US 2006/0189630 A1Published application

Mitotic kinesin inhibitors

AssigneeMerck & Co., Inc.

InventorsMark Fraley, Robert Garbaccio

Life of this patent

Estimating the term…

Abstract

The present invention relates to cycloalkylpyrimidinone compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Claims24

Dependent claims

A compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
n is 1 to 3;
r is 0 to 3;
u is 2, 3, 4 or 5;
R1 is selected from:
1) H,
2) C1-C10 alkyl,
3) aryl,
4) C2-C10 alkenyl,
5) C2-C10 alkynyl,
6) C1-C6 perfluoroalkyl,
7) C1-C6 aralkyl,
8) C3-C8 cycloalkyl, and
9) heterocyclyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R2 and R2′ are independently selected from:
1) H,
2) (C═O)aObC1-C10 alkyl,
3) (C═O)aObaryl,
4) (C═O)aObC2-C10 alkenyl,
5) (C═O)aObC2-C10 alkynyl,
6) CO2H,
7) C1-C6 perfluoroalkyl,
8) (C═O)aObC3-C8 cycloalkyl,
9) (C═O)aObheterocyclyl,
10) SO2NR7R8, and
11) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
or
R2 and R2′ are combined to form —(CH2)u— wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O)m, —NC(O)—, and —N(Rb)—, and wherein the ring formed when R2 and R2′ are combined is optionally substituted with one, two or three substituents selected from R5;
R3 and R3′ are independently selected from:
1) H,
2) (C═O)aObC1-C10 alkyl,
3) (C═O)aObaryl,
4) (C═O)aObC2-C10 alkenyl,
5) (C═O)aObC2-C10 alkynyl,
6) CO2H,
7) C1-C6 perfluoroalkyl,
8) (C═O)aObC3-C8 cycloalkyl,
9) (C═O)aObheterocyclyl,
10) SO2NR7R8, and
11) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
or R3 and R3′ along with the nitrogen to which they are attached are combined to form ring
which is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;
R4 is independently selected from:
1) (C═O)aObC1-C10 alkyl,
2) (C═O)aObaryl,
3) (C═O)aObC2-C10 alkenyl,
4) (C═O)aObC2-C10 alkynyl,
5) CO2H,
6) halo,
7) OH,
8) ObC1-C6 perfluoroalkyl,
9) (C═O)aNR7R8,
10) CN,
11) (C═O)aObC3-C8 cycloalkyl,
12) (C═O)aObheterocyclyl,
13) SO2NR7R8, and
14) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R5 is:
1) (C═O)aObC1-C10 alkyl,
2) (C═O)aObaryl,
3) C2-C10 alkenyl,
4) C2-C10 alkynyl,
5) (C═O)aObheterocyclyl,
6) CO2H,
7) halo,
8) CN,
9) OH,
10) ObC1-C6 perfluoroalkyl,
11) Oa(C═O)bNR7R8,
12) oxo,
13) CHO,
14) (N═O)R7R8, or
15) (C═O)aObC3-C8 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6;
R6 is selected from:
1) (C═O)rOs(C1-C10)alkyl, wherein r and s are independently 0 or 1,
2) Or(C1-C3)perfluoroalkyl, wherein r is 0 or 1,
3) (C0-C6)alkylene-S(O)mRa, wherein m is 0, 1, or 2,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O)rOs(C2-C10)alkenyl,
9) (C═O)rOs(C2-C10)alkynyl,
10) (C═O)rOs(C3-C6)cycloalkyl,
11) (C═O)rOs(C0-C6)alkylene-aryl,
12) (C═O)rOs(C0-C6)alkylene-heterocyclyl,
13) (C═O)rOs(C0-C6)alkylene-N(Rb)
14) C(O)Ra,
15) (C0-C6)alkylene-CO2Ra,
16) C(O)H,
17) (C0-C6)alkylene-CO2H, and
18) C(O)N(Rb)2,
said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (C1-C6)alkoxy, halogen, CO2H, CN, O(C═O)C1-C6 alkyl, oxo, and N(Rb)2;
R7 and R8 are independently selected from:
1) H,
2) (C═O)ObC1-C10 alkyl,
3) (C═O)ObC3-C8 cycloalkyl,
4) (C═O)Obaryl,
5) (C═O)Obheterocyclyl,
6) C1-C10 alkyl,
7) aryl,
8) C2-C10 alkenyl,
9) C2-C10 alkynyl,
10) heterocyclyl,
11) C3-C8 cycloalkyl,
12) SO2Ra, and
13) (C═O)NRb2,
said alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R6, or
R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6;
Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl;
and
Rb is H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C═O)OC1-C6 alkyl, (C═O)C1-C6 alkyl or S(O)2Ra.

