Substituted thieno[2,3-d]pyrimidines as HSP90 inhibitors
Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, Cancer: wherein R 2 is a group of formula —(Ar 1 ) m -(Alk 1 ) P -(Z) r -(Alk 2) S -Q wherein Ar 1 is an optionally substituted aryl or heteroaryl radical, Alk′ and Alk 2 are optionally substituted divalent C 1 -C 3 alkylene or C 2 -C 3 alkenylene radicals, m, 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 carbocyclic or heterocyclic radical; R 3 is hydrogen, an optional substituent, or an optionally substituted (C 1 -C 6 )alkyl, aryl or heteroaryl radical; and R 4 is a carboxylic ester, carboxamide or sulfonamide group.
1. A compound of formula (I), or a salt or N-oxide thereof:
wherein
R 2 is a group of formula (IA):
—(Ar 1 ) m -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q (IA)
wherein
Ar 1 is an optionally substituted aryl or heteroaryl radical,
Alk 1 and Alk 2 are optionally substituted divalent C 1 -C 3 alkylene or C 2 -C 3 alkenylene radicals,
m, 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 carbocyclic or heterocyclic radical;
R 3 is hydrogen, an optional substituent, or an optionally substituted (C 1 -C 6 )alkyl, aryl or heteroaryl radical; and
R 4 is a carboxylic ester, carboxamide or sulfonamide group,
wherein when optionally substituted, substituent(s) is/are selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, mercapto(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, —COO R F , —CO R F , —SO 2 R F , —CONH 2 , —SO 2 NH 2 , —CONHR F , —SO 2 NHR F , —CONR F R G , —SO 2 NR F R G , —NH 2 , —NHR F , —NR F R G , —OCONH 2 , —OCONHR F , —OCONR F R G , —NHCOR F , —NHCOOR F , —NR F COOR F , —NHSO 2 OR F , NR G SO 2 OR F , —NHCONH 2 , —NR F CONH 2 , —NHCONHR G , —NR F CONHR G , —NHCONR F R G , or —NR F CONR F R G wherein R F and R G are independently a (C 1 -C 6 )alkyl group;
provided that (i) R 3 is not —NH 2 and (ii) when R 4 is —COOCH 3 and R 3 is hydrogen then R 2 is not —NH 2 , ethylamino, diethylamino, phenylamino, N(Ph)(C 2 H 5 ) wherein Ph is phenyl, pyrrolidin—1—yl or morpholin—4—yl and (iii) when R 4 is —CONH 2 and R 3 is hydrogen then R 2 is not —NH 2 .
2. A compound as claimed in claim 1 wherein R 3 is hydrogen.
3. A compound as claimed in claim 1 wherein m is 1, each of p, r and s is 0, and Q is hydrogen.
4. A compound as claimed in claim 3 wherein R 2 is optionally substituted phenyl, 2- or 3-thienyl, 2- or 3- furanyl, 2-, 3- or 4-pyridinyl, morpholinyl, or piperidinyl.
5. A compound as claimed in claim 3 wherein R 2 is phenyl, optionally substituted by methyl, ethyl, n- or isopropyl, vinyl, allyl, methoxy, ethoxy, n-propyloxy, benzyloxy, allyloxy, cyanomethoxy, chloro, bromo, cyano, formyl, methyl-, ethyl-, or n-propyl-carbonyloxy, methyl- or ethylaminocarbonyl.
6. A compound as claimed in claim 5 wherein optional substituents are in the 2- and/or 4- and/or 5-position of the phenyl ring.
7. A compound as claimed in claim 1 wherein m is 1, and p, r and s are 0, and Q is an optionally substituted carbocyclic or heterocyclic ring.
8. A compound as claimed in claim 1 wherein m is 1 and at least one of p, r and s is 1.
9. A compound as claimed in claim 1 wherein Ar 1 is an optionally substituted phenyl ring.
10. A compound as claimed in claim 1 wherein m is 0.
11. A compound as claimed in claim 8 wherein Alk 1 when present is optionally substituted —CH 2 , CH 2 CH 2 — or —CH═CH—; Alk 2 when present is optionally substituted —CH 2 , CH 2 CH 2 — or —CH═CH—; Z when present is —O—or —NH—; and Q is hydrogen.
