Piperidinyl- and piperazinyl-substituted heteroaromatic carboxamides as modulators of GPR6

Patent metadata

Field	Value
Publication number	US-11426397-B2
Application number	US-201816497967-A
Country	US
Kind code	B2
Filing date	Mar 26, 2018
Priority date	Mar 26, 2017
Publication date	Aug 30, 2022
Grant date	Aug 30, 2022

Abstract

Disclosed are compounds of Formula 1 and pharmaceutically acceptable salts thereof, wherein L, R4, R5, R8, R10, R11, X1, X2, X3, X9, X12, and Z are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with GPR6.

First claim

What is claimed is:

1. A compound of Formula 1,

or a pharmaceutically acceptable salt thereof in which:
X 1 is selected from N and CR 1 ,
and
X 3 is selected from N and CR 3 , provided:
(a) if X 1 is CR 1 , X 3 is CR 3 and R 1 , R 2 and R 3 are each hydrogen, then R 5 cannot be 2-phenylthiazol-4-yl, and
(b) if X 1 is CR 1 , X 3 is CR 3 and R 1 and R 3 are each hydrogen, then R 2 cannot be Cl, and
(d) if X 1 is N, X 3 is CR 3 and R 2 and R 3 are each hydrogen, then R 5 cannot be benzo[d][1,3]dioxol-5-yl;

R 1 and R 3 are each independently selected from hydrogen, cyano, C 1-6 alkyl, —(CH 2 ) m OR a , —(CH 2 ) m N(R a )R b , —(CH 2 ) m N(R a )C(O)R b , —(CH 2 ) m NHC(O)NR a R b , —(CH 2 ) m NR a C(O)NHR b , —(CH 2 ) m C(O)R a , —(CH 2 ) m C(O)N(R a )R b , —(CH 2 ) m N(R a )S(O) 2 R c , —(CH 2 ) m SR a , —(CH 2 ) m S(O)R c , —(CH 2 ) m S(O) 2 R c , and —(CH 2 ) m S(O) 2 N(R a )R b , wherein R a and R b are each independently selected from hydrogen and C 1-4 alkyl, R c is selected from C 1-4 alkyl and C 2-6 heterocyclyl, and m is selected from 0, 1, 2, 3, and 4;
R 2 is selected from hydrogen, halo, cyano, C 1-6 alkyl optionally substituted with 1 to 3 halo, —(CH 2 ) n OR d , —(CH 2 ) n N(R d )R e , —(CH 2 ) n N(R d )C(O)R e , —(CH 2 ) n NHC(O)NR d R e , —(C H 2 ) n NR d C(O)NHR e , —(CH 2 ) n C(O)R d , —(CH 2 ) n C(O)N(R d )R e , —(CH 2 ) n N(R d )S(O) 2 R, —(C H 2 ) n SR d , —(CH 2 ) n S(O)R f , —(CH 2 ) n S(O) 2 R, and —(CH 2 ) n S(O) 2 N(R d )R e , wherein R d and R e are each independently selected from hydrogen, C 1-4 alkyl, and C 2-6 heterocyclyl, R f is selected from C 1-4 alkyl and C 2-6 heterocyclyl, and n is selected from 0, 1, 2, 3, and 4, provided if R 2 is halo then no more than one of R 1 and R 3 is hydrogen;
R 5 is selected from phenyl and C 1-9 heteroaryl, wherein phenyl is optionally substituted with from 1 to 3 substituents independently selected from:
(a) amino optionally substituted with 1 or 2 C 1-4 alkyl;
(b) halo, hydroxy, C 3-6 cycloalkyl, and C 2-6 heterocyclyl;
(c) C 1-6 alkyl optionally substituted with:
(i) from 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkoxy, and amino optionally substituted with 1 or 2 C 1-4 alkyl; or
(ii) a substituent selected from phenyl and pyridinyl, each optionally substituted with from 1 to 3 halo;

(d) C 1-6 alkoxy optionally substituted with from 1 to 3 halo; and
(e) phenyl optionally substituted with from 1 to 3 halo;
and wherein C 1-9 heteroaryl is optionally substituted with from 1 to 3 substituents independently selected from:
(a) amino optionally substituted with 1 or 2 C 1-4 alkyl;
(b) halo, hydroxy, oxo, C 3-6 cycloalkyl, and C 2-6 heterocyclyl;
(c) C 1-6 alkyl optionally substituted with:
(i) from 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkoxy, and amino optionally substituted with 1 or 2 C 1-4 alkyl; or
(ii) a substituent selected from phenyl and pyridinyl, each optionally substituted with from 1 to 3 halo;

(d) C 1-6 alkoxy optionally substituted with from 1 to 3 halo; and
(e) phenyl optionally substituted with from 1 to 3 halo;

R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from hydrogen, halo, cyano, C 1-6 alkyl optionally substituted with from 1 to 3 halo, and C 1-6 alkoxy optionally substituted with from 1 to 3 halo;
wherein each of the above-mentioned heteroaryl and heterocyclyl moieties independently has 1 to 3 heteroatoms as ring members, each of the heteroatoms independently selected from N, O, and S.