117 more elements

A compound of Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
n is 1 to 3;
r is 0 to 3;
u is 2, 3, 4 or 5;
R1 is selected from:
1) H,
2) C1-C10 alkyl,
3) aryl,
4) C2-C10 alkenyl,
5) C2-C10 alkynyl,
6) C1-C6 perfluoroalkyl,
7) C1-C6 aralkyl,
8) C3-C8 cycloalkyl, and
9) heterocyclyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R2 and R2′ are independently selected from:
1) H,
2) (C═O)aObC1-C10 alkyl,
3) (C═O)aObaryl,
4) (C═O)aObC2-C10 alkenyl,
5) (C═O)aObC2-C10 alkynyl,
6) CO2H,
7) C1-C6 perfluoroalkyl,
8) (C═O)aObC3-C8 cycloalkyl,
9) (C═O)aObheterocyclyl,
10) SO2NR7R8, and
11) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
or
R2 and R2′ are combined to form —(CH2)u— wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O)m, —NC(O)—, and —N(Rb)—, and wherein the ring formed when R2 and R2′ are combined is optionally substituted with one, two or three substituents selected from R5;
R3 and R3′ are independently selected from:
1) H,
2) (C═O)aObC1-C10 alkyl,
3) (C═O)aObaryl,
4) (C═O)aObC2-C10 alkenyl,
5) (C═O)aObC2-C10 alkynyl,
6) CO2H,
7) C1-C6 perfluoroalkyl,
8) (C═O)aObC3-C8 cycloalkyl,
9) (C═O)aObheterocyclyl,
10) SO2NR7R8, and
11) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
or R3 and R3′ along with the nitrogen to which they are attached are combined to form ring
which is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;
R4 is independently selected from:
1) (C═O)aObC1-C10 alkyl,
2) (C═O)aObaryl,
3) (C═O)aObC2-C10 alkenyl,
4) (C═O)aObC2-C10 alkynyl,
5) CO2H,
6) halo,
7) OH,
8) ObC1-C6 perfluoroalkyl,
9) (C═O)aNR7R8,
10) CN,
11) (C═O)aObC3-C8 cycloalkyl,
12) (C═O)aObheterocyclyl,
13) SO2NR7R8, and
14) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R5 is:
1) (C═O)aObC1-C10 alkyl,
2) (C═O)aObaryl,
3) C2-C10 alkenyl,
4) C2-C10 alkynyl,
5) (C═O)aObheterocyclyl,
6) CO2H,
7) halo,
8) CN,
9) OH,
10) ObC1-C6 perfluoroalkyl,
11) Oa(C═O)bNR7R8,
12) oxo,
13) CHO,
14) (N═O)R7R8, or
15) (C═O)aObC3-C8 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6;
R6 is selected from:
1) (C═O)rOs(C1-C10)alkyl, wherein r and s are independently 0 or 1,
2) Or(C1-C3)perfluoroalkyl, wherein r is 0 or 1,
3) (C0-C6)alkylene-S(O)mRa, wherein m is 0, 1, or 2,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O)rOs(C2-C10)alkenyl,
9) (C═O)rOs(C2-C10)alkynyl,
10) (C═O)rOs(C3-C6)cycloalkyl,
11) (C═O)rOs(C0-C6)alkylene-aryl,
12) (C═O)rOs(C0-C6)alkylene-heterocyclyl,
13) (C═O)rOs(C0-C6)alkylene-N(Rb)
14) C(O)Ra,
15) (C0-C6)alkylene-CO2Ra,
16) C(O)H,
17) (C0-C6)alkylene-CO2H, and
18) C(O)N(Rb)2,
said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (C1-C6)alkoxy, halogen, CO2H, CN, O(C═O)C1-C6 alkyl, oxo, and N(Rb)2;
R7 and R8 are independently selected from:
1) H,
2) (C═O)ObC1-C10 alkyl,
3) (C═O)ObC3-C8 cycloalkyl,
4) (C═O)Obaryl,
5) (C═O)Obheterocyclyl,
6) C1-C10 alkyl,
7) aryl,
8) C2-C10 alkenyl,
9) C2-C10 alkynyl,
10) heterocyclyl,
11) C3-C8 cycloalkyl,
12) SO2Ra, and
13) (C═O)NRb2,
said alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R6, or
R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6;
Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl;
and
Rb is H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C═O)OC1-C6 alkyl, (C═O)C1-C6 alkyl or S(O)2Ra.

