Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases

1. A compound having the general formula (I)

wherein

R 1 , R 2 , and R 4 are each hydrogen;

R 3 is a phenyl substituted with between one and four R S each independently selected from, Sub, —OR S1 , or —N(R S1 ) 2 , wherein each R S1 is independently selected from linear or branched C 5 -C 6 alkyl;

R 5 is a phenyl substituted with between zero and four R A each independently selected from Sub, —OR A1 , or —N(R A1 ) 2 , wherein each R A1 is independently selected from linear or branched C 5 -C 6 alkyl;

R 6 is hydrogen or is selected from the group consisting of:

linear or branched C 1 -C 8 alkyl, aryl, HA, HC, pyrrolidinyl, C 3 -C 8 cycloalkyl, cyclohexyl, cyclopentyl, C 5 -C 12 bicycloalkyl, adamantyl, in each case optionally substituted with Sub, or R 6 is selected from —(CH 2 ) q -group, wherein q is an integer from 1 to 3, under the proviso, if R 6 is selected to be a methylene chain —(CH 2 ) q -group, R 17 or R 19 are selected to be a methylene chain —(CH 2 ) s -group, wherein s is an integer from 1 to 3 or a —(CH 2 ) t A-group, t is an integer from 1 to 3 and A is selected from O or N, respectively, and R 6 and R 17 or R 6 and R 19 form together a 5 to 8 membered ring system,

or R 6 represents —(CH 2 ) p —Z, wherein p is an integer from 0 to 6 and Z is selected from the group comprising:

aryl, HA, HC, linear or branched C 1 -C 6 alkyl, in each case optionally substituted with Sub, and —N(R 7 R 8 ), wherein R 7 and R 8 represent independently from each other —H, or linear or branched C 1 -C 6 alkyl, or Z is selected from —(CR 9 R 10 R 11 ), wherein R 9 , R 10 and R 11 are independently of each other hydrogen or selected from the group consisting of:

linear or branched C 1 -C 8 alkyl, aryl in each case optionally substituted with Sub or —N(R 12 R 13 ),

wherein R 12 and R 13 represent independently of each other —H or linear or branched C 1 -C 6 alkyl optionally substituted with Sub,

under the proviso, if Z represents —(CR 9 R 10 R 11 ) as defined above, p is selected to be an integer from 0 to 6, and

if Z is selected from aryl, HA, HC, or —N(R 7 R 8 ) as defined above, p is selected to be an integer from 1 to 6;

L is in the meta- or para-position of the phenyl represented by R 5 and selected from the group comprising:

—NR 14 —SO 2 —, NR 14 —SO—,

wherein R 14 is selected from —H, linear or branched C 1 -C 6 alkyl, —SO 2 —R 15 , wherein R 15 is selected from linear or branched C 1 -C 6 alkyl or C 1 -C 6 alkylene, or R 14 represents —(CH 2 ) r —COOR 16 , wherein r is an integer from 0 to 6 and R 16 is selected from —H or linear or branched C 1 -C 6 alkyl,

—NR 17 —CO—,

wherein R 17 is selected from —H, linear or branched C 1 -C 6 alkyl, or a —(CH 2 ) s -group,

wherein s is an integer from 1 to 3, and

wherein if R 6 and R 17 both represent a methylene chain group, R 6 and R 17 may form together a 5 to 8 membered ring system:

—SO 2 —NR 18 —,

wherein R 18 is selected from —H, or linear or branched C 1 -C 6 alkyl,

—CO—NR 19 —,

wherein R 19 is selected from —H, linear or branched C 1 -C 6 alkyl, or a —(CH 2 ) t -A- group, wherein t is an integer from 1 to 3 and A is selected from N or O, and wherein if R 6 represents a —(CH 2 ) q -group and R 19 represents a —(CH 2 ) t -A- group, R 6 and R 19 may form together a 5 to 8 membered ring system

