C4 monomethyl triterpenoid derivatives and methods of use thereof

1. A compound of the formula:

wherein:

X 1 and X 2 are independently hydrogen, halo, hydroxy, amino or oxo, provided that X 1 is not oxo when carbon atoms 12 and 13 are connected to one another with a double bond, further provided that X 2 is not oxo when carbon atoms 9 and 11 are connected to one another with a double bond;

R 1 is —CN, iodo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ;

R 2 is hydrogen or R 2 is absent when the atom to which it is bound forms part of a double bond;

R 2 ′ is hydrogen, ═CH 2 , alkyl (C≦8) , or substituted alkyl (C≦8) ;

R 3 and R 4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group R c ; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkylsulfonylamino (C≦8) , or substituted versions of any of these groups;

-alkanediyl (C≦8) -R b , -alkenediyl (C≦8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or thio; or

heteroaryl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —OC(O)NH-alkyl (C≦8) , —OC(O)CH 2 NHC(O)O-t-butyl, —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH,

 or thio; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —NH-alkoxy (C≦8) , —NH-heterocycloalkyl (C≦8) , —NHC(NOH)-alkyl (C≦8) , —NH-amido (C≦8) , or a substituted version of any of these groups;

R c and R 3 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≦4) ; or

R c and R 4 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≦4) ; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

2. The compound of claim 1 , further defined by the formula:

wherein:

R 1 is —CN, iodo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ;

R 2 is hydrogen or R 2 is absent when the atom to which it is bound forms part of a double bond; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkylsulfonylamino (C≦8) , or substituted versions of any of these groups;

-alkanediyl (C≦8) -R b , -alkenediyl (C≦8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or thio; or

heteroaryl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —OC(O)NH-alkyl (C≦8) , —OC(O)CH 2 NHC(O)O-t-butyl, —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH,

 or thio; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkyl-sulfonylamino (C≦8) , amido (C≦8) , —NH-alkoxy (C≦8) , —NH-heterocycloalkyl (C≦8) , —NHC(NOH)-alkyl (C≦8) , —NH-amido (C≦8) , or a substituted version of any of these groups; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

3. The compound of claim 2 , further defined by the formula:

wherein:

R 1 is —CN, iodo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , aryl-amino (C≦8) , aralkylamino (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkyl-sulfonylamino (C≦8) , or substituted versions of any of these groups;

-alkanediyl (C≦8) -R b , -alkenediyl (C≦8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or thio; or

heteroaryl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —OC(O)NH-alkyl (C≦8) , —OC(O)CH 2 NHC(O)O-t-butyl, —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH,

 or thio; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyl-oxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —NH-alkoxy (C≦8) , —NH-heterocycloalkyl (C≦8) , —NHC(NOH)-alkyl (C≦8) , —NH-amido (C≦8) , or a substituted version of any of these groups; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

4. The compound of claim 3 , further defined by the formula:

wherein:

R 1 is —CN, iodo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , amido (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkyl-sulfonylamino (C≦8) , or substituted versions of any of these groups;

-alkanediyl (C≦8) -R b , -alkenediyl (C≦8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or thio; or

heteroaryl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonyl-OC(O)CH 2 NHC(O)O-t-butyl, —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH,

 or thio; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —NH-alkoxy (C≦8) , —NH-heterocycloalkyl (C≦8) , —NHC(NOH)-alkyl (C≦8) , —NH-amido (C≦8) , or a substituted version of any of these groups; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

5. The compound of claim 4 , wherein R 1 is —CN.

6. The compound of claim 5 , wherein Y is —(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is hydrogen, hydroxy, amino, —NHOH,

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkylsulfonylamino (C≦8) , amido (C≦8) , —NH-alkoxy (C≦8) , —NH— heterocycloalkyl (C≦8) , —NHC(NOH)-alkyl (C≦8) , —NH-amido (C≦8) , or a substituted version of any of these groups other than hydrogen, hydroxy, amino, and —NHOH.

7. The compound of claim 6 , wherein R c is alkoxy (C≦8) .

8. The compound of claim 6 , wherein R c is alkylamino (C≦8) or substituted alkylamino (C≦8) .

9. The compound of claim 6 , wherein R c is heteroaryl (C≦8) .

10. The compound of claim 6 , wherein R c is heterocycloalkyl (C≦8) or substituted heterocycloalkyl (C≦8) .

11. The compound of claim 6 , wherein R c is —NH-heterocycloalkyl (C≦8) .

12. The of claim 6 , wherein m is 0.

13. The compound of claim 5 , wherein Y is -alkanediyl (C≦8) -R b .

14. The compound of claim 13 , wherein Y is —CH 2 —R b .

15. The compound of claim 13 , wherein R b is acyloxy (C≦8) or substituted acyloxy (C≦8) .

16. The compound of claim 13 , wherein R b is alkoxy (C≦8) or substituted alkoxy (C≦8) .

17. The compound of claim 13 , wherein R b is heteroaryl (C≦8) .

18. The compound of claim 5 , wherein Y is alkylsulfonylamino (C≦8) or substituted alkylsulfonylamino (C≦8) .

19. The compound of claim 5 , wherein Y is heteroaryl (C≦8) .

20. The compound of claim 5 , wherein Y is —NHC(O)R e , wherein R e is hydrogen, hydroxy, amino, alkyl (C≦8) , aryl (C≦8) , alkoxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , or substituted version of any of these groups other than hydrogen, hydroxy and amino.

21. The compound of claim 20 , wherein R e is alkyl (C≦8) or substituted alkyl (C≦8) .

22. The compound of claim 20 , wherein R e is aryl (C≦8) .

23. The compound of claim 20 , wherein R e is alkoxy (C≦8) .

24. The compound of claim 20 , wherein R e is alkylamino (C≦8) or dialkylamino (C≦8) .

25. The compound of claim 1 , selected from the group consisting of:

or a pharmaceutically acceptable salt or tautomer thereof.

26. A pharmaceutical composition comprising:

a) the compound of claim 1 ; and

b) an excipient.

27. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.