Substituted azaheterocycles for the treatment of cancer

1. A compound of Formula (V)

or its stereoisomers or tautomers, or pharmaceutically acceptable salts of each of the foregoing, wherein

R 1 ′, R 1 ″ are each independently H, A, Hal, Cyc, or CO(Cyc),

R 2 is H, or Q 1 -(C(LA)H) n -Q 2 ,

R 3 is H, A, or -LA-Cyc

A is unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4 or 5 C atoms, in which one CH 2 group may be replaced by an O or S atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —CONH—, —NHCO—, —CH═CH—, —N═CH— or —CH═N— group, and in which 1-5 H atoms may be replaced by Hal, and in which one CH group may be replaced by N, and in which one CH 3 group may be replaced by CN,

Hal is F, CI, Br or I ,

Cyc is a monocyclic, non-aromatic or aromatic, homo- or heterocycle having 0, 1 or 2, N, O and/or S atoms and 4, 5 or 6 skeleton atoms, which is independently of one another, mono- or disubstituted by Hal, LA, OH, carbonyl oxygen, SH, O(LA), NH 2 , NH(LA), N(LA) 2 , NO 2 , CN, OCN, SCN, COOH, COO(LA), CONH 2 , CONH(LA), CON(LA) 2 , NHCO(LA), NHCONH(LA), NHCONH 2 , NHSO 2 (LA), CHO, CO(LA), SO 2 NH 2 , SO 2 (LA) and/or SO 2 Hal,

Q 1 is —NH—, —O—, —COO—, —CONH—, or a bond,

Q 2 is NH 2 , NH(LA), N(LA) 2 , CONH 2 , CONH(LA), CON(LA) 2 , COOH, COO(LA), Cyc, or CO(Cyc),

n is 0, 1, 2, 3 or 4,

Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms, which is independently of one another, mono-, di- or trisubstituted by Hal, A, OH, SH, OA, NH 2 , NHA, NA 2 , NO 2 , CN, OCN, SCN, COOH, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONHA, NHCONH 2 , NHSO 2 A, CHO, COA, SO 2 NH 2 , SO 2 A, SO 2 Hal and/or (X) m , -Cyc,

and in which a ring N-atom may be substituted by an O-atom to form an N-oxide group,

and in which in the case of a bicyclic ring system one ring may be aromatic, and the other ring non-aromatic,

X is CH 2 , NH, or O,

m is 0 or 1,and

LA is H, or unbranched or branched linear alkyl having 1, 2 or 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal.

2. A compound according to claim 1 , wherein:

Ar is phenyl, pyridyl, 2,1,3-benzothiadiazolyl, 1,3-benzodioxolyl, pyrazolo[1,5-a]pyridyl, pyrimidyl, morpholinyl, 2,3-dihydro-benzofuranyl, or pyrazolyl, all of which may be unsubstituted, or mono- or disubstituted by Hal, LA, OH, SH, O(LA), NH 2 , NH(LA), N(LA) 2 , NO 2 , CN, OCN, SCN, COOH, CONH 2 , CONH(LA), CON(LA) 2 , NHCO(LA), NHCONH(LA), NHCONH 2 , NHSO 2 (LA), CHO, CO(LA), SO 2 NH 2 , S 02 (LA), SO 2 Hal, or (X) m -Cyc, or its stereoisomers or tautomers, or pharmaceutically acceptable salts of each of the foregoing.

3. A compound according to claim 1 , wherein the compound is selected from the group consisting of:

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid carbamoylmethyl-amide,

[2-(2-Amino-5-chloro-pyridin-3-yl)-pyrimidin-4-yl]-(4-fluoro-2-trifluoromethyl-benzyl)-amine,

[2-(2-Amino-5-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yl]-(2-trifluoromethyl-benzyl)-amine,

1-[6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carbonyl]-piperidine-3-carboxylic acid amide,

[2-(5-Chloro-pyridin-3-yl)-pyrimidin-4-yl]-(4-fluoro-2-trifluoromethyl-benzyl)-amine,

(4-Chloro-2-fluoro-benzyl)-[2-(5-chloro-pyridin-3-yl)-pyrimidin-4-yl]-amine,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (2-carbamoyl-ethyl)-amide,

(4-Fluoro-2-trifluoromethyl-benzyl)-[2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yl]-amine,

[2-(5-Chloro-pyridin-3-yl)-pyrimidin-4-yl]-(2,4-difluoro-benzyl)-amine,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (2-acetylamino-ethyl)-amide,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (3-morpholin-4-yl-3-oxo-propyl)-amide,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (3-morpholin-4-yl-propyl)-amide,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (2-pyridin-3-yl-ethyl)-amide,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (3-dimethylamino-propyl)-amide,

[2-(5-Chloro-pyridin-3-yl)-pyrimidin-4-yl]-(4-chloro-2-trifluoromethyl-benzyl)-amine,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (1-methyl-pyrrolidin-3-ylmethyl)-amide,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (4-dimethylamino-butyl)-amide,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (2-dimethylamino-ethyl)-amide,

(4-Chloro-2-fluoro-benzyl)-[2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yl]-amine,

1-[6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carbonyl]-piperidine-4 -carboxylic acid amide,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid dimethylamide,

6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid (1-carbamoyl-ethyl)-amide,

[6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yl]-morpholin-4-yl-methanone,

(2,4-Difluoro-benzyl)-[4-(5-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-amine,

(4-Fluoro-2-trifluoromethyl-benzyl)-[4-(5-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-amine,

(2,4-Difluoro-benzyl)-(5′-trifluoromethyl-[2,3′]bipyridinyl-6-yl)-amine,

(2,4-Difluoro-benzyl)-[2-(5-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-amine,

(3,5-Difluoro-pyridin-2-ylmethyl)-[2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yl]-amine, and

(4-Fluoro-2-trifluoromethyl-benzyl)-[2-(5-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-amine,

or its stereoisomers or tautomers, or pharmaceutically acceptable salts of each of the foregoing.

4. A pharmaceutical composition comprising a compound of claim 1 , or its stereoisomers or tautomers, or pharmaceutically acceptable salts of each of the foregoing, as active ingredient, together with a pharmaceutically acceptable carrier.

5. A kit consisting of separate packs of

a) an effective amount of a compound of claim 1 , or its stereoisomers or tautomers, or pharmaceutically acceptable salts of each of the foregoing, and

b) an effective amount of a further medicament active ingredient.

6. Process for the manufacture of compounds of Formula (V) according to claim 1 ,

wherein a substituted pyrimidine according to Formula (X)

Wherein R 2 is H, or Q 1 -(C(LA)H) n -Q 2 , and W is N,

is reacted with an aryl amine according to Formula (IX)

Wherein

R 3 is H, A, or -LA-Cyc

Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms, which is independently of one another, mono-, di- or trisubstituted by Hal, A, OH, SH, OA, NH 2 , NHA, NA 2 , NO 2 , CN, OCN, SCN, COOH, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONHA, NHCONH 2 , NHSO 2 A, CHO, COA, SO 2 NH 2 , SO 2 A, SO 2 Hal and/or (X) m-Cyc,

and in which a ring N-atom may be substituted by an O-atom to form an N-oxide group,

and in which in the case of a bicyclic ring system one ring may be aromatic, and the other ring non-aromatic,

to yield an intermediate according to Formula (VIII)

which is then reacted with a boronic acid or ester substituted pyridine according to Formula (VII)

Wherein R 1 ′, R 1 ″ are each independently H, A, Hal, Cyc, or CO(Cyc),

to yield a product according to Formula (V),

wherein R is H, LA, or an alkyl chain, linking the boronic acid oxygen atoms, and all other substituents have the meaning as defined for Formula (V) according to claim 1 .

7. The compound of claim 1 , wherein

Ar is phenyl or pyridyl, which is, independently, mono- or disubstituted in ortho and/or para position by Hal, LA, OH, O(LA), NH 2 , NH(LA), N(LA) 2 , NHSO 2 (LA), CO(LA), SO 2 NH 2 , SO 2 (LA), or SO 2 Hal,

R 1 ′ is H, Hal, LA, O(LA), or CO(Cyc),

R 1 ″ is H, or NH 2 ,

R 2 is H, and

R 3 is H.

8. The compound of claim 1 , wherein

R 1 ′ is H, Hal, LA, O(LA), or CO(Cyc),

R 1 ″ is H, or NH 2 , and

R 2 is Q 1 -(CH 2 ) n -Q 2 .

9. The compound of claim 1 , wherein

R 1 ′ is H, Hal, LA, O(LA), or CO(Cyc),

R 1 ″ is H, or NH 2 ,

R 2 is Q 1 -(CH 2 ) n -Q 2 , and

R 3 is H.

10. The compound of claim 1 , wherein

Ar is phenyl or pyridyl, which is, independently, mono- or disubstituted in ortho and/or para position by Hal, LA, OH, O(LA), NH 2 , NH(LA), N(LA) 2 , NHSO 2 (LA), CO(LA), SO 2 NH 2 , S 02 (LA), or SO 2 Hal,

R 1 ′ is H, Hal, LA, O(LA), or CO(Cyc),

R 1 ″ is H, or NH 2 ,

R 2 is Q 1 -(CH 2 ) n -Q 2 , and

R 3 is H.

11. The compound of claim 1 , wherein

Ar is phenyl which is disubstituted in ortho and para position by F,

R 1 ′ is CF 3 ,

R 1 ″ is H,

R 2 is Q 1 -(CH 2 ) n -Q 2 , and

R 3 is H.

12. The compound of claim 1 , wherein R 3 is H.

13. The compound of claim 1 , wherein

R 1 ′ is H, Hal, LA, O(LA), or CO(Cyc), and

R 1 ″ is H, or NH 2 .

14. The compound of claim 1 , wherein R 2 is H.

15. The compound of claim 1 , wherein R 2 is Q 1 -(C(LA)H) n -Q 2 .

16. The compound of claim 1 , wherein Ar is phenyl which is, independently, mono- or disubstituted by Hal, LA, OH, SH, O(LA), NH 2 , NH(LA), N(LA) 2 , NO 2 , CN, OCN, SCN, COOH, CONH 2 , CONH(LA), CON(LA) 2 , NHCO(LA), NHCONH(LA), NHCONH 2 , NHSO 2 (LA), CHO, CO(LA), SO 2 NH 2 ,SO 2 (LA), SO 2 Hal, Cyc, or O-Cyc.

17. The compound of claim 1 , wherein Ar is phenyl or pyridyl, which is, independently, mono- or disubstituted in ortho and/or para position by Hal, LA, OH, O(LA), NH 2 , NH(LA), N(LA) 2 , NHSO 2 (LA), CO(LA), SO 2 NH 2 , SO 2 (LA), or SO 2 Hal.

18. The compound of claim 1 , wherein Ar is phenyl which is, independently, mono- or disubstituted in ortho and/or para position by F, Cl, methyl, or CF 3 .

19. The compound of claim 1 , wherein R 2 is H, and R 3 is H.

20. The compound of claim 1 , wherein

R 1 ′ is H, Hal, LA, O(LA), or CO(Cyc),

R 1 ″ is H, or NH 2 ,

R 2 is H, and

R 3 is H.

21. The compound of claim 1 , wherein R 2 is Q 1 -(CH 2 ) n -Q 2 .