5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-
View Patent ↗The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by Progesterone Receptor. Also provided are methods of making such compounds and pharmaceutical compositions.
1. A compound of the formula:
wherein:
R 1 is selected from the group of hydrogen, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, C 1 –C 4 heteroalkyl, COR 5 , CO 2 R 5 , SO 2 R 5 , and CONR 5 R 6 ;
R 2 and R 3 each independently is selected from the group of hydrogen, C 1 –C 6 alkyl, and C 1 –C 6 haloalkyl; or
R 2 and R 3 taken together form a cycloalkyl ring of from three to twelve carbons;
R 4 is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, and C 1 –C 4 heteroalkyl;
R 5 and R 6 each is independently selected from the group of hydrogen, C 1 –C 4 alkyl, C 1 –C 4 heteroalkyl, and C 1 –C 4 haloalkyl;
R 7 through R 9 each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , CO 2 R 5 , CONR 5 R 6 , C 1 –C 8 alkyl, C 1 –C 8 heteroalkyl, C 1 –C 8 haloalkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl;
R 10 through R 15 each independently is selected from the group of hydrogen, F, Cl, Br, OR 5 , C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, and C 1 –C 4 heteroalkyl; or
R 12 and R 14 taken together form a bond, when Y is CR 14 R 15 ; or
R 10 and R 14 taken together form a bond, when Z is CR 14 R 15 ;
Y and Z each independently is selected from the group of O, S, NR 6 and CR 14 R 15 ; and
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound of the formula:
wherein:
R 1 is selected from the group of hydrogen, C 1 –C 4 alkyl, COR 5 , CO 2 R 5 , and SO 2 R 5 ;
R 2 and R 3 each independently is selected from the group of C 1 –C 4 alkyl;
R 4 is selected from the group of hydrogen, F, Cl, Br, C 1 –C 4 alkyl, and C 1 –C4 haloalkyl;
R 5 and R 6 each is independently selected from the group of hydrogen, and C 1 –C 4 alkyl;
R 7 through R 9 each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 –C 8 alkyl, C 1 –C 8 heteroalkyl, and C 1 –C 8 haloalkyl;
R 10 through R 15 each independently is selected from the group of hydrogen, F, Cl, OR 5 , C 1 –C 4 alkyl, C 1 –C 4 haloalkyl; or
R 12 and R 14 taken together form a bond, when Y is CR 14 R 15 ; or
R 10 and R 14 taken together form a bond, when Z is CR 14 R 15 ;
Y and Z each independently is selected from the group of S, and CR 14 R 15 ; and
n is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 , wherein
R 1 is hydrogen;
R 2 and R 3 is CH 3 ;
R 4 is selected from the group of F, Cl, Br, CH 3 , and CF 3 ;
R 7 is hydrogen or F;
R 8 is selected from the group of H, CH 3 , OH, and OCH 3 ;
R 9 is selected from the group of hydrogen, F, Cl, Br, CN, OCH 3 , CH 3 , and CF 3 ;
R 10 , R 11 , R 13 , R 15 each independently is selected from the group of hydrogen, F, Cl, CH 3 , and CF 3 ; and
R 12 and R 14 taken together form a bond, when Y is CR 14 R 15 .
4. compound according to claim 1 , wherein said compound is selected from the group of:
9-Fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 10);
8-methoxy-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 13);
7,9-difluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 15);
7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 17);
7-fluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 19);
7,9-difluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 20);
7-fluoro-5-(1,3-dithio-2-cyclohexylidene)-1,2-dihydro-2,2-dimethyl-5H-chromeno[3,4-f]quinoline (compound 21); and
7-fluoro-5-(2-cyclohexenylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 23).
