BTK Inhibitors

Patent metadata

Field	Value
Publication number	US-9718828-B2
Application number	US-201615250978-A
Country	US
Kind code	B2
Filing date	Aug 30, 2016
Priority date	Jul 19, 2011
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

Provided are 6-5 membered fused pyridine ring compounds according to Formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising these compounds and their use in therapy. In particular, provided is the use of 6-5 membered fused pyridine ring compounds in the treatment of Bruton's Tyrosine Kinase (Btk) mediated disorders.

First claim

The invention claimed is:

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

wherein:
R 11 is independently selected from the group consisting of:
a) H,
b) halogen,
c) Si(CH 3 ) 3 ,
d) cyano,
e) C 2 H 3 ,
f) CO 2 H,
g) CO 2 (1-6C)alkyl,
h) CO(1-6C)alkyl,
i) CONH(1-6C)alkoxy,
j) CONH(1-6C)alkyl,
k) CONHdi(1-6C)alkyl,
l) CONHheterocycloalkyl,
m) CONHheteroaryl(1-6C)alkyl,
n) (1-6C)alkyl,
o) (3-7C)cycloalkyl,
p) (6-10C)aryl,
q) (1-5C)heteroaryl,
r) (2-6C)alkenyl,
s) (2-6C)alkynyl,
t) (6-10C)aryl(2-6C)alkenyl,
u) (3-7C)heterocycloalkyl, and
v) (3-7C)heterocycloalkenyl;

R 11 is optionally substituted with one or more groups selected from: halogen, (1-6C)alkyl, (1-5C)alkoxy, hydroxyl, oxo, (6-10C)aryl, or R 16 (CO);
Y is C(R 6 ), N, O or S;
R 7 is H, halogen, OH, CF 3 , (1-3C)alkyl, (1-3C)alkoxy or halo(1-3C)alkyl;
R 8 is H, halogen, OH, CF 3 , (1-3C)alkyl, (1-3C)alkoxy or halo(1-3C)alkyl;
R 5 is H, halogen, cyano, (1-4C)alkyl, (1-5C)alkoxy, (3-6C)cycloalkyl; (3-6C)cycloalkoxy; any alkyl group of R 5 may optionally be substituted with one, two or three halogen; or R 5 is (6-10C)aryl, (1-5C)heteroaryl or (2-6C)heterocycloalkyl; the aryl or heterocycloalkyl of which may optionally be substituted with halogen, (1-6C)alkyl, (1-3C)alkoxy;
R 6 is H, halogen, (1-3C)alkyl, cyano, (1-6C)alkyl, or (1-6C)alkoxy;
R 6 may optionally be substituted with one, two or three halogen or cyano; or
R 5 and R 6 together form a (3-7C)cycloalkenyl or (2-6C)heterocycloalkenyl; each optionally substituted with (1-3C)alkyl or with one or more halogen;
wherein

 is selected from the group consisting of

R 1 is
a) R 21 C(O),
b) R 22 NHC(O),
c) R 23 C(O)NH,
d) R 24 S(O),
e) R 25 SO 2 ,
f) NH 2 ,
g) H,
h) (3-7C)cycloalkyl(1-4C)alkyl,
i) (1 -6C)alkoxycarbonyl(3-7C)cycloalkyl(1-4C)alkyl,
j) (6-10C)aryl(1-4C)alkyl,
k) (1-6C)alkyl,
l) (1-5C)heteroaryl(1-4C)alkyl, wherein the (1-5C)heteroaryl is optionally substituted with one or two(1-4C)alkyl, hydroxyl or halogen,
m) (1-5C)heterocycloalkyl(1-4C)alkyl, wherein the (1-5C)heterocycloalkyl is optionally substituted with one or two(1-4C)alkyl, hydroxyl or halogen,
n) cyano(1-6C)alkyl,
o) halo(1-6C)alkyl,
p) hydroxy(1-6C)alkyl,
q) (1-4C)alkoxy(1-6C)alkyl, or
r) (1-6C)alkoxyl;

