Methods of use of cyclopamine analogs

1. A method of treating cancer of the hematopoietic system comprising administering to a patient a therapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, alkyl, —OR, amino, sulfonamido, sulfamido, —OC(O)R 5 , —N(R 5 )C(O)R 5 or a sugar;

R 2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;

or R 1 and R 2 taken together form ═O, ═S, ═N(OR), ═N(R), ═N(NR 2 ), or ═C(R) 2 ;

R 3 is H, alkyl, alkenyl, or alkynyl;

R 4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR, —C(O)R 5 , —CO 2 R 5 , —SO 2 R 5 , —C(O)N(R 5 )(R 5 ), —[C(R) 2 ] q —R 5 , —[(W)—N(R)C(O)] q R 5 , —[(W)—C(O)] q R 5 , —[(W)—C(O)O] q R 5 , —[(W)—OC(O)] q R 5 , —[(W)—SO 2 ] q R 5 , —[(W)—N(R 5 )SO 2 ] q R 5 , —[(W)—C(O)N(R 5 )] q R 5 , —[(W)—O] q R 5 , —[(W)—N(R)] q R 5 , —W—NR 3 + X − or —[(W)—S] q R 5 ;

wherein each W is, independently, a diradical;

each q is independently for each occurrence 1, 2, 3, 4, 5, or 6;

X − is a halide;

each R 5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R) 2 ] p —R 6 ; wherein p is 0-6; or

any two occurrences of R 5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;

each R 6 is independently hydroxyl, —N(R)COR, —N(R)C(O)OR, —N(R)SO 2 (R), —C(O)N(R) 2 , —OC(O)N(R)(R), —SO 2 N(R)(R), —N(R)(R), —COOR, —C(O)N(OH)(R), —OS(O) 2 OR, —S(O) 2 OR, —OP(O)(OR)(OR), —NP(O)(OR)(OR), or —P(O)(OR)(OR); and

each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;

provided that when R 2 , R 3 , and R 4 are H; R 1 is not hydroxyl or a sugar; further

provided that when R 4 is hydroxyl, then R 1 is not a sugar or hydroxyl; further

provided that when R 4 is hydroxyl, then R 1 and R 2 together are not C═O.

2. The method of claim 1 , wherein R 1 is H, —OR, amino, sulfonamido, sulfamido, OC(O)R 5 or N(R 5 )C(O)R 5 .

3. The method of claim 1 , wherein R 1 is sulfonamido.

4. The method of claim 1 , wherein R 2 is H or heterocycloalkyl.

5. The method of claim 4 , wherein R 2 is H.

6. The method of claim 1 , wherein R 3 is H.

7. The method of claim 1 , wherein R 4 is H, alkyl, aralkyl, —[(W)—C(O)N(R)] q R 5 or —[(W)—N(R)C(O)] q R 5 .

8. The method of claim 7 , wherein R 4 is H.

9. The method of claim 1 , wherein said compound is epimerically pure.

10. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 , wherein the cancer of the hematopoietic system is myeloma, leukemia or lymphoma.

13. The method of claim 12 , wherein the myeloma is multiple myeloma.

14. The method of claim 12 , wherein the leukemia is acute lymphatic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia or chronic lymphocytic leukemia.

15. The method of claim 12 , wherein the lymphoma is non-Hodgkin's lymphoma.

16. The method of claim 11 , wherein the cancer of the hematopoietic system is myelodysplastic syndrome.

17. The method of claim 11 , wherein the compound is used in combination with one or more other chemotherapeutic agent, anti-cancer agent or anti-cancer treatment.

18. The method of claim 17 , wherein the chemotherapeutic agent is doxorubicin, dexamethasone, prednisolone, chlorambucil, methotrexate, vinblastine, bortezomib, melphalan, carmustine, cyclophosphamide, vincristine, lenalidomide, thalidomide, cytarabine, fludarabine or idarubicin.

19. The method of claim 17 , wherein the other anti-cancer agent is a corticosteroid or an interferon.

20. The method of claim 17 , wherein the other anti-cancer treatment is radiation or surgery.

21. The method of claim 11 , wherein the compound is administered locally to a tumor.

22. The method of claim 11 , wherein the compound is administered systemically.

23. The method of claim 11 , wherein the mode of administration of said compound is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intra-arterial, intrathecal, subcutaneous, buccal, or nasal.

24. The method claim 23 , wherein the mode of administration is oral, intravenous, or topical.

25. The method of claim 11 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.