and m is 1,

Sub is independently selected from —OH, —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —O-cyclo-C 3 H 5 , —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OC 4 H 9 , —OPh, —OCH 2 Ph, —OCPh 3 , —SH, —SCH 3 , —SC 2 H 5 , —SC 3 H 7 , —S-cyclo-C 3 H 5 , —SCH(CH 3 ) 2 , —SC(CH 3 ) 3 , —NO 2 , —F, —Cl, —Br, —I, —N 3 , —CN, —OCN, —NCO, —SCN, —NCS, —CHO, —COCH 3 , —COC 2 H 5 , —COC 3 H 7 , —CO-cyclo-C 3 H 5 , —COCH(CH 3 ) 2 , —COC(CH 3 ) 3 , —COOH, —COCN, —COOCH 3 , —COOC 2 H 5 , —COOC 3 H 7 , —COO-cyclo-C 3 H 5 , —COOCH(CH 3 ) 2 , —COOC(CH 3 ) 3 , —OOC—CH 3 , —OOC—C 2 H 5 , —OOC—C 3 H 7 , —OOC-cyclo-C 3 H 5 , —OOC—CH(CH 3 ) 2 , —OOC—C(CH 3 ) 3 , —CONH 2 , —CONHCH 3 , —CONHC 2 H 5 , —CONHC 3 H 7 , —CONH-cyclo-C 3 H 5 , —CONH[CH(CH 3 ) 2 ], —CONH[C(CH 3 ) 3 ], —CON(CH 3 ) 2 , —CON(C 2 H 5 ) 2 , —CON(C 3 H 7 ) 2 , —CON(cyclo-C 3 H 5 ) 2 , —CON[CH(CH 3 ) 2 ] 2 , —CON[C(CH 3 ) 3 ] 2 , —NH 2 , —NHCH 3 , —NHC 2 H 5 , —NHC 3 H 7 , —NH-cyclo-C 3 H 5 , —NHCH(CH 3 ) 2 , —NHC(CH 3 ) 3 , —N(CH 3 ) 2 , —N(C 2 H 5 ) 2 , —N(C 3 H 7 ) 2 , —N(cyclo-C 3 H 5 ) 2 , —N[CH(CH 3 ) 2 ] 2 , —N[C(CH 3 ) 3 ] 2 , —SOCH 3 , —SOC 2 H 5 , —SOC 3 H 7 , —SO-cyclo-C 3 H 5 , —SOCH(CH 3 ) 2 , —SOC(CH 3 ) 3 , —SO 2 CH 3 , —SO 2 C 2 H 5 , —SO 2 C 3 H 7 , —SO2-cyclo-C 3 H 5 , —SO 2 CH(CH 3 ) 2 , —SO 2 C(CH 3 ) 3 , —SO 3 H, —SO 3 CH 3 , —SO 3 C 2 H 5 , —SO 3 C 3 H 7 , —SO 3 -cyclo-C 3 H 5 , —SO 3 CH(CH 3 ) 2 , —SO 3 C(CH 3 ) 3 , —OCF 3 , —OC 2 F 5 , —O—COOCH 3 , —O—COOC 2 H 5 , —O—COOC 3 H 7 , —O—COO-cyclo-C 3 H 5 , —O—COOCH(CH 3 ) 2 , —O—COOC(CH 3 ) 3 , —NH—CO—NH 2 , —NH—CO—NHCH 3 , —NH—CONHC 2 H 5 , —NH—CO—NHC 3 H 7 , —NH—CO—NH-cyclo-C 3 H 5 , —NH—CO—NH[CH(CH 3 ) 2 ], —NH—CO—NH[C(CH 3 ) 3 ], —NH—CO—N(CH 3 ) 2 , —NH—CO—N(C 2 H 5 ) 2 , —NH—CO—N(C 3 H 7 ) 2 , —NH—CO—N(cyclo-C 3 H 5 ) 2 , —NH—CO—N[CH(CH 3 ) 2 ] 2 , —NH—CO—N[C(CH 3 ) 3 ] 2 , —NH—CS—NH 2 , —NH—CS—NHCH 3 , —NH—CS—NHC 2 H 5 , —NH—CS—NHC 3 H 7 , —NH—CS—NH-cyclo-C 3 H 5 , —NH—CS—NH[CH(CH 3 ) 2 ], —NH—CS—NH[C(CH 3 ) 3 ], —NH—CS—N(CH 3 ) 2 , —NH—CS—N(C 2 H 5 ) 2 , —NH—CS—N(C 3 H 7 ) 2 , —NH—CS—N(cyclo-C 3 H 5 ) 2 , —NH—CS—N[CH(CH 3 ) 2 ] 2 , —NH—CS—N[C(CH 3 ) 3 ] 2 , —NH—C(═NH)—NH 2 , —NH—C(═NH)NHCH 3 , —NH—C(═NH)—NHC 2 H 5 , —NH—C(═NH)—NHC 3 H 7 , —NH—C(═NH)—NH-cyclo-C 3 H 5 , —NH—C(═NH)—NH[CH(CH 3 ) 2 ], —NH—C(═NH)—NH[C(CH 3 ) 3 ], —NH—C(═NH)—N(CH 3 ) 2 , —NH—C(═NH)—N(C 2 H 5 ) 2 , —NH—C(═NH)—N(C 3 H 7 ) 2 , —NH—C(═NH)—N(cyclo-C 3 H 5 ) 2 , —NH—C(═NH)—N[CH(CH 3 ) 2 ] 2 , —NH—C(═NH)—N[C(CH 3 ) 3 ] 2 , —O—CO—NH 2 , —O—CO—NHCH 3 , —O—CO—NHC 2 H 5 , —O—CO—NHC 3 H 7 , —O—CO—NH-cyclo-C 3 H 5 , —O—CO—NH[CH(CH 3 ) 2 ], —O—CO—NH[C(CH 3 ) 3 ], —O—CO—N(CH 3 ) 2 , —O—CO—N(C 2 H 5 ) 2 , —O—CO—N(C 3 H 7 ) 2 , —O—CO—N(cyclo-C 3 H 5 ) 2 , —O—CO—N[CH(CH 3 ) 2 ] 2 , —O—CO—N[C(CH 3 ) 3 ] 2 , —O—CO—OCH 3 , —O—CO—OC 2 H 5 , —O—CO—OC 3 H 7 , —O—CO—O-cyclo-C 3 H 5 , —O—CO—OCH(CH 3 ) 2 , —O—CO—OC(CH 3 ) 3 , —CH 2 F—CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 Br—CHBr 2 , —CBr 3 , —CH 2 I—CHI 2 , —Cl 3 , —CH 2 —CH 2 F, —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —CH 2 Cl, —CH 2 —CHCl 2 , —CH 2 —CCl 3 , —CH 2 —CH 2 Br —CH 2 —CHBr 2 , —CH 2 —CBr 3 , —CH 2 —CH 2 I—CH 2 —CHI 2 , —CH 2 —Cl 3 , —CH 3 , —C 2 H 5 , —C 3 H 7 , -cyclo-C 3 H 5 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —C 4 H 9 , —CH 2 —CH(CH 3 ) 2 , —CH(CH 3 )—C 2 H 5 , —C(CH 3 ) 3 , -Ph, —CH 2 -Ph, —CPh 3 , —CH═CH 2 , —CH 2 CH═CH 2 , —C(CH 3 )═CH 2 , —CH═CHCH 3 , —C 2 H 4 —CH═CH 2 , —CH═C(CH 3 ) 2 , —CCCH 3 , or —CH 2 —CCH,

