Thienopyrimidines

Patent metadata

Field	Value
Publication number	US-9540392-B2
Application number	US-201314403151-A
Country	US
Kind code	B2
Filing date	May 17, 2013
Priority date	May 21, 2012
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

The present invention relates to substituted thienopyrimidine compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of formula (I):

in which:
R 1 represents a group selected from:
—C(═O)O—R 3 , —C(═O)N(H)R 3 , and —C(═O)NR 3 R 4 ;
R 2a represents a hydrogen atom;
R 2b represents a hydrogen atom;
R 2c represents a hydrogen atom;
R 2d represents a hydrogen atom or a group selected from: C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-, —N(H)R 5 , —NR 5 R 4 ;
R 3 represents a hydrogen atom or a group selected from:
C 1 -C 6 -alkyl-, C 2 -C 6 -alkynyl-, C 3 -C 7 -cycloalkyl-, —(CH 2 ) q —(C 3 -C 7 -cycloalkyl), —(CH 2 ) q —O—(C 3 -C 7 -cycloalkyl),
3- to 10-membered heterocycloalkyl-, —(CH 2 ) q -(3- to 10-membered heterocycloalkyl), —(CH 2 ) q —O-(3- to 10-membered heterocycoalkyl),
aryl-, —(CH 2 ) q -aryl, —(CH 2 ) q —O-aryl, heteroaryl-, —(CH 2 ) q -heteroaryl, —(CH 2 ) q —O-heteroaryl;
said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
halo-, hydroxyl-, oxo (═O), cyano-, C 1 -C 6 -alkyl-, C 2 -C 6 -alkynyl-,
halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, —N(H)R 5 , —NR 5 R 6 , —R 4 —S(═O) 2 —;
or
when two substituents are present ortho to each other on an aryl- or heteroaryl-ring, said two substituents together form a bridge:
*O(CH 2 ) p O*, *NH(C(═O))NH*, wherein * represents the point of attachment to said aryl- or heteroaryl-ring;

R 4 represents a
C 1 -C 6 -alkyl-group

or
NR 3 R 4 together
represent a 3- to 10-membered heterocycloalkyl group, which is optionally substituted, one or more times, identically or differently, with —CN, —OH, C 1 -C 6 -alkyl-, R 6 R 7 N—, R 6 R 7 N—C 1 -C 6 -alkyl- or —C(═O)NR 6 R 7 ;

R 5 represents a hydrogen atom or a C 1 -C 6 -alkyl-group;
R 6 represents a hydrogen atom or a C 1 -C 6 -alkyl-group;
R 7 represents a hydrogen atom or a C 1 -C 6 -alkyl-group;
or
NR 6 R 7 together represent a 3- to 10-membered heterocycloalkyl group;
p represents 1;
q represents an integer of 1, 2 or 3;
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

2. The compound of claim 1 , wherein:
R 1 represents a group selected from:
—C(═O)O—R 3 , —C(═O)N(H)R 3 , and —C(═O)NR 3 R 4 ;
R 2a represents a hydrogen atom;
R 2b represents a hydrogen atom;
R 2c represents a hydrogen atom;
R 2c represents a hydrogen atom or a group selected from:
C 1 -C 3 -alkoxy-, halo-;
R 3 represents a hydrogen atom or a group selected from:
C 1 -C 6 -alkyl-, C 2 -C 6 -alkynyl-, C 3 -C 7 -cycloalkyl-, —(CH 2 ) q —(C 3 -C 7 -cycloalkyl),
3- to 10-membered heterocycloalkyl,
—(CH 2 ) q -(3- to 10-membered heterocycloalkyl), aryl, —(CH 2 ) q -aryl,
—(CH 2 ) q —O-aryl, heteroaryl, —(CH 2 ) q -heteroaryl, —(CH 2 ) q —O-heteroaryl;
said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
halo-, hydroxy-, oxo-(O═), cyano-, C 1 -C 6 -alkyl-, C 2 -C 6 -alkynyl-, halo-C 1 -C 6 -alkyl-,
C 1 -C 6 -alkoxy-, —N(H)R 5 , —NR 5 R 4 , S(═O) 2 —;
or
when two substituents are present ortho to each other on an aryl- or heteroaryl-ring, said two substituents together form a bridge:
*O(CH 2 ) p O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring;
R 4 represents a C 1 -C 6 -alkyl-group;
or
NR 3 R 4 together
represent a 3- to 10-membered heterocycloalkyl group;
which is optionally substituted, one or more times, identically or differently, with —CN, —OH, C 1 -C 6 -alkyl-, R 6 R 7 N—C 1 -C 6 -alkyl- or —C(═O)NR 6 R 7 ;
R 5 represents a hydrogen atom or a C 1 -C 6 -alkyl-group;
R 6 represents a hydrogen atom or a C 1 -C 6 -alkyl-group;
R 7 represents a hydrogen atom or a C 1 -C 6 -alkyl-group;
or
NR 6 R 7 together represent a 3- to 10-membered heterocycloalkyl group;
p represents 1;
q represents an integer of 1, 2 or 3;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