2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein:
(A) X 1 is CR 1 , X 3 is CR 3 , and at least one of R 1 , R 2 and R 3 is not hydrogen; or
(B) X is CR 1 , and X 3 is N; or
(C) X 1 is N, and X 3 is CR 3 ; or
(D) X 1 is N, and X 3 is N.

3. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is selected from hydrogen, cyano, C 1-6 alkyl, —(CH 2 ) m OR a , —(CH 2 ) m N(R a )C(O)R b , —(CH 2 ) m C(O)N(R a )R b , and —(CH 2 ) m S(O) 2 R c , wherein R a and R b are each independently selected from hydrogen and C 1-4 alkyl, R c is selected from C 1-4 alkyl and C 2-6 heterocyclyl, and m is selected from 0 and 1.

4. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is selected from hydrogen, halo, cyano, C 1-6 alkyl optionally substituted with 1 to 3 halo, —(CH 2 ) n OR d , —(CH 2 ) n C(O)N(R d )R e , and —(CH 2 ) n S(O) 2 R, wherein R d and R e are each independently selected from hydrogen, C 1-4 alkyl, and C 2-6 heterocyclyl, R f is C 1-4 alkyl, and n is selected from 0 and 1.

5. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from hydrogen, cyano, C 1-6 alkyl, —(CH 2 ) m OR a , —(CH 2 ) m N(R a )C(O)R b , —(CH 2 ) m C(O)N(R a )R b , and —(CH 2 ) m S(O) 2 R c , wherein R a and R b are each independently selected from hydrogen and C 1-4 alkyl, R c is selected from C 1-4 alkyl and C 2-6 heterocyclyl, and m is selected from 0 and 1.

6. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is selected from phenyl optionally substituted with from 1 to 3 substituents independently selected from:
(a) amino optionally substituted with 1 or 2 C 1-4 alkyl;
(b) halo, hydroxy, C 2-6 heterocyclyl, and phenyl; and
(c) C 1-6 alkyl and C 1-6 alkoxy, each optionally substituted with from 1 to 3 halo.

7. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from hydrogen, halo, cyano, C 1-4 alkyl optionally substituted from 1 to 3 halo, and C 1-4 alkoxy optionally substituted with from 1 to 3 halo.

8. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is C 1-9 heteroaryl optionally substituted with from 1 to 3 substituents independently selected from:
(a) amino optionally substituted with 1 or 2 C 1-4 alkyl;
(b) halo, hydroxy, oxo, C 3-6 cycloalkyl, and C 2-6 heterocyclyl;
(c) C 1-6 alkyl optionally substituted with:
(i) from 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkoxy, and amino optionally substituted with 1 or 2 C 1-4 alkyl; or
(ii) a substituent selected from phenyl and pyridinyl, each optionally substituted with from 1 to 3 halo;

(d) C 1-6 alkoxy optionally substituted with from 1 to 3 halo; and
(e) phenyl optionally substituted with from 1 to 3 halo.

9. The compound or pharmaceutically acceptable salt according to claim 8 , wherein each of the optional substituents on the R 5 heteroaryl moiety is independently selected from:
(a) amino optionally substituted with 1 or 2 C 1-4 alkyl;
(b) halo, hydroxy, oxo, C 3-6 cycloalkyl, and C 3-5 heterocyclyl;
(c) C 1-6 alkyl optionally substituted with:
(i) from 1 to 3 substituents independently selected from halo, oxo, C 1-4 alkoxy, and amino optionally substituted with 1 or 2 C 1-4 alkyl; or
(ii) a substituent selected from phenyl and pyridinyl, each optionally substituted with from 1 to 3 halo;

(d) C 1-6 alkoxy optionally substituted with from 1 to 3 halo; and
(e) phenyl optionally substituted with from 1 to 3 halo;

wherein the C 3-5 heterocyclyl moiety is monocyclic, has 5 or 6 ring members in which 1 or 2 ring members are heteroatoms, and the heteroatoms are independently selected from N, O and S.

10. The compound according to claim 1 , which is selected from the foll

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Green Jason
• Hopkins Maria
• Jones Benjamin
• Kiryanov Andre A
• Kuehler Jon
• Monenschein Holger
• Murphy Sean
• Nixey Thomas
• Sun Huikai

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D409/12

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D413/12

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