Purine and deazapurine derivatives as pharmaceutical compounds

摘要

The invention provides a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N═C(R6), (R7)C═N, (R8)N—C(O), (R8)2C—C(O), N═N or (R7)C═C(R6); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroatoms selected from O, N and S; Q1 is a bond or a saturated C1-3 hydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONRq or NRqCO where Rq is hydrogen or methyl, or Rq is a C1-4alkylene chain linked to R1 or a carbon atom of Q1 to form a cyclic moiety; and wherein the carbon atoms of the linker group Q1 may optionally bear one or more substituents selected from fluorine and hydroxy; Q2 is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the G group; and provided that when E is aryl or heteroaryl, then Q2 is other than a bond; G is hydrogen, NR2R3, OH or SH provided that when E is aryl or heteroaryl and Q2 is a bond, then G is hydrogen; R1 is hydrogen or an aryl or heteroaryl group, with the proviso that when R1 is hydrogen and G is NR2R3, then Q2 is a bond; and R2, R3R4, R6 and R8 are as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated.;

主权项

1. A method for inhibiting protein kinase P70S6K and/or ROCK kinase, which method comprises contacting the kinase with a compound of formula (Ic):or salts, tautomers or N-oxides thereof, wherein
T is N or a group CR5; J1-J2 represents a group selected from N═C(R6), (R7)C═N, (R8)N—C(O), (R8)2C—C(O), N═N and (R7)C═C(R6); E is piperidine substituted with 0-2 substituents R11 selected from the group R10; Q1 is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONRq or NRqCO where Rq is hydrogen, C1-4 alkyl or cyclopropyl, or Rq is a C1-4 alkylene chain that links to R1 or to another carbon atom of Q1 to form a cyclic moiety; and wherein the carbon atoms of the linker group Q1 may optionally bear one or more substituents selected from fluorine and hydroxy; Q2 is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the NR2R3 group; R1 is hydrogen or phenyl which is unsubstituted or substituted by one or more substituents R10 selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra—Rb wherein Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRC, SO2NRc or NRcSO2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C(X2), C(X2)X1 or X1C(X2)X1; with the proviso that when R1 is hydrogen, Q2 is a bond;Rc is selected from hydrogen and C1-4 hydrocarbyl; andX1 is O, S or NRc and X2 is ═O, ═S or ═NRc;provided that where the substituent group R10 comprises a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted with one or more further substituent groups R10;
R2 and R3 are independently selected from hydrogen; C1-4 hydrocarbyl and C1-4 acyl wherein the hydrocarbyl and acyl groups are optionally substituted by one or more substituents selected from fluorine, hydroxy, cyano, amino, methylamino, dimethylamino, methoxy and a monocyclic or bicyclic aryl or heteroaryl group; or R2 and R3 together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or one of R2 and R3 together with the nitrogen atom to which they are attached and one or more atoms from the group Q2 form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or NR2R3 and a carbon atom of linker group Q2 to which it is attached together form a cyano group; and R4 is hydrogen; R6 is selected from hydrogen, chlorine, fluorine and methyl; R8 is selected from hydrogen, chlorine, fluorine and methyl; R5 is selected from hydrogen, halogen, C1-5 saturated hydrocarbyl, cyano and CF3; and R7 is selected from hydrogen, chlorine, fluorine and methyl.