Benzothiepine ileal bile acid transport inhibitors

A compound of formula (I):

• wherein:
• One of R1 and R2 are selected from hydrogen, C1-6alkyl or C2-6alkenyl and the other is selected from C1-6alkyl or C2-6alkenyl;
• Rx and Ry are independently selected from hydrogen, hydroxy, amino, mercapto, C1-6alkyl, C1-6alkoxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkylS(O)a wherein a is 0 to 2;
• Rz is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6aIkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl and N,N-(C1-6alkyl)2sulphamoyl;
• v is 0–5;
• one of R4 and R5 is a group of formula (IA):
• R3 and R6 and the other of R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanoylamino, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl, C1-4alkylS(O)a wherein a is 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulphamoyl and N,N-(C1-4alkyl)2sulphamoyl;
• wherein R3 and R6 and the other of R4 and R5 may be optionally substituted on carbon by one or more R16;
• X is —O—, —N(Ra)—, —S(O)b—or —CH(Ra)—;
• wherein Ra is hydrogen or C1-6alkyl and b is 0–2;
• Ring A is aryl or heteroaryl;
• wherein Ring A is optionally substituted by one or more substituents selected from R17;
• R7 is hydrogen, C1-4alkyl, carbocyclyl or heterocyclyl;
• wherein R7 is optionally substituted by one or more substituents selected from R18;
• R8 is hydrogen or C1-4alkyl;
• R9 is hydrogen or C1-4alkyl;
• R10 is hydrogen, C1-4alkyl, carbocyclyl or heterocyclyl;
• wherein R10 is optionally substituted by one or more substituents selected from R19;
• R11 is carboxy, sulpho, sulphino, phosphono, —P(O)(ORc)(ORd), —P(O)(OH)(ORc), —P(O)(OH)(Rd) or —P(O)(ORc)(Rd) wherein Rc and Rd are independently selected from C1-6alkyl;
• or R11 is a group of formula (IB):
• wherein:
• Y is —N(Rn)—, —N(Rn)C(O)—, —O—, and —S(O)a-;
• wherein a is 0–2 and Rn is hydrogen or C1-4alkyl;
• R12 is hydrogen or C1-4alkyl;
• R13 and R14 are independently selected from hydrogen, C1-6alkyl, carbocyclyl or heterocyclyl;
• wherein R13 and R14 may be independently optionally substituted by one or more substituents selected from R20;
• R15 is carboxy, sulpho, sulphino, phosphono, —P(O)(ORe)(ORf), —P(O)(OH)(ORe), —P(O)(OH)(Re) or —P(O)(ORe)(Rf) wherein Re and Rf are independently selected from C1-6alkyl;
• or R15 is a group of formula (IC):
• wherein:
• R24 is selected from hydrogen or C1-4alkyl;
• R25 is selected from hydrogen, C1-4alkyl, carbocyclyl, heterocyclyl or R27;
• wherein said C1-4alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R28;
• R26 is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl, —P(O)(ORg)(ORh), —P(O)(OH)(ORg), —P(O)(OH)(Rg) or —P(O)(ORg)(Rh) wherein Rg and Rh are independently selected from C1-6alkyl;
• p is 1–3;
• wherein the values of R13 may be the same or different;
• q is 0–1;
• r is 0–3;
• wherein the values of R14 may be the same or different;
• m is 0–2;
• wherein the values of R10 may be the same or different;
• n is 1–3;
• wherein the values of R7 may be the same or different;
• z is 0–3;
• wherein the values of R25 may be the same or different;
• R16, R17 and R18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4 alkanoyl, C1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanoylamino, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl, C1-4alkylS(O)awherein a is 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulphamoyl and N,N-(C1-4alkyl)2sulphamoyl;
• wherein R16, R17 and R18 may be independently optionally substituted on carbon by one or more R21;
• R19, R20, R27 and R28 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4 alkanoyl, C1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanoylamino, N-(C1-4alkyl)carbamoyl, N,N-(C1-4 alkyl)2carbamoyl, C1-4 alkylS(O)a wherein a is 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulphamoyl, N,N-(C1-4alkyl)2sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, (C1-4alkyl)3silyl, phosphono, —P(O)(ORa)(ORb), —P(O)(OH)(ORa), —P(O)(OH)(Ra) or —P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-6alkyl;
• wherein R19 and R20 may be independently optionally substituted on carbon by one or more R22;
• R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;
• or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.