Cortistatin analogues and synthesis thereof
The present invention relates to analogs of cortistatin A, J, K, and L, having the general formula: I and salts thereof, wherein R 1 , R 2 , R 3 , R 4 , n, and m are as defined herein; processes for preparing such compounds and intermediates thereto; pharmaceutical compositions comprising such compounds; methods for treating a proliferative disease; methods for treating a disease associated with aberrant angiogenesis; methods for inhibiting angiogenesis; and processes for preparing cortistatin A, J, K, and L, and analogs thereof.
1. A compound of formula:
or a pharmaceutically acceptable salt thereof,
wherein:
each of the dashed lines independently represents the presence or absence of a bond;
each instance of m and n is 1;
R 1 is substituted or unsubstituted heteroaryl;
R 2 is C 1 -C 6 aliphatic;
R 3 is hydrogen;
R 4 is —N(R D ) 2 ; —NHC(═O)R D ; —NR A C(═O)N(R D ) 2 ; or —NR D C(═O)OR D ; and
R A is hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety, an aryl moiety, a heteroaryl moiety, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio moiety; and
each occurrence of R D is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, or heteroaryl.
2. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is substituted or unsubstituted heteroaryl;
X is hydrogen; and
each occurrence of R D is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl, aryl, or heteroaryl.
7. The compound of claim 6 , wherein each R D is independently hydrogen or C 1 -C 6 alkyl.
8. The compound of claim 6 , wherein each R D is independently C 1 -C 6 alkyl.
9. The compound of claim 6 , wherein each R D is methyl.
10. The compound of claim 1 , wherein R 4 is —N(R D ) 2 .
11. The compound of claim 1 , wherein R 4 is —N(R D ) 2 and each R D is independently hydrogen or C 1 -C 6 alkyl.
12. The compound of claim 1 , wherein R 4 is —N(R D ) 2 and each R D is methyl.
13. The compound of claim 1 , wherein R 2 is methyl.
14. The compound of claim 1 , wherein R 1 is substituted or unsubstituted isoquinolinyl.
15. The compound of claim 14 , wherein R 1 is substituted isoquinolinyl.
16. The compound of claim 14 , wherein R 1 is unsubstituted isoquinolinyl.
17. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
19. A method of treating cancer comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject suffering from cancer.