Inhibitors to tubulin polymerization
View Patent ↗The invention relates to the inhibition of tubulin polymerization. The invention provides compounds and methods for inhibiting tubulin polymerization. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
1. A compound of the formula (1)
or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are independently selected from the group consisting of —H, halo, C 1 –C 6 alkyl, halogenated-C 1 –C 6 -alkyl, and —OR 4 , or
R 1 and R 2 together with the carbon to which they are attached form a heterocyclyl;
R 4 is selected from the group consisting of C 1 –C 6 alkyl, or
R 4 is aryl or aryl-C 1 –C 6 -alkyl, wherein the aryl portion is optionally substituted with one to four groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, —(CH 2 ) 5 —NR 30 R 31 , or
C 1 –C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxy, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 –C 8 acyl, C 2 –C 8 acylamino, C 1 –C 8 alkylthio, arylalkylthio, arylthio, C 1 –C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C 0 –C 6 N-alkyl carbamoyl, C 2 –C 15 N,N-dialkylcarbamoyl, C 3 –C 7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3 –C 7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, each of which is optionally substituted with one or more groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino or guanidine;
R 30 and R 31 are each independently hydrogen, cyano, oxo, carboxamido, amidino, C 1 –C 8 hydroxyalkyl, C 1 –C 3 alkylaryl, aryl-C 1 –C 3 alkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, aryl-C 1 –C 3 alkoxycarbonyl, C 2 –C 8 acyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein each optionally substituted with one more groups selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidine, or
R 30 and R 31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidine;
L is selected from the group consisting of a covalent bond, C 1 –C 6 alkyl, —C(O)—, and —(CH 2 ) 0-3 C(H)(R 5 )—;
R 5 is selected from the group consisting of C 1 –C 6 alkyl, aryl, aryl-C 1 –C 6 -alkyl, —R 6 —S—R 7 , —R 6 —C(O)OR 7 , and —R 6 —O—R 7 , wherein R 6 and R 7 are C 1 –C 6 alkyl;
R 3 is selected from the group consisting of H, C 1 –C 6 alkyl, hydroxy C 1 –C 6 alkyl, —OR 8 , —C(O)OR 9 , —N(R 10 )R 11 , or
R 3 is C 3 –C 8 -cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, each of which is optionally substituted with one to four groups selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, —(CH 2 ) s —NR 30 R 31 , or
C 1 –C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxy, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 –C 8 acyl, C 2 –C 8 acylamino, C 1 –C 8 alkylthio, arylalkylthio, arylthio, C 1 –C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C 0 –C 6 N-alkyl carbamoyl, C 2 –C 15 N,N-dialkylcarbamoyl, C 3 –C 7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3 –C 7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, each of which is optionally substituted with one or more groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino or guanidine;
R 8 is C 1 –C 6 alkyl or hydroxy C 1 –C 6 alkyl; and
R 9 , R 10 , and R 11 are C 1 –C 6 alkyl.
2. The compound of claim 1 wherein R 2 is H.
3. The compound of claim 1 wherein R 1 and R 2 are independently selected from the group consisting of H, halogen, C 1 –C 6 alkyl, and —OR 4 , wherein R 4 is C 1 –C 6 alkyl, or wherein R 1 and R 2 together with the carbon to which they are attached form a heterocyclyl moiety.
4. The compound of claim 1 wherein R 1 and R 2 are independently selected from the group consisting of H, —Cl, —CH 3 , and —OCH 3 , or wherein R 1 and R 2 together with the carbon to which they are attached form a 5- or 6-membered heterocyclyl moiety.
5. The compound of claim 1 wherein L is a covalent bond.
6. The compound of claim 1 wherein L is C 1 –C 6 alkyl.
7. The compound of claim 1 wherein L is —(CH 2 ) 0-1 C(H)(R 5 )—.
8. The compound of claim 5 wherein
R 3 is selected from the group consisting of H, hydroxy alkyl, or
R 3 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one to four groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, —(CH 2 ) s —NR 30 R 31 , or
C 1 –C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxy, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 –C 8 acyl, C 2 –C 8 acylamino, C 1 –C 8 alkylthio, arylalkylthio, arylthio, C 1 –C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C 0 –C 6 N-alkyl carbamoyl, C 2 –C 15 N,N-dialkylcarbamoyl, C 3 –C 7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3 –C 7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, each of which is optionally substituted with one or more groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino or guanidine.
