Patent EA-005212-B1 (EA)
Title: Azaindoles
Inventor: COX PAUL JOSEPH
IPC: A61K31/4985
Filed: 2000-12-27
Abstract: 1. A pharmaceutical composition comprising an effective selective kinase inhibitory amount of a compound of general formula (I): wherein: R<1> represents aryl or heteroaryl each optionally substituted by one or more groups selected from acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, R<4>, -C(=O)-NY<1>Y<2>, -C(=O)-OR<5>, -NY<1>Y<2>, -N(R<6>)-C(=O)-R<7>, -N(R<6>)-C(=O)-NY<3>Y<4>, -N(R<6>)-C(=O)-OR<7>, -N(R<6>)-SO2-R<7>, -N(R<6>)-SO2-NY<3>Y<4>, -SO2-NY<1>Y<2> and -Z<2>R<4>; R<2> represents hydrogen, acyl, cyano, halo, C1-4alkenyl or C1-4alkyl optionally substituted by a substituent selected from cyano, heteroaryl, heterocycloalkyl, -Z<1>R<8>, -C(=O)-NY<3>Y<4>, -CO2R<8>, -NY<3>Y<4>, -N(R<6>)-C(=O)-R<7>, -N(R<6>)-C(=O)-NY<3>Y<4>, -N(R<6>)-C(=O)-OR<7>, -N(R<6>)-SO2-R<7>, -N(R<6>)-SO2-NY<3>Y<4> and one or more halogen atoms; R<3> represents hydrogen, aryl, cyano, halo, heteroaryl, C1-4alkyl, -C(=O)-OR<5> or R<4> represents alkyl, cycloalkyl or cycloalkylalkyl each optionally substituted by a substituent selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, -CHO (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), -C(=O)-NY<1>Y<2>, -C(=O)-OR<5>, -NY<1>Y<2>, -N(R<6>)-C(=O)-R<7>, -N(R<6>)-C(=O)-NY<3>Y<4>, -N(R<6>)-SO2-R<7>, -N(R<6>)-SO2-NY<3>Y<4>, -OR<7> and one or more groups selected from hydroxy and carboxy; R<5> represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R<6> represents hydrogen or C1-4alkyl; R<7> represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R<8> represents hydrogen or C1-4alkyl; X<1> represents N, CH, C-halo, C-CN, C-R<7>, C-NY<3>Y<4>, C-OH, C-Z2R<7>, C-C(=O)-OR<5>, C-C(=O)-NY<3>Y<4>, C-N(R<8>)-C(=O)-R<7>, C-SO2-NY<3>Y<4>, C-N(R<8>)-SO2-R<7>, C-alkenyl, C-alkynyl or C-NO2; Y<1> and Y<2> are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted by one or more groups selected from aryl, halo, heteroaryl, hydroxy, -C(=O)-NY<3>Y<4>, -C(=O)-OR<5>, -NY<3>Y<4>, -N(R<6>)-C(=O)-R<7>, -N(R<6>)-C(=O)-NY<3>Y<4>, -N(R<6>)-SO2-R<7>, -N(R<6>)-SO2-NY<3>Y<4> and -OR<7>; or the group -NY<1>Y<2> may form a cyclic amine; Y<3> and Y<4> are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY<3>Y<4> may form a cyclic amine; Z<1> represents O or S; Z<2> represents O or S(O)n; n is zero or an integer 1 or 2; "Heteroaryl" as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element (s) other than carbon, or (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure; and "Heterocycloalkyl" means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms or heteroatom-containing groups selected from O, S and NY<7> and may be optionally substituted by oxo; (ii) a partially saturated multicyclicheterocarbocyclic moiety in which an aryl (or heteroaryl) ring, each optionally substituted, and a heterocycloalkyl group are fused together to form a cyclic structure; provided that when R<1> is phenyl or substituted aryl, R<2> is C1-4alkyl, substituted -C(=O)-NY<3>Y<4>, -N(R<6>)-C(=O)-R<7>, -N(R<6>)-C(=O)-NY<3>Y<4> or -NY<3>Y<4> or R<2> is C1-4alkenyl, and R<3> represents hydrogen, halo or C1-4alkyl, then X<1> is other than CH; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e. g. hydrates) of such compounds and their N-oxides and their prodrugs, and their acid bioisosteres; together with one or more pharmaceutically acceptable carriers or excipients; such acid bioisosteres are compounds of formula (I) in which a carboxy group is substituted by a functional group selected from the group consisting of -C(=O)-NHOH, -C(=O)-CH2OH, -C(=O)-CH2SH, -C(=O)-NH-CN, sulfo, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3cyclobuten-1,2-dion, 3,5-dioxo-1,2,4-oxadiazolidinyl, 3-hydroxyizoxazolyl and 3-hydroxy-1-methylpyrrazolyl. 2. A compound of formula (I) according to claim 1, but excluding the compounds: 2-phenyl-1H-pyrrolo[2,3-b]pyridine, 2-(4-bromo-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid methyl ester, 2-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine, 2-(4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine, 5-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, 4-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, 2-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid, 2-(4-methoxy-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 2-(4-methyl-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid isopropyl ester, 2-phenyl-3methyl-1H-pyrrolo[2,3-b]pyridine, 6-phenyl-5H-pyrrolo[2,3-b]pyrazine, 6-(4-methoxy-phenyl)5H-pyrrolo[2,3-b]pyrazine, 6-(4-chloro-phenyl)-5H-pyrrolo[2,3-b]pyrazine, 6-(2-chloro-phenyl)5H-pyrrolo[2,3-b]pyrazine, 3-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine, 2-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine and 7-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine. 3. A compound according to claim 2 in which R<1> is optionally substituted heteroaryl. 