R 21 is selected from the group consisting of:
a) H,
b) trifluoromethylcarbonyl,
c) hydroxy(1-6C)alkyl,
d) di[hydroxy](1-6C)alkyl,
e) di[(1-6C)alkyl]amino(1-6C)alkyl,
f) CF 3 ,
g) CCl 3 ,
h) amino(3-7C)cycloalkyl,
i) (6-10C)aryloxy,
j) (6-10C)arylcarbonyl(2-5C)heterocycloalkyl,
k) (6-10C)arylcarbonyl,
l) (6-10C)aryl(1-6C)alkoxy,
m) (3-7C)cycloalkylcarbonyl(1-5C)heterocycloalkyl,
n) (3-7C)cycloalkyl(1-4C)alkyl,
o) (3-7C)cycloalkyl,
p) (3-10C)cycloalkylamino,
q) (3-10C)cycloalkyl,
r) (3-10C)cycloalkylcarbonyl,
s) (4-10C)bicycloalkyl,
t) (1-6C)heterocycloalkyl,
u) (1-6C)alkylsulfonyl(2-5C)heterocycloalkyl,
v) (1-6C)alkylcarbonyl(2-5C)heterocycloalkyl,
w) (1-6C)alkylcarbonyl,
x) (1-6C)alkylaminocarbonyl,
y) (6-10C)arylaminocarbonyl,
z) (1-6C)alkylamino,
aa) (1-6C)alkoxycarbonyl,
bb) (1-6C)alkoxycarbonyl(1-4C)alkylamino(3-7C)cycloalkyl,
cc) (1-6C)alkoxycarbonyl(1-4C)alkyl,
dd) (1-6C)alkoxycarbonyl(3-7C)cycloalkyl(1-4C)alkyl,
ee) (1-6C)alkoxy,
ff) (6-10C)aryl(1-6C)alkoxy,
gg) (1-5C)heteroarylcarbonyl,
hh) (1-5C)heteroaryl(1-4C)alkyl,
ii) (1-5C)heteroaryl(3-7C)cycloalkyl,
jj) (1-5C)heterocycloalkyl,
kk) (1-4C)thioalkyl(1-6C)alkyl,
ll) di[(1-4C)alkyl]aminocarbonyl,
mm) (1-4C)alkylsulfonyl(1-6C)alkyl,
nn) (1-4C)alkylaminocarbonyl,
oo) (1-4C)alkoxy(1-6C)alkyl,
pp) (1-8C)alkoxy(1-16C)alkyl,
qq) cyano(1-6C)alkyl,
rr) amino(1-6C)alkyl,
ss) (6-10C)arylamino,
tt) (3-7C)cycloalkoxy,
uu) (1-6C)alkyl,
vv) (1-5C)heteroaryl,
ww) (1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl, and
xx) amino(1-4C)alkoxy[(2-4C)alkoxy] m (1-6C)alkyl;

R 21 may optionally be substituted with one, two or three R 211 substituents;
m is 1-10;
R 22 is selected from the group consisting of:
a) (3-7C)cycloalkyl(1-4C)alkyl,
b) (3-7C)cycloalkyl,
c) (4-10C)bicycloalkyl,
d) (3-7C)cycloalkoxy(1-4C)alkyl,
e) (3-6C)cycloalkoxy,
f) (1-5C)heterocycloalkyl,
g) (1-5C)heterocycloalkyl(1-6C)alkyl,
h) (6-10C)aryl,
i) (1-6C)alkyl,
j) (1-6C)alkoxy,
k) (1-4C)thioalkyl(1-6C)alkyl,
l) (1-4C)alkylsulfonyl(1-6C)alkyl, and
m) (1-4C)alkoxy(1-6C)alkyl;

R 22 may optionally be substituted with one, two or three R 221 substituents;
R 23 is selected from the group consisting of:
a) (6-10C)aryl(1-6C)alkoxy,
b) (3-7C)cycloalkyl,
c) (3-7C)cycloalkoxy,
d) (1-6C)alkylamino,
e) (1-6C)alkyl, and
f) (1-4C)alkoxy(1-6C)alkyl;

R 23 may optionally be substituted with one, two or three R 231 substituents;
R 24 is selected from the group consisting of:
a) (3-7C)cycloalkyl,
b) (1-6C)alkyl,
c) (6-10C)aryl, and
d) (2-5C)heteroaryl;