9. The compound of claim 8 wherein
R 3 is H, or
R 3 is C 3 –C 6 cycloalkyl, 5- to 6-membered heterocyclyl, or aryl, each of which is optionally substituted with one to four groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, —(CH 2 ) s —NR 30 R 31 , or
C 1 –C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxy, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 –C 8 acyl, C 2 –C 8 acylamino, C 1 –C 8 alkylthio, arylalkylthio, arylthio, C 1 –C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C 0 –C 6 N-alkyl carbamoyl, C 2 –C 15 N,N-dialkylcarbamoyl, C 3 –C 7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3 –C 7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, each of which is optionally substituted with one or more groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino or guanidine.
10. The compound of claim 9 wherein
R 3 is selected from the group consisting of cyclopropyl, benzyl, or
R 3 is benzyl optionally substituted with one to four groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, —(CH 2 ) s —NR 30 R 31 , or
C 1 –C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxy, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 –C 8 acyl, C 2 –C 8 acylamino, C 1 –C 8 alkylthio, arylalkylthio, arylthio, C 1 –C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C 0 –C 6 N-alkyl carbamoyl, C 2 –C 15 N,N-dialkylcarbamoyl, C 3 –C 7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3 –C 7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, each of which is optionally substituted with one or more groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino or guanidine.
11. The compound of claim 10 wherein R 3 is benzyl optionally substituted with one to three substituents independently selected from the group consisting of —CH 3 , —CO 2 H, —CO 2 CH 2 CH 3 , —OCH 3 , —CF 3 , —CN, —NO 2 , —SO 2 NH 2 , and —Cl.
12. The compound of claim 6 wherein
R 3 is selected from the group consisting of H, —OR 8 , —C(O)OR 9 , and —N(R 10 )R 11 , or
R 3 is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one to four groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, —(CH 2 ) s —NR 30 R 31 , or
C 1 –C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxy, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 –C 8 acyl, C 2 –C 8 acylamino, C 1 –C 8 alkylthio, arylalkylthio, arylthio, C 1 –C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C 0 –C 6 N-alkyl carbamoyl, C 2 –C 15 N,N-dialkylcarbamoyl, C 3 –C 7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3 –C 7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, each of which is optionally substituted with one or more groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino or guanidine.
13. The compound of claim 12 wherein
R 3 is selected from the group consisting of H, C 3 –C 6 cycloalkyl, 4- to 6-membered heterocyclyl, —OR 8 , or
R 3 is optionally benzyl, each of which is optionally substituted with one to four groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, —(CH 2 ) s —NR 30 R 31 , or
C 1 –C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxy, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 –C 8 acyl, C 2 –C 8 acylamino, C 1 –C 8 alkylthio, arylalkylthio, arylthio, C 1 –C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C 0 –C 6 N-alkyl carbamoyl, C 2 –C 15 N,N-dialkylcarbamoyl, C 3 –C 7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3 –C 7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, each of which is optionally substituted with one or more groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino or guanidine.
14. The compound of claim 13 wherein
R 3 is H or —OCH 3 , or
R 3 is 5- to 6-membered heterocyclyl or benzyl, each of which is optionally substituted with one to four groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, —(CH 2 ) s —NR 30 R 31 , or
C 1 –C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C 1 –C 8 alkyl, C 1 –C 8 alkenyl, C 1 –C 8 alkoxy, C 1 –C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 –C 8 acyl, C 2 –C 8 acylamino, C 1 –C 8 alkylthio, arylalkylthio, arylthio, C 1 –C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C 1 –C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C 0 –C 6 N-alkyl carbamoyl, C 2 –C 15 N,N-dialkylcarbamoyl, C 3 –C 7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3 –C 7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, each of which is optionally substituted with one or more groups independently selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino or guanidine.
15. A compound of claim 1 selected from the group consisting of:
and their pharmaceutically acceptable salts.
16. A compound of claim 15 selected from the group consisting of:
and their pharmaceutically acceptable salts.
17. A compound of claim 16 selected from the group consisting of:
18. A compound of claim 17 selected from the group consisting of:
and their pharmaceutically acceptable salts.
19. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutical acceptable carrier, excipient, or diluent.
20. A method of inhibiting tubulin polymerization in a mammal comprising administering an effective amount of the compound of any one of claims 1 – 18 to said mammal.
21. A method of inhibiting cell proliferation comprising contacting cells with an effective amount of the compound of any one of claims 1 – 18 .
22. A method for treating a patient with a cell proliferative disease or condition comprising administering to a patient in need thereof an effective amount of the compound of any one of claims 1 – 18 , wherein the cell proliferative disease or condition is lung cancer.