Pyrazolo pyrimidine derivatives and their use as MALT1 inhibitors

Patent metadata

Field	Value
Publication number	US-9815842-B2
Application number	US-201515312321-A
Country	US
Kind code	B2
Filing date	May 27, 2015
Priority date	May 28, 2014
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

The present invention describes new pyrazolo-pyrimidine derivatives which are generally interacting with MALT1 proteolytic and/or autoproteolytic activity, and in particular which may inhibit said activity. The present invention further describes the synthesis of said new pyrazolo-pyrimidine derivatives, their use as a medicament, especially by interacting with MALT1 proteolytic and/or autoproteolytic activity.

First claim

The invention claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein,
R1 is halogen, cyano, or C 1 -C 3 alkyl optionally substituted by halogen;
R2 is C 1 -C 6 alkyl optionally substituted one or more times by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, hydroxyl, N,N-di-C 1 -C 6 alkyl amino, N-mono-C 1 -C 6 alkyl amino, O—Rg, Rg, phenyl, or by C 1 -C 6 alkoxy wherein said alkoxy again may optionally be substituted by C 1 -C 6 alkoxy, N,N-di-C 1 -C 6 alkyl amino, Rg or phenyl; C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, N,N-di-C 1 -C 6 alkyl amino or C 1 -C 6 alkoxy-C 1 -C 6 alkyl, or two of said C 3 -C 6 cycloalkyl optional substituents together with the atoms to which they are bound may form an annulated or spirocyclic 4-6 membered saturated heterocyclic ring comprising 1-2 O atoms; phenyl optionally substituted by C 1 -C 6 alkoxy; a 5-6 membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O said ring being optionally substituted by C 1 -C 6 alkyl which may be optionally substituted by amino or hydroxy; Rg; or N,N-di-C 1 -C 6 alkyl amino carbonyl; wherein
Rg is a 5-6 membered heterocyclic ring having 1-3 heteroatoms selected from N and O said ring being optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl;

R is phenyl independently substituted two or more times by Ra, 2-pyridyl independently substituted one or more times by Rb, 3-pyridyl independently substituted one or more times by Rc, or 4-pyridyl independently substituted one or more times by Rd; wherein
Ra independently from each other is halogen; cyano; —COOC 1 -C 6 alkyl; C 1 -C 6 alkoxy; C 1 -C 6 alkyl optionally substituted by halogen or a 5-6 membered heterocyclyl ring having 1 to 2 heteroatoms selected from N and O which ring is optionally substituted by C 1 -C 6 alkyl; a 5-6 membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O said ring being optionally substituted by amino, C 1 -C 6 alkyl optionally substituted by amino or hydroxy, or by N-mono- or N,N-di-C 1 -C 6 alkylamino carbonyl;
or
two Ra together with the ring atoms to which they are bound may form a 5 to 6 membered heterocyclic or heteroaromatic ring having 1 to 2 N atoms, any such ring being optionally substituted by C 1 -C 6 alkyl or oxo;
Rb, Rc and Rd independently from each other are halogen; oxo; hydroxyl; cyano; C 1 -C 6 alkoxy optionally substituted by halogen; C 1 -C 6 alkoxy carbonyl; phenyl; N,N-di-C 1 -C 6 alkyl amino; C 1 -C 6 alkyl optionally substituted by halogen or phenyl; a 5-6 membered heteroaryl ring having 1 to 3 N atoms said ring being optionally substituted by C 1 -C 6 alkyl optionally substituted by amino or hydroxy, or by mono- or di-N-C 1 -C 6 alkylamino carbonyl; O—Rh; or Rh; wherein
Rh is a 5-6 membered heterocyclyl ring having 1 to 4 heteroatoms selected from N, O and S said ring being optionally substituted by C 1 -C 6 alkyl, hydroxyl or oxo.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is halogen;
R2 is C 1 -C 6 alkyl optionally substituted by one or more times by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, hydroxyl, N,N-di-C 1 -C 6 alkyl amino, N-mono-C 1 -C 6 alkyl amino, O—Rg, Rg, phenyl, or by C 1 -C 6 alkoxy, wherein said alkoxy again may optionally be substituted by C 1 -C 6 alkoxy, N,N-di-C 1 -C 6 alkyl amino, Rg or phenyl; wherein
Rg is a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N and O said ring being optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl;