117 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/410,341Filed 24 Apr 2006
Priority: 6 Dec 2001
Published: 24 Aug 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 239/70
Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings: condensed with carbocyclic rings or ring systems
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms

Family

Application60/338,379Us provisional application · filed 6 Dec 2001
Application10/497,413Continuation · filed 2 Jun 2004
Application11/410,341Continuation · filed 24 Apr 2006
US 2005/0107404 A1Published application
US 7,192,949 B2Related patent
US 2006/0189630 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
n is 1 to 3;
r is 0 to 3;
u is 2, 3, 4 or 5;
R1 is selected from:
1) H,
2) C1-C10 alkyl,
3) aryl,
4) C2-C10 alkenyl,
5) C2-C10 alkynyl,
6) C1-C6 perfluoroalkyl,
7) C1-C6 aralkyl,
8) C3-C8 cycloalkyl, and
9) heterocyclyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R2 and R2′ are independently selected from:
1) H,
2) (C═O)aObC1-C10 alkyl,
3) (C═O)aObaryl,
4) (C═O)aObC2-C10 alkenyl,
5) (C═O)aObC2-C10 alkynyl,
6) CO2H,
7) C1-C6 perfluoroalkyl,
8) (C═O)aObC3-C8 cycloalkyl,
9) (C═O)aObheterocyclyl,
10) SO2NR7R8, and
11) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
or
R2 and R2′ are combined to form —(CH2)u— wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O)m, —NC(O)—, and —N(Rb)—, and wherein the ring formed when R2 and R2′ are combined is optionally substituted with one, two or three substituents selected from R5;
R3 and R3′ are independently selected from:
1) H,
2) (C═O)aObC1-C10 alkyl,
3) (C═O)aObaryl,
4) (C═O)aObC2-C10 alkenyl,
5) (C═O)aObC2-C10 alkynyl,
6) CO2H,
7) C1-C6 perfluoroalkyl,
8) (C═O)aObC3-C8 cycloalkyl,
9) (C═O)aObheterocyclyl,
10) SO2NR7R8, and
11) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
or R3 and R3′ along with the nitrogen to which they are attached are combined to form ring
which is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;
R4 is independently selected from:
1) (C═O)aObC1-C10 alkyl,
2) (C═O)aObaryl,
3) (C═O)aObC2-C10 alkenyl,
4) (C═O)aObC2-C10 alkynyl,
5) CO2H,
6) halo,
7) OH,
8) ObC1-C6 perfluoroalkyl,
9) (C═O)aNR7R8,
10) CN,
11) (C═O)aObC3-C8 cycloalkyl,
12) (C═O)aObheterocyclyl,
13) SO2NR7R8, and
14) SO2C1-C10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R5 is:
1) (C═O)aObC1-C10 alkyl,
2) (C═O)aObaryl,
3) C2-C10 alkenyl,
4) C2-C10 alkynyl,
5) (C═O)aObheterocyclyl,
6) CO2H,
7) halo,
8) CN,
9) OH,
10) ObC1-C6 perfluoroalkyl,
11) Oa(C═O)bNR7R8,
12) oxo,
13) CHO,
14) (N═O)R7R8, or
15) (C═O)aObC3-C8 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6;
R6 is selected from:
1) (C═O)rOs(C1-C10)alkyl, wherein r and s are independently 0 or 1,
2) Or(C1-C3)perfluoroalkyl, wherein r is 0 or 1,
3) (C0-C6)alkylene-S(O)mRa, wherein m is 0, 1, or 2,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O)rOs(C2-C10)alkenyl,
9) (C═O)rOs(C2-C10)alkynyl,
10) (C═O)rOs(C3-C6)cycloalkyl,
11) (C═O)rOs(C0-C6)alkylene-aryl,
12) (C═O)rOs(C0-C6)alkylene-heterocyclyl,
13) (C═O)rOs(C0-C6)alkylene-N(Rb)
14) C(O)Ra,
15) (C0-C6)alkylene-CO2Ra,
16) C(O)H,
17) (C0-C6)alkylene-CO2H, and
18) C(O)N(Rb)2,
said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (C1-C6)alkoxy, halogen, CO2H, CN, O(C═O)C1-C6 alkyl, oxo, and N(Rb)2;
R7 and R8 are independently selected from:
1) H,
2) (C═O)ObC1-C10 alkyl,
3) (C═O)ObC3-C8 cycloalkyl,
4) (C═O)Obaryl,
5) (C═O)Obheterocyclyl,
6) C1-C10 alkyl,
7) aryl,
8) C2-C10 alkenyl,
9) C2-C10 alkynyl,
10) heterocyclyl,
11) C3-C8 cycloalkyl,
12) SO2Ra, and
13) (C═O)NRb2,
said alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R6, or
R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6;
Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl;
and
Rb is H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C═O)OC1-C6 alkyl, (C═O)C1-C6 alkyl or S(O)2Ra.

117 more elements

Facts

Application

11/410,341Filed 24 Apr 2006

Priority

6 Dec 2001

Published

24 Aug 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 239/70
Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings: condensed with carbocyclic rings or ring systems
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms

Family

Application60/338,379Us provisional application · filed 6 Dec 2001

Application10/497,413Continuation · filed 2 Jun 2004

Application11/410,341Continuation · filed 24 Apr 2006

US 2005/0107404 A1Published application

US 7,192,949 B2Related patent

US 2006/0189630 A1This patent

From the US filing history. Foreign family members aren’t listed.