Progesterone receptor modulators comprising pyrrole-oxindole derivatives and uses thereof

1. A compound of formula I:

wherein,

R 1 is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3 to C 6 alkenyl, or C 3 to C 6 alkynyl;

R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1 to C 2 alkyl, and substituted C 1 to C 2 alkyl; or

R 2 and R 3 are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;

n is 0 or 1;

R 4 is fluorine;

R 5 is hydrogen;

R 6 is hydrogen or halogen;

R 7 is hydrogen, alkyl, or halogen;

R 8 is hydrogen;

R 9 is hydrogen, alkyl, substituted alkyl, or COOR A ;

R A is alkyl or substituted alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein

R 1 is hydrogen or alkyl;

R 2 and R 3 are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;

n is 1.

3. The compound according to claim 1 , wherein R 2 or R 3 is methyl or ethyl.

4. The compound according to claim 1 , wherein:

R 1 is hydrogen;

R 2 and R 3 are C 1 to C 2 alkyl;

R 6 is fluorine;

R 7 is hydrogen; and

R 9 is alkyl.

5. The compound according to claim 1 , wherein R 9 is methyl or COOR A and R A is tert-butyl.

6. The compound according to claim 1 , wherein said compound is 5-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile.

7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

8. A pharmaceutically useful kit adapted for daily oral administration which comprises:

(a) a first phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel;

(b) a second phase of from 1 to 11 daily dosage units of a compound of claim 1 , each daily dosage unit containing said compound at a daily dosage of from about 2 to 50 mg; and

(c) a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo;

wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28.

9. A method for preparing a compound of claim 1 comprising:

(a) alkylating an optionally substituted oxindole;

(b) brominating the product of step (a); and

(c) coupling the product of step (b) with a 2-cyanopyrrole.

10. The method according to claim 9 , wherein said optionally substituted oxindole is of the structure:

11. The method according to claim 9 , wherein the product of step (a) is of the structure:

12. The method according to claim 9 , wherein the product of step (b) is of the structure:

13. The method according to claim 9 , wherein said cyanopyrrole is of the structure:

or

said cyanopyrrole is the product of the reaction of lithium diisopropylamide, a tri-alkylborate, and a pyrrole of the following structure:

14. A method for preparing a compound of claim 1 comprising:

(a) coupling a 5-bromo substituted oxindole and a pyrrole boronic acid containing a protecting group;

(b) converting the product of step a) to the nitrile; and

(c) removing said protecting group from the product of step b).

15. The method according to claim 14 , wherein said 5-bromo substituted oxindole is of the structure:

16. The method according to claim 14 , wherein said pyrrole boronic acid is of the structure:

17. The method according to claim 14 , wherein the product of step (b) is of the structure:

18. A method for preparing a compound of claim 1 , comprising:

(a) alkylating an optionally substituted oxindole of the structure:

(b) brominating the product of step a) to form a compound of the structure:

and

(c) coupling the product of step b) with a 2-cyanopyrrole of the structure:

said cyanopyrrole is the product of the reaction of lithium diisopropylamide, a tri-alkylborate, and a pyrrole of the following structure:

19. The compound according to claim 1 which is 5-(4′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-5′yl)-1-methyl-1H-pyrrole-2-carbonitrile.

20. A compound of formula I:

wherein,

R 1 is hydrogen, alkyl, substituted alkyl, cycloalkyl, C 3 to C 6 alkenyl, or C 3 to C 6 alkynyl;

R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1 to C 2 alkyl, and substituted C 1 to C 2 alkyl; or

R 2 and R 3 are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;

n is 0 or 1;

R 4 is hydrogen or halogen;

R 5 is hydrogen;

R 6 is hydrogen or halogen;

R 7 is hydrogen, alkyl, or halogen;

R 8 is hydrogen;

R 9 is hydrogen, alkyl, substituted alkyl, or COOR A ;

R A is alkyl or substituted alkyl;

or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 20 , wherein said compound is selected from the group consisting of 5-(7′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclobutane-1,3′-indol]-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-2-oxo-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; and 5-(3,3-diethyl-7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile.

22. The compound according to claim 20 , wherein

R 1 is hydrogen or alkyl;

R 2 and R 3 are taken together to form a ring and together contain —CH 2 —(CH 2 ) n —CH 2 —;

n is 1.

23. The compound according to claim 20 , wherein R 2 or R 3 is methyl or ethyl.

24. The compound according to claim 20 , wherein R 9 is methyl or COOR A and R A is tert-butyl.

25. The compound according to claim 20 , wherein said compound is selected from the group consisting of 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; tert-butyl 2-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate; tert-butyl 2-cyano-5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate; 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-2-carbonitrile; Methyl-[5-(5-cyano-1-methyl-1H-pyrrole-2-yl)-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate; 5-(1-ethyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-3,3-dimethyl-2-oxo-1-prop-2-yn-1-yl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-[7-fluoro-3,3-dimethyl-2-oxo-1-(2-phenylethyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1-benzyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-3,3-dimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-1-isobutyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(7-fluoro-1-isopropyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1-allyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1-cyclohexyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1-cyclopentyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile.

26. A pharmaceutical composition comprising a compound of claim 20 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

27. A pharmaceutically useful kit adapted for daily oral administration which comprises:

(a) a first phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel;

(b) a second phase of from 1 to 11 daily dosage units of a compound of claim 20 , each daily dosage unit containing said compound at a daily dosage of from about 2 to 50 mg; and

(c) a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo;

wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28.

28. A method for preparing a compound of claim 20 , comprising:

(a) alkylating an optionally substituted oxindole;

(b) brominating the product of step (a); and

(c) coupling the product of step (b) with a 2-cyanopyrrole.

29. The method according to claim 28 , wherein said optionally substituted oxindole is of the structure:

30. The method according to claim 28 , wherein the product of step (a) is of the structure:

31. The method according to claim 28 , wherein the product of step (b) is of the structure:

32. The method according to claim 28 , wherein said cyanopyrrole is of the structure:

or

said cyanopyrrole is the product of the reaction of lithium diisopropylamide, a tri-alkylborate, and a pyrrole of the following structure:

33. A method for preparing a compound of claim 20 , comprising:

(a) coupling a 5-bromo substituted oxindole and a pyrrole boronic acid containing a protecting group;

(b) converting the product of step a) to the nitrile; and

(c) removing said protecting group from the product of step b).

34. The method according to claim 33 , wherein said 5-bromo substituted oxindole is of the structure:

35. The method according to claim 33 , wherein said pyrrole boronic acid is of the structure:

36. The method according to claim 33 , wherein the product of step (b) is of the structure:

37. A method for preparing a compound of claim 20 , comprising:

(a) alkylating an optionally substituted oxindole of the structure:

(b) brominating the product of step a) to form a compound of the structure:

and

(c) coupling the product of step b) with a 2-cyanopyrrole of the structure:

said cyanopyrrole is the product of the reaction of lithium diisopropylamide, a tri-alkylborate, and a pyrrole of the following structure: