Substituted heterocycles and methods of use

1. A compound of Formula I

R 1 —X—W—A—Y—R  (I)

wherein R is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, H, —OH, alkylamino, substituted or unsubstituted alkyl, and substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl;

wherein R 1 is

 wherein ring T is phenyl; wherein Z is CH; wherein R 10 is one or more substituents selected from C 1-6 -alkoxy, C 1-6 -haloalkoxy, C 1-6 -alkylamino-C 1-6 -alkoxy, aryl-C 1-6 -alkoxy, heterocyclyl-C 1-6 -alkoxy, cycloalkyl-C 1-6 -alkoxy, heterocyclyl-C 1-6 -(hydroxyalkoxy), cycloalkyl-C 1-6 -(hydroxyalkoxy), aryl-C 1-6 -(hydroxyalkoxy), C 1-6 -alkoxyalkoxy, aryloxy-C 1-6 -alkoxy, heterocyclyloxy-C 1-6 -alkoxy, cycloalkyloxy-C 1-6 -alkoxy, aryloxy, heterocyclyloxy, and cycloalkyloxy;

wherein W is an substituted or unsubstituted phenyl;

wherein A is an substituted or unsubstituted pyrimidine or pyridazine ring;

wherein X is selected from O, S, NR 2 and CR 3 R 4 ;

wherein Y is a direct bond;

wherein R a is selected from H, alkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, R 5 R 5 N—(C═O)—, and R 5 —(═O)—; wherein R a is optionally substituted;

wherein R 2 is selected from H, alkyl, haloalkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, alkenyl, alkynyl and R 5 -carbonyl;

wherein R 3 and R 4 is each independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, R 6 and alkyl substituted with R 6 ;

wherein R 5 is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl;

wherein R 5a is selected from H, alkyl, haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, alkenyl, alkynyl and cycloalkyl;

wherein R 6 is selected from cyano, —OR 2 , —SR 2 , halo, —SO 2 R 2 , —C(═O)R 2 , —SO 2 NR 2 R 5 , —NR 5 C(═O)OR 2 , —NR 5 C(═O)NR 5 R 2 , NR 5 C(═O)R 2 , CO 2 R 2 , C(═O)NR 2 R 5 and —NR 2 R 5 ;

wherein R 6a is selected from cyano, —OR 2 , —SR 2 , halo, —SO 2 R 2 , —C(═O)R 2 , —SO 2 NR 2 R 5 , —NR 5 C(═O)OR 2 , —NR 5 C(═O)NR 5 R 2 , —NR 5 C(═O)R 2 , ——CO 2 R 2 , —C(═O)NR 2 R 5 and —NR 2 R 5 ;

wherein each alkyl, aryl, heteroaryl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, and alkoxy moiety of any R, R 1 , R 2 , R 3 , R 4 , R 5 , and R a is optionally substituted with one or more groups selected from halo, R 6a , —NH 2 , —OR 5a , —CO 2 H, (C 1 -C 6 )alkylamino, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )haloalkyl, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylamino-(C 1 -C 6 )alkyl, (C 1 -C 6 )hydroxyalkylamino, (C 1 -C 6 )alkylamino-(C 1 -C 6 )alkylamino, phenyl, and heterocyclyl;

and pharmaceutically acceptable salts thereof.

2. Compound of claim 1 ,

wherein R is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, H, —OH, alkylamino, substituted or unsubstituted alkyl, and substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl,

and pharmaceutically acceptable salts thereof.

3. Compound of claim 2 wherein R is selected from H, phenyl, 4-6 membered cycloalkyl, C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl; wherein R is substituted or unsubstituted.

4. Compound of claim 2 wherein R is optionally substituted phenyl.

5. Compound of claim 2 wherein R is 4-6 membered cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

6. Compound of claim 2 wherein R is selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, 3,3-dimethylpropyl and pentyl.

7. Compound of claim 1 wherein A is selected from

wherein R 2 is selected from H, C 1-3 -alkyl, aryl-C 1-3 -alkyl, and heterocyclyl-C 1-3 -alkyl; and wherein R 2a is selected from H and methyl;

and pharmaceutically acceptable salts thereof.

8. Compound of claim 2 wherein A is

9. Compound of claim 2 wherein R 1 is selected from

and wherein R 10 is selected from C 1-3 -alkoxy, C 1-3 -alkylamino-C 1-3 -alkoxy, 5-6 membered heterocyclyl-C 1-3 -alkoxy, C 4-6 -cycloalkyl-C 1-3 -alkoxy, 5-6 membered heterocyclyl-C 1-3 -(hydroxyalkoxy), C 3-6 -cycloalkyl-C 1-3 -(hydroxyalkoxy), C 1-2 -alkoxy-C 1-3 -alkoxy, phenyloxy-C 1-3 alkoxy, 5-6 membered heterocyclyloxy-C 1-3 -alkoxy, cycloalkyloxy-C 1-3 -alkoxy, 5-6 membered heterocyclyloxy, and C 3-6 -cycloalkyloxy.

10. Compound of claim 2 wherein R 1 is selected from 6,7-dimethoxy-4-quinolinyl, 6-methoxy-7-(dimethylaminopropoxy)-4-quinolinyl, 6-methoxy-7-(3-(morpholin-4-yl)propoxy)-4-quinolinyl, 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-quinolinyl, 6-methoxy-7-(2-hydroxy-3-(morpholin-4-yl)propoxy)-4-quinolinyl, 6-methoxy-7-(3-(1,2,4-triazol-1-yl)propoxy)-4-quinolinyl, 6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-4-quinolinyl, 6-methoxy-7-(3-(piperidin-4-yl)propoxy)-4-quinolinyl, 6,7-dimethoxy-4-quinazolinyl and 6-methoxy-7-(dimethylaminopropoxy)-4-quinazolinyl.

11. Compound of claim 2 wherein R is selected from H, ethyl, isopropyl, (CH 3 ) 3 CCH 2 —, ethenyl, and an unsubstituted or substituted ring selected from phenyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein X is —O—; and; and pharmaceutically acceptable salts thereof.

12. Compound of claim 2 wherein W is phenyl; and pharmaceutically acceptable salts thereof.

13. A compound of Formula II

wherein Y a is selected from a bond,

wherein Z is CH;

wherein R′ is selected from H, C 1-6 -alkyl, di-C 1-3 -alkylamino and an unsubstituted or substituted ring selected from phenyl;

wherein R 8 is selected from H, fluoro, chloro and methyl;

wherein R 9 is selected from H, methyl and fluoro;

wherein R 10a , R 10b , R 10c and R 10d is each independently selected from C 1-3 -alkoxy, C 1-3 -alkylamino-C 1-3 -alkoxy, 5-6 membered heterocyclyl-C 1-3 -alkoxy, C 4-6 -cycloalkyl-C 1-3 -alkoxy, 5-6 membered heterocyclyl-C 1-3 -(hydroxyalkoxy), C 3-6 -cycloalkyl-C 1-3 -(hydroxyalkoxy), phenyl-C 1-3 -(hydroxyalkoxy), C 1-2 -alkoxy-C 1-3 -alkoxy, phenyloxy-C 1-3 alkoxy, 5-6 membered heterocyclyloxy-C 1-4 -alkoxy, cycloalkyloxy-C 1-3 -alkoxy, 5-6 membered heterocyclyloxy, and C 3-6 -cycloalkyloxy; and

wherein R 11 is H or methyl;

and pharmaceutically acceptable salts thereof.

14. Compound of claim 13 , wherein R′ is selected from ethyl, isopropyl, isobutyl, (CH 3 ) 3 CCH 2 —, dimethylamino, and an unsubstituted or substituted ring selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-pyrrolidinyl, 2-pyrrolyl, 5-imidazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl; and

wherein R 10a and R 10d are both H; and pharmaceutically acceptable salts thereof.

15. Compound of claim 13 wherein R 11 is methyl; and pharmaceutically acceptable salts thereof.

16. Compound of claim 13 wherein R′ is selected from isobutyl, (CH 3 ) 3 CCH 2 —, dimethylamino, cyclopropyl, cyclopentyl, 1-pyrrolidinyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, and 4-(dimethylamino)phenyl; and pharmaceutically acceptable salts thereof.

17. Compound of claim 13 wherein R 8 is H; and pharmaceutically acceptable salts thereof.

18. Compound of claim 13 wherein R 9 is H, methyl or fluoro; and pharmaceutically acceptable salts thereof.

19. Compound of claim 13 and pharmaceutically acceptable salts thereof; wherein R 10a and R 10d are both H; and wherein R 10b and R 10c are independently selected from 4-morpholinopropoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, (4-methylpiperazin-1-yl)propoxy, 3-(4-methylpiperazin-1-yl)propoxy, 3-(1,2,4-triazol-1-yl)propoxy, triazinylpropoxy, 3-(piperidin-4-yl)propoxy, dimethylaminoethoxy, dimethylaminopropoxy and methoxy.

20. A compound of Formula V

wherein Y a is a direct bond,

wherein Z is CH;

wherein R′ is selected from H, C 1-6 -alkyl, di-C 1-3 -alkylamino and an unsubstituted or substituted phenyl, C 3-6 -cycloalkyl;

wherein R 8 is selected from H, fluoro, chloro and methyl;

wherein R 9 is selected from H, methyl and fluoro; and

wherein R 10a , R 10b , R 10c and R 10d is each independently selected from C 1-3 -alkoxy, C 1-3 -alkylamino-C 1-3 -alkoxy, 5-6 membered heterocyclyl-C 1-3 -alkoxy, C 4-6 -cycloalkyl-C 1-3 -alkoxy, 5-6 membered heterocyclyl-C 1-3 -(hydroxyalkoxy), C 3-6 -cycloalkyl-C 1-3 -(hydroxyalkoxy), C 1-2 -alkoxy-C 1-3 -alkoxy, phenyloxy-C 1-3 alkoxy, 5-6 membered heterocyclyloxy-C 1 q-alkoxy, cycloalkyloxy-C 1-3 -alkoxy, 5-6 membered heterocyclyloxy, and

C 3-6 -cycloalkyloxy;

and pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound as in any of claims 1 - 4 , 5 - 7 , 8 , 9 - 10 , 11 - 12 , 13 - 19 , 20 .

22. A method of treating lung, gastric, hemangioblastoma, colon, liver, and renal cancer in a subject, said method comprising administering an effective amount of a compound of claim 1 .

23. The method of claim 22 comprising a combination with a compound selected from antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and miscellaneous agents.

24. A method of reducing metastasis in a tumor in a subject, said method comprising administering an effective amount of a compound of claim 1 .

25. A method of reducing tumor size in a subject, said method comprising administering an effective amount of a compound of claim 1 .