5. A compound of the formula:
wherein:
R 2 and R 3 each independently is selected from the group of C 1 –C 4 alkyl, and C 1 –C 4 haloalkyl;
R 4 is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, and C 1 –C 4 heteroalkyl;
R 5 is selected from the group of hydrogen, C 1 –C 4 alkyl, C 1 –C 4 heteroalkyl, and C 1 –C 4 haloalkyl;
R 7 and R 9 each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , C 1 –C 4 alkyl, C 1 –C 4 heteroalkyl, C 1 –C 4 haloalkyl, C 2 –C 4 alkenyl;
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
6. A compound of the formula:
wherein:
R 2 and R 3 are CH 3 ;
R 4 is selected from the group of F, Cl, Br, CH 3 , and CF 3 ;
R 5 is selected from the group of hydrogen, C 1 –C 4 alkyl, C 1 –C 4 heteroalkyl, and C 1 –C 4 haloalkyl;
R 7 is hydrogen or F;
R 9 selected from the group of hydrogen, F, Cl, Br, CN, OCH 3 , CH 3 , and CF 3 ;
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula:
wherein:
R 1 is selected from the group of hydrogen, C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, C 1 –C 4 heteroalkyl, COR 5 , CO 2 R 5 , SO 2 R 5 , and CONR 5 R 6 ;
R 2 and R 3 each independently is selected from the group of hydrogen, C 1 –C 6 alkyl, and C 1 –C 6 haloalkyl; or
R 2 and R 3 taken together form a cycloalkyl ring of from three to twelve carbons;
R 4 is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, and C 1 –C 4 heteroalkyl;
R 5 and R 6 each is independently selected from the group of hydrogen, C 1 –C 4 alkyl, C 1 –C 4 heteroalkyl, and C 1 –C 4 haloalkyl;
R 7 through R 9 each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , CO 2 R 5 , CONR 5 R 6 , C 1 –C 8 alkyl, C 1 –C 8 heteroalkyl, C 1 –C 8 haloalkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl;
R 10 through R 15 each independently is selected from the group of hydrogen, F, Cl, Br, OR 5 , C 1 –C 4 alkyl, C 1 –C 4 haloalkyl, and C 1 –C 4 heteroalkyl; or
R 12 and R 14 taken together form a bond, when Y is CR 14 R 15 ; or
R 10 and R 14 taken together form a bond, when Z is CR 14 R 15 ;
Y and Z each independently is selected from the group of O, S, NR 6 and CR 14 R 15 ;
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula:
wherein:
R 1 is selected from the group of hydrogen, C 1 –C 4 alkyl, COR 5 , CO 2 R 5 , and SO 2 R 5 ;
R 2 and R 3 each independently is selected from the group of C 1 –C 4 alkyl;
R 4 is selected from the group of hydrogen, F, Cl, Br, C 1 –C 4 alkyl, and C 1 –C 4 haloalkyl;
R 5 and R 6 each is independently selected from the group of hydrogen, and C 1 –C 4 alkyl;
R 7 through R 9 each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 –C 8 alkyl, C 1 –C 8 heteroalkyl, and C 1 –C 8 haloalkyl;
R 10 through R 15 each independently is selected from the group of hydrogen, F, Cl, OR 5 , C 1 –C 4 alkyl, C 1 –C 4 haloalkyl; or
R 12 and R 14 taken together form a bond, when Y is CR 14 R 15 ; or
R 10 and R 14 taken together form a bond, when Z is CR 14 R 15 ;
Y and Z independently is selected from the group of S, and CR 14 R 15 ; and
n is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition according to claim 8 , wherein
R 1 is hydrogen;
R 2 and R 3 is CH 3 ;
R 4 is selected from the group of F, Cl, Br, CH 3 , and CF 3 ;
R 7 is hydrogen or F;
R 8 is selected from the group of H, CH 3 , OH, and OCH 3 ;
R 9 selected from the group of hydrogen, F, Cl, Br, CN, OCH 3 , CH 3 , and CF 3 ;
R 10 , R 11 , R 13 , R 15 each independently is selected from the group of hydrogen, F, Cl, CH 3 , and CF 3 ; and
R 12 and R 14 taken together form a bond, when Y is CR 14 R 15 .
10. A compound according to claim 1 , wherein R 2 and R 3 each independently is selected from the group of hydrogen, C 1 –C 6 alkyl, and C 1 –C 6 haloalkyl.
11. A pharmaceutical composition according to claim 7 , wherein R 2 and R 3 each independently is selected from the group of hydrogen, C 1 –C 6 alkyl, and C 1 –C 6 haloalkyl.