Methods and therapeutic combinations for the treatment of demyelination

A composition comprising:

• (a) at least one sterol absorption inhibitor or a pharmaceutically acceptable salt or solvate thereof and (b) at least one antidemyelination agent, wherein the at least one sterol absorption inhibitor is selected from the group consisting of sterol absorption inhibitors represented by the following Formulae:
• (a) Formula (III):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (III) above:
• Ar1 is R3-substituted aryl;
• Ar2 is R4-substituted aryl;
• Ar3 is R5-substituted aryl;
• Y and Z are independently selected from the group consisting of —CH2—, —CH(lower alkyl)- and —C(dilower alkyl)-;
• A is selected from —O—, —S—, —S(O)— or —S(O)2—;
• R1 is selected from the group consisting of —OR6, —O(CO)R6, —O(OO)OR9 and —O(CO)NR6R7;
• R2 is selected from the group consisting of hydrogen, lower alkyl and aryl;
• or R1 and R2 together are ═O;
• q is 1, 2 or 3;
• p is 0, 1, 2, 3 or 4;
• R5 is 1-3 substituents independently selected from the group consisting of —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR9, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2-lower alkyl, —NR6SO2-aryl, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2-alkyl, S(O)0-2-aryl, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR6, and —CH═CH—COOR6;
• R3 and R4 are independently 1-3 substituents independently selected from the group consisting of R5, hydrogen, p-lower alkyl, aryl, —NO2, —CF3 and p-halogeno;
• R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
• and
• R9 is lower alkyl, aryl or aryl-substituted lower alkyl;
• (b) Formula (IV):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (IV) above:
• A is selected from the group consisting of R2-substituted heterocycloalkyl, R2-substituted heteroaryl, R2-substituted benzofused heterocycloalkyl, and R2-substituted benzofused heteroaryl;
• Ar1 is aryl or R3-substituted aryl;
• Ar2 is aryl or R4-substituted aryl;
• Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
• and
• R1 is selected from the group consisting of:
• —(CH2)q—, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
• —(CH2)e-G-(CH2)r—, wherein G is —O—, —C(O)—, phenylene, —NR8— or —S(O)0-2—, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
• —(C2-C6 alkenylene)-;
• and
• —(CH2)f—V—(CH2)g—, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
• R5 is selected from:
• R6 and R7 are independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)-, —C(di-(C1-C6) alkyl), —CH═CH— and —C(C1-C6 alkyl)═CH—;
• or R5 together with an adjacent R6, or R5 together with an adjacent R7, form a —CH═CH— or a —CH═C(C1-C6 alkyl)- group;
• a and b are independently 0, 1, 2 or 3, provided both are not zero;
• provided that when R6 is —CH═CH— or —C(C1-C6 alkyl)═CH—, a is 1;
• provided that when R7 is —CH═CH— or —C(C1-C6 alkyl)═CH—, b is 1;
• provided that when a is 2 or 3, the R6's can be the same or different;
• and provided that when b is 2 or 3, the R7's can be the same or different;
• and when Q is a bond, R1 also can be selected from:
• where M is —O—, —S—, —S(O)— or —S(O)2—;
• X, Y and Z are independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)- and —C(di-(C1-C6) alkyl);
• R10 and R12 are independently selected from the group consisting of —OR14, —O(CO)R14, —O(CO)OR16 and —O(CO)NR14R15;
• R11 and R13 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl and aryl;
• or R10 and R11 together are ═O, or R12 and R13 together are ═O;
• d is 1,2 or 3;
• h is 0, 1, 2, 3 or 4;
• s is 0 or 1;
• t is 0 or 1;
• m, n and p are independently 0-4;
• provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
• provided that when p is 0 and t is 1, the sum of m, s and n is 1-5;
• and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
• v is 0 or 1;
• j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
• R2 is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, R17-substituted aryl, R17-substituted benzyl, R17-substituted benzyloxy, R17-substituted aryloxy, halogeno, —NR14R15, NR14R15(C1-C6 alkylene)-, NR14R15C(O)(C1-C6 alkylene)-, —NHC(O)R16, OH, C1-C6 alkoxy, —OC(O)R16, —COR14, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-6)alkyl, NO2, —S(O)0-2R16, —SO2NR14R15 and —(C1-C6 alkylene)COOR14;
• when R2 is a substituent on a heterocycloalkyl ring, R2 is as defined, or is ═O or
• and, where R2 is a substituent on a substitutable ring nitrogen, it is hydrogen, (C1-C6)alkyl, aryl, (C1-C6)alkoxy, aryloxy, (C1-C6)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH2)1-6CONR18R18,
• wherein J is —O—, —NH—, —NR18— or —CH2—;
• R3 and R4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, —OR14, —O(CO)R14, —O(CO)OR16, —O(CH2)1-5OR14, —O(CO)NR14R15, —NR14R15, —NR14(CO)R15, —NR14(CO)OR16, —NR14(CO)NR15R19, —NR14SO2R16, —COOR14, —CONR14R15, —COR14, —SO2NR14R15, S(O)0-2R16, —O(CH2)1-10—COOR14, —O(CH2)1-10CONR14R15, —(C1-C6 alkylene)-COOR14, —CH═CH—COOR14, —CF3, —CN, —NO2 and halogen;
• R8 is hydrogen, (C1-C6)alkyl, aryl (C1-C6)alkyl, —C(O)R14 or —COOR14;
• R9 and R17 are independently 1-3 groups independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, —COOH, NO2, —NR14R15, OH and halogeno;
• R14 and R15 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
• R16 is (C1-C6)alkyl, aryl or R17-substituted aryl;
• R18 is hydrogen or (C1-C6)alkyl;
• and
• R19 is hydrogen, hydroxy or (C1-C6)alkoxy;
• (c) Formula (V):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (V) above:
• Ar1 is aryl, R10-substituted aryl or heteroaryl;
• Ar2 is aryl or R4-substituted aryl;
• Ar3 is aryl or R5-substituted aryl;
• X and Y are independently selected from the group consisting of —CH2—, —CH(lower alkyl)- and —C(dilower alkyl)-;
• R is —OR6, —O(CO)R6, —O(CO)OR9 or —O(CO)NR6R7;
• R1 is hydrogen, lower alkyl or aryl;
• or R and R1 together are ═O;
• q is 0 or 1;
• r is 0, 1 or 2;
• m and n are independently 0, 1, 2, 3, 4 or 5;
• provided that the sum of m, n and q is 1, 2, 3, 4 or 5;
• R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and —CH═CH—COOR6;
• R5 is 1-5 substituents independently selected from the group consisting of —OR5, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, —CF3, —CN, —NO2, halogen, -(lower alkylene)COOR6 and —CH═CH—COOR6;
• R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
• R9 is lower alkyl, aryl or aryl-substituted lower alkyl;
• and
• R10 is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R6, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, —S(O)0-2R9, —O(CH2)1-10—COOR6,
• —O(CH2)1-10CONR6R7, —CF3, —CN, —NO2 and halogen;
• (d) Formula (VI):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein:
• R1 is
• R2 and R3 are independently selected from the group consisting of:
• —CH2—, —CH(lower alkyl)-, —C(di-lower alkyl)-, —CH═CH— and —C(lower alkyl)═CH—;
• or R1 together with an adjacent R2, or R1 together with an adjacent R3, form a —CH═CH— or a —CH═C(lower alkyl)- group;
• u and v are independently 0, 1, 2 or 3, provided both are not zero;
• provided that when R2 is —CH═CH— or —C(lower alkyl)═CH—, v is 1;
• provided that when R3 is —CH═CH— or —C(lower alkyl)═CH—, u is 1;
• provided that when v is 2 or 3, the R2's can be the same or different;
• and provided that when u is 2 or 3, the R3's can be the same or different;
• R4 is selected from B—(CH2)mC(O)—, wherein m is 0, 1, 2, 3, 4 or 5;
• B—(CH2)q—, wherein q is 0, 1, 2, 3, 4, 5 or 6;
• B—(CH2)e-Z-(CH2)r—, wherein Z is —O—, —C(O)—, phenylene, —N(R8)— or —S(O)0-2—, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6;
• B—(C2-C6 alkenylene)-;
• B—(C4-C6 alkadienylene)-;
• B—(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
• B—(CH2)f—V—(CH2)g—, wherein V is C3-C6 cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;
• B—(CH2)t—V—(C2-C6 alkenylene)- or
• B—(C2-C6 alkenylene)-V—(CH2)t—, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
• B—(CH2)a-Z-(CH2)b—V—(CH2)d—, wherein Z and V are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6;
• or T-(CH2)s—, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6;
• or
• R1 and R4 together form the group
• B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or
• W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, —CF3, —OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2,—N(R8)(R9), N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, OH, halogeno, —CN, —N3, —NHC(O)OR10, —NHC(O)R10, R11O2SNH—, (R11O2S)2N—, —S(O)2NH2, —S(O)0-2R8, tert-butyldimethyl-silyloxymethyl, —C(O)R12, —COOR19, —CON(R8)(R9), —CH═CHC(O)R12, -lower alkylene-C(O)R12, R10C(O)(lower alkylenyloxy)-, N(R8)(R9)C(O)(lower alkylenyloxy)- and
• for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, —C(O)OR10, —C(O)R10, OH, N(R8)(R9)-lower alkylene-,N(R8)(R9)-lower alkylenyloxy-, —S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;
• R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, —COOH, NO2, —N(R8)(R9), OH, and halogeno;
• R8 and R9 are independently selected from H or lower alkyl;
• R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;
• R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl;
• R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,
• —N(R8)(R9), lower alkyl, phenyl or R7-phenyl;
• R13 is selected from —O—, —CH2—, —NH—, —N(lower alkyl)- or —NC(O)R19;
• R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W;
• or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;
• R19 is H, lower alkyl, phenyl or phenyl lower alkyl;
• and
• R20 and R21 are independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above;
• (e) Formula (VIIA) or (VIIB):
• or a pharmaceutically acceptable salt or solvate thereof,
• wherein:
• A is —CH═CH—, —C≡C— or —(CH2)p— wherein p is 0, 1 or 2;
• B is
• B′ is
