Imidazolyl derivatives

A compound of formula (II),

• 86
• or a pharmaceutically acceptable salt thereof,
• wherein
• ------- represents an optional bond, provided that only one of the optional bonds is present in a compound of formula (I);
• m, n, p, and q are each independently 0, 1 or 2;
• T1, T2, T3 and T4 for each occurrence are each independently selected from the group consisting of CR26R27, S, O, C(O), S(O)2 and NR28;
• X is N—Y, O or S where Y is selected from the group consisting of H, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32;
• Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(O)OR24, C(S)NR22R23, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32, provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;
• R1, R2, R3, R4, R5, R6, R11, R12, R13, R14, R15, R16, R26 and R27 for each occurrence are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;
• or each pair of R1 and R2, R4 and R5, and R11 and R12 when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of —O—CH2—O—, —O—CH2—CH2—O—, —O—CH═CH—, —O—CH2—CH2—, —O—CH2—CH2—CH2— and —CR33═CR34—CR35═CR36—;
• R7, R8 and R9 are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl, provided that when R7, R8 or R9 is bound to one of the nitrogen atoms of the imidazolyl ring, R7, R8 or R9 is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl;
• R10 is selected from the group consisting of H, amino, azido, hydroxy, halo, alkyl, substituted alkyl, cyano, hydroxycarbonyl, mono- or di-alkylamino, alkyloxy, cycloalkyl, cycloalkylamino, cycloalkyloxy, imidazolyl, substituted imidazolyl, aryloxy, thio, alkylthio, arylthio, OS(O)2R18, OC(O)R19, OC(O)NR20R21, OC(S)NR22R23, OS(O)NR29R30 and OS(O)2NR31R32;
• R17 and R18, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
• R19, R20, R21, R22, R23, R24, R25, R28, R29, R30, R31and R32 for each occurrence are each independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
• or each pair of R20 and R21, R22 and R23, R29 and R30, and R31 and R32 is independently taken together to form a bivalent radical selected from the group consisting of —(CH2)r—NR40—(CH2)s—, —(CH2)r—O—(CH2)s—, —(CR38R39)t— and —(CH2)r—NR40—(C(O))u—, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;
• R33, R34, R35, R36, R38 and R39 for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
• and R40 is H, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)2NR31R32 or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.

A process for synthesizing a compound of formula 3, according to the scheme below, which comprises reacting a compound of formula 1, according to the scheme below, with an arylalkylmagnesium chloride of formula 2, according to the scheme below, in which case X3 is Cl—Mg and p=1-2, or an aryllithium of formula 2, in which case X3 is Li and p=0, in an inert organic solvent, until the reaction is substantially complete,

• 112
• wherein P is a protecting group;
• m, n, p, and q are each independently 0, 1 or 2;
• T1, T2, T3 and T4 for each occurrence are each independently selected from the group consisting of CR26R27, S, O, C(O), S(O)2 and NR28;
• Y is selected from the group consisting of H, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32;
• Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(O)OR24, C(S)NR22R23, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32, provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;
• R1, R2, R3, R4, R5, R6, R11, R12, R13, R14, R15, R16, R26 and R27 for each occurence are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;
• or each pair of R1 and R2, R4 and R5, and R11 and R12 when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of —O—CH2—O—, —O—CH2—CH2—O—, —O—CH═CH—, —O—CH2—CH2—, —O—CH2—CH2—CH2— and —CR33═CR34—CR35═CR36—;
• R7, R8 and R9 are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl, provided that when R7, R8 or R9 is bound to one of the nitrogen atoms of the imidazolyl ring, R7, R8 or R9 is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl;
• R17 and R18, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
• R19, R20, R21, R22, R23, R24, R25, R28, R29, R30, R31and R32 for each occurrence are each independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
• or each pair of R20 and R21, R22 and R23, R29 and R30, and R31 and R32 is independently taken together to form a bivalent radical selected from the group consisting of —(CH2)r—NR40—(CH2)s—, —(CH2)r—O—(CH2)s—, —(CR38R39)t— and —(CH2)r—NR40—(C(O))u—, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;
• R33, R34, R35, R36, R38 and R39 for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
• and R40 is H, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)2NR31R32 or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.

