Substituted benzamides and substituted pyridinecarboxamides as Btk inhibitors

Patent metadata

Field	Value
Publication number	US-9481682-B2
Application number	US-201414762954-A
Country	US
Kind code	B2
Filing date	Jan 22, 2014
Priority date	Jan 23, 2013
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds in the treatment of Btk mediated disorders.

First claim

The invention claimed is:

1. A compound according to Formula I, or a pharmaceutically acceptable salt thereof,

wherein:
A 1 , A 2 , A 3 , and A 4 are independently C, CH, CR 11 or N and bicyclic ring system E-G is selected from the group consisting of:

R 11 is independently selected from the group consisting of:
a) deuterium,
b) H,
c) halogen,
d) cyano,
e) —CH═CH 2 ,
f) —COOH,
g) —CO 2 (1-6C)alkyl,
h) —CO(1-6C)alkyl,
i) —CONH(1-6C)alkoxy,
j) —CONH(1-6C)alkyl,
k) —CON((1-6C)alkyl) 2 ,
l) (1-6C)alkyl,
m) (3-7C)cycloalkyl,
n) (1-6C)alkoxy,
o) aryl,
p) (1-5C)heteroaryl,
q) (2-6C)alkenyl,
r) (2-6C)alkynyl, and
s) (4-7C)heterocycloalkyl,

wherein
R 11 is optionally substituted with one or more groups selected from: halogen, (1-6C)alkyl, (1-5C)alkoxy, OH, or oxo;
R 12 is independently selected from the group consisting of: H, (1-3C)alkyl, (1-3C)alkylNHC(O), (1-3C)alkylOC(O), and (1-3C)alkylC(O);
R 13 is independently selected from the group consisting of: H and (1-4C)alkoxy;
wherein in aromatic ring K
B 1 , B 2 , B 3 , B 4 together are selected from the following groups:
B 1 is C(R 7 ), B 2 is C(R 8 ), B 3 is C(R 9 ), and B 4 is C(R 10 );
B 1 is N, B 2 is C(R 8 ), B 3 is C(R 9 ), and B 4 is C(R 10 );
B 1 is C(R 7 ), B 2 is N, B 3 is C(R 9 ), and B 4 is C(R 10 );
B 1 is C(R 7 ), B 2 is C(R 8 ), B 3 is N, and B 4 is C(R 10 ); and
B 1 is C(R 7 ), B 2 is C(R 8 ), B 3 is C(R 9 ), and B 4 is N;

R 7 is H, halogen, OH, (1-3C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy, (1-5C)heterocycloalkoxy, halo(1-3C)alkyl, or CN; wherein R 7 may optionally be substituted with one, two or three halogens, OH, (2-4C)alkynyl, —C(O)NH 2 , —C(O)OH, or —C(O)(1-4C)alkyl;
R 8 is H, halogen, OH, (1-3C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy, (1-5C)heterocycloalkoxy, halo(1-3C)alkyl, or CN; wherein R 8 may optionally be substituted with one, two or three halogens, OH, (2-4C)alkynyl, —C(O)NH 2 , —C(O)OH, or —C(O)(1-4C)alkyl;
R 9 is H, halogen, OH, (1-3C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy, (1-5C)heterocycloalkoxy, halo(1-3C)alkyl, or CN; wherein R 9 may optionally be substituted with one, two or three halogens, OH, (2-4C)alkynyl, —C(O)NH 2 , —C(O)OH, or —C(O)(1-4C)alkyl;
R 10 is H, halogen, OH, (1-3C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy, (1-5C)heterocycloalkoxy, halo(1-3C)alkyl, or CN; wherein R 10 may optionally be substituted with one, two or three halogens, OH, (2-4C)alkynyl, —C(O)NH 2 , —C(O)OH, or —C(O)(1-4C)alkyl;
wherein in ring L
W is CH or N;
X is C(R 6a ), N, O or S;
Y is C(R 6 ), N(R 6b ), O or S;
Z is C(R 6a ), N or a bond;
R 5 is H, halogen, CN, (1-4C)alkyl, (1-5C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy, or —C(O)O(1-3C)alkyl; wherein R 5 may optionally be substituted with one, two or three halogens, OH, or (1-3C)alkoxy; or
R 5 is aryl, (1-5C)heteroaryl or (2-6C)heterocycloalkyl, wherein R 5 may optionally be substituted with halogen, (1-6C)alkyl, or (1-3C)alkoxy;
R 6 is H, halogen, CN, (1-6C)alkyl, or (1-6C)alkoxy; wherein R 6 may optionally be substituted with one, two or three halogens, or CN;
R 6a is H, (1-4C)alkyl or (3-6C)cycloalkyl;
R 6b is H, (1-3C)alkyl, (3-6C)cycloalkyl, or —C(O)O(1-4C)alkyl; or
R 5 and R 6 together can form a carbocyclic or heterocyclic 5- to 6-membered ring, and optionally be unsaturated or aromatic; or R 5 and R 6 together can form (3-7C)cycloalkenyl or (2-6C)heterocycloalkenyl; each optionally substituted with (1-3C)alkyl or with one or more halogen;
Q is C═O, C(R f ) 2 or C═N(R h );
T is C(R e ) 2 , O, NR e , or a bond;
U is C(R d ) 2 , O, or NR d ;
V is C(R g ) 2 , O, or a bond;
R c , R d , R e , and R f are each independently selected from H, halogen, (1-6C)alkyl, OH, (2-6C)alkenyl, or —C(O)R z , wherein R z is independently selected from (1-5C)heteroaryl, aryl and OH,
and further wherein any alkyl group of R c , R d , R e , or R f may optionally be substituted with OH, —C(O)(1-3C)alkoxy or —C(O)OH;
R g is independently selected from H, halogen, (1-6C)alkyl, (1-6C)alkoxy, halo(1-6C)alkyl, or OH; and
R h is independently selected from H or CN;
with the proviso that:
1) up to 2 atoms of X, Y, and Z can simultaneously be a heteroatom;
2) when one atom selected from X or Y is O or S, then Z is a bond and the other atom selected from X or Y cannot be O or S;
3) when Z is CH or N, then Y is C(R 6 ) or N and X is CH, or N;
5) when Q is C(R f ) 2 , then T is C(R e ) 2 ;
6) when T is NR e , then R e is not halogen; and
7) when U is NR d , then R d is not halogen.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein in aromatic ring K, B 1 , B 2 , B 3 and B 4 together are selected from the following groups:
B 1 is C(R 7 ), B 2 is C(R 8 ), B 3 is C(R 9 ), and B 4 is C(R 10 );
B 1 is N, B 2 is C(R 8 ), B 3 is C(R 9 ), and B 4 is)C(R 10 );
B 1 is C(R 7 ), B 2 is N, B 3 is C(R 9 ), and B 4 is)C(R 10 ); and
B 1 is C(R 7 ), B 2 is C(R 8 ), B 3 is N, and B 4 is)C(R 10 ).

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein in aromatic ring K, B 1 is C(R 7 ), B 2 is C(R 8 ), B 3 is C(R 9 ), and B 4 is C(R 10 ), wherein R 7 , R 8 , R 9 and R 10 are each independently selected from H, halogen, (1-3C)alkyl, (1-3C)alkoxy or halo(1-3C)alkyl; and further wherein any alkoxy may optionally be substituted with one, two or three halogens.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring L is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, and isothiazolyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein ring L is selected from the group consisting of:

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein ring L is pyridyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of H, fluoro, chloro, CN, cyclopropyl, cyclobutyl, oxetanyl, (1-3C)alkyl, (1-5C)alkoxy, and (3-5C)cycloalkoxy; wherein the alkyl, alkoxy, cycloalkyl and cycloalkoxy of R 5 are optionally substituted with one or more halogens.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of H, fluoro, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopropoxy, and trifluoromethyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from the group consisting of H, deuterium, fluoro, chloro, bromo, methyl, ethyl, cyclopropyl and vinyl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from the group consisting of H, fluro and chloro.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein bicyclic ring system E-G is selected from the group consisting of:

Assignees

• Merck Sharp & Dohme

Inventors

• Kim Ronald M
• Liu Jian
• Gao Xiaolei
• Boga Sobhana Babu
• Guiadeen Deodialsingh
• Kozlowski Joseph A
• Yu Wensheng
• Anand Rajan
• Yu Younong
• Selyutin Oleg B
• Gao Ying-Duo
• Wu Hao
• Liu Shilan
• Yang Chundao
• Wang Hongjian

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

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

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D455/02

  containing not further condensed quinolizine ring systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title