Sulfonylated heterocycles useful for modulation of the progesterone receptor

1. A compound of the structure:

wherein:

n is 1;

Z is CR 4 R 5 ;

R 1 is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3 to C 6 alkenyl, C 3 to C 6 substituted alkenyl, C 3 to C 6 alkynyl, and C 3 to C 6 substituted alkynyl;

R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, O—C 1 to C 6 substituted alkyl, —O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; or

R 2 and R 4 ; or R 2 and R 5 ; or R 3 and R 4 ; or R 3 and R 5 are joined to form a carbocyclic or heterocyclic ring containing from 3 to 8 atoms;

R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, (CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, O—C 1 to C 6 substituted alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;

X is halogen;

m and r are, independently, 0 to 2, provided that m+r=2;

p and q are, independently, 0 to 3, provided that p+q=3;

z is 0 to 10; and

R 9 is selected from the group consisting of H, C 1 to C 6 alkyl, C(O)O—C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, and substituted C 3 to C 6 cycloalkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

2. The compound according to claim 1 , wherein R 1 is C 1 to C 6 alkyl.

3. The compound according to claim 1 , wherein R 2 , R 3 , R 6 , or R 8 is H.

4. The compound according to claim 1 , wherein R 4 or R 5 is H or C 1 to C 6 alkyl.

5. The compound according to claim 1 , wherein R 7 is H or halogen.

6. The compound according to claim 1 , wherein R 9 is C 1 to C 6 alkyl.

7. The compound according to claim 1 , wherein:

R 1 is C 1 to C 6 alkyl;

R 2 , R 3 , R 6 , and R 8 are H;

R 4 and R 5 are, independently, H or C 1 to C 6 alkyl;

R 7 is H or halogen; and

R 9 is C 1 to C 6 alkyl.

8. The compound according to claim 1 , selected from the group consisting of 1-methyl-5-[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1H-pyrrole-2-carbonitrile; 5-[3,3-dimethyl-1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; 5-[1-(ethylsulfonyl)-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; 5-[1-(ethylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; 5-[1-(isopropylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; 1-methyl-5-[1-(propylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1H-pyrrole-2-carbonitrile; 5-[7-fluoro-1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; and 5-[1-(ethylsulfonyl)-7-fluoro-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; or a pharmaceutically acceptable salt or tautomer thereof.

9. A method of contraception, treating fibroids, uterine leiomyomata, endometriosis, dysfunctional bleeding, or polycystic ovary syndrome, providing hormone replacement therapy, stimulating food intake, synchronizing estrus, or treating cycle-related symptoms, said method comprising administering to a mammal in need thereof a compound of claim 1 .

10. A method for preparing a compound of formula I:

wherein:

n is 1;

Z is CR 4 R 5 ;

R 1 is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3 to C 6 alkenyl, C 3 to C 6 substituted alkenyl, C 3 to C 6 alkynyl, C 3 to C 6 substituted alkynyl;

R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, (CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, O—C 1 to C 6 substituted alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; or

R 2 and R 4 ; or R 2 and R 5 ; or R 3 and R 4 ; or R 3 and R 5 are joined to form a carbocyclic or heterocyclic ring containing from 3 to 8 atoms;

R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, (CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, O—C 1 to C 6 substituted alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;

X is halogen;

m and r are, independently, 0 to 2, provided that m+r=2;

p and q are, independently, 0 to 3, provided that p+q=3;

z is 0 to 10; and

R 9 is selected from the group consisting of H, C 1 to C 6 alkyl, C(O)O—C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, and substituted C 3 to C 6 cycloalkyl;

or a pharmaceutically acceptable salt or tautomer thereof;

said method comprising:

(a) reacting a cyanopyrrole boronic acid or a tin derivative thereof and a substituted heterocycle of the structure:

wherein, LG is a leaving group;

(b) sulfonylating the product of step (a); and (c) optionally converting the product of step (b) to a pharmaceutically acceptable salt thereof.

11. The method according to claim 10 , wherein the product of step (a) is of the structure:

wherein Z, R 2 , R 3 , R 6 , R 7 , R 8 , R 9 and n are as defined in claim 12 .

12. The method according to claim 10 , wherein said boronic acid is of the structure:

wherein R 9 is as defined in claim 12 .

13. A method for preparing a compound of the structure:

wherein:

n is 1;

Z is CR 4 R 5 ;

R 1 is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3 to C 6 alkenyl, C 3 to C 6 substituted alkenyl, C 3 to C 6 alkynyl, C 3 to C 6 substituted alkynyl;

R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, (CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, O—C 1 to C 6 substituted alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; or

R 2 and R 4 ; or R 2 and R 5 ; or R 3 and R 4 ; or R 3 and R 5 are joined to form a carbocyclic or heterocyclic ring containing from 3 to 8 atoms;

R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, (CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, O—C 1 to C 6 substituted alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;

X is halogen;

m and r are, independently, 0 to 2, provided that m+r=2;

p and q are, independently, 0 to 3, provided that p q=3;

z is 0 to 10; and

R 9 is selected from the group consisting of H, C 1 to C 6 alkyl, C(O)O—C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, and substituted C 3 to C 6 cycloalkyl;

or a pharmaceutically acceptable salt or tautomer thereof;

said method comprising:

(a) sulfonylating a compound of the structure:

(b) coupling the product of step (a) with a cyanopyrrole boronic acid or a tin derivative thereof; and (c) optionally converting the product of step (b) to a pharmaceutically acceptable salt thereof.

14. The method according to claim 13 , wherein the product of step (a) is of the structure:

wherein, LG is bromine and Z, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and n are as defined in claim 15 .

15. A method for preparing a compound of the structure:

wherein:

n is 1;

7 is CR 4 R 5 ;

R 1 is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3 to C 6 alkenyl, C 3 to C 6 substituted alkenyl, C 3 to C 6 alkynyl, C 3 to C 6 substituted alkynyl;

R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, (CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, O—C 1 to C 6 substituted alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; or

R 2 and R 4 ; or R 2 and R 5 ; or R 3 and R 4 ; or R 3 and R 5 are joined to form a carbocyclic or heterocyclic ring containing from 3 to 8 atoms;

R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, (CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, O—C 1 to C 6 substituted alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;

X is halogen;

m and r are, independently, 0 to 2, provided that m+r=2;

p and q are, independently, 0 to 3, provided that p+q=3;

z is 0 to 10; and

R 9 is selected from the group consisting of H, C 1 to C 6 alkyl, C(O)O—C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, and substituted C 3 to C 6 cycloalkyl;

or a pharmaceutically acceptable salt or tautomer thereof;

said method comprising:

(a) sulfonylating a compound of the structure:

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

(c) coupling the product of step (b) with a cyanopyrrole boronic acid or a tin derivative thereof; and (d) optionally converting the product of step (c) to a pharmaceutically acceptable salt thereof.

16. The method according to claim 15 , wherein the product of step (a) is of the structure:

wherein Z, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and n are as defined in claim 17 .

17. The method according to claim 15 , wherein the product of step (b) is of the structure:

wherein, LG is bromine and Z, R 2 , R 3 , R 6 , R 7 , R 8 and n are as defined in claim 15 .