HA is a partially or fully unsaturated 5 to 10 membered mono- or bicyclic ring system, containing one to three heteroatoms independently selected from oxygen, sulfur or nitrogen independently;

HC is a 5 to 10 membered mono- or bicyclic ring system, containing one to three heteroatoms independently selected from oxygen, sulfur or nitrogen; or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein each RS is independently selected from —F, —Cl, —Br, I, —OR S2 , or N(R S2 ) 2 , wherein each R S2 is independently selected from hydrogen or linear or branched C 1 -C 6 alkyl or benzyl.

3. The compound according to claim 1 , wherein the phenyl of R 3 is substituted with one R S selected from —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —O-cyclo-C 3 H 5 , —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , or —OC 4 H 9 .

4. The compound according to claim 1 , wherein the phenyl of R 3 is substituted with one R S selected from —NH 2 , —NHCH 3 , —NHC 2 H 5 , —NHC 3 H 7 , —NH-cyclo-C 3 H 5 , —NHCH(CH 3 ) 2 , —NHC(CH 3 ) 3 , —N(CH 3 ) 2 , —N(C 2 H 5 ) 2 , —N(C 3 H 7 ) 2 , —N(cyclo-C 3 H 5 ) 2 , —N[CH(CH 3 ) 2 ] 2 , or —N[C(CH 3 ) 3 ] 2 .

5. The compound according to claim 1 , wherein the phenyl of R 5 is substituted with one R A selected from —F, —Cl, —Br, I, —OR A2 , or N(R A2 ) 2 , wherein each R A2 is independently selected from hydrogen or linear or branched C 1 -C 6 alkyl.

