HSP90 INHIBITORS CONTAINING A ZINC BINDING MOIETY
First Claim
Patent Images
1. A compound represented by formula I or II:
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or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Cy and Cy1 are each independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl and substituted cycloalkyl;
X and Y are independently O, S, N, NR8 or CR8, where R8 is hydrogen, acyl, aliphatic or substituted aliphatic;
W is hydrogen, hydroxy, substituted hydroxy, amino, substituted amino, thiol, substituted thiol, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO2, N3, acyl, aliphatic or substituted aliphatic, C(O)W10;
where W10 is OR′
, SR′ and
NR7R8, wherein R7 is hydrogen, OR′
, aliphatic or substituted aliphatic;
R′
is hydrogen, aliphatic, substituted aliphatic or acyl; and
R8 is hydrogen, acyl, aliphatic or substituted aliphatic;
or R7 and R8 together with nitrogen atom to which they are attached to form a heterocyclic ring;
B is linker;
C is selected from;
(a)
where W1 is O or S;
Y1 is absent, N, or CH;
Z1 is N or CH;
R7 and R9 are independently hydrogen, OR′
, aliphatic or substituted aliphatic, wherein R′
is hydrogen, aliphatic, substituted aliphatic or acyl;
provided that if R7 and R9 are both present, one of R7 or R9 must be OR′ and
if Y is absent, R9 must be OR′
; and
R8 is hydrogen, acyl, aliphatic or substituted aliphatic;
(b)
where W1 is O or S;
J is O, NH or NCH3; and
R10 is hydrogen or lower alkyl;
(c)
where W1 is O or S;
Y2 and Z2 are independently N, C or CH; and
(d)
where Z1, Y1, and W1 are as previously defined;
R11 and R12 are independently selected from hydrogen or aliphatic;
R1, R2 and R3 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, NO2, N3, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
1 Assignment
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Abstract
The present invention relates to HSP90 inhibitors containing a zinc binding moiety and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.
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Citations
13 Claims
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1. A compound represented by formula I or II:
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or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Cy and Cy1 are each independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl and substituted cycloalkyl; X and Y are independently O, S, N, NR8 or CR8, where R8 is hydrogen, acyl, aliphatic or substituted aliphatic; W is hydrogen, hydroxy, substituted hydroxy, amino, substituted amino, thiol, substituted thiol, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO2, N3, acyl, aliphatic or substituted aliphatic, C(O)W10;
where W10 is OR′
, SR′ and
NR7R8, wherein R7 is hydrogen, OR′
, aliphatic or substituted aliphatic;
R′
is hydrogen, aliphatic, substituted aliphatic or acyl; and
R8 is hydrogen, acyl, aliphatic or substituted aliphatic;
or R7 and R8 together with nitrogen atom to which they are attached to form a heterocyclic ring;B is linker; C is selected from; (a)
where W1 is O or S;
Y1 is absent, N, or CH;
Z1 is N or CH;
R7 and R9 are independently hydrogen, OR′
, aliphatic or substituted aliphatic, wherein R′
is hydrogen, aliphatic, substituted aliphatic or acyl;
provided that if R7 and R9 are both present, one of R7 or R9 must be OR′ and
if Y is absent, R9 must be OR′
; and
R8 is hydrogen, acyl, aliphatic or substituted aliphatic;(b)
where W1 is O or S;
J is O, NH or NCH3; and
R10 is hydrogen or lower alkyl;(c)
where W1 is O or S;
Y2 and Z2 are independently N, C or CH; and(d)
where Z1, Y1, and W1 are as previously defined;
R11 and R12 are independently selected from hydrogen or aliphatic;
R1, R2 and R3 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, NO2, N3, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X1-X5 are independently N or CR21, where R21 is independently selected from hydrogen, hydroxy, substituted hydroxy, amino, substituted amino, halogen, substituted or unsubstituted alkoxy, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, and heteroarylalkyl;
substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted thiol, CF3, CN, NO2, N3, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroarylalkyl;
B1 is absent, O, S, SO, SO2, N(R8), CO, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic or aryl;
B2 is absent, O, S, SO, SO2, N(R8) or CO;
B3 is absent, O, S, SO, SO2, N(R8), CO, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;
B4 is absent, O, S, SO, SO2, N(R8), CO, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;
B5 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;
Cy, W, X, Y, R′ and
R8 are as previously defined in claim 1.
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3. A compound according to claim 2 wherein at least one of X1 to X5 is CR21, where R21 is heterocyclylalkyl.
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4. A compound according to claim 3 wherein at least one of X1 to X5 is CR21, where R21 is morpholinomethyl.
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5. A compound according to claim 1 represented by formula (VII) or (VIII):
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or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X1-X10 are independently N or CR21, where R21 is independently selected from hydrogen, hydroxy, substituted hydroxy, amino, substituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroarylalkyl;
substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted thiol, CF3, CN, NO2, N3, substituted carbonyl, sulfonyl, acyl, aliphatic, and substituted aliphatic;
B2 is absent, O, S, SO, SO2, N(R8) or CO;
W10 is OR′
, SR′
or NR7R8, wherein R7 and R8 are as previously defined in claim 1.
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6. A compound according to claim 1 represented by formula (IX):
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or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X1-X10 are independently N or CR21, where R21 is independently selected from hydrogen, hydroxy, substituted hydroxy, amino, substituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroarylalkyl;
substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted thiol, CF3, CN, NO2, N3, substituted carbonyl, sulfonyl, acyl, aliphatic, and substituted aliphatic;
B1 is CO, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
B2 is absent, O, S, SO, SO2, or N(R8);
W10 is OR′
, SR′
or NR7R8, wherein R7 and R8 are as previously defined in claim 1.
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7. A compound according to claim 1 selected from the compounds delineated in Table A or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:
TABLE A Compound # Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
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8. A pharmaceutical composition comprising as an active ingredient a compound of claim 1 and a pharmaceutical acceptable carrier.
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9. A method of treating cell proliferative disorder that requires or is facilitated by expression of an HSP90 protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 8.
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10. The method of claim 9, wherein said cell proliferative disorder is selected from the group consisting of papilloma, blastoglioma, Kaposi'"'"'s sarcoma, melanoma, non-small cell lung cancer, ovarian cancer, prostate cancer, colon cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, renal cell carcinoma, gastric cancer, hepatocellular carcinoma, neuroblastoma, leukemia, lymphoma, vulcar cancer, Hodgkin'"'"'s disease and Burkitt'"'"'s disease.
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11. A method of treating an HDAC-mediated disease comprising administering to a subject in need thereof a pharmaceutical composition of claim 8.
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12. A method of treating cell proliferative disorder that relates to expression of an HSP90 protein and HDAC comprising administering to a subject in need thereof a pharmaceutical composition of claim 8.
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13. A method for the treatment or prophylaxis of cancer in a subject in need thereof, comprising administering to the subject a compound of claim 8.
Specification
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Current AssigneeCuris, Inc.
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Original AssigneeCuris, Inc.
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InventorsZhai, Haixiao, Cai, Xiong, Qian, Changgeng
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Application NumberUS12/207,751Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/235.800CPC Class CodesA61P 35/00 Antineoplastic agentsC07D 261/18 Carbon atoms having three b...C07D 413/10 linked by a carbon chain co...C07D 413/14 containing three or more he...
