Substituted phenyl-Spleen Tyrosine Kinase (Syk) inhibitors

Patent metadata

Field	Value
Publication number	US-9353066-B2
Application number	US-201314422419-A
Country	US
Kind code	B2
Filing date	Aug 15, 2013
Priority date	Aug 20, 2012
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

The invention provides certain substituted phenyl compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R cy , and t are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk).

First claim

What is claimed is:

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, 2,8-diazaspiro[4.5]decyl, and 4-piperidinyloxy;
R 2 is selected from the group consisting of H, methyl, methoxy, —CHF 2 , —CF 3 , halo, and cyano;
R 3 is selected from the group consisting of H, C 1 -C 3 alkyl, and halo;
R 4 is selected from the group consisting of H, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, halo, —N(R 4a ) 2 , —N(R 4a )C(O)R 4b , —N(R 4a )C(O)N(R 4a ) 2 ,
—N(R 4a )S(O) 2 R 4b , —N(R 4a )C(O)N(R 4a )—S(O) 2 R 4a , —CO 2 H, and R 4c ,
wherein R 4c is -G-R 4c1 or —R 4c1 , wherein
G is a —O—, —C(O)—, or —CH 2 —;
R 4c1 is:
(i) a 5-8 membered heterocyclyl containing 1 nitrogen atom and 0 to 1 additional heteroatoms selected from the group consisting of N, O, and S;
(ii) a 9-10 membered spiroheterocyclyl containing 1 nitrogen atom and 0 to 1 additional heteroatoms selected from the group consisting of N, O, and S; and
(iii) phenyl;
wherein said R 4c1 is unsubstituted or substituted by 1 to 2 R 4c2 moieties selected from the group consisting of C 1 -C 3 alkyl, —S(O) 2 —(C 1 -C 3 alkyl), —CH 2 —O—(C 1 -C 3 alkyl), —CH 2 —N(C 1 -C 3 alkyl) 2 , and —CH 2 O—C(O)—(C 1 -C 3 alkyl), or optionally, wherein 2 R c2 moieties are geminally substituted on a common ring carbon, the 2 R 4c2 moieties together with said ring carbon form a carbonyl;

each R 4a is independently selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 fluoroalkyl;
R 4b is selected from the group consisting of C 1 -C 3 alkyl and phenyl, wherein said phenyl is unsubstituted or substituted by one halo;

t is 0, 1, 2, or 3;
each R cy is independently selected from the group consisting of:
A. a group of the formula

wherein
 Y 1 is a bond, —(CH 2 ) z1 —, —S(O) 2 (CH 2 ) z1 —, —S(O) 2 N(H)(CH 2 ) z2 —, —O(CH 2 ) z2 —, or —C(O)—;
the subscript z1 is 0, 1, 2, or 3;
the subscript z2 is 2 or 3;

 D i is
(i) a 4- to 9-membered mono- or bicyclic heterocyclic ring optionally containing one to two additional heteroatoms selected from the group consisting of N, O, S, S(O), and S(O) 2 ;
(ii) a 9- to 11-membered spiroheterocyclic ring containing one to two additional heteroatoms selected from the group consisting of N and O;

 each R 10 is independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, hydroxyl, C 1 -C 3 fluoroalkyl, —(CH 2 ) n5 CO 2 R g , hydroxyl(C 1 -C 3 )alkyl, —(CH 2 ) n5 OCH 3 , —C(O)—(C 1 -C 3 ) alkyl, —(CH 2 ) n5 C(O)N(R h ) 2 , —S(O) 2 —(C 1 -C 3 ) alkyl, —C(O)CH 2 CN, and —C(O)CH 2 OH,
 or wherein when two R 10 moieties are geminally substituted on a common ring carbon atom of D 1 , the two geminally substituted R 10 moieties together with the carbon atom on which they are attached form —C(O)—;
each R h is independently H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —CH 2 CO 2 H,
—CH 2 C(O)NH 2 , —S(O) 2 —C 1 -C 3 alkyl, or —S(O) 2 —NH 2 ;

the subscript n5 is 0, 1, 2, or 3;

 the subscript q is 0, 1, 2, 3, 4, or 5;
B. a group of the formula

wherein
 Y 2 is a bond, —C(O)—, —N(R k )—, —O—, —C(O)—N(R k )—, —S(O) 2 —N(R k )—, or —N(R k )—S(O) 2 —;
R k is H or C 1 -C 3 alkyl;
each R i is independently H, C 1 -C 3 alkyl, hydroxyl, —CO 2 H, or —N(H)C(O)NH 2 ;
each R j is independently H, C 1 -C 4 alkyl, or cyclopropyl;
the subscript s is 0, 1, 2, 3, 4, or 5; and