• D is —(CH2)mC(O)— or —(CH2)q— wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4;
• E is C10 to C20 alkyl or —C(O)—(C9 to C19)-alkyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;
• R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing one or more double bonds, or B—(CH2)r—, wherein r is 0, 1, 2, or 3;
• R1, R2, R3, R1′, R2′, and R3′are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino, dilower alkylamino, —NHC(O)OR5, R6O2SNH— and —S(O)2NH2;
• R4 is
• wherein n is 0, 1, 2 or 3;
• R5 is lower alkyl;
• and
• R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino and dilower alkylamino;
• or a pharmaceutically acceptable salt thereof or a prodrug thereof;
• (f) Formula (VIII):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (VIII) above,
• R26 is H or OG1;
• G and G1 are independently selected from the group consisting of H,
• provided that when R26 is H or OH, G is not H;
• R, Ra and Rb are independently selected from the group consisting of H, —OH, halogeno, —NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy or —W—R30;
• W is independently selected from the group consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R31)—, —NH—C(O)—N(R31)— and —O—C(S)—N(R31)—;
• R2 and R6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
• R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, —C(O)(C1-C6)alkyl and —C(O)aryl;
• R30 is selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
• R31 is selected from the group consisting of H and (C1-C4)alkyl;
• T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
• R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C1-C4)alkyl, —OH, phenoxy, —CF3, —NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —N(CH3)2, —C(O)—NH(C1-C4)alkyl, —C(O)—N((C1-C4)alkyl)2, —C(O)—(C1-C4)alkyl, —C(O)—(C1-C4)alkoxy and pyrrolidinylcarbonyl;
• or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
• Ar1 is aryl or R10-substituted aryl;
• Ar2 is aryl or R11-substituted aryl;
• Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
• and
• R1 is selected from the group consisting of
• —(CH2)q—, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
• —(CH2)e-E-(CH2)r—, wherein E is —O—, —C(O)—, phenylene, —NR22— or —S(O)0-2—, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
• —(C2-C6)alkenylene-;
• and
• —(CH2)f—V—(CH2)g—, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
• R12 is
• R13 and R14 are independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)-, —C(di-(C1-C6) alkyl), —CH═CH— and —C(C1-C6 alkyl)=CH—;
• or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a —CH═CH— or a —CH═C(C1-C6 alkyl)- group;
• a and b are independently 0, 1, 2 or 3, provided both are not zero;
• provided that when R13 is —CH═CH— or —C(C1-C6 alkyl)═CH—, a is 1;
• provided that when R14 is —CH═CH— or —C(C1-C6 alkyl)═CH—, b is 1;
• provided that when a is 2 or 3, the R13's can be the same or different;
• and
• provided that when b is 2 or 3, the R14's can be the same or different;
• and when Q is a bond, R1 also can be:
• M is —O—, —S—, —S(O)— or —S(O)2—;
• X, Y and Z are independently selected from the group consisting of —CH2—, —CH(C1-C6)alkyl- and —C(di-(C1-C6)alkyl);
• R10 and R11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Cl -C6)alkyl, —OR19, —O(CO)R19, —O(CO)OR21, —O(CH2)1-5OR19, —O(CO)NR19R20, —NR19R20, —NR19(CO)R20, —NR19(CO)OR21, —NR19(CO)NR20R25, —NR19SO2R21, —COOR19, —CONR19R20, —COR19, —SO2NR19R20, S(O)0-2R21, —O(CH2)1-10—COOR19, —O(CH2)1-10CONR19R20, —(C1-C6 alkylene)-COOR19, —CH═CH—COOR19, —CF3, —CN, —NO2 and halogen;
• R15 and R17 are independently selected from the group consisting of —OR19, —O(CO)R19, —O(CO)OR21 and —O(CO)NR19R20;
• R16 and R18 are independently selected from the group consisting of H, (C1-C6)alkyl and aryl;
• or R15 and R16 together are ═O, or R17 and R18 together are ═O;
• d is 1, 2 or 3;
• h is 0, 1, 2, 3 or 4;
• s is 0 or 1;
• t is 0 or 1;
• m, n and p are independently 0-4;
• provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
• provided that when p is 0 and t is 1, the sum of m, s and n is 1-5;
• and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
• v is 0 or 1;
• j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
• and when Q is a bond and R1 is
• Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
• R19 and R20 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
• R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
• R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, —C(O)R19 or —COOR19;
• R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, —COOH, NO2, —NR19R20, —OH and halogeno;
• and
• R25 is H, —OH or (C1-C6)alkoxy;
• and
• (g) Formula (IX):
• or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula (IX):
• R1 is selected from the group consisting of H, G, G1, G2, —SO3H and —PO3H;
• G is selected from the group consisting of:
• H,
