Amino pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9512084-B2
Application number	US-201414540140-A
Country	US
Kind code	B2
Filing date	Nov 13, 2014
Priority date	Nov 29, 2013
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The present invention describes new amino pyrimidine derivatives and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel amino pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.

First claim

What is claimed is:

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

wherein,
R1 is hydrogen or C 1 -C 6 alkyl optionally substituted by hydroxy;
R2 is hydrogen or halogen;
R3 is hydrogen or halogen;
R4 is hydrogen;
R5 is hydrogen or halogen;
or R4 and R5 are attached to each other and stand for a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CH═CH—CH 2 —; —CH 2 —CH═CH—; or —CH 2 —CH 2 —CH 2 —;
R6 and R7 stand independently from each other for H, C 1 -C 6 alkyl optionally substituted by hydroxyl, C 3 -C 6 cycloalkyl optionally substituted by halogen or hydroxy, or halogen;
R8, R9, R, R′, R10 and R11 independently from each other stand for H, or C 1 -C 6 alkyl optionally substituted by C1-C6 alkoxy; or any two of R8, R9, R, R′, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;
R12 is hydrogen or C 1 -C 6 alkyl optionally substituted by halogen or C 1 -C 6 alkoxy;
or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
n is 0 or 1; and
R13 is C 2 -C 6 alkenyl optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or N,N-di-C 1 -C 6 alkyl amino; C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or C 2 -C 6 alkylenyl oxide optionally substituted by C 1 -C 6 alkyl.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or C 1 -C 6 alkyl optionally substituted by hydroxy;
R2 is halogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is halogen;
or R4 and R5 are attached to each other and stand for a bond, —CH2-, —CH2-CH2-, —CH═CH—, —CH═CH—CH2-; —CH2-CH═CH—; or —CH2-CH2-CH2-;
R6 and R7 stand independently from each other for H, C 1 -C 6 alkyl optionally substituted by hydroxyl, C 3 -C 6 cycloalkyl optionally substituted by halogen or hydroxy, or halogen;
R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6 alkyl; or any two of R8, R9, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;
R and R′ are hydrogen;
R12 is hydrogen or C 1 -C 6 alkyl optionally substituted by halogen;
or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
n is 0 or 1; and
R13 is C 2 -C 6 alkenyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or C 2 -C 6 alkylenyl oxide optionally substituted by C 1 -C 6 alkyl.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or C 1 -C 6 alkyl optionally substituted by hydroxy;
R2 is halogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is halogen;
R6 and R7 stand independently from each other for H, C 1 -C 6 alkyl optionally substituted by hydroxyl, C 3 -C 6 cycloalkyl optionally substituted by halogen or hydroxy, or halogen;
R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6 alkyl;
or any two of R8, R9, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;
R and R′ are hydrogen;
R12 is hydrogen or C 1 -C 6 alkyl optionally substituted by halogen;
or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
n is 0 or 1; and
R13 is C 2 -C 6 alkenyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or C 2 -C 6 alkylenyl oxide optionally substituted by C 1 -C 6 alkyl.

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or C 1 -C 6 alkyl optionally substituted by hydroxy;
R2 is hydrogen or halogen;
R3 is hydrogen or halogen;
R4 and R5 are attached to each other and stand for a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CH═CH—CH 2 —; —CH 2 —CH═CH—; or —CH 2 —CH 2 —CH 2 —;
R6 and R7 stand independently from each other for H, C 1 -C 6 alkyl optionally substituted by hydroxyl, C 3 -C 6 cycloalkyl optionally substituted by halogen or hydroxy, or halogen;
R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6 alkyl;
or any two of R8, R9, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;

R and R′ are hydrogen;
R12 is hydrogen or C 1 -C 6 alkyl optionally substituted by halogen;
or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
n is 0 or 1; and
R13 is C 2 -C 6 alkenyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or C 2 -C 6 alkylenyl oxide optionally substituted by C 1 -C 6 alkyl.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or C 1 -C 6 alkyl optionally substituted by hydroxy;
R2 is hydrogen or halogen;
R3 is hydrogen or halogen;
R4 and R5 are attached to each other and stand for a —CH 2 —CH 2 —, or —CH═CH—;
R6 and R7 stand independently from each other for H, C 1 -C 6 alkyl optionally substituted by hydroxyl, C 3 -C 6 cycloalkyl optionally substituted by halogen or hydroxy, or halogen;
R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6 alkyl; or any two of R8, R9, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;
R and R′ are hydrogen;
R12 is hydrogen or C i -C 6 alkyl optionally substituted by halogen;
or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C 1 -C 6 alkyl or C i -C 6 alkoxy;
n is 0 or 1; and
R13 is C 2 -C 6 alkenyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C i -C 6 alkoxy; or C 2 -C 6 alkylenyl oxide optionally substituted by C 1 -C 6 alkyl.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or C 1 -C 6 alkyl optionally substituted by hydroxy;
R2 is halogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is halogen;
R6 and R7 stand independently from each other for H, C 1 -C 6 alkyl optionally substituted by hydroxyl, C 3 -C 6 cycloalkyl optionally substituted by halogen or hydroxy, or halogen;
R8, R9, R10 and R11 independently from each other stand for H, or C 1 -C 6 alkyl;
R and R′ are hydrogen;
R12 is hydrogen or C 1 -C 6 alkyl optionally substituted by halogen;
n is 0 or 1; and
R13 is C 2 -C 6 alkenyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or C 2 -C 6 alkylenyl oxide optionally substituted by C 1 -C 6

Assignees

• Angst Daniela
• Gessier François
• Vulpetti Anna
• Novartis Ag

Inventors

• Angst Daniela
• Gessier François
• Vulpetti Anna

Classifications

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title