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US 8,273,785 B2Granted
Substituted 2-indolinone as PTK inhibitors containing a zinc binding moiety
AssigneeCuris, Inc.
InventorsXiong Cai, Changgeng Qian, Stephen Gould
Life of this patent
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Abstract
The present invention relates to substituted 2-indolinone containing zinc-binding moiety based derivatives that have enhanced or unique properties as inhibitors of protein tyrosine kinase (PTK) receptors and their use in the treatment of PTK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
Claims8
A compound represented by formula I:
- or a pharmaceutically acceptable salt prodrug or solvate thereof, wherein
- X1 is N or CR4, where R4 is hydrogen or aliphatic;
- L is absent or NH;
- Cy is optionally substituted pyrrolyl;
- G is O or S;
- B is selected from straight or branched, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, or alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), SO2, N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic;
- C is
- where W is O;
- Y is absent, N, or CH;
- Z is N;
- R7 is hydrogen, OR′ or aliphatic group, wherein R′ is hydrogen, aliphatic, substituted aliphatic or acyl;
- R9 is OH or O-acyl;
- and R8 is hydrogen, acyl, aliphatic, or substituted aliphatic;
- R20, R21 and R22 are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, CN, N3, NO2, sulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
- and
- R23 is hydrogen, acyl, aliphatic or substituted aliphatic.
13 more elements
A compound represented by formula III:
- or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein B1 is absent, O, S, SO, SO2, aryl, heteroaryl, or heterocylic, N(R8), CO;
- B2 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclic, N(R8), CO, SO, or SO2;
- B3 is absent, O, N(R8), CO, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, or heterocyclic;
- B4 is absent, O, S, SO, SO2, N(R8), or CO;
- B5 is absent, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, heterocyclic, heteroaryl or aryl;
- R′ is H or acyl;
- and R20, R21, and R22 are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, CN, N3, NO2, sulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
4 more elements
A compound selected from the compounds delineated in Table A or a pharmaceutically acceptable salt, prodrug or solvate thereof:
- TABLE A
- Compound No.
- Structure
- 1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 14
- 15
- 16
- 17
- 18
- 19
- 20
- 21
- 23
- 24
- 25
- 26
- 27
- 28
- 29
24 more elements
Dependencies are inferred from the claim text.