US 2008/0306069 A1 · Pyrazole Derivatives for the Inhibition of CDK'S and GSK'S

Abstract

The invention provides compounds of the formula (I), or salts, tautomers, N-oxides or solvates thereof wherein: R1 is selected from: (a) 2,6-dichlorophenyl; (b) 2,6-difluorophenyl; (c) a 2,3,6-trisubstituted phenyl group wherein the substituents for the phenyl group are selected from fluorine, chlorine, methyl and methoxy; (d) a group RO; (e) a group R a; (f) a group RIb; (g) a group RIc; (h) a group RId; and 0) 2,6-difluorophenylamino; wherein R) 0υ, r R>llaa, T Rj HbD, T R) HcC, r R>Iidα, r R>>2zaa, r R>22bD and RJ are as defined in the claims. The compounds have activity as inhibitors of cdk kinase (such as cdk1 or cdk2) and glycogen synthase kinase-3 activity.

A compound of the formula (I):

or a salt, tautomer, N-oxide or solvate thereof
wherein:
R1 is selected from:
(a) 2,6-dichlorophenyl;
(b) 2,6-difluorophenyl;
(c) a 2,3,6-trisubstituted phenyl group wherein the substituents for the phenyl group are selected from fluorine, chlorine, methyl and methoxy;
(d) a group R0;
(e) a group R1a;
(f) a group R1b;
(g) a group R1c;
(h) a group R1d;
and
(j) 2,6-difluorophenylamino;
R0 is a carbocyclic or heterocyclic group having from 3 to 12 ring members;
or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from fluorine, hydroxy, cyano;
C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2;
R1a is selected from cyclopropyl-cyano-methyl;
furyl;
benzoisoxazolyl;
methylisoxazolyl;
2-monosubstituted phenyl and 2,6-disubstituted phenyl wherein the substituents on the phenyl moiety are selected from methoxy, ethoxy, fluorine, chlorine, and difluoromethoxy;
provided that R1a is not 2,6-difluorophenyl or 2,6-dichlorophenyl;
R1b is selected from tetrahydrofuryl;
and mono-substituted and disubstituted phenyl wherein the substituents on the phenyl moiety are selected from fluorine;
chlorine;
methoxy;
ethoxy and methylsulphonyl;
R1c is selected from;
benzoisoxazoyl;
five membered heteroaryl rings containing one or two heteroatoms selected from O and N and six-membered heteroaryl rings containing one or two nitrogen heteroatom ring members, the heteroaryl rings in each case being optionally substituted by methyl, fluorine, chlorine or trifluoromethyl;
and phenyl substituted by one, two or three substituents selected from bromine, chlorine, fluorine, methyl, trifluoromethyl, ethoxy, methoxy, methoxyethoxy, methoxymethyl, dimethylaminomethyl and difluoromethoxy;
provided that R1a is not 2,6-difluorophenyl;
R1d is a group R1e—CH(CN)— where R1e is a carbocylic or heterocyclic group having from 3 to 12 ring members;
R2a and R2b are each hydrogen or methyl;
and wherein:
A. when R1 is (a) 2,6-dichlorophenyl and R2a and R2b are both hydrogen;
then R3 can be selected from:
(i) a group
where R9 is selected from C(O)NR5R6, where R5 and R6 are selected from hydrogen and C1-4 alkyl, C1-2 alkoxy and C1-2 alkoxy-C1-4 alkyl, provided that no more than one of R5 and R6 is C1-2alkoxy, or NR5R6 forms a five or six membered saturated heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, the heterocyclic ring being optionally substituted by one or more methyl groups;
C(O)—R10 where R10 is a C1-4 alkyl group optionally substituted by one or more substituents chosen from fluorine, chlorine, cyano and methoxy;
2-pyrimidinyl;
and R11 where R11 is a C1-4 alkyl group substituted by one or more substituents chosen from fluorine, chlorine and cyano;
(ii) a group
where R12 is C2-4 alkyl;
(iii) a group
wherein R13 is selected from methylsulphonyl, 4-morpholino, 4-thiomorpholino, 1-piperidino, 1-methyl-4-piperazino and 1-pyrrolidino;
(iv) a substituted 3-pyridyl or 4-pyridyl group of the formula
wherein the group R14 is meta or para with respect to the bond labelled with an asterisk and is selected from methyl, methylsulphonyl, 4-morpholino, 4-thiomorpholino, 1-piperidino, 1-methyl-4-piperazino, 1-pyrrolidino, 4-piperidinyloxy, 1-C1-4alkoxycarbonyl-piperidin-4-yloxy, 2-hydroxyethoxy and 2-methoxyethoxy;
