Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors

Patent metadata

Field	Value
Publication number	US-9718803-B2
Application number	US-201514973491-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	May 13, 2010
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

Unsaturated nitrogen heterocyclic compounds of formula (I):

as defined in the specification, compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, Huntington's Disease, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

First claim

What is claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
the group

R 1 is L 1 or C 1-4 alk-L 1 ;
Y is a bond or —C(═O);
each R 2 and R 3 is independently H, halo, CN, OH, —OC 1-4 alk, C 1-4 alk, C 1-4 haloalk, —C 1-6 alkOR a , —C(═O)C 1-4 alk, —C(═O)NR a R a , or —C 0-4 alkNH—C(═O)R a ;
R 4a is H, OH, halo, C 1-4 alk, or C 1-4 haloalk;
R 4b is halo, CN, OH, OC 1-4 alk, C 1-4 alk, C 1-4 haloalk, or oxo;
R 5 is 5- to 6-membered heteroaryl or unsaturated 9- to 10-membered bicyclo-heterocyclic ring; wherein each R 5 ring is substituted by 0, 1, 2, 3, or 4 R 8 groups;
R 6 is independently H, halo, CN, OH, OC 1-4 alk, C 1-4 alk or C 1-4 haloalk;
m is 0;
each of p and q is independently 2; wherein the sum of p and q is 4;
the ring containing p and q contains 0 or 1 double bonds;
R a is independently H or R b ;
R b is independently phenyl, benzyl, or C 1-6 alk, wherein said phenyl, benzyl, and C 1-6 alk are substituted by 0, 1, 2 or 3 substituents which are, independently, halo, C 1-4 alk, C 1-3 haloalk, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk;
R c is L 2 or C 1-4 alk-L 2 ;
each L 1 is independently a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a saturated, partially-saturated or unsaturated 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are O or S; L′ is independently substituted by 0, 1, 2 or 3 R 9 groups;
each L 2 is independently a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a saturated, partially-saturated or unsaturated 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are 0 or S; L 2 is independently substituted by 0, 1, 2 or 3 R 11 groups;
R 8 is halo, CN, OH, C 1-4 alk, C 1-4 haloalk, —OC 1-4 haloalk, —C(═O)R b , —C(═O)R c , —C(═O)NHR b , —C(═O)NHR c , —S(═O) 2 R b , —S(═O) 2 R c , —S(═O) 2 NR a R a , R b , R c , NO 2 , OR b , or OR c ;
R 9 is halo, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC(═O)R b , —OC(═O)NR a R a , —OC 1-6 alkNR a R a , —OC 1-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 1-6 alkNR a R a , —NR a C 1-6 alkOR a , —C 1-6 alkNR a R a , —C 1-6 alkOR a , —C 1-6 alkN(R a )C(═O)R b , —C 1-6 alkOC(═O)R b , —C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a , oxo, or R c ;
and
R 11 is halo, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC(═O)R b , —OC(═O)NR a R a , —OC 1-6 alkNR a R a , —OC 1-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 1-6 alkNR a R a , —NR a C 1-6 alkOR a , —C 1-6 alkNR a R a , —C 1-6 alkOR a , —C 1-6 alkN(R a )C(═O)R b , —C 1-6 alkOC(═O)R b , —C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a , or oxo.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring containing p and q contains 0 double bond.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring containing p and q contains 1 double bond.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is L 1 .

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein is a carbon-linked-unsaturated 5- to 6-membered monocyclic ring, wherein each said ring contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and wherein each said L 1 substituted by 0, 1 or 2 R 9 groups which are F, Cl, Br, C 1-6 alk, —OR a , CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , or —N(R a )C(═O)OR b .

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein is phenyl substituted by 0, 1 or 2 R 9 groups which are F, Cl, Br, C 1-6 alk, —OR a , CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , or —N(R a )C(═O)OR b .

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 and R 3 is independently H.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is halo.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4a is H.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group —Y—R 5 is:

wherein R 5 is substituted by 1 or 2 R 8 groups.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group —Y—R 5 is:

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is F, Cl, CF 3 , methyl, or CN.

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is Cl.

17. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is F.

18. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is:
(1H-benzoimidazol-2-yl)-[4-(3-phenyl-pyrazin-2-yl)-piperidin-1-yl]-methanone;
(1H-Benzoimidazol-2-yl)-[3-(2,3-dihydro-indol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl]-methanone;
(1H-Benzoimidazol-2-yl)-(3-phenyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone;
(1H-Benzoimidazol-2-yl)-{4-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]-piperidin-1-yl}-methanone;
7-chloro-2-(4-(3-(4-fluoro-3-methoxyphenyl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)quinoline;
7-chloro-2-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)quinoline;
1-(3-(1-(7-chloroquinolin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)piperidine-4-carbonitrile;
1-(3-(1-(7-chloro-6-fluoroquinazolin-2-yl)-1,2,3,6-tetrahy

Assignees

• Amgen Inc

Inventors

• Allen Jennifer R
• Chen Jian J
• Frohn Michael J
• Harrington Essa Hu
• Liu Qingyian
• Pickrell Alexander J
• Rumfelt Shannon
• Rzasa Robert M
• Zhong Wenge

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title

• A61P25/36

  Opioid-abuse · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title