Piperidinyl- and piperazinyl-substituted heteroaromatic carboxamides as modulators of GPR6
AssigneeTakeda Pharmaceutical Company Limited
InventorsJason Green, Maria Hopkins, Benjamin Jones, Andre A. Kiryanov, Jon Kuehler, Holger Monenschein, Sean Murphy, Thomas Nixey, Huikai Sun
Life of this patent
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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.
Claims17
A compound of Formula 1,
- or a pharmaceutically acceptable salt thereof in which:
- X1 is selected from N and CR1,
- and
- X3 is selected from N and CR3, provided:
- (a) if X1 is CR1, X3 is CR3 and R1, R2 and R3 are each hydrogen, then R5 cannot be 2-phenylthiazol-4-yl, and
- (b) if X1 is CR1, X3 is CR3 and R1 and R3 are each hydrogen, then R2 cannot be Cl, and
- (d) if X1 is N, X3 is CR3 and R2 and R3 are each hydrogen, then R5 cannot be benzo[d][1,3]dioxol-5-yl;
- 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)NRa Rb, —(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)Rc, —(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)2R, —(C H2)nSRd, —(CH2)nS(O)Rf, —(CH2)nS(O)2R, 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;
- 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;
- 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.
N-(4-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-methylpyrimidin-5-yl)-2-methoxynicotinamide or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising N-(4-(4-(2,4-difluorophenoxy) piperidin-1-yl)-2-methylpyrimidin-5-yl)-2-methoxynicotinamide or a pharmaceutically acceptable salt thereof;
- and a pharmaceutically acceptable excipient.
A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of N-(4-(4-(2,4-difluorophenoxy) piperidin-1-yl)-2-methylpyrimidin-5-yl)-2-methoxynicotinamide or a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from Parkinson's disease, levodopa-induced dyskinesias, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder, epilepsy, and depression.
Dependencies are inferred from the claim text.