US 8,618,302 B2 · Methods and compositions of targeted drug development

Abstract

Provided herein are compounds having anti-proliferative effect. Also provided are compounds that can modulate the activity of multi-domain proteins comprising a dimerization arm and interdomain tether, such as EGFR, where an untethered, extended conformation is the active state and a tethered conformation is the inactive state, resulting in an autoinhibited configuration. Also provided are methods and pharmacophores for identifying such compounds. Other aspects provide methods or therapeutic treatment for proliferative diseases, disorders, or conditions, such as those associated with EGFR.

A compound having a formula of:

or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
X is selected from the group consisting of:
hydrogen, 2-Methyl, 5-Chloro, 5-Nitro, and 6-Hydroxyl;
R1 is selected from the group consisting of:
(i) a 2-Pyridyl ring of Formula (3)
wherein
R23 is selected from the group consisting of hydrogen;
fluoro;
chloro;
trifluoromethyl;
methyl;
ethyl;
and methoxy;
R3 is selected from the group consisting of hydrogen;
fluoro;
chloro;
methyl;
ethyl;
methoxy;
a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms;
and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R24 is selected from the group consisting of:
hydrogen;
fluoro;
chloro;
and trifluoromethyl;
and
R4 is selected from the group consisting of hydrogen;
methyl;
a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms;
and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(ii) a 3-Pyridyl ring of Formula (4)
wherein R5, R6, and R7 are independently selected from the group consisting of:
hydrogen, a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
Aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
and
(iii) a 4-Pyridyl ring of Formula (5)
wherein R8 and R9 are independently selected from the group consisting of:
a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms;
and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
and
R2 is selected from the group consisting of:
(i) an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups independently selected from the group consisting of:
straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms;
alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
2,3-methylenedioxy;
3,4-methylenedioxy;
dialkylamino having formula —NR13R14 wherein R13 and R14 are independently selected from hydrogen or a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
trifluoromethyl;
trifluoromethoxy;
difluoromethoxy;
3,4-methylenedioxy;
2,3-methylenedioxy;
nitro;
and halogen;
wherein if R1 is a 3-Pyridyl ring of Formula (4) where each of R5, R6, and R7 are hydrogen, and R2 is a phenyl ring, the phenyl ring is substituted with one or more groups independently selected from the group consisting of:
a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
a heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms;
alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
2,3-methylenedioxy;
3,4-methylenedioxy;
dialkylamino having formula —NR13R14 wherein R13 and R14 are independently selected from hydrogen or a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
trifluoromethoxy;
difluoromethoxy;
3,4-methylenedioxy;
2,3-methylenedioxy;
and nitro;
(ii) a 2-Pyridyl ring substituted at 4- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of:
straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) an unsubstituted 3-Pyridyl ring or a 3-Pyridyl ring substituted at the 2-, 4- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of:
straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
and
(iv) an unsubstituted 4-Pyridyl ring or a 4-Pyridyl ring substituted at the 2- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of:
straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
wherein if each of R3, R4, R23, and R24 is hydrogen, then R2 is a substituted pyridyl ring or a phenyl substituted with straight chain or branched C-3 to C-4 lower alkyl optionally containing unsaturation;
C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms;
alkoxy —OR10 where R10 is a straight chain or branched C-3 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
2,3-methylenedioxy;
3,4-methylenedioxy;
dialkylamino having formula —NR13R14 wherein R13 and R14 are independently selected from hydrogen or a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
trifluoromethoxy;
difluoromethoxy;
3,4-methylenedioxy;
2,3-methylenedioxy;
or nitro;
wherein if one of R3, R4, R23, or R24 is methyl and the other three of R3, R4, R23, or R24 are hydrogen, then R2 is a substituted pyridyl ring or a phenyl substituted with straight chain or branched C-3 to C-4 lower alkyl optionally containing unsaturation;
C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms;
2,3-methylenedioxy;
3,4-methylenedioxy;
dialkylamino having formula —NR13R14 wherein R13 and R14 are independently selected from hydrogen or a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation;
trifluoromethyl;
trifluoromethoxy;
difluoromethoxy;
3,4-methylenedioxy;
or 2,3-methylenedioxy;
or
a stereoisomer or pharmaceutically acceptable salt thereof;
and
Formula (2) excludes the compound of Formula (1):

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Methods and compositions of targeted drug development

Life of this patent

Methods and compositions of targeted drug development

Life of this patent

Abstract

Claims26