6. The compound according to claim 1 , wherein the phenyl of R 5 is not substituted with R A .

7. The compound according to claim 1 , wherein R 6 is hydrogen, or linear or branched C 1 -C 6 alkyl.

8. The compound according to claim 1 , wherein R 6 is selected from —H, —CH 3 , —C 2 H 5 , —C 3 H 7 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 or —CH 2 C(CH 3 ) 3 .

9. The compound according to claim 1 , wherein R 6 is selected from H, CH 3 , or C(CH 3 ) 3 .

10. The compound according to claim 1 , wherein R 6 is aryl, optionally substituted with Sub.

11. The compound according to claim 1 , wherein R 6 is phenyl, optionally substituted with Sub.

12. The compound according to claim 1 , wherein R 6 is a C 3 -C 8 cycloalkyl, optionally substituted with Sub.

13. The compound according to claim 1 , wherein R 6 is cyclopentyl or cyclohexyl, optionally substituted with between one and three linear or branched C 1 -C 6 alkyl, —OH, —NH 2 or —NHCOOR 3 5 , wherein R 3 5 represents —H or linear or branched C 1 -C 6 alkyl.

14. The compound according to claim 1 , wherein R 6 is cyclopentyl or cyclohexyl, substituted with one —NH 2 .

15. The compound according to claim 1 , wherein R 6 is selected from thiazolyl, oxazolyl, isothioazolyl, isoxazolyl, piperidinyl, piperazinyl or morpholinyl.

16. The compound according to claim 1 , wherein L is —NR 14 —SO 2 —, R 14 is selected from H, linear or branched C 1 -C 4 alkyl, —SO 2 —R 15 —, wherein R 15 is selected from linear or branched C 1 -C 4 alkyl or C 1 -C 4 alkylene, or R 14 represents —(CH 2 ) r —COOR 16 —, wherein r is an integer from 0 to 4 and R 16 is selected from —H or linear or branched C 1 -C 4 alkyl.

17. The compound according to claim 1 , wherein L is —NR 17 —CO—, R 17 is selected from —H, linear or branched C 1 -C 4 alkyl, or a —(CH 2 ) s — group, wherein s is an integer from 1 to 3, and wherein if R 6 represents a —(CH 2 ) q group, wherein q is an integer from 1 to 3, and R 17 represents a methylene chain —(CH 2 ) s — group, R 6 and R 17 may form together a 5 to 8 membered ring system.

18. The compound according to claim 1 , wherein L is —SO 2 —NR 18 —, R 18 is selected from —H or linear or branched C 1 -C 4 alkyl.

19. The compound according to claim 1 , wherein L is —CO—NR 19 —, wherein R 19 is selected from —H, linear or branched C 1 -C 4 alkyl, or a —(CH 2 ) t -A- group, wherein t is an integer from 1 to 3 and A is selected from N or O, and wherein if R 6 represents a —(CH 2 ) q — group wherein q is an integer from 1 to 3, and R 19 represents a —(CH 2 ) t -A- group, wherein t is selected to be 2 and A represents O,

R 6 and R 19 may form together a 6-membered ring system

20. The compound according to claim 1 , wherein L is —NR 14 —SO 2 —, wherein R 14 is selected from —H, —(CH 2 ) 2 CH 3 , —SO 2 R 15 , wherein R 15 represents —(CH 2 ) 2 CH 3 , or —(CH 2 ), COOR 16 , wherein r is selected to be an integer from 0 to 2, and R 16 represents —CH 3 .

21. The compound according to claim 20 , wherein r is 1.

22. The compound according to claim 1 , wherein L is selected from the group: —NHSO 2 —, —NHCO—, —CONH—, —SO 2 NH—, —NHCONH— or —SO 2 —.

23. A pharmaceutical composition comprising at least one compound according to claim 1 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.

24. The compound of claim 1 wherein HA is selected from the group: pyrrolyl, furanyl, thiophenyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrazinyl, pyrazyl, pyradizinyl, pyradizyl, 3-methylpyridyl, benzothienyl, 4-ethylbenzothienyl, 3,4-diethylfuranyl, pyrrolyl, tetrahydroquinolyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoimidazolyl, benzothiazolyl, benzooxyzolyl, benzo[1,3]dioxolyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl and chrom-2-onyl.

25. The compound of claim 24 wherein HC is independently selected from the group: aziridinyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperadizinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl and morpholinyl.