• wherein R, Ra and Rb are each independently selected from the group consisting of H, —OH, halo, —NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy or —W—R30;
• W is independently selected from the group consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R31)—, —NH—C(O)—N(R31)— and —O—C(S)—N(R31)—;
• R2 and R6 are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl and aryl(C1-C6)alkyl;
• R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl(C1-C6)alkyl, —C(O)(C1-C6)alkyl and —C(O)aryl;
• R30 is independently selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
• R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
• T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
• R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C1-C4)alkyl, —OH, phenoxy, —CF3, —NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —N(CH3)2, —C(O)—NH(C1-C4)alkyl, —C(O)—N((C1-C4)alkyl)2, —C(O)—(C1-C4)alkyl, —C(O)—(C1-C4)alkoxy and pyrrolidinylcarbonyl;
• or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
• G1 is represented by the structure:
• wherein R33 is independently selected from the group consisting of unsubstituted alkyl, R34-substituted alkyl, (R35)(R36)alkyl-,
• R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC—, HO—, HS—, (CH3)S—, H2N—, (NH2)(NH)C(NH)—, (NH2)C(O)— and HOOCCH(NH3+)CH2SS—;
• R35 is independently selected from the group consisting of H and NH2—;
• R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl and R34-substituted cycloalkyl;
• G2 is represented by the structure:
• wherein R37 and R38 are each independently selected from the group consisting of (C1-C6)alkyl and aryl;
• R26 is one to five substituents, each R26 being independently selected from the group consisting of:
• a) H;
• b) —OH;
• c) —OCH3;
• d) fluorine;
• e) chlorine;
• f) —O-G;
• g) —O-G1;
• h) —O-G2;
• i) —SO3H;
• and
• j) —PO3H;
• provided that when R1 is H, R26 is not H, —OH, —OCH3 or —O-G;
• Ar1 is aryl, R10-substituted aryl, heteroaryl or R10-substituted heteroaryl;
• Ar2 is aryl, R11-substituted aryl, heteroaryl or R11-substituted heteroaryl;
• L is selected from the group consisting of:
• a) a covalent bond;
• b) —(CH2)q—, wherein q is 1-6;
• c) —(CH2)e-E-(CH2)r—, wherein E is —O—, —C(O)—, phenylene, —NR22— or —S(O)0-2—, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
• d) —(C2-C6)alkenylene-;
• e) —(CH2)f—V—(CH2)g—, wherein V is C3-C6cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
• and
• f)
• wherein M is —O—, —S—, —S(O)— or —S(O)2—;
• X, Y and Z are each independently selected from the group consisting of —CH2—, —CH(C1-C6)alkyl- and —C(di-(C1-C6)alkyl)-;
• R8 is selected from the group consisting of H and alkyl;
• R10 and R11 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of (C1-C6)alkyl, —OR19, —O(CO)R19, —O(CO)OR21, —O(CH2)1-5OR19, —O(CO)NR19R20, —NR19R20, —NR19(CO)R20, —NR19(CO)OR21, —NR19(CO)NR20R25, —NR19SO2R21, —COOR19, —CONR19R20, —COR19, —SO2NR19R20, S(O)0-2R21, —O(CH2)1-10—COOR19, —O(CH2)1-10CONR19R20, —(C1-C6 alkylene)-COOR19, —CH═CH—COOR19, —CF3, —CN, —NO2 and halo;
• R15 and R17 are each independently selected from the group consisting of —OR19, —OC(O)R19, —OC(O)OR21, —OC(O)NR19R20;
• R16 and R18are each independently selected from the group consisting of H, (C1-C6)alkyl and aryl;
• or R15 and R16 together are ═O, or R17and R18 together are ═O;
• d is 1, 2 or 3;
• h is 0, 1, 2, 3 or 4;
• s is 0 or 1;
• t is 1 or 1;
• m, n and p are each independently selected from 0-4;
• provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
• provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;
• and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
• v is 0 or 1;
• j and k are each independently 1-5, provided that the sum of j, k and v is 1-5;
• Q is a bond, —(CH2)q—, wherein q is 1-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group
• wherein R12 is
• R13 and R14 are each independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)-, —C(di-(C1-C6) alkyl), —CH═CH— and —C(C1-C6 alkyl)=CH—;
• or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a —CH═CH— or a —CH═C(C1-C6 alkyl)- group;
• a and b are each independently 0, 1, 2 or 3, provided both are not zero;
• provided that when R13 is —CH═CH— or —C(C1-C6 alkyl)═CH—, a is 1;
• provided that when R14 is —CH═CH— or —C(C1-C6 alkyl)═CH—, b is 1;
• provided that when a is 2 or 3, the R13's can be the same or different;
• and provided that when b is 2 or 3, the R14's can be the same or different;
• and when Q is a bond and L is
• then Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
• R19 and R20 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
• R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
• R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, —C(O)R19 or —COOR19;
• R23 and R24 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, —COOH, NO2, —NR19R20, —OH and halo;
• and
• R25 is H, —OH or (C1-C6)alkoxy.

