SUBSTITUTED 5-AMINOTHIENO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4

摘要

In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6-carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

主权项

1. A compound having a structure represented by a formula: wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NH2, —CF3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, —(C1-C3 alkyl)-Ar10, Ar10, —(C1-C3 alkyl)-Cy10, and Cy10;
wherein each Ar10, when present, is selected from phenyl and monocyclic heteroaryl; and wherein Ar10 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;wherein each Cy10, when present, is selected from C3-C9 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy10 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein R2 is selected from hydrogen, halogen, —OH, —CN, —NH2, —CF3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, —(C1-C3 alkyl)-Ar11, Ar11, —(C1-C3 alkyl)-Cy11, and Cy11;
wherein each Ar11, when present, is selected from phenyl and monocyclic heteroaryl; and wherein Ar11 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;wherein each Cy11, when present, is selected from C3-C9 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy11 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein R1 and R2 are optionally covalently bonded and, together with the intermediate atoms, comprise a 3- to 7-membered cycle substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, Ar10, Ar11, Cy10, and Cy11; wherein each of R3a and R3b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C3-C9 cycloalkyl, C2-C7 heterocycloalkyl, —(C1-C8 alkyl)-(C3-C9 cycloalkyl), and —(C1-C8 alkyl)-(C2-C7 heterocycloalkyl); wherein R3a and R3b are optionally covalently bonded and, together with the intermediate nitrogen, comprise a 3- to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R4a and R4b is independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C3-C8 hydroxyalkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR20R21, —(C1-C6 alkyl)-NR20(C═O)R21, —(C1-C6 alkyl)-NR20(C═O)OR21, —(C1-C6 alkyl)-NR20(C═O)NR21, —(C1-C6 monohaloalkyl)-NR20(C═O)OR21, —(C1-C6 polyhaloalkyl)-NR20(C═O)OR21, —(C1-C8 alkyl)-Cy1, Cy1, —(CH2)—Ar1, —(CH2)2—Ar3, —(C3-C8 alkyl)-Ar1, —(C2-C8 alkynyl)-Ar1, and Ar2;
wherein R4a and R4b are not simultaneously hydrogen;wherein each R20, when present, is independently selected from hydrogen and C1-C8 alkyl;wherein each R21, when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-Cy1, Cy1, —(C1-C8 alkyl)-Ar1, and Ar1;wherein each Ar1, when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar1 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —N3, —SF5, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR31R32, —(C1-C6 alkyl)-NR30(C═O)R35, —(C1-C6 alkyl)-NR30(C═O)OR35, —(C1-C6 alkyl)-NR30(C═O)NR35, —(C1-C6 alkyl)-NR30S(O)nR35, —NR30(C1-C6 alkyl)-(C═O)R35, —NR30(C1-C6 alkyl)-(C═O)OR35, —NR30(C1-C6 alkyl)-(C═O)NR35, —NR30(C1-C6 alkyl)-S(O)nR35, —NR30(C1-C6 alkyl)-S(O)nNR33R34, —NR30(C═O)R35, —NR30(C═O)OR35, —NR30(C═O)NR35, —NR30S(O)nR35, —(C1-C6 alkyl)-(C═O)R35, —(C1-C6 alkyl)-(C═O)OR35, —(C1-C6 alkyl)-(C═O)NR35, —(C1-C6 alkyl)-S(O)nR35, —(C1-C6 alkyl)-S(O)nNR33R34, —(C═O)R35, —(C═O)OR35, —S(O)nR35, —S(O)NR33R34, —(C1-C8 alkyl)-Ar20, Ar20, —(C1-C8 alkyl)-Cy20, Cy20, and R37;wherein each n is an integer independently selected from 0, 1 and 2;wherein each Ar20, when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar20 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —S(O)nR36, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;wherein