Heteroaryl derivatives as alpha7 nAChR modulators

摘要

Disclosed is a compound of formula (I), wherein Z, m and R1-R6 are as described herein, as a modulator of nicotinic acetylcholine receptors particularly the α7 subtype, in a subject in need thereof, as well as analogs, prodrugs, isotopically substituted analogs, metabolites, pharmaceutically acceptable salts, polymorphs, solvates, isomers, clathrates, and co-crystal thereof, for use either alone or in combinations with suitable other medicaments, and pharmaceutical compositions containing such compounds and analogs. Also disclosed are a process of preparation of the compounds and the intended uses thereof in therapy, particularly in the prophylaxis and therapy of disorders such as Alzheimer's disease, mild cognitive impairment, senile dementia, and the like.;

主权项

1. A compound of formula I, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: Z is S, O, or NRa, wherein Ra is hydrogen, optionally substituted alkyl, or cycloalkyl; R1 is selected from the group consisting of optionally substituted aryl, cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; R2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, perhaloalkyl, cycloalkyl, and (R7)(R8)N—; R3 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocyclyl, (R7)(R8)N—, (R7)N(OR8)—, and R7A1-; [R4]m is ‘m’ times repetition of ‘R4’ groups, each R4 is independently selected from the group consisting of halogen, R7A1-, and alkyl, wherein m=0, 1 or 2; or two R4 groups and the carbon atoms to which they are attached together form an optionally substituted 5- to 6-membered cyclic system; R5 and R6 are independently hydrogen or alkyl; or R5 and R6 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring system containing a nitrogen atom; wherein R7 and R8 are independently selected from the group consisting of hydrogen and optionally substituted alkyl; and A1 is selected from the group consisting of O and S; wherein, the term “optionally substituted alkyl” means an alkyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, cycloalkyl, R10aSO2—, R10A1-, R10aOC(═O)—, R10aC(═O)O—, (R10)(H)NC(═O)—, (R10)(alkyl)NC(═O)—, R10aC(═O)N(H)—, (R10)(H)N—, (R10)(alkyl)N—, (R10)(H)NC(=A1)N(H)—, and (R10)(alkyl)NC(=A1)N(H)—; the term “optionally substituted aryl” means (i) an aryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 perhaloalkyl, alkyl-O—, perhaloalkyl-O—, alkyl-N(alkyl)-, alkyl-N(H)—, H2N—, alkyl-SO2—, perhaloalkyl-SO2—, alkyl-C(═O)N(alkyl)-, alkyl-C(═O)N(H)—, alkyl-N(alkyl)C(═O)—, alkyl-N(H)C(═O)—, H2NC(═O)—, alkyl-N(alkyl)SO2—, alkyl-N(H)SO2—, H2NSO2—, 3- to 6-membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein said 3- to 6-membered heterocycle is optionally substituted with alkyl, or alkyl-C(═O)— or (ii) said substituted or unsubstituted aryl ring optionally fused with cycloalkane ring or heterocycle ring containing 1 to 3 heteroatoms selected from S, O, and N across a bond, wherein the said cycloalkane ring or heterocycle ring is optionally substituted with oxo, alkyl, or alkyl-C(═O)—; the term “optionally substituted heterocyclyl” means a (i) heterocyclyl group unsubstituted or substituted on ring carbons with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, R10A1-, R10aOC(═O)—, R10aC(═O)O—, (R10)(H)NC(═O)—, (R10)(alkyl)NC(O)—, R10aC(═O)N(H)—, (R10)(H)N—, (R10)(alkyl)N—, (R10)(H)NC(=A1)N(H)—, and (R10)(alkyl)NC(=A1)N(H)—; (ii) heterocyclyl group optionally substituted on ring nitrogen(s) with one or more substituents selected from the group consisting of heteroaryl, alkyl, R10aC(═O)—, R10aSO2—, R10aOC(═O)—, (R10)(H)NC(═O)—, (R10)(alkyl)NC(═O)—, and aryl unsubstituted or substituted with 1 to 3 substituents selected independently from halogen, alkyl, cyano, and nitro; the term “optionally substituted heteroaryl” means a heteroaryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 perhaloalkyl, alkyl-O—, perhaloalkyl-O—, alkyl-N(alkyl)-, alkyl-N(H)—, H2N—, alkyl-SO2, perhaloalkyl-SO2—, alkyl-C(═O)N(alkyl)-, alkyl-C(═O)N(H)—, alkyl-N(alkyl)C(═O)—, alkyl-N(H)C(═O)—, H2NC(═O), alkyl-N(alkyl)SO2—, alkyl-N(H)SO2—, H2NSO2—, and 3- to 6-membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted with one to four substituents selected from the group consisting of alkyl and alkyl-C(═O)—; the term “optionally substituted 5- to 6-membered cyclic system” means the 5- to 6-membered cyclic system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, R10aC(═O)—, R10aSO2—, R10A1-, R10aOC(═O)—, R10aC(═O)O—, (R10(H)NC(═O)—, (R10)(alkyl)NC(═O)—, R10aC(═O)N(H)—, (R10)(H)N—, (R10)(alkyl)N—, (R10)(H)NC(=A1)N(H)—, and (R10)(alkyl)NC(=A1)N(H)—; the term “3- to 10-membered optionally substituted heterocyclic ring system” means a 3- to 10-membered heterocyclic ring system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, R10aC(═O)—, R10aSO2—, R10A1-, R10aOC(═O)—, R10aC(═O)O—, (R10)(H)NC(═O)—, (R10)(alkyl)NC(═O)—, R10aC(═O)N(H)—, (R10)(H)N—, (R10)(alkyl)N—, (R10)(H)NC(=A1)N(H)—, and (R10)(alkyl)NC(=A1)N(H)—; wherein R10 is selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; and R10a is selected from the group consisting of alkyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl.