BIARYL DERIVATIVES AS NACHR MODULATORS

摘要

Disclosed is a compound of formula (I): wherein ‘D’, ‘E’, ‘m’, ‘n’ and R1-R4 are as described herein, as a modulator of nicotinic acetylcholine receptors particularly the α7 subtype, in a subject in need thereof, as well as analogues, 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 analogues. 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), its tautomeric forms, its stereoisomers, its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, wherein, ‘D’ is selected from N and CR5; ‘E’ is selected from S and NR6; with a proviso that when ‘E’ is NR6, ‘D’ is not selected as N; R1 is selected from hydrogen or substituted- or unsubstituted-alkyl, substituted- or unsubstituted-alkenyl, halogen, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-heterocyclyl, cyano, nitro, (R7)(R8)N—, R7cC(═O)N(R8)—, (R7a)(R8)NC(=A1)N(R9)—, R7bOC(═O)NR8a—, R7bSO2N(R8a)—, R7A1-, (R7a)(R8)NC(═O)—, and R7bS(O)p—, wherein ‘p’ is an integer ranging from 1 to 2; R2 is selected from substituted- or unsubstituted-alkyl, substituted- or unsubstituted-alkenyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-heterocyclyl, (R7)(R8)N—, (R7)N(OR7c)—, and R7A1-; R3 is selected independently at each occurrence from halogen, cyano, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-heterocyclyl, (R7a)(R8a)NC(═O)—, R7aA1-, (R7b)C(═O)N(R8a)—, (R7a)(R8a)N—, (R7a)(R8a)NC(=A1)N(R9)—, (R7a)(R8a)NC(═O)O—, R7bOC(═O)N(R8a)—, R7bS(O)p—, wherein ‘p’ is an integer ranging from 1 to 2, and two R3s and the carbon atoms to which they are attached can combine to form an substituted- or unsubstituted-5 to 8 member cyclic system which may contain 1 to 3 heteroatoms/groups selected from —NH—, —S—, —O—, —C(═O)—, and —C(═S)—; ‘n’ is selected from 0, 1, 2 and 3; R4 is selected independently at each occurrence from halogen, cyano, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-heterocyclyl, (R7a)(R8a)NC(═O)—, R7aA1-, (R7b)C(═O)N(R8a)—, (R7a)(R8a)N—, and two R4s and the carbon atoms to which they are attached can combine to form a substituted- or unsubstituted-5 to 8 membered cyclic system which may contain 1 to 3 heteroatoms/groups such as —NH—, —S—, —O—, —C(═O)—, and —C(═S)—; ‘m’ is selected from 0, 1, 2 and 3; R5 is selected from hydrogen, halogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-heterocyclyl, (R7)(R8)N—, and R7cC(═O)—; R6 is selected from hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl, and R7cC(═O)—; R7 and R8 are independently selected from hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-cycloalkyl, and substituted- or unsubstituted-heterocyclyl; R7a, R8a, and R9 are independently selected from hydrogen, substituted- or unsubstituted-alkyl, and substituted- or unsubstituted-cycloalkyl; R7b is selected from substituted- or unsubstituted-alkyl, and substituted- or unsubstituted-cycloalkyl; R7c is selected from substituted- or unsubstituted-alkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-cycloalkyl, and substituted- or unsubstituted-heterocyclyl; the substituents on ‘alkyl’ and ‘alkenyl’ are selected from the group consisting of oxo, halogen, nitro, cyano, perhaloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, R10bA1-, R10aSO2—, R10aOC(═O)—, R10aC(═O)O—, R10N(H)C(═O)—, R10N(alkyl)C(═O)—, R10aC(═O)N(H)—, R10N(H)—, R10N(alkyl)-, R10N(H)C(=A1)N(H)—, and R10N(alkyl)C(=A1)N(H)—; the substituents on ‘cycloalkyl’ and ‘cycloalkenyl’ are selected from the group consisting of oxo, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, perhaloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, R10bA1-, R10aSO2—, R10aC(═O)—, R10aOC(═O)—, R10aC(═O)O—, R10(H)NC(═O)—, R10N(alkyl)C(═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 substituents on ‘aryl’ are selected from the group consisting of halogen, nitro, cyano, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, perhaloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted- or unsubstituted-heterocycle, alkyl-O—, perhaloalkyl-O—, alkyl(alkyl)N—, alkyl(H)N—, H2N—, alkyl-SO2—, perhaloalkyl-SO2—, alkyl-C(═O)N(alkyl)-, alkyl-C(═O)N(H)—, alkyl(alkyl)NC(═O)—, alkyl(H)NC(═O)—, H2NC(═O)—, alkyl(alkyl)NSO2—, alkyl(H)NSO2—, and H2NSO2—; the substituents on ‘heteroaryl’ are selected from the group consisting of halogen, nitro, cyano, hydroxy, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-alkenyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-cycloalkenyl, substituted- or unsubstituted-heterocycle, alkyl-O—, perhaloalkyl-O—, alkyl(alkyl)N—, alkyl(H)N—, H2N—, alkyl-SO2—, perhaloalkyl-SO2—, alkyl-C(═O)N(alkyl)-, alkyl-C(═O)N(H)—, alkyl(alkyl)NC(═O)—, alkyl(H)NC(═O)—, H2NC(═O)—, alkyl(alkyl)NSO2—, alkyl(H)NSO2—, and H2NSO2—; the substituents on ring carbon of ‘heterocycle’ is selected from the group consisting of halogen, nitro, cyano, oxo, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-alkenyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-cycloalkenyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-heterocyclyl, substituted- or unsubstituted-alkyl, R10bA1-, —R10aOC(═O)—, R10aC(═O)O—, R10(H)NC(O═)—, R10N(alkyl)C(═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 substituents on ring nitrogen of ‘heterocycle’ is selected from the group consisting of substituted- or unsubstituted-alkyl, substituted- or unsubstituted-alkenyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-cycloalkenyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, R10aSO2—, R10aC(═O)—, R10aOC(═O)—, R10(H)NC(═O)—, and R10N(alkyl)C(═O)—; the “5 to 8 membered cyclic system” is substituted with 1 to 3 substituents selected from the group consisting of halogen, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, R10aC(═O)—, R10aSO2—, R10bA1-, 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)—; R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl; R10a is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl; R10b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl; A1 is selected from S and O.