 D 2 is selected from the group consisting of:
(i) a C 3 -C 10 carbocycle,
(ii) a 5- to 9-membered mono- or bicyclic heterocyclyl containing 1 or 3 heteroatoms selected from the group consisting of N, O, S, S(O), and S(O) 2 ; and
(iii) a 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S;

C. a group of the formula

wherein
 Y 3 is (i) a bond, (ii)

 R e is H, C 1 -C 3 alkyl, hydroxyl(C 2 -C 3 ) alkyl, or —(CH 2 ) n3 CN;
 each Ra is independently selected from the group consisting of H, fluoro, C 1 -C 6 alkyl, and C 1 -C 3 fluoroalkyl;
 each R b is independently selected from the group consisting of H, hydroxyl, fluoro, C 1 -C 6 alkyl, C 1 -C 3 fluoroalkyl, hydroxy(C 1 -C 3 ) alkyl, —(CH 2 ) n4 —O—(C 1 -C 3 ) alkyl, —(CH 2 ) n4 C(O)NH 2 , —(CH 2 ) n4 S—(C 1 -C 3 ) alkyl, and —(CH 2 ) n4 S(O) 2 —(C 1 -C 3 ) alkyl;
 each R e is independently H or C 1 -C 3 alkyl;
 R f is H, —CHF 2 , —CF 3 , —C(O)—(C 1 -C 3 alkyl), —CO 2 R g , —C(O)N(R h ) 2 , —CN, hydroxyl,
—N(R h ) 2 , —SO 3 H, —(C 1 -C 3 ) alkoxy, —O(CH 2 ) n3 OH;

 the subscript n1 is 0, 1, 2, or 3;
 the subscript n2 is 0 or 1;
 each subscript n3 is independently 2 or 3;
 each subscript n4 is independently 1, 2 or 3; and
D. a moiety selected from the group consisting of halo, —S—(C 1 -C 3 alkyl), and —S(O) 2 —(C 1 -C 3 alkyl);
each R g is independently selected from the group consisting of:
(i) H;
(ii) C 1 -C 8 alkyl;
(iii) a group of the formula -M-R CH , wherein
M is a bond or —(CH 2 ) n6 —, wherein the subscript n6 is 1 or 2;
R CH is (a) aryl or C 3 -C 6 cycloalkyl optionally substituted with 1-3 groups independently selected from halo, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; or (b) a 5- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein said heterocycle of R CH is optionally substituted with 1 or 2 groups independently selected from the group consisting of oxo and C 1-3 alkyl;

(iv) a group of the formula —(CH 2 ) n6 —R m or —(CH 2 ) 2 —O—(CH 2 ) 2 —R m wherein R m is —CO 2 R m1 , —C(O)N(R m2 ) 2 , or —O(CO)R m1 ;
R m1 is C 1 -C 4 alkyl; and
R m2 is H or C 1 -C 4 alkyl;

(v) a group of the formula —(CH 2 ) 2 —R n ,
R n is —OH, —O—(C 1 -C 4 alkyl), —O—(CH 2 ) 2 —O—(C 1 -C 4 alkyl), —NH 2 , —N(H)(C 1 -C 4 alkyl) or —N(C 1 -C 4 alkyl) 2 ;

(vi) a group of the formula

wherein
 R o is H or C 1 -C 4 alkyl; and
 R p is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or phenyl; and,
(vii) a group of the formula

wherein R o and R p are as set forth above.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the subscript t is 1 or 2 and at least one R cy is a group of the formula

wherein Y 1 , D 1 , R 10 , and q are as set forth in claim 1 .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2 and at least one R cy is:
a group of the formula

wherein Y 2 , D 2 , R i , R j , R 10 , s and q are as set forth in cla

Assignees

• Merck Sharp & Dohme
• Merck Canada Inc

Inventors

• Haidle Andrew M
• Burch Jason
• Guay Daniel
• Gauthier Jacques Yves
• Robichaud Joel
• Fournier Jean Francois
• Ellis John Michael
• Christopher Matthew
• Kattar Solomon D
• Smith Graham F
• Northrup Alan B

Classifications

• C07D239/42 Primary

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D403/12

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

• C07D239/47

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

• C07D401/12

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title