US 7,405,220 B2Granted

Pyrazolopyrimidines

AssigneeHoffmann-La Roche Inc.

InventorsQingjie Ding, Nan Jiang, John Lawson Roberts

Life of this patent

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Abstract

Novel pyrazolopyrimidines of formula (I): are discussed. These pyrazolopyrimidines are capable of inhibiting the activity of cyclin-dependent kinases, most particularly cyclin-dependent kinase 1 (Cdk1), cyclin-dependent kinase 2 (Cdk2), and cyclin-dependent kinase 4 (Cdk4) and are thus useful, inter alia, in the treatment or control of cancer, in particular solid tumors. This invention also provides pharmaceutical compositions containing such compounds and to methods of treating or controlling cancer, most particularly the treatment or control of breast, lung, colon and prostate tumors.

Claims13

Dependent claims

A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of:
(a) piperidine, piperazine or pyrrolidine which may be substituted by up to four substituents independently selected from the group consisting of:
(i) lower alkyl which may be substituted by OH, CO2R3, COR4, CONR5R6, NR5R6, OR7, or S(O)nR8;
and
(ii) CO2R3, COR4, CONR5R6, NR5R6, OR7, or S(O)nR8;
(b) phenyl, tolyl or xylyl which is substituted by up to four substituents independently selected from the group consisting of:
SO2CH3, SO2NH2, NH2, N(CH3)2, OH, OCH3 or COOCH2CH3;
and
(c) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl that is substituted by OR7, NR5R6, or S(O)nR8;
R2 is phenyl which may be substituted with fluorine and methoxy;
R3 is selected from the group consisting of:
(i) lower alkyl which may be substituted by OR7, COR4, NR5R6 or CONR5R6;
and
(ii) cycloalkyl which may be substituted by OH or NH2;
R4 is selected from the group consisting of:
(i) H;
and
(ii) lower alkyl which may be substituted by OR7 or NR5R6;
R5 and R6 are each independently selected from the group consisting of:
(i) H;
(ii) lower alkyl which may be substituted by OH, CO2R3, CONR10R11, SO2R3, OR7, NR10R11, heterocycle, or heteroaryl;
(iii) cycloalkyl which may be substituted by CO2R3, CONR10R11, SO2R4, OR7, or NR10R11;
(iv) aryl which may be substituted by CO2R3, CONR10R11, SO2R3, OR7, NR10R11, halogen, lower alkyl, and lower alkyl substituted by halogen, CO2R3, CONR10R11, OR7, NR10R11, or OH;
(v) SO2R3;
(vi) CO2R3, and
(vii) COR3;
or
alternatively, NR5R6 can form a ring having a total of 3-7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R5 and R6 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms or the group SO2, and said ring atoms optionally being substituted by OH, oxo, NR5R6, lower alkyl, and lower alkyl substituted by OR7;
R7 is selected from the group consisting of H and lower alkyl optionally substituted by NR5R6 or OR9;
R8 is selected from the group consisting of:
(i) aryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, and OH;
(ii) heteroaryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
(iii) NR5R6;
(iv) lower alkyl which may be substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
and
(v) heterocycle which may be substituted by CO2R3, COR3, SO2R3, CONR5R6, OR7, or NR5R6;
R9 is selected from the group consisting of H, lower alkyl, and lower alkyl substituted by OH or halogen;
R10 and R11 are each independently selected from the group consisting of:
(i) H;
(ii) lower alkyl which may be substituted by OH, CO2R3, CONR5R6, SO2R3, OR7, NR5R6, heterocycle, or heteroaryl;
(iii) cycloalkyl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, or NR5R6;
(iv) aryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
(v) SO2R3;
(vi) CO2R3 and
(vii) COR3;
or
alternatively, NR10R11 can form a ring having a total of 3-7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R10 and R11 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms or the group SO2, and said ring atoms optionally being substituted by OH, oxo, NR5R6, lower alkyl and lower alkyl substituted by OR7 and n is 1 or 2.

