Pyrido [2, 3-B] pyrazine compounds and their therapeutical uses such as for inhibiting ATP consuming proteins and treating diseases associated therewith

Patent metadata

Field	Value
Publication number	US-9051318-B2
Application number	US-201214002991-A
Country	US
Kind code	B2
Filing date	Feb 13, 2012
Priority date	Mar 9, 2011
Publication date	Jun 9, 2015
Grant date	Jun 9, 2015

Abstract

The present invention relates to novel pyrido[2,3-b]pyrazine compounds of formula (I):

and to the use of such compounds in which the inhibition, regulation and/or modulation of signal transduction by ATP consuming proteins like kinases plays a role, particularly to inhibitors of TGF-beta receptor kinases, and to the use of such compounds for the treatment of kinase-induced diseases, in particular for the treatment of tumors.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
X denotes absent, NR4 or CR5R6;
R1 denotes monocyclic aryl having 3, 4, 5, 6, 7 or 8 C atoms or a monocyclic heteroaryl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms and 1, 2, 3, 4 or 5 N, O and/or S atoms, each of which can independently from each other be substituted by at least one substituent selected from the group consisting of Y, Hal, CN, CF 3 and OY;
R2 denotes H, A, —OY, —NH 2 or —NAA;
R3 denotes H, A, —OY or —NYY;
R4, R5 and R6 independently from each other denote absent, H or A;
R7 denotes Hal, A, —(CYY) n —OY, —(CYY) n —NYY, (CYY) n -Het 2 , (CYY) n —O-Het 2 , SY, NO 2 , CN, COOY, —CO—NYY, —NY—COA, —NY—SO 2 A, —SO 2 —NYY, S(O) m A, —CO-Het 2 , —O(CYY) n —NYY, —O(CYY) n -Het 2 , —NH—COOA, —NH—CO—NYY, —NH—COO—(CYY) n —NYY, —NH—COO—(CYY) n -Het 2 , —NH—CO—NH—(CYY) n —NYY, —NH—CO—NH(CYY) n -Het 2 , —OCO—NH—(CYY) n —NYY, —OCO—NH—(CYY) n -Het 2 , CHO, COA, ═S, ═NY or ═O;
Y denotes H or A;
A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, wherein 1, 2, 3, 4, 5, 6 or 7 H atoms can be replaced independently from one another by Hal and/or wherein one or two CH 2 groups can be replaced independently of one another by O, S, SO, SO 2 , a —CY═CY— group and/or a —C≡C— group, or denotes cyclic alkyl with 3, 4, 5, 6 or 7 C atoms;
Het denotes a saturated or unsaturated, monocyclic, bicyclic or tricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 C atoms and 1, 2, 3, 4 or 5 N, O and/or S atoms, which can independently from each other be substituted by at least one substituent R7;
Het 2 denotes a saturated or unsaturated, monocyclic, bicyclic or tricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 C atoms and 1, 2, 3, 4 or 5 N, O and/or S atoms, which can independently from each other be substituted by at least one substituent selected from the group consisting of Hal, A, —(CYY) n —OY, —(CYY) n —NYY, (CYY) n -Het 3 , (CYY) n —O-Het 3 , SY, NO 2 , CN, COOY, —CO—NYY, —NY—COA, —NY—SO 2 A, —SO 2 —NYY, S(O) m A, —CO-Het 3 , —O(CYY) n —NYY, —O(CYY) n -Het 3 , —NH—COOA, —NH—CO—NYY, —NH—COO—(CYY) n —NYY, —NH—COO—(CYY) n -Het 3 , —NH—CO—NH—(CYY) n —NYY, —NH—CO—NH(CYY) n -Het 3 , —OCO—NH—(CYY) n —NYY, —OCO—NH—(CYY) n -Het 3 , CHO, COA, ═S, ═NY and ═O;
Het 3 denotes a saturated or unsaturated, monocyclic, bicyclic or tricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 C atoms and 1, 2, 3, 4 or 5 N, O and/or S atoms, which can independently from each other be substituted by at least one substituent selected from the group consisting of Hal, A, —(CYY) n —OY, —(CYY) n —NYY, SY, NO 2 , CN, COOY, —CO—NYY, —NY—COA, —NY—SO 2 A, —SO 2 —NYY, S(O) m A, —NH—CODA, —NH—CO—NYY, CHO, COA, ═S, ═NY and ═O;
Hal denotes F, Cl, Br or I;
m denotes 0, 1, or 2;
n denotes 0, 1, 2, 3 or 4;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

