4-aminopyrimidine-5-thione derivatives
Novel 4-aminopyrimidine-5-thione derivatives are disclosed. These compounds inhibit cyclin-dependent kinases, in particular Cdk1, Cdk2 and Cdk4. These compounds and their pharmaceutically acceptable salts have antiproliferative activity and are useful in the treatment or control of cancer, in particular solid tumors. This invention is also directed to 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.
1. A compound of the formula
wherein
R 1 is selected from the group
heterocycle and lower alkyl-heterocycle, wherein the heterocycle moiety in both instances optionally may be substituted by up to four substituents independently selected from
H,
lower alkyl,
lower alkyl substituted by oxo, OR 12 , CO 2 R 12 , NR5R6, S(O) n R 15 or C(O)NR 5 R 6 ,
CO 2 R 7 ,
COR 11 ,
COR 12 ,
C(O)NR 13 R 14 ,
S(O) n R 15 ,
oxo,
OR 12 ; or
NR 5 R 6 ,
aryl,
aryl substituted by
H,
S(O) n —R 15 ,
NR 5 R 6 ,
carbonyl,
carbonyl substituted by lower alkyl, OR 12 or NR 5 R 6 ,
lower alkyl,
lower alkyl substituted by OR 10 or NR 5 R 6 ,
OR 8 ;
halogen,
cycloalkyl,
cycloalkyl substituted by OR 7 , NR 5 R 6 or S(O) n R 15 ,
lower alkyl, and
lower alkyl substituted by
NR 5 R 6 ,
NR 11 SO 2 R 15 ,
CO 2 R 10 ,
S(O) n R 15 ,
heterocycle,
heterocycle substituted by
lower alkyl,
CO 2 R 12 or
SO 2 R 15 ,
heteroaryl,
heteroaryl substituted by
lower alkyl,
CO 2 R 12 , or
SO 2 R 15 ,
aryl, and
aryl substituted by
lower alkyl,
halogen,
NR 5 R 6 ,
COR 12 , or
CO 2 R 12 ;
R 2 is selected from the group
aryl, heteroaryl, cycloalkyl and heterocycle, wherein each may be substituted by up to four substituents independently selected from the group
lower alkyl,
lower alkyl substituted by halogen or OR 10 ,
halogen,
OR 12 ,
NO 2 ,
CN,
NR 5 R 6 ,
S(O) n —R 9 , and
SO 2 —NR 16 R 17 ;
R 5 and R 6 are each independently selected from the group
H,
lower alkyl,
lower alkyl substituted by oxo, CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 or SO 2 R 15 ,
aryl,
aryl substituted by NR 13 R 14 , OR 12 , CO 2 R 12 , C(O)NR 13 R 14 , SO 2 R 15 , halogen, lower alkyl, or lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 13 R 14 or NR 13 R 14 ,
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 5 R 6 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 5 and R 6 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 SO 2 , and said ring atoms optionally being substituted by OH, oxo, NR 13 R 14 , lower alkyl and lower alkyl substituted by OR 12 ;
R 7 is selected from the group
H,
lower alkyl,
lower alkyl substituted by OR 12 , CO 2 R 12 , NR 5 R 6 , C(O)NR 5 R 6 , halogen, oxo, aryl or aryl substituted by up to three substituents independently selected from lower alkyl, halogen and NR 5 R 6 ,
cycloalkyl,
cycloalkyl substituted by OH, oxo, or NH 2 ,
SO 2 R 15 , and
COR 12 ;
R 8 is selected from the group
H,
lower alkyl,
lower alkyl substituted by NR 5 R 6 ,
heterocycle, and
heterocycle substituted by lower alkyl, CO 2 R 12 or SO 2 R 15 ;
R 9 is selected from the group
H, and
lower alkyl;
R 10 is selected from the group
lower alkyl,
aryl, and
aryl substituted by halogen or NR 5 R 6 ;
R 11 is selected from the group
H,
lower alkyl, and
lower alkyl substituted by oxo and halogen;
R 12 is selected from the group
H,
lower alkyl, and
lower alkyl substituted by NR 5 R 6 or OR 11 ;
R 13 and R 14 are each independently selected from the group
H,
lower alkyl,
lower alkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , CONR 5 R 6 or SO 2 R 15 ,
aryl,
aryl substituted by NR 5 R 6 , OR 12 , CO 2 R 12 , CONR 5 R 6 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 13 R 14 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 13 and R 14 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms, and said ring atoms optionally being substituted by OH, oxo, NR 5 R 6 , lower alkyl and lower alkyl substituted by OR 12 ;
R 15 is selected from the group
aryl,
aryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heteroaryl,
heteroaryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , NR 5 R 6 or NR 5 R 6 ,
