Isoxazole compounds as inhibitors of heat shock proteins

Patent metadata

Field	Value
Publication number	US-11234987-B2
Application number	US-201916528278-A
Country	US
Kind code	B2
Filing date	Jul 31, 2019
Priority date	Feb 11, 2003
Publication date	Feb 1, 2022
Grant date	Feb 1, 2022

Abstract

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers:wherein R1, is a group of formula (IA): —Ar1-(Alk1)p-(Z)r-(Alk2)s-Q, wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NRA—, —C(═S) NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA); and R3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

First claim

What is claimed is:

1. A method of treatment of a disease, in mammals, which is responsive to inhibition of HSP90 activity wherein the disease is selected from angiogenesis-related diseases; scrapie/CJD, and Huntingdon's disease comprising administering to the mammal an amount of a compound of formula (A) or (B) or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof effective to inhibit HSP90 activity:

wherein
R 1 is a group of formula (IB)

wherein in any compatible combination
R represents one or more optional substituents
Alk 1 and Alk 2 are optionally substituted divalent C 1 -C 6 alkylene or C 2 -C 6 alkenylene radicals,
p, r and s are independently 0 or 1,
Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO 2 —, —C(═O)O—, —C(═O)NR A —, —C(═S)NR A —, —SO 2 NR A —, —NR A C(═O)—, —NR A SO 2 — or —NR A — wherein R A is hydrogen or C 1 -C 6 alkyl, and
Q is hydrogen or an optionally substituted phenyl or pyridinyl radical;

R 2 is
(i) a group of formula (IAa):
—Ar 1 (Alk 1 ) p -(Z) r -(Alk 2 ) s -Q 1   (IAa)

wherein in any compatible combination
Ar 1 is an optionally substituted aryl or heteroaryl radical, and
Alk 1 , Alk 2 , p, r, s, Z, and R A are as defined in relation to R 1 ;
Q 1 is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
(ii) a carboxamide radical; or
(iii) a non-aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q 1 , wherein Q 1 , Alk 1 , Alk 2 , Z, p, r and s are as defined above in relation to group of formula (IAa); and
R 3 is carboxyl, carboxamide, or carboxyl ester group.

2. A method of treatment of a disease, in mammals, which is responsive to inhibition of HSP90 activity wherein the disease is selected from angiogenesis-related diseases; scrapie/CJD, and Huntingdon's disease comprising administering to the mammal an amount of a compound of formula (A) or (B) or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof, effective to inhibit HSP90 activity:

wherein
R 1 is a group of formula (IA):
—Ar 1 (Alk 1 ) p -(Z) r -(Alk 2 ) s -Q  (IA)

wherein in any compatible combination
Ar 1 is an optionally substituted aryl or heteroaryl radical,
Alk 1 and Alk 2 are optionally substituted divalent C 1 -C 6 alkylene or C 2 -C 6 alkenylene radicals,
p, r and s are independently 0 or 1,
Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO 2 —, —C(═O)O—, —C(═O)NR A —, —C(═S)NR A —, —SO 2 NR A —, —NR A C(═O)—, —NR A SO 2 — or —NR A — wherein R A is hydrogen or C 1 -C 6 alkyl, and
Q is hydrogen or an optionally substituted phenyl or pyridinyl radical;

R 2 is
(i) a group of formula (IAa):
-Ar 1 -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q 1   (IAa)

wherein in any compatible combination
Ar 1 is an optionally substituted aryl or heteroaryl radical, and
Alk 1 , Alk 2 , p, r, s, Z, and R A are as defined in relation to R 1 ;
Q 1 is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
(ii) a carboxamide radical; or
(iii) a non-aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q 1 wherein Q 1 , Alk 1 , Alk 2 , Z, p, r and s are as defined above in relation to group (IAa); and
R 3 is a carboxamide group.

3. The method as claimed in claim 1 wherein the compound is one of formula (A), or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof.

4. The method as claimed in claim 2 wherein R 1 has formula (IB)

wherein Alk 1 , Alk 2 , p, r, s, Z and Q are as defined in claim 2 , and R represents one or more optional substituents.

5. The method as claimed in claim 1 wherein the ring carbon atom adjacent the hydroxyl group in radical (IB) is unsubstituted.

6. The method as claimed in claim 1 wherein, in R 1 , each of p, r and s is 0, and Q is hydrogen.

7. The method as claimed in claim 2 wherein R 1 is optionally substituted phenyl.

8. The method as claimed in claim 6 wherein R 1 is 2-hydroxyphenyl, optionally further substituted by one or more of hydroxy, methyl, ethyl, methoxy, ethoxy, chloro, or bromo.

9. The method as claimed in claim 6 wherein R 1 is 2,4-dihydroxyphenyl, substituted in the 5-position by a small lipophilic substituent.

10. The method as claimed in claim 9 wherein the small lipophilic substituent is methyl, ethyl, isopropyl, isobutyl, tertbutyl, chloro, or bromo.

11. The method as claimed in claim 1 wherein, in R 1 , p, r, and s are each 0, and Q is an optionally substituted phenyl or pyridyl ring.

12. The method as claimed in claim 11 , wherein Q is an optionally substituted phenyl ring.

13. The method as claimed in claim 1 wherein, in R 1 , p and/or s are each 1 and r is 0.

14. The method as claimed in claim 1 wherein, in R 1 , each of p, r, and s is 1.

15. The method as claimed in claim 1 wherein, in R 1 , p and s are each 0 and r is 1.

16. The method as claimed in claim 1 wherein R 2 is a group of formula (IA).

17. The method as claimed in claim 16 wherein R 2 is optionally substituted 2-, 3-, or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl, or thiazolyl.

18. The method as claimed in claim 17 wherein optional substituents present in R 2 are selected from methoxy, ethoxy, methylenedioxy, ethylenedioxy, fluoro, chloro, bromo, and trifluoromethyl.

19. The method as claimed in claim 16 wherein R 2 is phenyl substituted in the 4 position by methoxy, ethoxy, fluoro, chloro, bromo, piperazinyl, N-methylpiperazinyl, or piperidinyl.

20. The method as claimed in claim 1 wherein R 2 has the partial structure:

wherein the substituted amino group —NR 10 R 11 is selected from morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, ethylamino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, methoxyethylamino, piperidin-4-yl, N-acetylpiperazinyl, methylsulfonylamino, thiomorpholinyl, thiomorpholinyldioxide, 4-hydroxyethylpiperidinyl, and 4-hydroxypiperidinyl.

21. The method as claimed in claim 1 wherein R 2 is a carboxamide group of formula —CONR B (Alk) n R A wherein
Alk is a divalent alkylene, alkenylene or alkynylene radical, and the Alk radical may be optionally substituted,
n is 0 or 1,
R B is hydrogen or a C 1 -C 6 alkyl or C 2 -C 6 alkenyl group
R A is hydroxy or optionally substituted carbocyclic, heterocyclyl,
or R A and R B taken together with the nitrogen to which they are attached to form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may optionally be substituted on one or more ring C or N atoms.

22. The method as claimed in claim 1 wherein R 3 is a carboxamide group —CONR B (Alk) n R A wherein
Alk is a divalent alkylene, al

Assignees

• Vernalis R&D Ltd
• The Institute Of Cancer Res
• Cancer Research Tech Ltd

Inventors

• Drysdale Martin James
• Dymock Brian William
• Finch Harry
• Webb Paul
• Mcdonald Edward
• James Karen Elizabeth
• Cheung Kwai Ming
• Matthews Thomas Peter

Classifications

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D261/08 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title