2. A compound of formula (II) according to claim 1 ,

wherein:
A′ denotes absent or together with X, W5 and W6 denotes monocyclic or bicyclic aryl having 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, each of which can independently from each other be substituted by at least one substituent R7, or together with X, W5 and W6 denotes Het;
X denotes absent, NR4 or CR5R6 or together with A′, W5 and W6 denotes monocyclic or bicyclic aryl having 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, each of which can independently from each other be substituted by at least one substituent R7, or together with A′, W5 and W6 denotes Het; with the first proviso that, if X is absent, A′ is also absent and W5 is directly linked to the pyrido[2,3-b]pyrazine moiety;
W, W2, W3, W4 and W6 independently from each other denote N or CR8, with the proviso that at least one of W1, W2, W3, W4 and W6 is N and, when A′ together with X, W5 and W6 denotes monocyclic or bicyclic aryl having 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, then W6 is C and one of W1, W2, W3 and W4 is N;
W5 is C;
R8 denotes absent, H, A, —OY, —NYY, —NY—COY or Het 2 ;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

3. A compound according to claim 2 , wherein X denotes NR4 or CR5R6 and A′ is absent;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

4. A compound according to claim 2 , wherein X and A′ are both absent and W5 is directly linked to the pyrido[2,3-b]pyrazine moiety or X together with A′,W5 and W6 denotes monocyclic or bicyclic aryl having 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, each of which can independently from each other be substituted by at least one substituent R7;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

5. A compound according to claim 2 , wherein
X is absent or denotes NR4, wherein if X is absent, A′ is also absent and W5 is directly linked to the pyrido[2,3-b]pyrazine moiety; or
X, A′, W5 and W6 together denote monocyclic aryl having 5 or 6 C atoms, each of which can independently from each other be substituted by at least one substituent R7, or together denote Het;
Het denotes a saturated or unsaturated, monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8 or 9 C atoms and 1 or 2 N atoms, which can independently from each other be substituted by at least one substituent R7;
Het 2 denotes a saturated or unsaturated, monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8 or 9 C atoms and 1 or 2 N atoms, which can independently from each other be substituted by at least one substituent selected from the group consisting of Hal, A, —(CYY) n —OY and —(CYY) n -Het 3 ;
Het 3 denotes a saturated or unsaturated, monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8 or 9 C atoms and 1 or 2 N atoms, which can independently from each other be substituted by at least one substituent selected from Hal or A;
R1 denotes monocyclic aryl having 5 or 6 C atoms which can be substituted by at least one substituent selected from the group consisting of Y, Hal, CN, CF 3 and OY;
R2, R3 and R4 independently from each other denote H or A;
R7 denotes A, —(CYY) n —NYY or —(CYY) n -Het 2 ;
R8 denotes absent, H, A, —NYY or Het 2 ;
Y denotes H or A;
A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms;
Hal denotes F or Cl; and
n is 0, 1 or 2;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

6. A compound according to claim 1 , wherein X denotes NR4 or CR5R6
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

7. A compound according to claim 1 , wherein X is absent;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

8. A compound according to claim 1 , wherein Het is selected from the group consisting of: pyridinyl, naphthyridinyl, isoquinolinyl, pyrrolopyridinyl, and furopyridinyl;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

9. A compound according to claim 1 , wherein
X is absent or denotes NR4
Het denotes a saturated or unsaturated, monocyclic or bicyclic heterocycle ha

Assignees

• Dorsch Dieter
• Jonczyk Alfred
• Hoelzemann Guenter
• Amendt Christiane
• Zenke Frank
• Merck Patent Gmbh

Inventors

• Dorsch Dieter
• Jonczyk Alfred
• Hoelzemann Guenter
• Amendt Christiane
• Zenke Frank

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P31/18

  for HIV · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title