3. The compound of claim 1 , wherein:
R 1 represents a group selected from —C(═O)N(H)R 3 , and —C(═O)NR 3 R 4 ;
R 2a represents a hydrogen atom;
R 2b represents a hydrogen atom;
R 2c represents a hydrogen atom;
and
R 2d represents a hydrogen atom or a C 1 -C 3 -alkoxy-group;
R 3 represents a hydrogen atom or a group selected from C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, —(CH 2 ) q —(C 3 -C 7 -cycloalkyl), aryl-, —(CH 2 ) q -aryl, —(CH 2 ) q —O-aryl, heteroaryl-, —(CH 2 ) q -heteroaryl;
said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
halo-, hydroxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-,
—NR 5 R 4 , —S(═O) 2 N(H)R 5 ;
or
when two substituents are present ortho to each other on an aryl- or heteroaryl-ring, said two substituents together form a bridge:
*O(CH 2 ) p O*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring;
R 4 represents a group selected from: C 1 -C 6 -alkyl-, C 2 -C 6 -alkynyl-;
or
NR 3 R 4 together
represent a 3- to 10-membered heterocycloalkyl-group;
which is optionally substituted, one or more times, identically or differently, with —CN, halo-, hydroxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, hydroxy-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-;
R 5 represents a hydrogen atom, a C 1 -C 6 -alkyl- or C 3 -C 7 -cycloalkyl-group;
p represents an integer of 1;
q represents an integer of 1 or 2;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

4. A compound of claim 1 , wherein:
R 1 represents a —C(═O)O—R 3 group;
R 2a represents a hydrogen atom;
R 2b represents a hydrogen atom;
R 2c represents a hydrogen atom;
R 2d represents a hydrogen atom or a group selected from C 1 -C 3 -alkoxy-, halo-;
R 3 represents a hydrogen atom or a C 1 -C 6 -alkyl-group;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

5. The compound of claim 1 , wherein:
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

6. The compound of claim 1 , which is selected from the group consisting of:
Ethyl 4-(1H-indazol-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate,
4-(1H-Indazol-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid,
4-(1H-Indazol-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
4-(1H-Indazol-5-ylamino)-N-[3-(methylsulfonyl)propyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
4-(1H-Indazol-5-ylamino)-N-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
4-(1H-Indazol-5-ylamino)-N-isopropyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
N-(Cyclopropylmethyl)-4-(1H-indazol-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
[4-(1H-Indazol-5-ylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]4-methylpiperazin-1-yl)methanone,
4-(1H-indazol-5-ylamino)-N-[3-(trifluoromethyl)benzyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
4-(1H-indazol-5-ylamino)-N,N-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
4-(1H-indazol-5-ylamino)-N-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
4-(1H-indazol-5-ylamino)-N-(2-methoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide,
4-(1H-indazol-5-ylamino)-N-(3-methoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-

Assignees

• Bayer Pharma AG

Inventors

• Kettschau Georg
• Puehler Florian
• Eis Knut
• Klar Ulrich
• Kosemund Dirk
• Sülzle Detlev
• Lienau Philip
• Hägebarth Andrea
• Bömer Ulf
• Wortmann Lars
• Graham Keith
• Wengner Antje Margret

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title