Piperidinyl- and piperazinyl-substituted heteroaromatic carboxamides as modulators of gpr6

A compound of Formula 1,

• or a pharmaceutically acceptable salt thereof in which:
• X1 is selected from N and CR1,
• X2 is selected from N and CR2, and
• X3 is selected from N and CR3, provided:
• (a) no more than two of X1, X2, and X3 can be N, and
• (b) if X1 is CR1, X2 is CR2, X3 is CR3 and R1, R2 and R3 are each hydrogen, then Z must be CH and R5 cannot be 2-phenylthiazol-4-yl, and
• (c) if X1 is CR1, X2 is CR2, X3 is CR3 and R1 and R3 are each hydrogen, then R2 cannot be Cl, and
• (d) if X1 is N, X2 is CR2, X3 is CR3 and R2 and R3 are each hydrogen, then R5 cannot be benzo[d][1,3]dioxol-5-yl;
• X9 is selected from N and CR9, and
• X12 is selected from N and CR12, wherein no more than one of X9 and X12 is N;
• L is selected from O, S, S(O2), and C(R6)R7;
• Z is selected from CH and N;
• R1 and R3 are each independently selected from hydrogen, cyano, C1-6 alkyl, —(CH2)mORa, —(CH2)mN(Ra)Rb, —(CH2)mN(Ra)C(O)Rb, —(CH2)mNHC(O)NRaRb, —(CH2)mNRaC(O)NHRb, —(CH2)mC(O)Ra, —(CH2)mC(O)N(Ra)Rb, —(CH2)mN(Ra)S(O)2Rc, —(CH2)mSRa, —(CH2)mS(O)2Rc, —(CH2)mS(O)2Rc, and —(CH2)mS(O)2N(Ra)Rb, wherein Ra and Rb are each independently selected from hydrogen and C1-4 alkyl, Rc is selected from C1-4 alkyl and C2-6 heterocyclyl, and m is selected from 0, 1, 2, 3, and 4;
• R2 is selected from hydrogen, halo, cyano, C1-6 alkyl optionally substituted with 1 to 3 halo, —(CH2)nORd, —(CH2)nN(Rd)Re, —(CH2)nN(Rd)C(O)Re, —(CH2)nNHC(O)NRdRe, —(C H2)nNRdC(O)NHRe, —(CH2)nC(O)Rd, —(CH2)nC(O)N(Rd)Re, —(CH2)nN(Rd)S(O)2Rf, —(C H2)nSRd, —(CH2)nS(O)Rf, —(CH2)nS(O)2Rf, and —(CH2)nS(O)2N(Rd)Re, wherein Rd and Re are each independently selected from hydrogen, C1-4 alkyl, and C2-6 heterocyclyl, Rf is selected from C1-4 alkyl and C2-6 heterocyclyl, and n is selected from 0, 1, 2, 3, and 4, provided if R2 is halo then no more than one of R1 and R3 is hydrogen;
• R4 is selected from hydrogen and C1-4 alkyl;
• R5 is selected from phenyl and C1-9 heteroaryl, wherein phenyl is optionally substituted with from 1 to 3 substituents independently selected from:
• (a) amino optionally substituted with 1 or 2 C1-4 alkyl;
• (b) halo, hydroxy, C3-6 cycloalkyl, and C2-6 heterocyclyl;
• (c) C1-6 alkyl optionally substituted with:
• (i) from 1 to 3 substituents independently selected from halo, oxo, C1-4 alkoxy, and amino optionally substituted with 1 or 2 C1-4 alkyl;
• or
• (ii) a substituent selected from phenyl and pyridinyl, each optionally substituted with from 1 to 3 halo;
• (d) C1-6 alkoxy optionally substituted with from 1 to 3 halo;
• and
• (e) phenyl optionally substituted with from 1 to 3 halo;
• and wherein C1-9 heteroaryl is optionally substituted with from 1 to 3 substituents independently selected from:
• (a) amino optionally substituted with 1 or 2 C1-4 alkyl;
• (b) halo, hydroxy, oxo, C3-6 cycloalkyl, and C2-6 heterocyclyl;
• (c) C1-6 alkyl optionally substituted with:
• (i) from 1 to 3 substituents independently selected from halo, oxo, C1-4 alkoxy, and amino optionally substituted with 1 or 2 C1-4 alkyl;
• or
• (ii) a substituent selected from phenyl and pyridinyl, each optionally substituted with from 1 to 3 halo;
• (d) C1-6 alkoxy optionally substituted with from 1 to 3 halo;
• and
• (e) phenyl optionally substituted with from 1 to 3 halo;
• R6 and R7 are each independently selected from hydrogen, halo, C1-4 alkyl, and C1-4 alkoxy, or together with the carbon atom to which they are attached form a carbonyl;
• R8, R9, R10, R11, and R12 are each independently selected from hydrogen, halo, cyano, C1-6 alkyl optionally substituted with from 1 to 3 halo, and C1-6 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.