A process for synthesizing a compound of formula 2, according to the scheme below, which comprises reacting a compound of formula 1, according to the scheme below, with a chlorinating reagent until the reaction is substantially complete,

• 113
• wherein
• m, n, p, and q are each independently 0, 1 or 2;
• T1, T2, T3 and T4 for each occurrence are each independently selected from the group consisting of CR26R27, S, O, C(O), S(O)2 and NR28;
• X is N—Y, O or S where Y is selected from the group consisting of H, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32;
• Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(O)OR24, C(S)NR22R23, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32, provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;
• R1, R2, R3, R4, R5, R6, R11, R12, R13, R14, R15, R16, R26 and R27 for each occurrence are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;
• or each pair of R1 and R2, R4 and R5, and R11 and R12 when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of —O—CH2—O—, —O—CH2—CH2—O—, —O—CH═CH—, —O—CH2—O—CH2—, —CH2—CH2—CH2— and —CR33═CR34—CR35═CR36—;
• R7, R8 and R9 are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl, provided that when R7, R8 or R9 is bound to one of the nitrogen atoms of the imidazolyl ring, R7, R8 or R9 is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl;
• R17 and R18, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
• R19, R20, R21, R22, R23, R24, R25, R28, R29, R30, R31and R32 for each occurrence are each independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
• or each pair of R20 and R21, R22 and R23, R29 and R30, and R31 and R32 is independently taken together to form a bivalent radical selected from the group consisting of —(CH2)r—NR40—(CH2)s—, —(CH2)r—O—(CH2)s—, —(CR38R39)t— and —(CH2)r—NR40—(C(O))u—, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;
• R33, R34, R35, R36, R38 and R39 for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
• and R40 is H, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)2NR31R32 or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.

A process for synthesizing a compound of formula 3, according to the scheme below which comprises reacting a compound of formula 2 with anhydrous liquid ammonia or an inert organic solvent saturated with anhydrous ammonia when n, p and q are each 0, or ammonium hydroxide when n, p and q are each not 0, until the reaction is substantially complete

• 114
• wherein m, n, p, and q are each independently 0, 1 or 2;
• T1, T2, T3 and T4 for each occurrence are each independently selected from the group consisting of CR26R27, S, O, C(O), S(O)2 and NR28;
• X is N—Y, O or S where Y is selected from the group consisting of H, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32;
• Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(O)OR24, C(S)NR22R23, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32, provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;
• R1, R2, R3, R4, R5, R6, R11, R12, R13, R14, R15, R16, R26 and R27 for each occurrence are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;
• or each pair of R1 and R2, R4 and R5, and R11 and R12 when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of —O—CH2—O—, —O—CH2—CH2—O—, —O—CH═CH—, —O—CH2—CH2—, —O—CH2—CH2—CH2— and —CR33═CR34—CR35═CR36—;
• R7, R8 and R9 are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl, provided that when R7, R8 or R9 is bound to one of the nitrogen atoms of the imidazolyl ring, R7, R8 or R9 is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl;
• R17 and R18, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
• R19, R20, R21, R22, R23, R24, R25, R28, R29, R30, R31and R32 for each occurrence are each independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
• or each pair of R20 and R21, R22 and R23, R29 and R30, and R31 and R32 is independently taken together to form a bivalent radical selected from the group consisting of —(CH2)r—NR40—(CH2)s—, —(CH2)r—O—(CH2)s—, —(CR38R39)t— and —(CH2)r—NR40—(C(O))u—, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;
• R33, R34, R35, R36, R38 and R39 for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
• and R40 is H, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)2NR31R32 or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.