Compositions and methods for the production of pyrimidine and pyridine compounds with BTK inhibitory activity

Patent metadata

Field	Value
Publication number	US-9580449-B2
Application number	US-201514727050-A
Country	US
Kind code	B2
Filing date	Jun 1, 2015
Priority date	Jun 10, 2011
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

The present invention provides novel pyrimidine and pyridine compounds according to Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V) their manufacture and use for the treatment of hyperproliferative diseases including, but not limited to, cancer, lupus, allergic disorders, Sjogren's disease and rheumatoid arthritis. In preferred embodiments, the present invention describes irreversible kinase inhibitors including, but not limited to, inhibitors of Bruton's tyrosine kinase.

First claim

What is claimed is:

1. A compound of formula II

wherein:
X is H or CH 3 or NH 2 ,
Y is H, Hal or is absent,
B is N or CH,
E is NH 2 or H,
W is NR, O or a cyclic amine,
Z is, independently, CH 2 , CH 3 , CH 2 —CH 2 , CH—CH 2 , H, NH or is absent,
“linker” is (CH 2 ) n , wherein: n is 1, 2 or 3; or “linker” is an optionally substituted group selected from a phenyl ring, an aryl ring, heteroaryl ring, branched or unbranched alkyl group, a 5-6membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, or oxygen, a 4-7membered saturated or partially unsaturated heterocycle having 1-3heteroatoms independently selected from nitrogen, or oxygen, a 7-10membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5heteroatoms independently selected from nitrogen, or oxygen, a 7-10membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5heteroatoms attached to a hetero saturated ring;
A is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton C atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, OH or OR,
Hal is F, Cl, Br or I,
R is independently hydrogen, oxygen or an optionally substituted group selected from C 1-6 linear or cyclic aliphatic, benzyl, phenyl, a phenyl group optionally substituted with 1, 2 or 3 O atoms, a 4-7membered heterocylic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or a 5-6membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, or oxygen or a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O atoms and 5, 6, 7, or 8 C skeleton atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, A, OH, NH 2 , nitrile, and/or CH(Hal) 3 or is an unbranched or branched linear alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH 2 groups may be replaced by an O atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —CONH—, —NHCO—or —CH═CH—group, and in which 1-3 H atoms may be re-placed by Hal,
R q is selected from —R, —A, halogen, —OR, —O(CH 2 ) r OR, —R(NH), —NO 2 , —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)NR 2 , —NRSO 2 R, or —N(R) 2 ,
r is 1-4
n is 0-4, and
Q is an electrophilic group;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. The compound according to claim 1 , wherein Q is

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3. The compound according to claim 2 , wherein Q is

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

4. The compound according to claim 2 , wherein Q is

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

5. A compound of formula IV

wherein:
Z is N or CH,
X is O or NH, and
R 3 is

wherein, “R” denotes the bonding point to Z in Formula IV
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

6. The compound according to claim 1 , selected from the group

No.
Chemical Name

″A1″
(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)

pyrrolidin-1-yl)prop-2-en-1-one

″A2″
(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)

piperidin-1-yl)prop-2-en-1-one

″A3″
N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)

phenyl)acrylamide

″A4″
(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)

amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one

″A5″
N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pyrrolidin-

3-yl)methyl)acrylamide

″A6″
1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)

piperidin-1-yl)prop-2-en-1-one

″A7″
N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-

4-yl)methyl)acrylamide

″A8″
4-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)

methyl)piperidine-1-carbonyl)-1-methylpyridin-2(1H)-one

″A9″
1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)

methyl)piperidin-1-yl)but-2-yn-1-one

″A10″
5-(4-phenoxyphenyl)-N4-((1-(vinylsulfonyl)piperidin-4-yl)

methyl)pyrimidine-4,6-diamine

″A11″
(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)

amino)methyl)piperidin-1-yl)-4-((2-methoxyethyl)(methyl)

amino)but-2-en-1-one

″A12″
(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)

methyl)piperidin-1-yl)(2-fluoropyridin-3-yl)methanone

″A13″
(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)

amino)methyl)piperidin-1-yl)but-2-en-1-one

″A14″
N4-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-5-(4-

phenoxyphenyl)pyrimidine-4,6-diamine

″A15″
(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)

amino)methyl)piperidin-1-yl)but-2-en-1-one

″A16″
1-(4-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)

ethyl)piperidin-1-yl)prop-2-en-1-one

″A17″

Assignees

• Merck Patent Gmbh

Inventors

• Hodous Brian L
• Liu-Bujalski Lesley
• Jones Reinaldo
• Bankston Donald
• Johnson Theresa L
• Mochalkin Igor
• Nguyen Ngan
• Qiu Hui
• Goutopoulos Andreas
• Brugger Nadia

Classifications

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P29/00

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

• A61P31/02

  Local antiseptics · CPC title