and
(v) a group selected from 2-pyrazinyl, 5-pyrimidinyl, cyclohexyl, 1,4-dioxa-spiro[4.5]decan-8-yl (4-cyclohexanone ethylene glycol ketal), 4-methylsulphonylamino-cyclohexyl, tetrahydrothiopyran-4-yl, 1,1-dioxo-tetrahydrothiopyran-4-yl, tetrahydropyran-4-yl, 4,4-difluorocyclohexyl and 3,5-dimethylisoxazol-4-yl;
and
B. when R1 is (b) 2,6-difluorophenyl and R2a and R2b are both hydrogen;
then R3 can be selected from:
(vi) 1-methyl-piperidin-3-yl;
4-(2-dimethylaminoethoxy)-cyclohexyl;
and an N-substituted 4-piperidinyl group wherein the N-substituent is selected from cyanomethyl and cyanoethyl;
and
(vii) a group
wherein R13 is as hereinbefore defined;
and
C. when R1 is (c) a 2,3,6-trisubstituted phenyl group wherein the substituents for the phenyl group are selected from fluorine, chlorine, methyl and methoxy;
and
R2a and R2b are both hydrogen;
then R3 can be selected from groups (ii), (xi), (xii) and (xiii) as defined herein;
and
(viii) 4-piperidinyl and 1-methyl-4-piperidinyl;
(ix) tetrahydropyran-4-yl;
and
(x) a group:
where R4 is C1-4 alkyl;
D. when R1 is (d), a group R0, where R0 is a carbocyclic or heterocyclic group having from 3 to 12 ring members;
or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from fluorine, hydroxy, cyano;
C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2;
then R3 can be selected from:
(xi) a group:
where R7 is:
unsubstituted hydrocarbyl other than C1-4 alkyl;
substituted C1-4 hydrocarbyl bearing one or more substituents chosen from fluorine, chlorine, hydroxy, methylsulphonyl, cyano, methoxy, NR5R6, and 4 to 7 membered saturated carbocyclic or heterocyclic rings containing up to two heteroatom ring members selected from O, N and S;
a group NR5R6 where R5 and R6 are selected from hydrogen and C1-4 alkyl, C1-2 alkoxy and C1-2 alkoxy-C1-4 alkyl, provided that no more than one of R5 and R6 is C1-2 alkoxy, or NR5R6 forms a five or six membered saturated heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, the heterocyclic ring being optionally substituted by one or more methyl groups;
a five or six membered heteroaryl group containing one or two heteroatom ring members selected from N, S and O and being optionally substituted by methyl, methoxy, fluorine, chlorine, or a group NR5R6;
a phenyl group optionally substituted by methyl, methoxy, fluorine, chlorine, cyano or a group NR5R6;
C3-6 cycloalkyl;
and
a five or six membered saturated heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, the heterocyclic ring being optionally substituted by one or more methyl groups;
and
(xii) a group:
where R12a is C1-4 alkyl substituted by one or more substituents chosen from fluorine, chlorine, C3-6 cycloalkyl, oxa-C4-6 cycloalkyl, cyano, methoxy and NR5R6, provided that there are at least two carbon atoms between the oxygen atom to which R12 is attached and a group NR5R6 when present;
and
E. when R1 is (e) a group R1a and R2a and R2b are both hydrogen, then R3 can be (xiii) a group
and
F. when R1 is (f) a group R1b, and R2a and R2b are both hydrogen, then R3 can be (xiv) a methyl group;
and
G. when R1 is (g) a group R1c and R2a and R2b are both hydrogen, then R3 can be (xv) a group
and:
H. when R1 is (h), a group R1d, then R3 is a group -Y—R3a where Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length and R3a is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members;
J. when R1 is (j), 2,6-difluorophenylamino, and R2a and R2b are both hydrogen;
then R3 can be methyl;
and
K. when R1 is 2,6-dichlorophenyl and either (k) R2a is methyl and R2b is hydrogen, or (1) R2a is hydrogen and R2b is methyl;
then R3 can be a 4-piperidine group;
or salts, tautomers, solvates and N-oxides thereof.

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Pyrazole Derivatives for the Inhibition of CDK'S and GSK'S

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Pyrazole Derivatives for the Inhibition of CDK'S and GSK'S

Life of this patent

Abstract

Claims52