NR 5 R 6 ,
lower alkyl,
lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heterocycle, and
heterocycle substituted by the group CO 2 R 12 , COR 12 , SO 2 R 12 , lower alkyl, C(O)NR 5 R 6 or NR 5 R 6 ;
R 16 and R 17 are each independently selected from the group
H, and
lower alkyl,
or, alternatively, the group —NR 16 R 17 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 16 and R 17 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms, and said ring atoms optionally being substituted by lower alkyl, OH, oxo and NH 2 ; and
n is 0, 1 or 2;
or the pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein R 2 is phenyl substituted by two F molecules and one OR 12 and wherein R 12 is methyl.
3. The compound of claim 1 wherein R 2 is heteroaryl selected from benzofuran, benzooxazole and benzoazole.
4. The compound of claim 1 wherein R 2 is cyclohexyl that optionally is substituted by alkoxy.
5. The compound of claim 1 wherein R 1 is ethyl or propyl that optionally is substituted by NR 5 R 6 wherein one of R 5 or R 6 is SO 2 R 15 and R 15 is lower alkyl.
6. The compound of claim 5 which is N-{3-[4-Amino-5-(5-fluoro-2-methoxy-thiobenzoyl)-pyrimidin-2-ylamino]-propyl}-methanesulfonamide.
7. The compound of claim 1 wherein R 1 selected from the group
wherein
R 3 is selected from the group
H,
lower alkyl,
lower alkyl substituted by oxo, OR 12 , CO 2 R 12 , NR 5 R 6 , SO 2 R 15 or C(O)NR 5 R 6 ,
CO 2 R 7 ,
COR 12 ,
C(O)NR 5 R 6 , and
SO 2 R 15 ;
R 4 is selected from the group
H,
OR 11 ,
lower alkyl,
NR 5 R 6 ,
NO 2 ,
oxo
CN, and
halogen;
R 4′ is selected from the group
H,
OR 11 ,
lower alkyl,
NR 5 R 6 ,
NO 2 ,
CN, and
halogen;
R 5 and R 6 are each independently selected from the group
H,
lower alkyl,
lower alkyl substituted by oxo, CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 or SO 2 R 15 ,
aryl,
aryl substituted by NR 13 R 14 , OR 12 , CO 2 R 12 , CONR 13 R 14 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , CONR 13 R 14 or NR 13 R 14 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 5 R 6 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 5 and R 6 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 SO 2 , and said ring atoms optionally being substituted by OH, oxo, N 13 R 14 , lower alkyl and lower alkyl substituted by OR 12 ;
R 7 is selected from the group
H,
lower alkyl,
lower alkyl substituted by OR 12 , CO 2 R 12 , NR 5 R 6 , or CONR 5 R 6 , halogen, oxo, aryl, aryl substituted by up to three substituents independently selected from lower alkyl, halogen, or NR 5 R 6 ,
cycloalkyl,
cycloalkyl substituted by OH, oxo, or NH 2 ,
SO 2 R 15 , and
COR 12 ;
R 10 is selected from the group
lower alkyl,
aryl, and
aryl substituted by halogen or NR 5 R 6 ;
R 11 is selected from the group
H,
lower alkyl, and
lower alkyl substituted by oxo and halogen;
R 12 is selected from the group
H
lower alkyl, and
lower alkyl substituted by halogen, oxo, NR 5 R 6 or OR 11 ;
R 13 and R 14 are independently selected from
H,
lower alkyl,
lower alkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 or SO 2 R 15 ,
aryl,
aryl substituted by NR 5 R 6 , OR 12 , CO 2 R 12 , C(O)NR 5 R 6 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 and NR 5 R 6 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 13 R 14 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 13 and R 14 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms, and said ring atoms optionally being substituted by OH, oxo, NR 5 R 6 , lower alkyl and lower alkyl substituted by OR 12 ;
R 15 is selected from the group
aryl,
aryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heteroaryl,
heteroaryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
NR 5 R 6 ,
lower alkyl,
lower alkyl substituted by the group halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heterocycle, and
heterocycle substituted by the group CO 2 R 12 , COR 12 , SO 2 R 12 , lower alkyl, C(O)NR 5 R 6 or NR 5 R 6 ; and
n is 0, 1 or 2,
or the pharmaceutically acceptable salts thereof.
