Substituted imidazopyridazines

Patent metadata

Field	Value
Publication number	US-9255100-B2
Application number	US-201113822175-A
Country	US
Kind code	B2
Filing date	Sep 6, 2011
Priority date	Sep 10, 2010
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

Abstract

The present invention relates to substituted imidazopyridazine compounds of general formula (I), which are Mps-1 (Monopolar Spindle 1) Kinase inhibitors (also known as Tyrosine Threonine Kinase, TTK) in which R 3 , R 5 , and A are as defined in the claims, to methods of 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 general formula I:

in which:
A represents a

-group;
wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

R 2 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl- or C 3 -C 6 -cycloalkyl- group;
wherein said C 3 -C 6 -cycloalkyl- group is optionally substituted, identically or differently, with 1, 2, 3 or 4 groups selected from: halogen, —OH, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-;

R 3 represents an aryl-X— or heteroaryl-X— group;
wherein said aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a represents hydrogen;
R 4d represents hydrogen;
one of the groups R 4b and R 4c represents a hydrogen atom while the other one represents a group selected from: halo, CN, OH, C 1 -C 6 -alkyl- and C 1 -C 6 -alkoxy-;
R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl- group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl- group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 8 groups;
R 6 , R 6a , R 6b , R 6c ,
represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, C 2 -C 6 -alkenyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, aryl-C 1 -C 6 -alkyl- or heteroaryl-C 1 -C 6 -alkyl- group;

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b or —S(═O)(═NR 6c )R 6 group;
wherein said C 1 -C 6 -alkoxy-, aryl- or heteroaryl- group is optionally substituted, identically or differently, with 1, 2 or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups;
or
when 2 R 7 groups are present ortho to each other on an aryl- or heteroaryl-ring, said 2 R 7 groups together form a bridge:
*O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl- ring;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 or —S(═O) 2 -(3- to 7-membered heterocycloalkyl) group;
wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl- group is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl- groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;
n is an integer of 0, 1, 2, 3, 4 or 5;
X represents S(═O) p , O, NR 6 , CR 6a R 6b or C═CR 6a R 6b ;
p is an integer of 0, 1 or 2;
or a stereoisomer, a tautomer, or a salt thereof, or a mixture of same.

2. A compound according to claim 1 , wherein
R 2 is selected from the groups consisting of:
C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-;

or a stereoisomer, a tautomer, or a salt thereof, or a mixture of same.

3. A compound according to claim 1 , wherein
R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, or heteroaryl- group;
said C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, heteroaryl- group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

or a stereoisomer, a tautomer, or a salt thereof, or a mixture of same.

4. A compound according to claim 1 , wherein
R 7 represents a halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, —C(═O)N(H)R 6a , —N(R 6a )R 6b , —N(H)C(═O)R 6 , or —SR 6 group;
wherein said C 1 -C 6 -alkoxy-, or 3- to 7-membered heterocycloalkyl- group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups;
or
when 2 R 7 groups are present ortho to each other on an aryl or heteroaryl ring, said 2 R 7 groups together form a bridge:
*CH 2 (CH 2 ) 2 NH*, *CH 2 CH 2 N(R 6a )CH 2 *, *C(H)═C(H)—C(═O)—N(H)*, wherein * represent the point of attachment to said aryl or heteroaryl ring;

or a stereoisomer, a tautomer, or a salt thereof, or a mixture of same.

5. A compound according to claim 1 , wherein
R 6 , R 6a , R 6b , and R 6c represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl- group;
or a stereoisome

Assignees

• Klar Ulrich
• Koppitz Marcus
• Jautelat Rolf
• Kosemund Dirk
• Bohlmann Rolf
• Lienau Philip
• Siemeister Gerhard
• Wengner Antje Margret
• Bayer Ip Gmbh

Inventors

• Klar Ulrich
• Koppitz Marcus
• Jautelat Rolf
• Kosemund Dirk
• Bohlmann Rolf
• Lienau Philip
• Siemeister Gerhard
• Wengner Antje Margret

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title