each Cy20, when present, is independently selected from C3-C9 cycloalkyl and C2-C7 heterocycloalkyl, and wherein each Cy20 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —S(O)nR36, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;wherein each R30, when present, is independently selected from hydrogen and C1-C8 alkyl;wherein each R31, when present, is independently selected from hydrogen and C1-C8 alkyl;wherein each R32, when present, is independently selected from hydrogen and C1-C8 alkyl;wherein each R33, when present, is independently selected from hydrogen and C1-C8 alkyl;wherein each R34, when present, is independently selected from hydrogen, C1-C8 alkyl, C3-C9 cycloalkyl, C2-C7 heterocycloalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C6)-Ar21, and Ar21;
wherein each Ar21, when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar21 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;wherein each R35, when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C3-C9 cycloalkyl, C2-C7 heterocycloalkyl, —(C1-C6)-Ar22, and Ar22;
wherein each Ar22, when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar22 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;wherein each R36, when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C3-C9 cycloalkyl, C2-C7 heterocycloalkyl, —(C1-C6)-Ar23, and Ar23;
wherein each Ar23, when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar23 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;wherein each R37, when present, is independently selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monoalkylamino, or C1-C4 dialkylamino substituted with 1 or 2 groups selected from —F, —CH3, —CF3, —OH, —NH2, and —CN;wherein each Ar2, when present, is a heteroaryl, and wherein each Ar2 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —N3, —SF5, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR31R32, —(C1-C6 alkyl)-NR30(C═O)R35, —(C1-C6 alkyl)-NR30(C═O)OR35, —(C1-C6 alkyl)-NR30(C═O)NR35, —(C1-C6 alkyl)-NR30S(O)nR35, —NR30(C1-C6 alkyl)-(C═O)R35, —NR30(C1-C6 alkyl)-(C═O)OR35, —NR30(C1-C6 alkyl)-(C═O)NR35, —NR30(C1-C6 alkyl)-S(O)nR35, —NR30(C1-C6 alkyl)-S(O)nNR33R34, —NR30(C═O)R35, —NR30(C═O)OR35, —NR30(C═O)NR35, —NR30S(O)nR35, —(C1-C6 alkyl)-(C═O)R35, —(C1-C6 alkyl)-(C═O)OR35, —(C1-C6 alkyl)-(C═O)NR35, —(C1-C6 alkyl)-S(O)nR35, —(C1-C6 alkyl)-S(O)nNR33R34, —(C═O)R35, —(C═O)OR35, —S(O)nR35, —S(O)NR33R34, —(C1-C8 alkyl)-Ar20, Ar20, —(C1-C8 alkyl)-Cy20, Cy20, and R37;wherein each Ar3, when present, is a heteroaryl, and wherein each Ar3 is independently substituted with 0, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —N3, —SF5, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR31R32, —(C1-C6 alkyl)-NR30(C═O)R35, —(C1-C6 alkyl)-NR30(C═O)OR35, —(C1-C6 alkyl)-NR30(C═O)NR35, —(C1-C6 alkyl)-NR30S(O)nR35, —NR30(C1-C6 alkyl)-(C═O)R35, —NR30(C1-C6 alkyl)-(C═O)OR35, —NR30(C1-C6 alkyl)-(C═O)NR35, —NR30(C1-C6 alkyl)-S(O)nR35, —NR30(C1-C6 alkyl)-S(O)nNR33R34, —NR30(C═O)R35, —NR30(C═O)OR35, —NR30(C═O)NR35, —NR30S(O)nR35, —(C1-C6 alkyl)-(C═O)R35, —(C1-C6 alkyl)-(C═O)OR35, —(C1-C6 alkyl)-(C═O)NR35, —(C1-C6 alkyl)-S(O)nR35, —(C1-C6 alkyl)-S(O)nNR33R34, —(C═O)R35, —(C═O)OR35, —S(O)nR35, —S(O)NR33R34, —(C1-C8 alkyl)-Ar20, Ar20, —(C1-C8 alkyl)-Cy20, Cy20, and R37; or and wherein each Ar3 is independently monosubstituted with a groups selected from —Cl, —Br, —I, —NH2, —OH, —CN, —N3, —SF5, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR31R32, —(C1-C6 alkyl)-NR30(C═O)R35, —(C1-C6 