8. A compound of formula
wherein
R 3 is selected from the group
H,
lower alkyl,
lower alkyl substituted by oxo, OR 12 , CO 2 R 12 , NR 5 R 6 , SO 2 R 15 or C(O)NR 5 R 6 ,
CO 2 R 7 ,
COR 12 ,
C(O)NR 5 R 6 , and
SO 2 R 15 ;
R 4 is selected from the group
H,
OR 11 ,
lower alkyl,
NR 5 R 6 ,
NO 2 ,
oxo
CN, and
halogen;
R 5 and R 6 are each independently selected from the group
H,
lower alkyl,
lower alkyl substituted by oxo, CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 or SO 2 R 15 ,
aryl,
aryl substituted by NR 13 R 14 , OR 12 , CO 2 R 12 , CONR 13 R 14 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , CONR 13 R 14 or NR 13 R 14 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 5 R 6 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 5 and R 6 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 SO 2 , and said ring atoms optionally being substituted by OH, oxo, N 13 R 14 , lower alkyl and lower alkyl substituted by OR 12 ;
R 7 is selected from the group
H,
lower alkyl,
lower alkyl substituted by OR 12 , CO 2 R 12 , NR 5 R 6 , or CONR 5 R 6 , halogen, oxo, aryl, aryl substituted by up to three substituents independently selected from lower alkyl, halogen, or NR 5 R 6 ,
cycloalkyl,
cycloalkyl substituted by OH, oxo, or NH 2 ,
SO 2 R 15 , and
COR 12 ;
R 11 is selected from the group
H,
lower alkyl, and
lower alkyl substituted by oxo and halogen;
R 12 is selected from the group
H
lower alkyl, and
lower alkyl substituted by halogen, oxo, NR 5 R 6 or OR 11 ;
R 13 and R 14 are independently selected from
H,
lower alkyl,
lower alkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 or SO 2 R 15 ,
aryl,
aryl substituted by NR 5 R 5 , OR 12 , CO 2 R 12 , C(O)NR 5 R 6 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 and NR 5 R 6 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 13 R 14 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 13 and R 14 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms, and said ring atoms optionally being substituted by OH, oxo, NR 5 R 6 , lower alkyl and lower alkyl substituted by OR 12 ;
R 15 is selected from the group
aryl,
aryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heteroaryl,
heteroaryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
NR 5 R 6 ,
lower alkyl,
lower alkyl substituted by the group halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heterocycle, and
heterocycle substituted by the group CO 2 R 12 , COR 12 , SO 2 R 12 , lower alkyl, C(O)NR 5 R 6 or NR 5 R 6 ;
R 18 , R 19 , R 20 and R 21 are each independently selected from
lower alkyl,
halogen, and
OR 12 ;
or the pharmaceutically acceptable salts thereof.
