US2006276489A1PendingUtilityA1
Inhibitors of Tubulin Polymerization
Est. expiryFeb 15, 2022(expired)· nominal 20-yr term from priority
C07D 495/04
56
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . A method of treating a patient with colon cancer, the method comprising administering to the patient an effective amount of a compound of the formula (1):
or a pharmaceutically acceptable salt thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent 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 ) s —NR 5 R 6 , 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 5 and R 6 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 alkoxy, 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 5 and R 6 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 5 R 6 , 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 method of claim 1 wherein R 2 is H.
3 . The method 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 method 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 method of claim 1 wherein L is a covalent bond.
6 . The method of claim 1 wherein L is C 1 -C 6 alkyl.
7 . The method of claim 1 wherein L is —(CH 2 ) 0-1 C(H)(R 5 )—.
8 . The method 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 method 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 method 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 method 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 method 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 R, 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 method 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 —N 30 R 31 R, 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 method 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 —N 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 . The method of claim 1 selected from the group consisting of:
16 . The method of claim 15 selected from the group consisting of:
17 . The method of claim 16 selected from the group consisting of:
18 . The method of claim 17 selected from the group consisting of:Join the waitlist — get patent alerts
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