Ortho-condensed pyridine and pyrimidine derivatives (e.g., purines) as protein kinases inhibitors
The invention provides a compound for use as a protein kinase B inhibitor, the compound being a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR 5 ; J 1 -J 2 is N═C(R 6 ), (R 7 )C═N, (R 8 )N—C(O), (R 8 ) 2 C—C(O), N═N or (R 7 )C═C(R 6 ); 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; Q 1 is a bond or a saturated C 1-3 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 CONR q or NR q CO where R q is hydrogen or methyl, or R q is a C 1-4 alkylene chain linked to R 1 or a carbon atom of Q 1 to form a cyclic moiety; and wherein the carbon atoms of the linker group Q 1 may optionally bear one or more substituents selected from fluorine and hydroxy; Q 2 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 a with respect to the G group; and provided that when E is aryl or heteroaryl, then Q 2 is other than a bond; G is hydrogen, NR 2 R 3 , OH or SH provided that when E is aryl or heteroaryl and Q 2 is a bond, then G is hydrogen; R 1 is hydrogen or an aryl or heteroaryl group, with the proviso that when R 1 is hydrogen and G is NR 2 R 3 , then Q 2 is a bond; and R 2 , R 3 , R 4 , R 6 and R 8 are as defined in the claims.
1. A method of treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, wherein the disease or condition is selected from a carcinoma of the bladder, breast, colon, kidney, epidermal, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, endometrium, thyroid, prostate, or skin; a hematopoietic tumour of lymphoid lineage; a hematopoietic tumour of myeloid lineage; a tumour of mesenchymal origin; a tumour of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentosum; keratoctanthoma; thyroid follicular cancer; and Kaposi's sarcoma; which method comprises administering to the mammal a therapeutically effective amount of a compound of the formula (I):
or a salt, tautomer or N-oxide thereof, wherein;
T is N;
J 1 -J 2 is HC═CH;
Q 1 and Q 2 each represent a bond;
G is NR 2 R 3 ;
R 1 is hydrogen;
R 2 and R 3 are independently selected from hydrogen and methyl;
R 4 is hydrogen; and
E is a piperidine group bearing 0-1 substituents R 11 selected from the group R 10 consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group R a -R b wherein R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ; and R b is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C 1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C 1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(X 2 )X 1 or X 1 C(X 2 )X 1 ;
R c is selected from hydrogen and C 1-4 hydrocarbyl; and
X 1 is O, S or NR c and X 2 is ═O, ═S or ═NR c ;
provided that where the substituent group R 10 comprises or includes 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 R 10 wherein (i) the said further substituent groups R 10 include carbocyclic or heterocyclic groups, which are not themselves further substituted; or (ii) the said further substituent groups R 10 do not include carbocyclic or heterocyclic groups but are otherwise selected from the groups listed above in the definition of R 10 .
2. A method according to claim 1 wherein NR 2 R 3 is an amino group or a methylamino group.
3. A method according to claim 2 wherein NR 2 R 3 is an amino group.
4. A method according to claim 1 wherein R 11 is selected from the group R 10b consisting of halogen, hydroxy, trifluoromethyl, cyano, amino, mono- or di-C 1-4 alkylamino, cyclopropylamino, carbocyclic and heterocyclic groups having from 3 to 7 ring members; a group R a -R b wherein R a is a bond, O, CO, OC(O), NR c (O), OC(NR c ), C(O)O, C(O)NR c , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ; and R b is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 7 ring members, and a C 1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, amino, mono- or di-C 1-4 alkylamino, carbocyclic and heterocyclic groups having from 3 to 7 ring members and wherein one or more carbon atoms of the C 1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 or NR c ; provided that R a is not a bond when R b is hydrogen; and R c is selected from hydrogen and C 1-4 alkyl.
5. A method according to claim 1 wherein the nitrogen atom of the piperidine ring is attached to the bicyclic group.
6. A method according to claim 1 wherein Q 1 and Q 2 are attached to different atoms in the group E.
7. A method according to claim 1 wherein Q 2 and the bicyclic group are attached to the group E in a meta or para relative orientation.
8. A method according to claim 1 wherein the compound of formula (I) is in the form of a salt or N-oxide.
9. A method according to claim 1 wherein the disease or condition is selected from a carcinoma of the bladder or breast; colorectal carcinomas; kidney, epidermal and liver carcinomas; adenocarcinoma; small cell lung cancer; non-small cell lung carcinomas; carcinomas of the oesophagus, gall bladder, ovary, pancreas, stomach, cervix, endometrium, thyroid, prostate, or skin; leukaemia; acute lymphocytic leukaemia; B-cell lymphoma; T-cell lymphoma; Hodgkin's lymphoma; non-Hodgkin's lymphoma; hairy cell lymphoma; Burkett's lymphoma; acute and chronic myelogenous leukaemias; myelodysplastic syndrome; promyelocytic leukaemia; thyroid follicular cancer; fibrosarcoma; habdomyosarcoma; astrocytoma; neuroblastoma; glioma; schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentosum; keratoctanthoma; thyroid follicular cancer; and Kaposi's sarcoma.
10. A method according to claim 9 wherein the disease or condition is selected from breast cancer, ovarian cancer, prostate cancer, endometrial cancer and glioma.
11. A method according to claim 9 wherein the disease or condition is selected from breast cancer, ovarian cancer, colon cancer, prostate cancer, oesophageal cancer, squamous cancer and non-small cell lung carcinomas.
12. A method according to claim 1 wherein the disease or condition is selected from tumours with deletions or inactivating mutations in PTEN or loss of PTEN expression.
13. A method of using a compound of the formula (I):
or a salt, tautomer or N-oxide thereof, wherein;
T is N;
J 1 -J 2 is HC═CH;
Q 1 and Q 2 each represent a bond;
G is NR 2 R 3 ;
R 1 is hydrogen;
R 2 and R 3 are independently selected from hydrogen and methyl;
R 4 is hydrogen; and
E is a piperidine group bearing 0-1 substituents R 11 selected from the group R 10 consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group R a -R b wherein R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ; and R b is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C 1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C 1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(X 2 )X 1 or X 1 C(X 2 )X 1 ;
R c is selected from hydrogen and C 1-4 hydrocarbyl; and
X 1 is O, S or NR c and X 2 is ═O, ═S or ═NR c ;
provided that where the substituent group R 10 comprises or includes 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 R 10 wherein (i) the said further substituent groups R 10 include carbocyclic or heterocyclic groups, which are not themselves further substituted; or (ii) the said further substituent groups R 10 do not include carbocyclic or heterocyclic groups but are otherwise selected from the groups listed above in the definition of R 10 ;
which method comprises:
(a) inhibiting protein kinase A or protein kinase B by contacting the kinase with a kinase-inhibiting compound of formula (I); or
(b) modulating a cellular process by inhibiting the activity of a protein kinase A or protein kinase B using the compound of formula (I); or
(c) treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, the method comprising administering to the mammal the compound of formula (I) in an amount effective to inhibit protein kinase A or protein kinase B activity; or
(d) treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, the method comprising administering to the mammal the compound of formula (I) in an amount effective in inhibiting abnormal cell growth; or
(e) alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, the method comprising administering to the mammal the compound of formula (I) in an amount effective in inhibiting abnormal cell growth; or
(f) the diagnosis and treatment of a disease state or condition mediated by protein kinase B, the method comprising (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against protein kinase B; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient the compound of formula (I); or
(g) the diagnosis and treatment of a disease state or condition mediated by protein kinase A, the method comprising (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against protein kinase A; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient the compound of formula (I).