9. The compound of claim 8 wherein R 3 is selected from the group CO 2 R 7 , COR 12 and SO 2 R 15 and R 4 is H, OR 11 or lower alkyl.
10. The compound of claim 8 that is selected from the group:
[4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanethione;
4-[4-Amino-5-(2,3-difluoro-6-methoxy-thiobenzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonic acid amide;
[4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanethione;
[4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5,6-difluoro-benzofuran-7-yl)-methanethione;
[4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5,6-difluoro-benzooxazol-7-yl)-methanethione;
{4-Amino-2-[1-(3-morpholin-4-yl-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl}(2,3-difluoro-6-methoxy-phenyl)-methanethione;
{4-Amino-2-[1-(pyridine-2-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl}-(2,3-difluoro-6-methoxy-phenyl)-methanethione;
[4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-thiophen-2-yl-methanethione; and
[4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(6-chloro-2,3-difluoro-phenyl)-methanethione.
11. The compound of claim 8 that is selected from the group:
[4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,6-difluoro-phenyl)-methanethione;
[4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-phenyl-methanethione;
4-[4-Amino-5-(5-fluoro-2-methoxy-thiobenzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester; and
[4-Amino-2-(1-methanesulfonyl-pyrrolidin-3-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanethione.
12. A compound of formula
wherein
R 4 is selected from the group
H,
OR 11 ,
lower alkyl,
NR 5 R 6 ,
NO 2 ,
oxo
CN, and
halogen;
R 5 and R 6 are each independently selected from the group
H,
lower alkyl,
lower alkyl substituted by oxo, CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 or SO 2 R 15 ,
aryl,
aryl substituted by NR 13 R 14 , OR 12 , CO 2 R 12 , CONR 13 R 14 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , CONR 13 R 14 or NR 13 R 14 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 5 R 6 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 5 and R 6 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 SO 2 , and said ring atoms optionally being substituted by OH, oxo, N 13 R 14 , lower alkyl and lower alkyl substituted by OR 12 ;
R 10 is selected from the group
lower alkyl,
aryl, and
aryl substituted by halogen or NR 5 R 6 ;
R 11 is selected from the group
H,
lower alkyl, and
lower alkyl substituted by oxo and halogen;
R 12 is selected from the group
H
lower alkyl, and
lower alkyl substituted by halogen, oxo, NR 5 R 6 or OR 11 ;
R 13 and R 14 are independently selected from
H,
lower alkyl,
lower alkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 or SO 2 R 15 ,
aryl,
aryl substituted by NR 5 R 6 , OR 12 , CO 2 R 12 , C(O)NR 5 R 6 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 and NR 5 R 6 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 13 R 14 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 13 and R 14 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms, and said ring atoms optionally being substituted by OH, oxo, NR 5 R 6 , lower alkyl and lower alkyl substituted by OR 12 ;
R 15 is selected from the group
aryl,
aryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heteroaryl,
heteroaryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
NR 5 R 6 ,
lower alkyl,
lower alkyl substituted by the group halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heterocycle, and
heterocycle substituted by the group CO 2 R 12 , COR 12 , SO 2 R 12 , lower alkyl, C(O)NR 5 R 6 or NR 5 R 6 ; and
R 18 , R 19 , R 20 and R 21 are each independently selected from
lower alkyl,
halogen, and
OR 12 ;
or the pharmaceutically acceptable salts thereof.
13. The compound of claim 12 wherein R 4 is H, one of R 5 or R 6 is H or lower alkyl and the other is SO 2 R 15 , wherein R 15 is lower alkyl, and two of R 18 -R 21 are halogen, and one of R 18 -R 21 is COR 12 , wherein R 12 is lower alkyl.
14. The compound of claim 12 which is selected from the group:
N-{4-[4-Amino-5-(2,3-difluoro-6-methoxy-thiobenzoyl)-pyrimidin-2-ylamino]-cyclohexyl}methanesulfonamide; and
N-{4-[4-Amino-5-(2,3-difluoro-6-methoxy-thiobenzoyl)-pyrimidin-2-ylamino]-cyclohexyl}-N-methylmethanesulfonamide.
