SUBSTITUTED 1H-PYRAZOLO[3',4',4,5]THIENO[2,3-B]PYRIDIN-3-AMINE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYCHOLINE RECEPTOR M4

摘要

In one aspect, the invention relates to substituted 1H-pyrazolo[3′,4′:4,5]thieno[2,3-b]pyridin-3-amine 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, -Cy1, —OR6, and —NR6R7; wherein Cy1, when present, is selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy1 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, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or wherein R1 and R4a are optionally covalently bonded and, together with the intermediate carbon, and 0-2 heteroatoms comprise a 3- to 7-membered cycloalkyl or heterocycloalkyl 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, C1-C6 dialkylamino, aryl and heteroaryl; or wherein R1 and R4b are optionally covalently bonded and, together with the intermediate carbon, and 0-2 heteroatoms comprise a 3- to 7-membered cycloalkyl or heterocycloalkyl 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, C1-C6 dialkylamino, aryl and heteroaryl; wherein R2 is selected from hydrogen, C1-C8 alkyl, —CF3, —(C1-C8 alkyl)-Ar1, —(C1-C8 alkyl)-Cy2, —Ar1, and -Cy2;
wherein Ar1, when present, is selected from phenyl and heteroaryl; and wherein Ar1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NH2, —SF5, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, —(C1-C6 alkyl)-(C═O)R20, —(C1-C6 alkyl)-(C═O)OR20, —(C1-C6 alkyl)-S(O)mR20, —(C═O)R20, —(C═O)OR20, and —S(O)mR20; and wherein two of the groups are optionally covalently bonded, and together with the intermediate atoms, comprise an optionally substituted 3- to 6-membered fused ring group; and
wherein m is an integer selected from 0, 1, or 2; andwherein each R20, when present, is independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C3)-Ar9, and Ar9;
wherein each Ar9, when present, is independently selected from phenyl and heteroaryl, and wherein each Ar9 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, C1-C8 dialkylamino, and —S(O)yR30; wherein each R30, when present, is independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl; and wherein y is an integer selected from 0, 1, or 2;wherein Cy2, when present, is selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy2 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, C1-C6 dialkylamino, —(C1-C6 alkyl)-(C═O)R20, —(C1-C6 alkyl)-(C═O)OR20, —(C═O)R20, and —(C═O)OR20; wherein R3 is selected from C1-C8 alkyl, —CF3, —(C1-C8 alkyl)-Ar2, —(C0-C8 alkyl)-Cy3, —Ar2, and -Cy3;
wherein Ar2, when present, is selected from phenyl and heteroaryl; and wherein Ar2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NH2, —SF5, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, —(C1-C6 alkyl)-(C═O)R21, —(C1-C6 alkyl)-(C═O)OR21, —(C1-C6 alkyl)-S(O)qR21, —(C═O)R21, —(C═O)OR21, and —S(O)qR21; and wherein two of the groups are optionally covalently bonded, and together with the intermediate atoms, comprise an optionally substituted 3- to 6-membered fused ring group; and
wherein q is an integer selected from 0, 1, or 2; andwherein each R21, when present, is independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C3)-Ar10, and Ar10;
wherein each Ar10, when present, is independently selected from phenyl and heteroaryl, and wherein each Ar9 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, C1-C8 dialkylamino, and —S(O)zR31; wherein each R31, when present, is independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl; and wherein z is an integer selected from 0, 1, or 2;wherein Cy3, when present, is selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy3 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, C1-C6 dialkylamino, —(C1-C6 alkyl)-(C═O)R21, —(C1-C6 alkyl)-(C═O)OR21, —(C═O)R21, and —(C═O)OR21; or wherein R2 and R3 are 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, —OH, —CN, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl and heteroaryl; wherein each of R4a and R4b are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, —O—(C1-C8 alkyl)-Ar3, —O—(C1-C8 alkyl)-Cy4, —Ar3, -Cy4, —(C═O)R8, —SO2R8, and —(C═O)OR8;
wherein each Ar3, when present, is independently selected from phenyl and heteroaryl; and wherein each Ar3, when present, is independently 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 Cy4, when present, is independently selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy4 is independently 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 R5 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-C6 alkyl), C1-C6 polyhaloalkyl, —(C1-C8)-(C═O)R9, —(C1-C8)-(C═O)OR9; —(C1-C8)-SO2R9, —(C═O)R9, —(C═O)OR9, —SO2R9, —(C═O)—Cy9, —Ar8, -Cy9, and —Ar8;
wherein Ar8, when present, is selected from phenyl and heteroaryl; and wherein Ar8 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 Cy9, when present, is selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy9 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 R6, when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, —(C1-C8 alkyl)-Ar4, —(C1-C8 alkyl)-Cy5, —Ar4, and -Cy5;
wherein Ar4, when present, is selected from phenyl and heteroaryl; and wherein Ar4 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 Cy5, when present, is selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy5 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 R7, when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, —(C1-C8 alkyl)-Ar5, —(C1-C8 alkyl)-Cy6, —Ar5, and -Cy6;
wherein Ar5, when present, is selected from phenyl and heteroaryl; and wherein Ar5 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 Cy6, when present, is selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy6 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 R8, when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, —(C1-C8 alkyl)-Ar6, —(C1-C8 alkyl)-Cy7, —Ar6, and -Cy7;
wherein Ar6, when present, is selected from phenyl and heteroaryl; and wherein Ar6 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 Cy7, when present, is selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy7 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 R9, when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, —(C1-C8 alkyl)-Ar7, —(C1-C8 alkyl)-Cy8, —Ar7, and -Cy8;
wherein Ar7, when present, is selected from phenyl and heteroaryl; and wherein Ar7 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; andwherein Cy8, when present, is selected from C3-C8 cycloalkyl and C3-C8 heterocycloalkyl; and wherein Cy8 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; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.