmaceutical composition according to claim 34 , wherein R 12 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted.

46. A pharmaceutical composition according to claim 34 , wherein:

R 3 and R 5 taken together form a bond; or

R 4 and R 6 taken together form a four to six membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted.

47. A pharmaceutical composition according to claim 34 , wherein:

R 5 and R 7 taken together form a bond.

48. A pharmaceutical composition according to claim 34 , wherein:

R 6 and R 8 each independently is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, heteroaryl and aryl groups are optionally substituted; or

R 6 and R 8 taken together form a three to eight membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted.

49. A pharmaceutical composition according to claim 34 , wherein:

R 1 is selected from among hydrogen, F, Cl, Br, I, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 2 is selected from among F, Cl, Br, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , substituted C 1 –C 6 alkyl; C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the haloalkyl and heteroalkyl groups are optionally substituted; and

50. A pharmaceutical composition according to claim 49 , wherein:

R 6 and R 8 taken together form a four to six membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted.

51. A pharmaceutical composition according to claim 50 , wherein:

R 12 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted; and

52. A pharmaceutical composition according to claim 50 , wherein Y is O or S.

53. A compound of formula:

wherein:

R 1 is selected from among hydrogen, F, Cl, Br, I, NO 2 , OR 12 SR 12 , SOR 12 , SO 2 R 12 , NR 12 R 12 , C 1 –C 8 alkyl, C 1 –C 8 haloalkyl and C 1 –C 8 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 2 is selected from among hydrogen F, Cl, Br, CF 3 , CHF 2 , CH 2 F, CF 2 Cl, CF 2 OR 12 , CH 2 OR, OR 12 , SR 12 , SOR 12 , SO 2 R 12 , NR 12 R 13 , substituted C 1 –C 6 alkyl C 1 –C 6 haloalkyl, and C 1 –C 6 heteroalkyl, wherein the haloalkyl, and heteroalkyl groups are optionally substituted;

R 3 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 4 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 5 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 6 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, heteroaryl and aryl groups are optionally substituted;

R 7 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;

R 8 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, heteroaryl and aryl groups are optionally substituted; or

R 3 and R 5 taken together form a bond; or

R 5 and R 7 taken together form a bond; or

R 4 and R 6 taken together form a three- to eight-membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted; or

R 6 and R 8 taken together form a three- to eight-membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted;

R 11 is selected from among hydrogen, F, Br, Cl, I, CN, OR 14 , NR 14 R 13 and SR 14 ;

W is O or S;

X is N{R 14 };

Y is selected from the groups of O, S, N{R 12 } and NO{R 12 };

Z is N{R 12 };

n is 0; and

m is 0 or 1;

or a pharmaceutically acceptable salts thereof.

54. A compound according to claim 53 , wherein R 1 is selected from among hydrogen, F, Cl, Br, I, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

55. A compound according to claim 53 , wherein R 9 and R 10 each independently is selected from among hydrogen, F, Cl, Br, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl and C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted.

56. A compound according to claim 53 , wherein R 11 is selected from among F, Cl, CN, OR 14 , NR 14 R 13 and SR 14 .

57. A compound according to claim 53 , wherein Y is O or S.

58. A compound according to claim 53 , wherein R 12 is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted.

59. A compound according to claim 53 , wherein:

R 3 and R 5 taken together form a bond; or

R 4 and R 6 taken together form a four to six membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted.

60. A compound according to claim 34 , wherein:

R 5 and R 7 each independently is selected from among hydrogen, C 1 –C 6 alkyl, C 1 –C 6 haloalkyl, C 1 –C 6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; or

R 5 and R 7 taken together form a bond.

61. A compound according to claim 34 , wherein:

R 6 and R 8 taken together form a three to eight membered saturated or unsaturated carbocyclic ring, wherein the carbocyclic ring is optionally substituted.

Assignments (1)

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 →