Novel Protein Kinase B Inhibitors - 060
First Claim
Patent Images
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
- wherein;
Y represents CH or N;
Z1-Z2 represents a group selected from C(R6)═
CH, N═
CH and C(R6)═
N;
whereR6 represents hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl or cyclopropyl;
n is 0, 1 or 2;
R1 represents C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, fluoroC1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, cyano, cyanoC1-4alkyl, C3-6cycloalkyl, —
(CH2)pNHCOCH3, —
(CH2)pNHSO2CH3, —
(CH2)pNHCONH2, —
(CH2)pNHCONR2R3, —
(CH2)pNR2R3, —
(CH2)pSO2NH2, —
(CH2)pSO2NR2R3, —
(CH2)pCONH2, —
(CH2)pCONR2R3 or —
(CH2)p—
R7;
wherep is 0, 1, 2 or 3;
R2 represents hydrogen or C1-3alkyl;
R3 represents C1-3alkyl; and
R7 represents phenyl;
R7 represents a 5 or 6 membered monocyclic heteroaryl ring which comprises 1, 2 or 3 heteroatoms selected from O, N or S;
orR7 represents a monocyclic 4, 5, or 6 membered heterocyclic ring which comprises 1, 2 or 3 heteroatoms selected from O, N or S;
wherein R7 is optionally substituted by 1 or 2 substituents selected from C1-4alkyl, trifluoromethyl, C1-4alkoxy, fluoro, chloro, bromo, and cyano;
R4 represents hydrogen, fluoro, chloro, bromo, cyano or trifluoromethyl; and
R5 represents hydrogen, fluoro, chloro or bromo.
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Abstract
The invention relates to a novel group of compounds of Formula (I) or salts thereof:
wherein Y, Z1, Z2, R1, R4, R5 and n are as described in the specification, which may be useful in the treatment or prevention of a disease or medical condition mediated through protein kinase B (PKB) such as cancer. The invention also relates to pharmaceutical compositions comprising said compounds, methods of treatment of diseases mediated by PKB using said compounds and methods for preparing compounds of Formula (I).
17 Citations
15 Claims
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1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
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wherein; Y represents CH or N; Z1-Z2 represents a group selected from C(R6)═
CH, N═
CH and C(R6)═
N;
whereR6 represents hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl or cyclopropyl; n is 0, 1 or 2; R1 represents C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, fluoroC1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, cyano, cyanoC1-4alkyl, C3-6cycloalkyl, —
(CH2)pNHCOCH3, —
(CH2)pNHSO2CH3, —
(CH2)pNHCONH2, —
(CH2)pNHCONR2R3, —
(CH2)pNR2R3, —
(CH2)pSO2NH2, —
(CH2)pSO2NR2R3, —
(CH2)pCONH2, —
(CH2)pCONR2R3 or —
(CH2)p—
R7;
wherep is 0, 1, 2 or 3; R2 represents hydrogen or C1-3alkyl; R3 represents C1-3alkyl; and R7 represents phenyl; R7 represents a 5 or 6 membered monocyclic heteroaryl ring which comprises 1, 2 or 3 heteroatoms selected from O, N or S;
orR7 represents a monocyclic 4, 5, or 6 membered heterocyclic ring which comprises 1, 2 or 3 heteroatoms selected from O, N or S; wherein R7 is optionally substituted by 1 or 2 substituents selected from C1-4alkyl, trifluoromethyl, C1-4alkoxy, fluoro, chloro, bromo, and cyano; R4 represents hydrogen, fluoro, chloro, bromo, cyano or trifluoromethyl; and R5 represents hydrogen, fluoro, chloro or bromo. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15)
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3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents N.
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4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z1-Z2 represents CH═
- CH.
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5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents methoxyC1-4alkyl, fluoroC1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, C3-6cycloalkyl, —
- (CH2)pNHCOCH3, —
(CH2)pNHSO2CH3, —
(CH2)pNHCONH2, —
(CH2)pNHCONR2R3, —
(CH2)pNR2R3, —
(CH2)pSO2NH2, —
(CH2)pCONH2, —
(CH2)pCONR2R3 or —
(CH2)p—
R7.
- (CH2)pNHCOCH3, —
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6. A compound according to claim 5 wherein R1 represents —
- (CH2)p—
R7, p represents 1, 2 or 3, R7 is selected from phenyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, imidazolyl, isoxazolyl, pyrazolyl and thiazolyl and R7 is optionally substituted by a single methyl group.
- (CH2)p—
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7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents hydroxyethyl.
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8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 represents chloro or bromo.
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9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 represents hydrogen.
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10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
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11. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically-acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
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15. A process for the preparation of a compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which comprises a process (a), (b), (c) or (d):
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(a) reaction of an acid of Formula (II) with an amine of Formula (III); wherein P1 represents a suitable protecting group; (b) reaction of a carboxamide of Formula (IV) with a bicyclic heterocycle of Formula (V); wherein L1 represents a suitable leaving group; (c) when n is 1, hydrogenation of a compound of Formula (VI);
or(d) when R1 represents aminomethyl, hydrogenation of a compound of Formula (VII); wherein P1 represents a suitable protecting group; and thereafter, if necessary; (i) converting a compound of Formula (I) into another compound of Formula (I); (ii) removing any protecting groups; and
/or(iii) forming a pharmaceutically acceptable salt thereof.
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12-14. -14. (canceled)
Specification