Endothelin receptor antagonists

A compound of Formula (I):

• 20
• wherein:
• R1 is —X(CH2)nAr or —X(CH2)nR8 or
• 21
• R2 is hydrogen, Ar, C1-4 alkyl or (c);
• P1 is —X(CH2)nR8;
• P2 is —X(CH2)nR8, or —X—R9—Y;
• R3 and R5 are independently hydrogen, R11, OH, C1-8alkoxy, S(O)qR11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, R13CO2R7, —X—R9—Y, or —X(CH2)nR8 wherein each methylene group within —X(CH2)nR8 may be unsubstituted or substituted by one or two —(CH2)nAr groups;
• R4 is hydrogen, R11, OH, C1-5alkoxy, S(O)qR11, N(R6)2, Br, F, I, Cl or NHCOR6 wherein the C1-5alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
• R6 is independently hydrogen or C1-4alkyl;
• R7 is independently hydrogen, C1-10alkyl, C2-10alkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, CO2R12, halogen or XCl-5alkyl;
• or R7 is (CH2)nAr;
• R8 is hydrogen, R11, CO2R7, CO2C(R11)2 O(CO)XR7, PO3(R7)2, SO2NR7R11, NR7SO2R11, CONR7SO2R11, SO3R7, SO2R7, P(O)(OR7)R7, CN, —CO2(CH2)mC(O)N(R6)2, C(R11)2N(R7)2, C(O)N(R6)2, tetrazole or OR6;
• R9 is a bond, C1-10alkylene, C1-10alkenylene, C1-10alkylidene, C1-10alkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, COOH or halogen;
• R10 is R3 or R4;
• R11 is hydrogen, Ar, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2 or halogen;
• R12 is hydrogen, C1-6alkyl, C2-6alkenyl or C2-7alkynyl;
• R13 is divalent Ar, C1-10alkylene, C1-10alkylidene, C2-10alkenylene, C2-10alkynylene, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2 or halogen;
• X is (CH2)n, O, NR6 or S(O)q;
• Y is CH3 or X(CH2)nAr;
• Ar is:
• 22
• naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl;
• all of which may be unsubstituted or substituted by one or more R3 or R4 groups;
• A is C═O, or (C(R6)2)m;
• B is —CH2—or —O—;
• Z1 and Z2 are independently hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, OH, C1-8alkoxy, S(O)qC1-8alkyl, N(R6)2, Br, F, I, Cl, NHCOR6, —X—R9—Y, —X(CH2)nR8, phenyl, benzyl or C3-6cycloalkyl wherein the C1-8alkyl, C2-8alkenyl or C2-8alkynyl may be optionally substituted by COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2, or halogen;
• or Z1 and Z2 together may be —O—A—O—on contiguous carbons;
• Z3 is Z1 or —X—R9—Y;
• q is zero, one or two;
• n is an integer from 0 to six;
• m is 1, 2 or 3;and the dotted line indicates the optional presence of a double bond;
• or a pharmaceutically acceptable salt thereof;
• provided that
• R2 is not hydrogen when X is S(O)q;
• when the optional double bond is present there is only one R10 and there is no P1 and P2 is not NR6R9Y;
• and if X-R2 is attached to the double bond, X is not NR6;
• and if R1 is attached directly to the double bond, R1 is not NR6Ar;
• when R3, R5, Z1, Z2, or Z3 is X(CH2)nR8 and n is not 0, X is oxygen or NR6 when R8 is OR6 or CO2H;
• when R8 is CO2C(R11)2O(CO)XR7 X is not S(O)q;
• the compound of Formula I is not (1RS)-1,3-diphenylindene-2-carboxylic acid;
• (cis,cis)-(1RS,3SR)-1,3-diphenylindane-2-carboxylic acid;
• (1RS)-3-[3-Methyl-1-phenyl-(1H)-ind-2-en-1-yl]propionic acid;
• or (1RS)-2-[1,3-diphenyl-(1H)-ind-2-en-2-yl]ethanoic acid;
• 1,3-diphenyl-1-ethoxyindene-2-carboxylic acid;
• 1,2,3-triphenylindene;
• 1,3 diphenylindene;
• 1-(2,3-dimethyl-2-buten-yl)-1,3-diphenylindene;
• 1,3-diphenyl-2-methylindene;
• 1,3-diphenyl-2-methylindane;
• 1,3-diphenylindane;
• 5,6-dimethoxy-1,3-dimethoxyindene;
• 1,3-bis(4,5-dimethoxy-2-hydroxyphenyl)-5,6-dimethoxyindane;
• 1,3-bis(3,4-dimethoxyphenyl)-5,6-dimethoxyindane;
• 1,3-diphenyl-2-methoxyidene, 1,3-diphenyl-2-ethoxyindene, 5-fluoro-2-methyl-indene-3-acetic acid, methyl 1,3-diphenylindene-2-carboxylate, ethyl 1,3-diphenylindene-2-carboxylate, or 2-cyano-1,3-diphenylindene.