A therapeutic combination comprising:

• (a) a first amount of at least one sterol absorption inhibitor or a pharmaceutically acceptable salt or solvate thereof;
• and (b) a second amount of at least one antidemyelination agent, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment of demyelination in a subject and wherein the at least one sterol absorption inhibitor is selected from the group consisting of sterol absorption inhibitors represented by the following Formulae:
• (a) Formula (III):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (III) above:
• Ar1 is R3-substituted aryl;
• Ar2 is R4-substituted aryl;
• Ar3 is R5-substituted aryl;
• Y and Z are independently selected from the group consisting of —CH2—, —CH(lower alkyl)- and —C(dilower alkyl)-;
• A is selected from —O—, —S—, —S(O)— or —S(O)2—;
• R is selected from the group consisting of —OR6, —O(CO)R6, —O(CO)OR9 and —O(CO)NR6R7;
• R2 is selected from the group consisting of hydrogen, lower alkyl and aryl;
• or R1 and R2 together are ═O;
• q is 1, 2 or 3;
• p is 0, 1, 2, 3 or 4;
• R5 is 1-3 substituents independently selected from the group consisting of —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR9, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2-lower alkyl, —NR6SO2-aryl, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2-alkyl, S(O)0-2-aryl, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR6, and —CH═CH—COOR6;
• R3 and R4 are independently 1-3 substituents independently selected from the group consisting of R5, hydrogen, p-lower alkyl, aryl, —NO2, —CF3 and p-halogeno;
• R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
• and
• R9 is lower alkyl, aryl or aryl-substituted lower alkyl;
• (b) Formula (IV):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (IV) above:
• A is selected from the group consisting of R2-substituted heterocycloalkyl, R2-substituted heteroaryl, R2-substituted benzofused heterocycloalkyl, and R2-substituted benzofused heteroaryl;
• Ar1 is aryl or R3-substituted aryl;
• Ar2 is aryl or R2-substituted aryl;
• Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
• and
• R1 is selected from the group consisting of:
• —(CH2)q—, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
• —(CH2)e-G-(CH2)r—, wherein G is —O—, —C(O)—, phenylene, —NR8— or —S(O)0-2, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
• —(C2-C6 alkenylene)-;
• and
• —(CH2)f—V—(CH2)g—, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
• R5 is selected from:
• R6 and R7 are independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)-, —C(di-(C1-C6) alkyl), —CH═CH— and —C(C1-C6 alkyl)═CH—;
• or R5 together with an adjacent R6, or R5 together with an adjacent R7, form a —CH═CH— or a —CH═C(C1-C6 alkyl)- group;
• a and b are independently 0, 1, 2 or 3, provided both are not zero;
• provided that when R6 is —CH═CH— or —C(C1-C6 alkyl)═CH—, a is 1;
• provided that when R7 is —CH═CH— or —C(C1-C6 alkyl)═CH—, b is 1;
• provided that when a is 2 or 3, the R6's can be the same or different;
• and provided that when b is 2 or 3, the R6's can be the same or different;
• and when Q is a bond, R1 also can be selected from:
• where M is —O—, —S—, —S(O)— or —S(O)2—;
• X, Y and Z are independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)- and —C(di-(C1-C6) alkyl);
• R10 and R12 are independently selected from the group consisting of —OR14, —O(CO)R14, —O(CO)OR16 and —O(CO)NR14R15;
• R11 and R13 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl and aryl;
• or R10 and R11 together are ═O, or R12 and R13 together are ═O;
• d is 1, 2 or 3;
• h is 0, 1, 2, 3 or 4;
• s is 0 or 1;
• t is 0 or 1;
• m, n and p are independently 0-4;
• provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
• provided that when p is 0 and t is 1, the sum of m, s and n is 1-5;
• and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
• v is 0 or 1;
• j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
• R2 is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, R17-substituted aryl, R17-substituted benzyl, R17-substituted benzyloxy, R17-substituted aryloxy, halogeno, —NR14R15, NR14R15(C1-C6 alkylene)-,—NR14R15C(O)(C1-C6alkylene)-,—NHC(O)R16, OH, C1-C6 alkoxy, —OC(O)R16, —COR14, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, NO2, —S(O)0-2R16, —SO2NR14R15 and —(C1-C6 alkylene)COOR14;
