Thiazole Derivatives as Alpha 7 nAChR Modulators

摘要

Disclosed is a compound of formula (I) wherein Y, Ring D, m 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 pharmaceutically acceptable salts, polymorphs, solvates, and isomers thereofs, for use either alone or in combinations with suitable other medicaments, and pharmaceutical compositions containing such compounds. 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 tautomeric form, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, in the compound of formula I, ring D is substituted- or unsubstituted-5 to 12 membered heterocycle optionally containing 1 to 3 additional heteroatom(s)/group(s) selected from —S(O)n—, —NR5—, and —O—; ring D may be substituted on ring carbons with 1 to 6 substituent(s) independently selected from halogen, nitro, cyano, oxo, substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-heterocyclyl, R6bO—, R6N(H)C(═O)—, R6aC(═O)N(H)—, R6N(R7)—, and R6N(H)C(═O)N(H)—; Y is a bond, —CH2—, or —C(═O)—; R1 is selected from substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-cycloalkyl, and substituted- or unsubstituted-heterocyclyl; R2 is independently selected at each occurrence from halogen, nitro, cyano, substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-heterocyclyl, R6bO—, and R6aC(═O)—, or two R2 groups and the carbon atoms to which they are attached together form a 5- to 6-membered cyclic system which optionally contains 1 to 3 heteroatom(s) selected from —N—, —S—, and —O—, said 5 to 6-membered cyclic system may be substituted with 1 to 3 substituent(s) independently selected from oxo, halogen, cyano, and alkyl; R3 and R4 are independently selected from hydrogen, R6aC(═O)—, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl, and substituted- or unsubstituted-heterocyclyl; or R3 and R4 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring system containing one to three heteroatom(s) selected from —S—, —N—, and —O—, said 3- to 10-membered heterocyclic ring system may be substituted with 1 to 3 substituent(s) independently selected from oxo, halogen, alkyl, OR6b, and R6N(H)—; R5 is selected from hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heterocyclyl, R6aC(═O)—, and R6N(R7)C(═O)—; R6 and R7 are each independently selected from hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl, and substituted- or unsubstituted-heterocyclyl; R6a is selected from substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, and substituted- or unsubstituted-heterocyclyl; R6b is selected from hydrogen, substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, and substituted- or unsubstituted-heterocyclyl; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, and 2; when the alkyl group is a substituted alkyl group, the alkyl group is substituted with 1 to 4 substituents selected independently from oxo, halogen, nitro, cyano, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-heterocyclyl, R8bO—, R8aS(O2)—, R8aOC(═O)—, R8aC(═O)O—, R8N(H)C(═O)—, R8N(alkyl)C(═O)—, R8aC(═O)N(H)—, R8N(H)—, R8N(alkyl)-, R8N(H)C(═O)N(H)—, and R8N(alkyl)C(═O)N(H)—; when the cycloalkyl and the carbocyclic groups are substituted, each of them is substituted with 1 to 3 substituents selected independently from oxo, halogen, nitro, cyano, substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-heterocyclyl, R8bO—, R8cS(O2)—, R8cC(═O)—, R8cOC(═O)—, R8cC(═O)O—, R8dN(H)C(═O)—, R8dN(alkyl)C(═O)—, R8cC(═O)N(H)—, R8dN(H)—, R8dN(alkyl)-, R8dN(H)C(═O)N(H)—, and R8dN(alkyl)C(═O)N(H)—; when the aryl group is substituted, it is substituted with 1 to 3 substituents selected independently from halogen, nitro, cyano, hydroxy, substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-heterocycle, (alkyl)O—, (perhaloalkyl)O—, (alkyl)N(alkyl)-, (alkyl)N(H)—, H2N—, (alkyl)S(O2)—, (perhaloalkyl)S(O2)—, (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)S(O2)—, (alkyl)N(H)S(O2)—, and H2NS(O2)—; when the heteroaryl group is substituted, it is substituted with 1 to 3 substituents selected independently from halogen, nitro, cyano, hydroxy, substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-hetero cycle, (alkyl)O—, (perhaloalkyl)O—, (alkyl)N(alkyl)-, (alkyl)N(H)—, H2N—, (alkyl)S(O2)—, (perhaloalkyl)S(O2)—, (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)S(O2)—, (alkyl)N(H)S(O2)—, and H2NS(O2)—; when the heterocyclic group is substituted, it can be substituted either on a ring carbon atom or on a ring hetero atom, and when the heterocyclic group is substituted on a ring carbon atom, it is substituted with 1-3 substituents selected independently from halogen, nitro, cyano, oxo, substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, substituted- or unsubstituted-heterocyclyl, R8bO—, R8cOC(═O)—, R8cC(═O)O—, R8dN(H)C(═O)—, R8dN(alkyl)C(═O)—, R8cC(═O)N(H)—, R8dN(H)—, R8dN(alkyl)-, R8dN(H)C(═O)N(H)—, and R8dN(alkyl)C(═O)N(H)—; when the heterocyclic group is substituted on a ring nitrogen, it is substituted with a substituent selected from substituted- or unsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl, substituted- or unsubstituted-aryl, substituted- or unsubstituted-heteroaryl, R8aS(O2)—, R8aC(═O)—, R8aOC(═O)—, R8N(H)C(═O)—, and R8N(alkyl)C(═O)—; R8 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R8a is selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R8b is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R8c is selected from alkyl, perhaloalkyl, and cycloalkyl; and R8d is selected from hydrogen, alkyl, and cycloalkyl.