Amino pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-10457647-B2
Application number	US-201815974190-A
Country	US
Kind code	B2
Filing date	May 8, 2018
Priority date	Nov 29, 2013
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

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

The invention claimed is:

1. A method of treating a disease which is treated by the modulation of Btk, wherein the method comprising administration of a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,
R1 is methyl or hydroxymethyl;
R2 is fluoro;
R3 is hydrogen;
R4 is hydrogen;
R5 is fluoro;
or R4 and R5 are attached to each other and stand for —CH 2 —CH 2 —, or —CH═CH—;
R6 is H and R7 is cyclopropyl;
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 H;
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 C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy,

and wherein the disease is selected from chronic autoimmune urticaria.

2. The method of claim 1 , wherein
R1 is methyl or hydroxymethyl;
R2 is fluoro;
R3 is hydrogen;
R4 is hydrogen;
R5 is fluoro;
R6 is H and R7 is cyclopropyl;
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;
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; or C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy.

3. The method of claim 1 , wherein
R1 is methyl or hydroxymethyl;
R2 is fluoro;
R3 is hydrogen;
R4 is hydrogen;
R5 is fluoro;
R6 is H and R7 is cyclopropyl;
R8, R9, R10 and R11 independently from each other stand for H;
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; or C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy.

4. The method of claim 1 , wherein
R1 is;
R2 is fluoro;
R3 is hydrogen;
R4 is hydrogen;
R5 is fluoro;
R6 is H and R7 is cyclopropyl;
R8 and R9, independently from each other stand for H, or C 1 -C 6 alkyl;
R and R′ are hydrogen;
R12 and any one of 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; or C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy.

5. The method of claim 1 , wherein
R1 is methyl or hydroxymethyl;
R2 is fluoro;
R3 is hydrogen;
R4 is hydrogen;
R5 is fluoro;
R6 is H and R7 is cyclopropyl;
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.

6. The method of claim 1 , wherein
R1 is methyl or hydroxymethyl;
R2 is fluoro;
R3 is hydrogen;
R4 is hydrogen;
R5 is fluoro;
R6 is H and R7 is cyclopropyl;
R8 and R9 independently from each other stand for H, or C 1 -C 6 alkyl;
R12 and any one of 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; and
R13 is C 2 -C 6 alkenyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or C 2 -C 6 alkynyl optionally substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy.

7. The method of claim 1 , wherein
R1 is C 1 -C 6 alkyl;
R2 is fluoro;
R3 is hydrogen;
R4 is hydrogen;
R5 is fluoro;
R6 is H and R7 is cyclopropyl;
R8, R9, R10 and R11 stand for H;
R12 is hydrogen;
n is 0; and
R13 is C 2 -C 6 alkenyl optionally substituted by C 1 -C 6 alkyl.

8. The method of claim 1 , wherein the compound of claim 1 , or a pharmaceutically acceptable salt thereof, is selected from:
N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(E)-N-(3-(6-Amino-5-((1-(but-2-enoyl)azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(6-Amino-5-((1-(but-2-ynoyl)azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(5-((1-Acryloylpiperidin-4-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(E)-N-(3-(6-Amino-5-(2-(N-methylbut-2-enamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(E)-N-(3-(6-Amino-5-(2-(4-methoxy-N-methylbut-2-enamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(2-((4-Amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl)pyrimidin-5-yl)oxy)ethyl)-N-methyl acryl amide;
N-(3-(5-(2-Acrylamidoethoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(5-((1-Acrylamidocyclopropyl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(S)—N-(3-(5-(2-Acrylamidopropoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(S)—N-(3-(6-Amino-5-(2-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
N-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(S)—N-(3-(5-((1-Acryloylpyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(S)—N-(3-(6-Amino-5-((1-(but-2-ynoyl)pyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;
(S)-2-(3-(5-((1-Acryloylpyrrolidin-2-yl)metho

Assignees

• Novartis Ag

Inventors

• Angst Daniela
• Gessier Francois
• Vulpetti Anna

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/12

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

• A61K31/505

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

• A61P29/00

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

• C07D239/47 Primary

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title