• when R2 is a substituent on a heterocycloalkyl ring, R2 is as defined, or is ═O or
• and, where R2 is a substituent on a substitutable ring nitrogen, it is hydrogen, (C1-C6)alkyl, aryl, (C1-C6)alkoxy, aryloxy, (C1-C6)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH2)1-6CONR18R18,
• wherein J is —O—, —NH—, —NR18— or —CH2—;
• R3 and R4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, —OR14, —O(CO)R14, —O(CO)OR16, —O(CH2)1-5OR14, —O(CO)NR14R15,—NR14R15, —NR14(CO)R15, —NR14(CO)OR16, —NR14(CO)NR15R19, —NR14SO2R16, —COOR14, —CONR14R15, —COR14, SO2NR14R15, S(O)0-2R16, —O(CH2)1-10—COOR14, —O(CH2)1-10CONR14R15, —(C1-C6 alkylene)-COOR14, —CH═CH—COOR14, —CF3, —CN, —NO2 and halogen;
• R8 is hydrogen, (C1-C6)alkyl, aryl (C1-C6)alkyl, —C(O)R14 or —COOR14;
• R9 and R17 are independently 1-3 groups independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, —COOH, NO2, —NR14R15, OH and halogeno;
• R14 and R15 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
• R16 is (C1-C6)alkyl, aryl or R17-substituted aryl;
• R18 is hydrogen or (C1-C6)alkyl;
• and
• R19 is hydrogen, hydroxy or (C1-C6)alkoxy;
• (c) Formula (V):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (V) above:
• Ar1 is aryl, R10-substituted aryl or heteroaryl;
• Ar2 is aryl or R4-substituted aryl;
• Ar3 is aryl or R5-substituted aryl;
• X and Y are independently selected from the group consisting of —CH2—, —CH(lower alkyl)- and —C(dilower alkyl)-;
• R is —OR6, —O(CO)R6, —O(CO)OR6, or —O(CO)NR6R7;
• R1 is hydrogen, lower alkyl or aryl;
• or R and R1 together are ═O;
• q is 0 or 1;
• r is 0, 1 or 2;
• m and n are independently 0, 1, 2, 3, 4 or 5;
• provided that the sum of m, n and q is 1, 2, 3, 4 or 5;
• R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7,S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and —CH═CH—COOR6;
• R5 is 1-5 substituents independently selected from the group consisting of —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, S(O)0-2R9, —O(CH2)1-10—COOR6, —O(CH2)1-10CONR6R7, —CF3, —CN, —NO2, halogen, -(lower alkylene)COOR6 and —CH═CH—COOR6;
• R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
• R9 is lower alkyl, aryl or aryl-substituted lower alkyl;
• and
• R10 is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR6, —O(CO)R6, —O(CO)OR9, —O(CH2)1-5OR6, —O(CO)NR6R7, —NR6R7, —NR6(CO)R7, —NR6(CO)OR9, —NR6(CO)NR7R8, —NR6SO2R9, —COOR6, —CONR6R7, —COR6, —SO2NR6R7, —S(O)0-2R9, —O(CH2)1-10—COOR6,
• —O(CH2)1-10CONR6R7, —CF3, —CN, —NO2 and halogen;
• (d) Formula (VI):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein:
• R1 is
• R2 and R3 are independently selected from the group consisting of:
• —CH2—, —CH(lower alkyl)-, —C(di-lower alkyl)-, —CH═CH— and —C(lower alkyl)=CH—;
• or R1 together with an adjacent R2, or R1 together with an adjacent R3, form a —CH═CH— or a —CH═C(lower alkyl)- group;
• u and v are independently 0, 1, 2 or 3, provided both are not zero;
• provided that when R2 is —CH═CH— or —C(lower alkyl)═CH—, v is 1;
• provided that when R3 is —CH—CH— or —C(lower alkyl)═CH—, u is 1;
• provided that when v is 2 or 3, the R2's can be the same or different;
• and provided that when u is 2 or 3, the R3's can be the same or different;
• R4 is selected from B—(CH2)mC(O)—, wherein m is 0, 1, 2, 3, 4 or 5;
• B—(CH2)q—, wherein q is 0, 1, 2, 3, 4, 5 or 6;
• B—(CH2)e-Z-(CH2)r—, wherein Z is —O—, —C(O)—, phenylene, —N(R8)— or —S(O)0-2—, e is 0, 1, 2, 3, 4 or 5and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6;
• B—(C2-C6 alkenylene)-;
• B—(C4-C6 alkadienylene)-;
• B—(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
• B—(CH2)f—V—(CH2)g—, wherein V is C3-C6 cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;
• B—(CH2)t—V—(C2-C6 alkenylene)- or
• B—(C2-C6 alkenylene)-V—(CH2)t—, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
• B—(CH2)a-Z-(CH2)b—V—(CH2)d—, wherein Z and V are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6;
• or T-(CH2)s—, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6;
• or
• R1 and R4 together form the group
• B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or