R is 2-pyridyl independently substituted one or more times by Rb, 3-pyridyl independently substituted one or more times by Rc, or 4-pyridyl independently substituted one or more times by Rd; and
Rb, Rc and Rd independently from each other are halogen; oxo; hydroxyl; cyano; C 1 -C 6 alkoxy optionally substituted by halogen; C 1 -C 6 alkoxy carbonyl; phenyl; N,N-di-C 1 -C 6 alkyl amino; C 1 -C 6 alkyl optionally substituted by halogen or phenyl; a 5-6 membered heteroaryl ring having 1 to 3 N atoms said ring being optionally substituted by C 1 -C 6 alkyl optionally substituted by amino or hydroxy, or by mono- or di-N-C 1 -C 6 alkylamino carbonyl; O—Rh; or Rh; wherein
Rh is a 5-6 membered heterocyclyl ring having 1 to 4 heteroatoms selected from N, O and S said ring being optionally substituted by C 1 -C 6 alkyl, hydroxyl or oxo.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R1 is chloro.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R1 is chloro;
R is 2-pyridyl independently substituted one or more times by Rb;
or R is 3-pyridyl independently substituted one or more times by Rc;
or R is 4-pyridyl independently substituted one or more times by Rd;
R2 is C 1 -C 6 alkyl optionally substituted one or more times by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, hydroxyl, N,N-di-C 1 -C 6 alkyl amino, N-mono-C 1 -C 6 alkyl amino, O—Rg, Rg, phenyl, or by C 1 -C 6 alkoxy, wherein said alkoxy again may optionally be substituted by C 1 -C 6 alkoxy, N,N-di-C 1 -C 6 alkyl amino, Rg or phenyl; wherein
Rg is a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N and O said ring being optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl;

Rb, Rc and Rd independently from each other are halogen; oxo; hydroxyl; cyano; C 1 -C 6 alkoxy optionally substituted by halogen; C 1 -C 6 alkoxy carbonyl; phenyl; N,N-di-C 1 -C 6 alkyl amino; C 1 -C 6 alkyl optionally substituted by halogen or phenyl; a 5-6 membered heteroaryl ring having 1 to 3 N atoms said ring being optionally substituted by C 1 -C 6 alkyl optionally substituted by amino or hydroxy, or by mono- or di-N-C 1 -C 6 alkylamino carbonyl; O—Rh; or Rh; wherein
Rh is a 5-6 membered heterocyclyl ring having 1 to 4 heteroatoms selected from N, O and S said ring being optionally substituted by C 1 -C 6 alkyl, hydroxyl or oxo.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is halogen, cyano, or C 1 -C 3 alkyl optionally substituted by halogen;
R2 is C 1 -C 6 alkyl optionally substituted one or more times by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, hydroxyl, N,N-di-C 1 -C 6 alkyl amino, N-mono-C 1 -C 6 alkyl amino, O—Rg, Rg, phenyl, or by C 1 -C 6 alkoxy wherein said alkoxy again may optionally be substituted by C 1 -C 6 alkoxy, N,N-di-C 1 -C 6 alkyl amino, Rg or phenyl; C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, N,N-di-C 1 -C 6 alkyl amino or C 1 -C 6 alkoxy-C 1 -C 6 alkyl, or two of said C 3 -C 6 cycloalkyl optional substituents together with the atoms to which they are bound may form an annulated or spirocyclic 4-6 membered saturated heterocyclic ring comprising 1-2 O atoms; phenyl optionally substituted by C 1 -C 6 alkoxy; a 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N and O optionally substituted by C 1 -C 6 alkyl which may optionally be substituted by amino or hydroxy; Rg; or N,N-di-C 1 -C 6 alkyl amino carbonyl; wherein
Rg is a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N and O said ring being optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl;

R is phenyl independently substituted two or more times by Ra; wherein
Ra independently from each other is halogen; cyano; —COOC 1 -C 6 alkyl; C 1 -C 6 alkoxy; C 1 -C 6 alkyl optionally substituted by halogen or a 5-6 membered heterocyclic ring containing 1 to 2 N atoms said ring being

Assignees

• Soldermann Carole Pissot
• Quancard Jean
• Schlapbach Achim
• Simic Oliver
• Tintelnot-Blomley Marina
• Zoller Thomas
• Novartis Ag

Inventors

• Soldermann Carole Pissot
• Quancard Jean
• Schlapbach Achim
• Simic Oliver
• Tintelnot-Blomley Marina
• Zoller Thomas

Classifications

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title