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A pharmaceutical formulation which comprises a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of:
(a) piperidine, piperazine or pyrrolidine which may be substituted by up to four substituents independently selected from the group consisting of:
(i) lower alkyl which may be substituted by OH, CO2R3, COR4, CONR5R6, NR5R6, OR7,
or S(O)nR8;
and
(ii) CO2R3, COR4, CONR5R6, NR5R6, OR7, or S(O)nR8;
(b) phenyl, tolyl or xylyl that is substituted by up to four substituents independently selected from the group consisting of:
(i) SO2CH3, SO2NH2, NH2, N(CH3)2, OH, OCH3 or COOCH2CH3;
and
(c) cyclopentyl, cyclobutyl, cyclopentyl or cyclohexyl that is substituted by OR7, NR5R6, or S(O)nR8;
R2 is
phenyl which may be substituted with fluorine and methoxy;
R3 is selected from the group consisting of:
(i) lower alkyl which may be substituted by OR7, COR4, NR5R6 or CONR5R6;
and
(ii) cycloalkyl which may be substituted by OH or NH2;
R4 is selected from the group consisting of:
(i) H;
and
(ii) lower alkyl which may be substituted by OR7 or NR5R6;
R5 and R6 are each independently selected from the group consisting of:
(i) H;
(ii) lower alkyl which may be substituted by OH, CO2R3, CONR10R11, SO2R3, OR7, NR10R11, heterocycle, or heteroaryl;
(iii) cycloalkyl which may be substituted by CO2R3, CONR10R11, SO2R4, OR7, or NR10R11;
(iv) aryl which may be substituted by CO2R3, CONR10R11, SO2R3, OR7, NR10R11, halogen, lower alkyl, and lower alkyl substituted by halogen, CO2R3, CONR10R11, OR7, NR10R11, or OH;
(v) SO2R3;
(vi) CO2R3, and
(vii) COR3;
or
alternatively, NR5R6 can form a ring having a total of 3-7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R5 and R6 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms or the group SO2, and said ring atoms optionally being substituted by OH, oxo, NR5R6, lower alkyl, and lower alkyl substituted by OR7;
R7 is selected from the group consisting of H and lower alkyl optionally substituted by NR5R6 or OR9;
R8 is selected from the group consisting of:
(i) aryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, and OH;
(ii) heteroaryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
(iii) NR5R6;
(iv) lower alkyl which may be substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
and
(v) heterocycle which may be substituted by CO2R3, COR3, SO2R3, CONR5R6, OR7, or NR5R6;
R9 is selected from the group consisting of H, lower alkyl, and lower alkyl substituted by OH or halogen;
R10 and R11 are each independently selected from the group consisting of:
(i) H;
(ii) lower alkyl which may be substituted by OH, CO2R3, CONR5R6, SO2R3, OR7, NR5R6, heterocycle, or heteroaryl;
(iii) cycloalkyl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, or NR5R6;
(iv) aryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
(v) SO2R3;
(vi) CO2R3 and
(vii) COR3;
or
alternatively, NR10R11 can form a ring having a total of 3-7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R10 and R11 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms or the group SO2, and said ring atoms optionally being substituted by OH, oxo, NR5R6, lower alkyl and lower alkyl substituted by OR7
and n is 1 or 2
and a pharmaceutically acceptable excipient.

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Dependencies are inferred from the claim text.

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Abstract

A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of:
(a) piperidine, piperazine or pyrrolidine which may be substituted by up to four substituents independently selected from the group consisting of:
(i) lower alkyl which may be substituted by OH, CO2R3, COR4, CONR5R6, NR5R6, OR7, or S(O)nR8;
and
(ii) CO2R3, COR4, CONR5R6, NR5R6, OR7, or S(O)nR8;
(b) phenyl, tolyl or xylyl which is substituted by up to four substituents independently selected from the group consisting of:
SO2CH3, SO2NH2, NH2, N(CH3)2, OH, OCH3 or COOCH2CH3;
and
(c) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl that is substituted by OR7, NR5R6, or S(O)nR8;
R2 is phenyl which may be substituted with fluorine and methoxy;
R3 is selected from the group consisting of:
(i) lower alkyl which may be substituted by OR7, COR4, NR5R6 or CONR5R6;
and
(ii) cycloalkyl which may be substituted by OH or NH2;
R4 is selected from the group consisting of:
(i) H;
and
(ii) lower alkyl which may be substituted by OR7 or NR5R6;
R5 and R6 are each independently selected from the group consisting of:
(i) H;
(ii) lower alkyl which may be substituted by OH, CO2R3, CONR10R11, SO2R3, OR7, NR10R11, heterocycle, or heteroaryl;
(iii) cycloalkyl which may be substituted by CO2R3, CONR10R11, SO2R4, OR7, or NR10R11;
(iv) aryl which may be substituted by CO2R3, CONR10R11, SO2R3, OR7, NR10R11, halogen, lower alkyl, and lower alkyl substituted by halogen, CO2R3, CONR10R11, OR7, NR10R11, or OH;
(v) SO2R3;
(vi) CO2R3, and
(vii) COR3;
or
alternatively, NR5R6 can form a ring having a total of 3-7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R5 and R6 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms or the group SO2, and said ring atoms optionally being substituted by OH, oxo, NR5R6, lower alkyl, and lower alkyl substituted by OR7;
R7 is selected from the group consisting of H and lower alkyl optionally substituted by NR5R6 or OR9;
R8 is selected from the group consisting of:
(i) aryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, and OH;
(ii) heteroaryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
(iii) NR5R6;
(iv) lower alkyl which may be substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
and
(v) heterocycle which may be substituted by CO2R3, COR3, SO2R3, CONR5R6, OR7, or NR5R6;
R9 is selected from the group consisting of H, lower alkyl, and lower alkyl substituted by OH or halogen;
R10 and R11 are each independently selected from the group consisting of:
(i) H;
(ii) lower alkyl which may be substituted by OH, CO2R3, CONR5R6, SO2R3, OR7, NR5R6, heterocycle, or heteroaryl;
(iii) cycloalkyl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, or NR5R6;
(iv) aryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl, or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6, or OH;
(v) SO2R3;
(vi) CO2R3 and
(vii) COR3;
or
alternatively, NR10R11 can form a ring having a total of 3-7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R10 and R11 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms or the group SO2, and said ring atoms optionally being substituted by OH, oxo, NR5R6, lower alkyl and lower alkyl substituted by OR7 and n is 1 or 2.

45 more elements