15. A compound of formula
wherein
R 4′ is selected from the group
H,
OR 11 ,
lower alkyl,
NR 5 R 6 ,
NO 2 ,
CN, and
halogen;
R 5 and R 6 are each independently selected from the group
H,
lower alkyl,
lower alkyl substituted by oxo, CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 13 R 14 , C(O)NR 13 R 14 or SO 2 R 15 ,
aryl,
aryl substituted by NR 13 R 14 , OR 12 , CO 2 R 12 , CONR 13 R 14 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , CONR 13 R 14 or NR 13 R 14 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 5 R 6 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 5 and R 6 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 SO 2 , and said ring atoms optionally being substituted by OH, oxo, N 13 R 14 , lower alkyl and lower alkyl substituted by OR 12 ;
R 11 is selected from the group
H,
lower alkyl, and
lower alkyl substituted by oxo and halogen;
R 12 is selected from the group
H
lower alkyl, and
lower alkyl substituted by halogen, oxo, NR 5 R 6 or OR 11 ;
R 13 and R 14 are independently selected from
H,
lower alkyl,
lower alkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 , SO 2 R 15 , NSO 2 R 12 , heteroaryl, heterocycle, or heterocycle substituted by oxo,
cycloalkyl,
cycloalkyl substituted by CO 2 R 12 , OR 12 , NR 5 R 6 , C(O)NR 5 R 6 or
SO 2 R 15 ,
aryl,
aryl substituted by NR 5 R 6 , OR 12 , CO 2 R 12 , C(O)NR 5 R 6 , SO 2 R 15 , halogen, lower alkyl, and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 and NR 5 R 6 ;
SO 2 R 15 ,
CO 2 R 12 , and
COR 12 ,
or alternatively, the group —NR 13 R 14 can form a ring having a total of from 3 to 7 ring atoms, said ring atoms comprising in addition to the nitrogen to which R 13 and R 14 are bonded, carbon ring atoms, said carbon ring atoms optionally being replaced by one or more additional N or O ring atoms, and said ring atoms optionally being substituted by OH, oxo, NR 5 R 6 , lower alkyl and lower alkyl substituted by OR 12 ;
R 15 is selected from the group
aryl,
aryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heteroaryl,
heteroaryl substituted by the group halogen, CO 2 R 12 , SO 2 R 10 , COR 12 , lower alkyl and lower alkyl substituted by halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
NR 5 R 6 ,
lower alkyl,
lower alkyl substituted by the group halogen, OR 12 , oxo, CO 2 R 12 , C(O)NR 5 R 6 or NR 5 R 6 ,
heterocycle, and
heterocycle substituted by the group CO 2 R 12 , COR 12 , SO 2 R 12 , lower alkyl, C(O)NR 5 R 6 or NR 5 R 6 ;
R 18 , R 19 , R 20 and R 21 are each independently selected from
lower alkyl,
halogen, and
OR 12 ; and
n is 0, 1 or 2,
or the pharmaceutically acceptable salts thereof.
16. The compound of claim 15 wherein n is 2, R 4′ is H and R 15 is lower alkyl or NR 5 R 6 .
17. The compound of claim 16 wherein R 15 is NR 5 R 6 and wherein R 5 and R 6 are H.
18. The compound of claim 16 wherein two of R 18-21 are halogen and one of R 18-21 is OR 12 , wherein R 12 is lower alkyl.
19. The compound of claim 15 which is selected from:
[4-Amino-2-(4-methanesulfonyl-phenylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanethione, and
4-[4-Amino-5-(2,3-difluoro-6-methoxy-thiobenzoyl)-pyrimidin-2-ylamino]-benzenesulfonamide.
20. A composition comprising as an active ingredient a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.