12. A compound as claimed in claim 11 wherein Z and Alk 2 are present, and Alk 2 is substituted by di(C 1 -C 3 alkyl)amino or C 1 -C 3 alkoxy.
13. A compound as claimed in claim 1 wherein R 4 is a carboxamide group of formula —CONR B (Alk) n R D or a sulphonamide group of formula —SO 2 NR B (Alk) n R D wherein
Alk is an optionally substituted divalent alkylene, alkenylene or alkynylene radical,
n is 0 or 1,
R B is hydrogen or a C 1 -C 6 alkyl or C 2 -C 6 alkenyl group,
—R D is hydroxy or optionally substituted carbocyclic, or heterocyclyl, any of which heterocyclic rings may be substituted,
or —R D and R B taken together with the nitrogen to which they are attached form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may be optionally substituted on one or more ring C or N atoms: wherein optionally substituted is as defined in claim 1 .
14. A compound as claimed in claim 13 wherein
Alk is optionally substituted —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH═CH—, or —CH 2 CCCH 2 —,
R B is hydrogen or methyl, ethyl, n- or iso-propyl, or allyl,
—R D is hydroxy or optionally substituted phenyl, 3,4 methylenedioxyphenyl, pyridyl, furyl, thienyl, N-piperazinyl, or N-morpholinyl,
or —R D and R B taken together with the nitrogen to which they are attached form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may be optionally substituted on one or more ring C or N atoms: wherein optionally substituted is as defined in claim 13 .
15. A compound as claimed in claim 13 wherein R 4 is the carboxamide group of formula —CONR B (Alk) n R D .
16. A compound as claimed in claim 1 wherein R 4 is a carboxylic ester group of formula —COOR C wherein R C is a C 1 -C 6 alkyl or C 2 -C 6 alkenyl group, or an optionally substituted aryl or heteroaryl group, or an optionally substituted aryl(C 1 -C 6 alkyl)- or heteroaryl(C 1 -C 6 alkyl)- group or an optionally substituted cycloalkyl group: wherein optionally substituted is as defined in claim 1 .
17. A compound as claimed in claim 1 wherein R 4 is a carboxylic ester group of formula —COOR C wherein R C is optionally substituted methyl, ethyl, n- or iso- propyl, allyl, phenyl, pyridyl, thiazolyl, benzyl, pyridylmethyl, cyclopentyl or cyclohexyl;
wherein optionally substituted is as defined in claim 1 .
18. A compound as claimed in claim 1 having formula (II):
wherein
A is a secondary amino group
R 10 is H, Cl, Br, or CH 3 ;
R 11 is hydrogen, Cl, Br, CN, methyl, ethyl, n- or iso-propyl, vinyl or allyl;
R 12 is (i) a radical of formula —O(CH 2 ) n Z 1 wherein n is 1, 2 or 3 and Z 1 is a primary, secondary, tertiary or cyclic amino group, or a C 1 -C 6 alkoxy group; or (ii) a radical of formula -(Alk 3 ) m Z 1 wherein Alk 3 is a divalent straight or branched chain (C 1 -C 3 ) alkylene, m is 0 or 1, and Z 1 is a primary, secondary, tertiary or cyclic amino group, or a C 1 -C 6 alkoxy group.
19. A compound as claimed in claim 18 wherein A is a secondary C 1 -C 6 alkylamino group.
20. A compound as claimed in claim 18 wherein R 12 is (i) a radical of formula —O(CH 2 ) n Z 1 wherein n is 1, 2 or 3 and Z 1 is di(C 1 -C 3 alkyl)amino or C 1 -C 3 alkoxy.
21. A compound having the structure
or a salt thereof.
22. A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1 , together with one or more pharmaceutically or veterinarily acceptable carriers and/or excipients.
23. A compound as claimed in claim 13 wherein R D is hydroxyl-substituted phenyl, chloro-substituted phenyl, 3,4-methylenedioxyphenyl, pyridyl, furyl, thienyl, N-piperazinyl, or N-morpholinyl.