Tricyclic heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-9216972-B2
Application number	US-201013504541-A
Country	US
Kind code	B2
Filing date	Oct 29, 2010
Priority date	Oct 29, 2009
Publication date	Dec 22, 2015
Grant date	Dec 22, 2015

Abstract

Disclosed are compounds of Formula (I)

or stereoisomers or salts thereof, wherein: X 1 , X 2 , X 3 , W, Q 1 , Q 2 , and G 2 are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P 1 , and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer or a salt thereof, wherein:
(i) X 1 is C-G 2 , one of X 2 and X 3 is N, and the other of X 2 and X 3 is O or S;
(ii) X 2 is C-G 2 , one of X 1 and X 3 is N, and the other of X 1 and X 3 is O or S;
(iii) X 1 is C-G 2 , one of X 2 and X 3 is N, and the other of X 2 and X 3 is NH or NCH 3 ; or
(iv) X 1 is N-G 2 , X 2 is N, and X 3 is CH;
wherein the broken circle represents two non-adjacent double bonds within Ring A;
Q 1 is CH, C(CH 3 ), or CF;
Q 2 is CH;
W is —CH 2 —, —CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH 2 CF 2 —, —CH═CH—, —CH 2 N(CH 3 )—, —CH 2 O—, or —CH 2 CH 2 O—;
G 1 is —OH, —CH 2 OH, —CH(OH)CH 2 OH, —(CH 2 ) 0-2 COOH, —CH(OH)(CH 2 ) 0-2 COOH, —CH 2 NH(CH 2 ) 1-2 OH, —CH 2 NR g (CH 2 ) 1-2 COOH, —CH 2 NR g (CH 2 ) 1-2 C(O)NH 2 , —CH 2 NR g (CH 2 ) 1-2 OP(O)(OH) 2 , —OCH 2 CH(OH)CH 2 OH, —(CH 2 ) 0-2 C(NH 2 )(CH 3 )CH 2 OH, —(CH 2 ) 0-2 CR g (NH 2 )C(O)OH, —(CH 2 ) 0-2 C(NH 2 )(CH 3 )(CH 2 ) 1-2 OP(O)(OH) 2 , —CH 2 CH 2 C(NH 2 )(CH 2 OH) 2 , —CH 2 NHCH(CH 2 OH) 2 , —CH 2 N(CH 2 CH 2 OH) 2 , —CH 2 NHCH 2 CH(OH)CH 2 OH, —CH(OH)C(O)NHCH 2 CN, —CH(OH)C(O)NHCH 2 CH 2 S(O) 2 CH 3 , —CR g (OH)C(O)NHCH 2 CH 2 OH, —CH 2 (hydroxy pyrrolidinyl), —CH 2 (hydroxymethyl pyrrolidinyl),

G 2 is:
(i) pentyl;
(ii) phenyl substituted with one or two substituents independently selected from propyl, butyl, —CN, —CF 3 , cyclohexyl, —OCH 2 CH 3 , and/or —OCH(CH 3 ) 2 ;
(iii) pyrazolyl, isoxazolyl, isothiazolyl, or pyrimidinyl substituted with one or two substituents independently selected from —CF 3 , —CN, butyl, methyl cyclopropyl, cyclohexyl, phenyl, chlorophenyl, pyridinyl, and/or fluoropyridinyl;
(iv) cyclohexyl substituted with chlorophenyl;
(v) —NHC(O)—(CH 2 ) 0-2 -(phenyl) or —NHC(O)(pentyl);
(vi) —C(O)NHCH 2 C(CH 3 ) 3 , —C(O)NR g —(CHR g ) 0-3 -A 1 , —C(O)NR g —CH 2 C(R g )(A 1 )(A 1 ), or —C(O)NHCH 2 (tetrahydronaphthalenyl), wherein A 1 is phenyl substituted with zero to 2 substituents independently selected from Cl, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , and/or phenoxy;
(vii)

 wherein R e is naphthalenyl or —(CH 2 ) 0-2 (phenyl) and said phenyl is substituted with zero to 1 substituents selected from F, Cl, or OCH 3 ; or
(viii) —(CR 5 R 5 ) a CR e R e B 4 , —CH═CH—CR e R e B 4 , or —(CR 5 R 5 ) a O(CR 5 R 5 ) a CR e R e B 4 , wherein B 4 is phenyl substituted with zero to 2 substituents independently selected from F, Cl, —OH, and/or butyl; and each R e is independently H and/or —CH 3 , or two geminal R e along with the carbon atom to which they are attached form a C 4-6 spirocycloalkyl ring;

each a is independently zero, 1, 2, 3, 4, and/or 5;
each R 5 is H; and
each R g is independently H and/or —CH 3 .

2. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein: X 1 is C-G 2 , one of X 2 and X 3 is N, and the other of X 2 and X 3 is O or S.

3. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein: X 2 is C-G 2 , one of X 1 and X 3 is N, and the other of X 1 and X 3 is O or S.

4. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein: X 1 is C-G 2 , one of X 2 and X 3 is N, and the other of X 2 and X 3 is NH or NCH 3 .

5. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein: X 1 is N-G 2 , X 2 is N and X 3 is CH.

6. A pharmaceutical composition comprising a compound according to claim 1 or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

7. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein:
X 1 is C-G 2 , one of X 2 and X 3 is N, and the other of X 2 and X 3 is O;
W is —CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, or —CH 2 CF 2 —;
Q 1 is CH or C(CH 3 ); and
Q 2 is CH.

8. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein:
X 2 is C-G 2 , one of X 1 and X 3 is N, and the other of X 1 and X 3 is S;
W is —CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, or —CH 2 CF 2 —;
Q 1 is CH or C(CH 3 ); and
Q 2 is CH.

9. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein G 1 is: —OH, —CH 2 OH, —CH(OH)CH 2 OH, —(CH 2 ) 0-2 COOH, —CH(OH)(CH 2 ) 0-2 COOH, —CH 2 NH(CH 2 ) 1-2 OH, —CH 2 NR g (CH 2 ) 1-2 COOH, —CH 2 NR g (CH 2 ) 1-2 C(O)NH 2 , —CH 2 NR g (CH 2 ) 1-2 OP(O)(OH) 2 , —OCH 2 CH(OH)CH 2 OH, —(CH 2 ) 0-2 CNH 2 )(CH 3 )CH 2 OH, —(CH 2 ) 0-2 CR g (NH 2 )C(O)OH, —(CH 2 ) 0-2 C(NH 2 )(CH 3 )(CH 2 ) 1-2 OP(O)(OH) 2 , —CH 2 CH 2 C(NH 2 )(CH 2 OH) 2 , —CH 2 NHCH(CH 2 OH) 2 , —CH 2 N(CH 2 CH 2 OH) 2 , —CH 2 NHCH 2 CH(OH)CH 2 OH, —CH(OH)C(O)NHCH 2 CN, —CH(OH)C(O)NHCH 2 CH 2 S(O) 2 CH 3 , —CR g (OH)C(O)NHCH 2 CH 2 OH, —CH 2 (hydroxy pyrrolidinyl), or —CH 2 (hydroxymethyl pyrrolidinyl).

10. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein G 1 is:

11. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein G 2 is:
(i) phenyl substituted with one or two substituents independently selected from propyl, butyl, —CN, —CF 3 , cyclohexyl, —OCH 2 CH 3 , and/or —OCH(CH 3 ) 2 ;
(ii) pyrazolyl, isoxazolyl, isothiazolyl, or pyrimidinyl substituted with one or two substituents independently selected from —CF 3 , —CN, butyl, methyl cyclopropyl, cyclohexyl, phenyl, chlorophenyl, pyridinyl, and/or fluoropyridinyl; or
(iii) cyclohexyl substituted with chlorophenyl.

12. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein G 2 is:
(i) —NHC(O)—(CH 2 ) 0-2 -(phenyl) or —NHC(O)(pentyl);
(ii) —C(O)NHCH 2 C(CH 3 ) 3 , —C(O)NR g —(CHR g ) 0-3 -A 1 , —C(O)NR g —CH 2 C(R g )(A 1 )(A 1 ), or —C(O)NHCH 2 (tetrahydronaphthalenyl), wherein A 1 is phenyl substituted with zero to 2 substituents independently selected from Cl, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , and/or phenoxy; or
(iii)

wherein R e is naphthalenyl or —(CH 2 ) 0-2 (phenyl) and said phenyl is substituted with zero to 1 substituents selected from F, Cl, or OCH 3 .

13. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein G 2 is: —(CR 5 R 5 ) a CR e R e B 4 , —CH═CH—CR e R e B 4 , or —(CR 5 R 5 ) a O(CR 5 R 5 ) a CR e R e B 4 , wherein B 4 is phenyl substituted with zero to 2 substituents independently selected from F, Cl, —OH, and/or butyl; and each R e is independently H and/or —CH 3 , or two geminal R e along with the carbon atom to which they are attached form a C 4-6 spirocycloalkyl ring.

14. The compound according to claim 1 or a stereoisomer or a salt thereof, wherein said compound is selected from:
1-((5,5-dimethyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid;
1-((3-(4-propylphenyl)-4H-chromeno[4,3-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, trifluoroacetic acid salt;
1-((3-(4-propylphenyl)-4H-chromeno[3,4-d]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, trifluoroacetic acid salt;

Assignees

• Dhar T G Murali
• Xiao Hai-Yun
• Watterson Scott Hunter
• Ko Soo S
• Dyckman Alaric J
• Langevine Charles M
• Das Jagabandhu
• Cherney Robert J
• Bristol Myers Squibb Co

Inventors

• Dhar T G Murali
• Xiao Hai-Yun
• Watterson Scott Hunter
• Ko Soo S
• Dyckman Alaric J
• Langevine Charles M
• Das Jagabandhu
• Cherney Robert J

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

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

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title