• W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, —CF3, —OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2,—N(R8)(R9), N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, OH, halogeno, —CN, —N3, —NHC(O)OR10, —NHC(O)R10, R11O2SNH—, (R11O2S)2N—, —S(O)2NH2, —S(O)0-2R8,tert-butyldimethyl-silyloxymethyl, —C(O)R12, —COOR19, —CON(R8)(R9), —CH═CHC(O)R12, -lower alkylene-C(O)R12, R10C(O)(lower alkylenyloxy)-, N(R8)(R9)C(O)(lower alkylenyloxy)- and
• for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, —C(O)OR10, —C(O)R10, OH, N(R8)(R9)-lower alkylene-,N(R8)(R9)-lower alkylenyloxy-, —S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;
• R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, —COOH, NO2, —N(R8)(R9), OH, and halogeno;
• R8 and R9 are independently selected from H or lower alkyl;
• R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;
• R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl;
• R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,
• —N(R8)(R9), lower alkyl, phenyl or R7-phenyl;
• R13 is selected from —O—, —CH2—, —NH—, —N(lower alkyl)- or —NC(O)R19;
• R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W;
• or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;
• R19 is H, lower alkyl, phenyl or phenyl lower alkyl;
• and
• R20 and R21 are independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above;
• (e) Formula (VIIA) or (VIIB):
• or a pharmaceutically acceptable salt or solvate thereof,
• wherein:
• A is —CH═CH—, —C≡C— or —(CH2)p— wherein p is 0, 1 or 2;
• B is
• B′ is
• D is —(CH2)mC(O)— or —(CH2)q— wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4;
• E is C10 to C20 alkyl or —C(O)—(C9 to C19)-alkyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;
• R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing one or more double bonds, or B—(CH2)r—, wherein r is 0, 1, 2, or 3;
• R1, R2, R3, R1′, R2′, and R3′ are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino, dilower alkylamino, —NHC(O)OR5, R6O2SNH— and —S(O)2NH2;
• R4 is
• wherein n is 0, 1, 2 or 3;
• R5 is lower alkyl;
• and
• R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino and dilower alkylamino;
• or a pharmaceutically acceptable salt thereof or a prodrug thereof;
• (f) Formula (VIII):
• or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (VIII) above,
• R26 is H or OG1;
• G and G1 are independently selected from the group consisting of H,
• and
• provided that when R26 is H or OH, G is not H;
• R, Ra and Rb are independently selected from the group consisting of H, —OH, halogeno, —NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy or —W—R30;
• W is independently selected from the group consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R31)—, —NH—C(O)—N(R31)— and —O—C(S)—N(R31)—;
• R2 and R6 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl(C1-C6)alkyl;
• R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, —C(O)(C1-C6)alkyl and —C(O)aryl;
• R30 is selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
• R31 is selected from the group consisting of H and (C1-C4)alkyl;
• T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
• R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C1-C4)alkyl, —OH, phenoxy, —CF3, —NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —N(CH3)2, —C(O)—NH(C1-C4)alkyl, —C(O)—N((C1-C4)alkyl)2, —C(O)—(C1-C4)alkyl, —C(O)—(C1-C4)alkoxy and pyrrolidinylcarbonyl;
• or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
• Ar1 is aryl or R10-substituted aryl;
• Ar2 is aryl or R11-substituted aryl;
• Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the spiro group
• and
• R1 is selected from the group consisting of
• —(CH2)q—, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1;
• —(CH2)e-E-(CH2)r—, wherein E is —O—, —C(O)—, phenylene, —NR22— or —S(O)0-2—, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
• —(C2-C6)alkenylene-;
• and
• —(CH2)f—V—(CH2)g—, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
• R12 is
• R13 and R14 are independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)-, —C(di-(C1-C6) alkyl), —CH═CH— and —C(C1-C6 alkyl)=CH—;
• or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a —CH═CH— or a —CH═C(C1-C6 alkyl)- group;
• a and b are independently 0, 1, 2 or 3, provided both are not zero;
• provided that when R13 is —CH═CH— or —C(C1-C6 alkyl)═CH—, a is 1;