alkyl)-NR30(C═O)OR35, —(C1-C6 alkyl)-NR30(C═O)NR35, —(C1-C6 alkyl)-NR30S(O)nR35, —NR30(C1-C6 alkyl)-(C═O)R35, —NR30(C1-C6 alkyl)-(C═O)OR35, —NR30(C1-C6 alkyl)-(C═O)NR35, —NR30(C1-C6 alkyl)-S(O)nR35, —NR30(C1-C6 alkyl)-S(O)NR33R34, —NR30 (C═O)R35, —NR30 (C═O)OR35, —NR30 (C═O)NR35, —NR30S(O)nR35, —(C1-C6 alkyl)-(C═O)R35, —(C1-C6 alkyl)-(C═O)OR35, —(C1-C6 alkyl)-(C═O)NR35, —(C1-C6 alkyl)-S(O)nR35, —(C1-C6 alkyl)-S(O)nNR33R34, —(C═O)R35, —(C═O)OR35, —S(O)nR35, —S(O)nNR33R34, —(C1-C8 alkyl)-Ar20, Ar20, —(C1-C8 alkyl)-Cy20, Cy20, and R37;wherein each Cy1, when present, is independently selected from C3-C9 cycloalkyl and C2-C7 heterocycloalkyl, and wherein each Cy1 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —N3, —SF5, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR31R32, —(C1-C6 alkyl)-NR30(C═O)R35, —(C1-C6 alkyl)-NR30(C═O)OR35, —(C1-C6 alkyl)-NR30(C═O)NR35, —(C1-C6 alkyl)-NR30S(O)nR35, —NR30(C1-C6 alkyl)-(C═O)R35, —NR30(C1-C6 alkyl)-(C═O)OR35, —NR30(C1-C6 alkyl)-(C═O)NR35, —NR30(C1-C6 alkyl)-S(O)nR35, —NR30(C1-C6 alkyl)-S(O)nNR33R34, —NR30(C═O)R35, —NR30(C═O)OR35, —NR30(C═O)NR35, —NR30S(O)nR35, —(C1-C6 alkyl)-(C═O)R35, —(C1-C6 alkyl)-(C═O)OR35, —(C1-C6 alkyl)-(C═O)NR35, —(C1-C6 alkyl)-S(O)nR35, —(C1-C6 alkyl)-S(O)nNR33R34, —(C═O)R35, —(C═O)OR35, —S(O)nR35, —S(O)nNR33R34, —(C1-C8 alkyl)-Ar20, Ar20, —(C1-C8 alkyl)-Cy20, Cy20, and R37; wherein R4a and R4b are optionally covalently bonded and, together with the intermediate nitrogen, comprise a 3- to 10-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —N3, —SF5, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR31R32, —(C1-C6 alkyl)-NR30(C═O)R35, —(C1-C6 alkyl)-NR30(C═O)OR35, —(C1-C6 alkyl)-NR30(C═O)NR35, —(C1-C6 alkyl)-NR30S(O)nR35, —NR30(C1-C6 alkyl)-(C═O)R35, —NR30(C1-C6 alkyl)-(C═O)OR35, —NR30(C1-C6 alkyl)-(C═O)NR35, —NR30(C1-C6 alkyl)-S(O)nR35, —NR30(C1-C6 alkyl)-S(O)nNR33R34, —NR30(C═O)R35, —NR30(C═O)OR35, —NR30(C═O)NR35, —NR30S(O)nR35, —(C1-C6 alkyl)-(C═O)R35, —(C1-C6 alkyl)-(C═O)OR35, —(C1-C6 alkyl)-(C═O)NR35, —(C1-C6 alkyl)-S(O)nR35, —(C1-C6 alkyl)-S(O)nNR33R34, —(C═O)R35, —(C═O)OR35, —S(O)nR35, —S(O)NR33R34, —(C1-C8 alkyl)-Ar30, Ar30, —(C1-C8 alkyl)-Cy30, Cy30, and R37; wherein each Ar30, when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar30 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —S(O)nR45, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C8 alkyl)-Ar40, Ar40, —(C1-C8 alkyl)-Cy40, and Cy40;
wherein each R45, when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C3-C9 cycloalkyl, C2-C7 heterocycloalkyl, phenyl, and monocyclic heteroaryl;wherein each Ar40, when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar40 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —S(O)nR46, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;
wherein each R46, when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C3-C9 cycloalkyl, C2-C7 heterocycloalkyl, phenyl, and monocyclic heteroaryl;wherein each Cy40, when present, is independently selected from C3-C9 cycloalkyl and C2-C7 heterocycloalkyl, and wherein each Cy40 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —S(O)nR46, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;wherein each Cy30, when present, is independently selected from C3-C9 cycloalkyl and C2-C7 heterocycloalkyl, and wherein each Cy30 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH2, —OH, —CN, —S(O)nR45, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C8 alkyl)-Ar40, Ar40, —(C1-C8 alkyl)-Cy40, and Cy40; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.