4. A compound according to claim 3 in which R<1> is optionally substituted azaheteroaryl. 5. A compound according to claim 2 in which RI is optionally substituted indolyl, optionally substituted furanyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted imidazolyl, optionally substituted indazolyl, optionally substituted indolizinyl, optionally substituted tetrahydroindolizinyl or optionally substituted indazolinyl. 6. A compound according to any one of claims 3-5 in which the optionally substituents within R<1> are one or more groups selected from alkylenedioxy, alkenyl, alkenyloxy, aryl, carboxy (or an acid bioisostere), cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, R<4>, -C(=O)-R<4>, -C(=O)-NY<1>Y<2>, -C(=O)-OR<5>, -NY<1>Y<2> and -OR<4>. 7. A compound according to claim 2 in which R<1> is optionally substituted aryl. 8. A compound according to claim 7 in which R<1> is phenyl substituted by one or more groups selected from alkylenedioxy, halo, R<4>, -NY<1>Y<2> and -OR<4>. 9. A compound according to any one of claims 2-8 in which R<2> is hydrogen. 10. A compound according to any one of claims 2-8 in which R<2> is halo. 11. A compound according to any one of claims 2-8 in which R<2> is C1-4alkyl optionally substituted by carboxy, cyano, halo, hydroxy, tetrazolyl, or -CONY<3>Y<4>. 12. A compound according to any one of claims 2-8 in which R<2> is C1-4alkenyl. 13. A compound according to any one of claims 2-12 in which R<3> is hydrogen. 14. A compound according to any one of claims 2-12 in which R<3> is optionally substituted aryl. 15. A compound according to any one of claims 2-12 in which R<3> is optionally substituted phenyl. 16. A compound according to any one of claims 2-12 in which R<3> is C1-4alkyl. 17. A compound according to any one of claims 2-16 in which X<1> is N. 18. A compound according to any one of claims 2-16 in which X<1> is CH. 19. A compound according to any one of claims 2-16 in which X<1> is C-C1-4alkoxy. 20. A compound according to any one of claims 2-16 in which X<1> is C-aryl. 21. A compound according to any one of claims 2-16 in which X<1> is C-Cl. 22. A compound according to any one of claims 2-16 in which X<1> is C-CN. 23. A compound of formula (Ia): in which R<2>, R<3> and X<1> are as hereinbefore defined in claim 1; R<9> is hydrogen, R<4>, alkenyl or heterocycloalkyl; R<10> is alkenyloxy, carboxy (or an acid bioisostere), cyano, halo, hydroxy, heteroaryl, R<4>, -C(=O)-R<4>, -C(=O)-NY<1>Y<2>, -OR<4>, -N(R<6>)-C(=O)-R<7>, -N(R<6>)-SO2-R<7> or -NY<1>Y<2>; and p is zero, an integer 1 or 2; and their prodrugs and pharmaceutically acceptable salts, and solvates (e. g. hydrates) of compounds of formula (Ia) and their prodrugs. 24. A compound according to claim 23 in which R<2> is hydrogen and/or R<3> is hydrogen, optionally substituted aryl or C1-4alkyl and/or X<1> is CH, C-C1-4alkoxy, C-aryl, C-halo, C-CN, or N and/or R<9> is: (i) hydrogen; (ii) C1-4alkyl; (iii) C1-4alkyl substituted by hydroxy; (iv) C1-4alkyl substituted by -N(R<6>)C(=O)-R<7>; (v) C1-4alkyl substituted by -C(=O)-NY<1>Y<2>; or (vi) cycloalkylalkyl substituted by hydroxy and/or R<10> is: (i) hydroxy; (ii) -OR<4> in which R<4> is alkyl; (iii) -OR<4> in which R<4> is alkyl or cycloalkylalkyl, each substituted by one or more hydroxy groups; (iv) -OR<4> in which R<4> is alkyl substituted by one or more alkoxy groups; (v) -OR<4> in which R<4> is alkyl or cycloalkyl, each substituted by one or more carboxy; (vi) -OR<4> in which R<4> is cycloalkyl substituted by -C(-O)-NY<1>Y<2>; (vii) -N(R<6>)-C(=O)-R<7>; (viii) -CONY<1>Y<2>; (ix) carboxy; (x) alkyl substituted by carboxy; (xi) heteroaryl; (xii) -C(=O)-R<4> in which R<4> is alkyl; or (xiii) tetrazolyl or N-methyltetrazolyl. 25. A compound according to claim 24 in which R<10> is attached to position 5 of the indolyl ring. 26. A compound of formula (Ib): in which R<2>, R<3>, R<9>, R<10>, X<1> and p are as hereinbefore defined in claim 23, and their prodrugs and pharmaceutically acceptable salts, and solvates (e. g. hydrates) of compounds of formula (Ib) and their prodrugs. 27. A compound according to claim 26 in which R<2> is hydrogen and/or R<3> is hydrogen, optionally substituted aryl or C1-4alkyl and/or X<1> is CH, C-