CORTISTATIN ANALOGUES AND SYNTHESES 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:
wherein:
each of the dashed lines independently represents the presence or absence of a bond;
m is an integer between 0 and 6, inclusive;
n is an integer between 0 and 8, inclusive;
each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ═O; ═N(R A ); ═S; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a 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;
R 2 is hydrogen or C 1 -C 6 aliphatic;
R 3 is hydrogen or C 1 -C 6 aliphatic;
each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C(═O)R D ; —CO 2 R D ; —CN; —SCN; —SR S ; —SOR A ; —SO 2 R D ; —NO 2 ; —N 3 ; ═O; ═N(R D ); ═S; —N(R D ) 2 ; —NHC(═O)R D ; —NR A C(═O)N(R D ) 2 ; —OC(═O)OR D ; —OC(═O)R D ; —OC(═O)N(R D ) 2 ; —NR D C(═O)OR D ; or —C(R D ) 3 ; wherein each occurrence of R D is independently a 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; heteroarylthio; a
moiety; or a
moiety wherein z is an integer between 2 and 10, inclusive; provided that the compound is not any of the following formulae:
and pharmaceutically acceptable salts thereof.
2 . The compound of claim 1 , wherein m is 1.
3 . The compound of claim 1 , wherein R 1 is aryl.
4 . The compound of claim 1 , wherein R 1 is heteroaryl.
5 . The compound of claim 4 , wherein R 1 is isoquinolinyl, naphthyl or quinazolinyl.
6 . The compound of claim 1 , wherein R 1 is alkyl.
7 . The compound of claim 1 , wherein R 2 is methyl.
8 . The compound of claim 1 , wherein R 3 is hydrogen.
9 . The compound of claim 1 , wherein n is 1, 2, or 3.
10 - 11 . (canceled)
12 . The compound of claim 1 , wherein R 4 is —OR D .
13 . The compound of claim 1 , wherein R 4 is —N(R D ) 2 .
14 . The compound of claim 13 , wherein each R D is methyl.
15 . (canceled)
16 . The compound of claim 1 of formula:
17 - 18 . (canceled)
19 . The compound of claim 1 of formula:
20 . The compound of claim 1 of formula:
21 . (canceled)
22 . The compound of claim 1 , wherein said compound is of formula:
23 . (canceled)
24 . The compound of claim 22 of formula:
25 - 26 . (canceled)
27 . The compound of claim 1 of formula:
28 - 61 . (canceled)
62 . A method of treating a condition associated with aberrant angiogenesis, comprising the step of administering a therapeutically effective amount of a compound of formula:
wherein:
each of the dashed lines independently represents the presence or absence of a bond;
m is an integer between 0 and 6, inclusive;
n is an integer between 0 and 8, inclusive;
each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ═O; ═N(R A ); ═S; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a 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;
R 2 is hydrogen or C 1 -C 6 aliphatic;
R 3 is hydrogen or C 1 -C 6 aliphatic;
each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C(═O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N 3 ; ═O; ═N(R D ); ═S; —N(R D ) 2 ; —NHC(═O)R D ; —NR A C(═O)N(R D ) 2 ; —OC(═O)OR D ; —OC(═O)R D ; —OC(═O)N(R D ) 2 ; —NR D C(═O)OR D ; or —C(R D ) 3 ; wherein each occurrence of R D is independently a 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; heteroarylthio; a
moiety; or a
moiety wherein z is an integer between 2 and 10, inclusive; provided that the compound is not any of the following formulae:
to a subject.
63 . A method of treating a proliferative disease, comprising the step of administering a therapeutically effective amount of a compound of formula:
wherein:
each of the dashed lines independently represents the presence or absence of a bond;
m is an integer between 0 and 6, inclusive;
n is an integer between 0 and 8, inclusive;
each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ═O; ═N(R A ); ═S; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a 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;
R 2 is hydrogen or C 1 -C 6 aliphatic;
R 3 is hydrogen or C 1 -C 6 aliphatic;
each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C(═O)R D ; —CO 2 R D ; —CN; —SCN; —SR S ; —SOR A ; —SO 2 R D ; —NO 2 ; —N 3 ; ═O; ═N(R D ); ═S; —N(R D ) 2 ; —NHC(═O)R D ; —NR A C(═O)N(R D ) 2 ; —OC(═O)OR D ; —OC(═O)R D ; —OC(═O)N(R D ) 2 ; —NR D C(═O)OR D ; or —C(R D ) 3 ; wherein each occurrence of R D is independently a 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; heteroarylthio; a
moiety; or a
moiety wherein z is an integer between 2 and 10, inclusive; provided that the compound is not any of the following formulae:
to a subject.
64 - 107 . (canceled)