Bicycloheteroaryl compounds as P2X7 modulators and uses thereof

A bicycloheteroaryl compound capable of modulating P2X7 receptor activity, in vivo, having a formula:

• wherein
• A is selected from CR2aR2b;
• B and Y are independently selected from CR2a and CR2aR2b;
• W, W′ and Z are independently selected from CR4 and N, provided that all three of W, W′ and Z can not be N at the same time;
• L1 is a bond, —CO—, —SO2— or a C1-C5 alkylene group which can be optionally substituted by a substituent selected from alkyl, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halogen, carbamoyl, and C1-C6 alkoxy;
• n is 0, 1, 2 or 3;
• R1 is selected from a 3-13 membered cycloalkyl, heterocycloalkyl, aryl and heteroaryl ring system, which can be optionally substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, sulfanyl, sulfinyl, amido, carboxy, ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and sulfonamido;
• each of R2a, R2b, R2′ and R2″ is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;
• or any of R2′ and R2″ can join together to form a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms;
• R3 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted bicycloaryl, and substituted or unsubstituted bicycloheteroaryl;
• provided when R3 is hydrogen L1 is a bond or a C1-C5 alkylene group;
• R4 is selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio;
• and the dotted bond is a single or a double bond;
• or a pharmaceutically acceptable salt, solvate or prodrug thereof;
• and stereoisomers and tautomers thereof;
• and provided when the compound is of formula II and each of W, Z and W′ is independently CR4 and n is 0, then R1 is selected from substituted cyclohexyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cycloheptyl, and substituted or unsubstituted admantyl.

A compound according to claim 43 wherein the compound is selected from

• 2-(1-adamantyl)-N-(9-benzyl-2,4,9-triazabicyclo[4.4.0]deca-2,4,11-trien-5-yl)acetamide;
• N-(cyclohexylmethyl)-4,7,9-triazabicyclo[4.4.0]deca-7,9,11-triene-10-carboxamide;
• N-phenethyl-4,7,9-triazabicyclo[4.4.0]deca-7,9,11-triene-10-carboxamide;
• 2-(1-adamantyl)-N-[4-[(2,4-dimethoxyphenyl)methyl]-4,7,9-triazabicyclo[4.4.0]deca-7,9,11-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(o-tolylmethyl)-4,7,9-triazabicyclo[4.4.0]deca-7,9,11-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2,5-dioxabicyclo[4.4.0]deca-6,8,10-trien-9-ylmethyl)-4,7,9-triazabicyclo[4.4.0]deca-7,9,11-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-[(2,4-difluorophenyl)methyl]-4,7,9-triazabicyclo[4.4.0]deca-7,9,11-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-[(2-fluoro-4-methoxy-phenyl)methyl]-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-(4-benzylsulfonyl4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl)acetamide;
• 2-(1-adamantyl)-N-[4-[3-(trifluoromethyl)phenyl]sulfonyl4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(5-methyl-1-phenyl-pyrazol4-yl)sulfonyl4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(3-chlorophenyl)sulfonyl4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-[(4-fluorophenyl)methylsulfonyl]-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-[(3,5-dichlorophenyl)methylsulfonyl]-4,7,9-triazabicyclo-4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-[(4-chlorophenyl)methylsulfonyl]-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2,4-difluorophenyl)sulfonyl4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-(4-benzoyl4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl)acetamide;
• 2-(1-adamantyl)-N-[4-(3-methylbenzoyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-[3-(trifluoromethyl)benzoyl]-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(cyclopentanecarbonyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(3-cyanobenzoyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2,6-difluorobenzoyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2,4-dichlorobenzoyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2-cyclopentylacetyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2-chloro-6-fluoro-benzoyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2,5-difluorobenzoyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2,3-dichlorobenzoyl)-4,7,9-triazabicyclo[4.4.0]deca -6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(2,3-dihydrobenzofuran-5-carbonyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(chroman-3-carbonyl)-4,7,9-triazabicyclo[4.4.0]deca-6,8,10-trien-10-yl]acetamide;
• 2-(1-adamantyl)-N-[4-(benzo[1,3]dioxol-5-ylmethyl)-4,7,9-triazabicyclo[4.4.0]deca-7,9,11-trien-10-yl]acetamide;
• and
• 2-(3,5-dimethyl-1-adamantyl)-N-[4-(7,10-dioxabicyclo[4.4.0]deca-1,3,5-trien-4-ylmethyl)-4,7,9-triazabicyclo[4.4.0]deca-7,9,11-trien-10-yl]acetamide.