R 24 may optionally be substituted with one, two or three R 241 substituents;
R 25 is independently selected from the group consisting of:
a) (3-7C)cycloalkyl,
b) (1-6C)alkyl,
c) (6-10C)aryl, and
d) (2-5C)heteroaryl;

R 25 may optionally be substituted with one, two or three R 251 substituents;
R 211 , R 221 , R 231 , R 241 , and R 251 are independently selected from the group consisting of:
a) halogen,
b) CF 3 ,
c) OCF 3 ,
d) oxo,
e) hydroxyl,
f) cyano,
g) amino,
h) (1-6C)alkyl,
i) (1-4C)alkoxyl,
j) (3-7C)cycloalkyl,
k) (3-7C)cycloalkoxy,
l) (di[(1-6C)alkyl]amino,
m) (1-4C)akoxy(1-6C)alkyl,
n) (1-5C)heteroaryl, and
o) (2-5C)heterocycloalkyl.

2. The compound of claim 1 , wherein R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, CN, cyclopropyl, (1-3C)alkyl and(1-2C) alkoxy; the (1-3C)alkyl group of which is optionally substituted with one or more halogen.

3. The compound of claim 2 , wherein R 5 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, cyclopropyl, methoxy and trifluoromethyl.

4. The compound of claim 1 , wherein R 1 is selected from the group consisting of: R 21 C(O), R 22 NHC(O), R 23 C(O)NH, R 25 SO 2 , (3-7C)cycloalkyl(1-4C)alkyl, (6-10C)aryl(1-4C)alkyl, (1-6C)alkyl, (1-5C)heteroaryl(1-4C)alkyl, halo 1-6C)alkyl, hydroxyl(1-6Calkyl, (1-4C)alkoxy(1-6C)alkyl, (1-4C)alkoxy(1-6C)alkyl and(1-6C)alkoxyl.

5. The compound of claim 4 , wherein R 1 is selected from the group consisting of: R 21 C(O), R 22 NHC(O), R 23 C(O)NH, (6-10C)aryl(1-4C)alkyl, (1-5C)heteroaryl(1-4C)alkyl, halo(1-6C)alkyl, hydroxyl(1-6Calkyl, (1-4C)alkoxy(1-6C)alkyl, (1-4C)alkoxy(1-6C)alkyl and (1-6C)alkoxyl.

6. The compound of claim 5 , wherein R 1 is selected from the group consisting of R 21 C(O), R 22 NHC(O), and R 23 C(O)NH.

7. The compound of claim 1 , wherein
R 21 is selected from the group consisting of di[hydroxy](1-6C)alkyl, di[(1-6C)alkyl]amino(1-6C)alkyl, amino(3-7C)cycloalkyl, (6-10C)aryloxy, (6-10C)arylcarbonyl(2-5C)heterocycloalkyl, (3-7C)cycloalkylcarbonyl(1-5C)heterocycloalkyl, (3-7C)cycloalkyl, (3-6C)cycloalkoxy, (3-10C)cycloalkylamino, (3-10C)cycloalkyl, (1-6C)alkylsulfonyl(2-5C)heterocycloalkyl, (1-6C)alkylcarbonyl(2-5C)heterocycloalkyl, (1-6C)alkylamino, (1-6C)alkoxy, (1-5C)heteroarylcarbonyl, (1-5C)heteroaryl(1-4C)alkyl, (1-5C)heterocycloal

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• De Man Adrianus Petrus Antonius
• Sterrenburg Jan-Gerard
• Raaijmakers Hans C A
• Kaptein Allard
• Oubrie Arthur A
• Rewinkel Johannes Bernardus Maria
• Jans Christiaan Gerardus Johannes Maria
• Wijkmans Jacobus C H M
• Barf Tjeerd A
• Cooper Alan B
• Kim Ronald M
• Boga Sobhana Babu
• Zhu Hugh Y
• Gao Xiaolei
• Yao Xin
• Anand Rajan
• Wu Hao
• Liu Shilan
• Yang Chundao
• Alhassan Abdul-Basit
• Wang James
• Yu Younong
• Liu Jian
• Vaccaro Henry M

Classifications

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title