• provided that when R14 is —CH═CH— or —C(C1-C6 alkyl)═CH—, b is 1;
• provided that when a is 2 or 3, the R13's can be the same or different;
• and
• provided that when b is 2 or 3, the R14's can be the same or different;
• and when Q is a bond, R1 also can be:
• M is —O—, —S—, —S(O)— or —S(O)2—;
• X, Y and Z are independently selected from the group consisting of —CH2—, —CH(C1-C6)alkyl- and —C(di-(C1-C6)alkyl);
• R10 and R11 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, —OR19, —O(CO)R19, —O(CO)OR21, —O(CH2)1-5OR19, —O(CO)NR19R20, —NR19R20, —NR19(CO)R20, —NR19(CO)OR21, —NR19(CO)NR20R25, —NR19SO2R21, —COOR19, —CONR19R20, —COR19, —SO2NR19R20, S(O)0-2R21, —O(CH2)1-10—COOR19,—O(CH2)1-10CONR19R20, —(C1-C6 alkylene)-COOR19, —CH═CH—COOR19, —CF3, —CN, —NO2 and halogen;
• R15 and R17 are independently selected from the group consisting of —OR19, —O(CO)R19, —O(CO)OR21 and —O(CO)NR19R20;
• R16 and R18 are independently selected from the group consisting of H, (C1-C6)alkyl and aryl;
• or R15 and R16 together are ═O, or R17 and R18 together are ═O;
• d is 1,2 or 3;
• h is 0, 1, 2, 3 or 4;
• s is 0 or 1;
• t is 0 or 1;
• m, n and p are independently 0-4;
• provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
• provided that when p is 0 and t is 1, the sum of m, s and n is 1-5;
• and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
• v is 0 or 1;
• j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
• and when Q is a bond and R1 is
• Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
• R19 and R20 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
• R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
• R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, —C(O)R19 or —COOR19;
• R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, —COOH, NO2, —NR19R20, —OH and halogeno;
• and
• R25 is H, —OH or (C1-C6)alkoxy;
• and
• (g) Formula (IX):
• or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula (IX):
• R1 is selected from the group consisting of H, G, G1, G2, —SO3H and —PO3H;
• G is selected from the group consisting of:
• H,
• wherein R, Ra and Rb are each independently selected from the group consisting of H, —OH, halo, —NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy or —W—R30;
• W is independently selected from the group consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R31)—, —NH—C(O)—N(R31)— and —O—C(S)—N(R31)—;
• R2 and R6 are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl and aryl(C1-C6)alkyl;
• R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl(C1-C6)alkyl, —C(O)(C1-C6)alkyl and —C(O)aryl;
• R30 is independently selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
• R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
• T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
• R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C1-C4)alkyl, —OH, phenoxy, —CF3, —NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —N(CH3)2, —C(O)—NH(C1-C4)alkyl, —C(O)—N((C1-C4)alkyl)2, —C(O)—(C1-C4)alkyl, —C(O)—(C1-C4)alkoxy and pyrrolidinylcarbonyl;
• or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
• G1 is represented by the structure:
• wherein R33 is independently selected from the group consisting of unsubstituted alkyl, R34-substituted alkyl, (R35)(R36)alkyl-,
• R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC—, HO—, HS—, (CH3)S—, H2N—, (NH2)(NH)C(NH)—, (NH2)C(O)— and HOOCCH(NH3+)CH2SS—;
• R35 is independently selected from the group consisting of H and NH2—;
• R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl and R34-substituted cycloalkyl;
• G2 is represented by the structure:
• wherein R37 and R38 are each independently selected from the group consisting of (C1-C6)alkyl and aryl;
• R26 is one to five substituents, each R26 being independently selected from the group consisting of:
• a) H;
• b) —OH;
• c) —OCH3;
• d) fluorine;
• e) chlorine;
• f) —O-G;
• g) —O-G1;
• h) —O-G2;
• i) —SO3H;
• and
• j) —PO3H;
• provided that when R1 is H, R26 is not H, —OH, —OCH3 or —O-G;
• Ar1 is aryl, R10-substituted aryl, heteroaryl or R10-substituted heteroaryl;
• Ar2 is aryl, R11-substituted aryl, heteroaryl or R11-substituted heteroaryl;
• L is selected from the group consisting of:
• a) a covalent bond;
• b) —(CH2)q—, wherein q is 1-6;
• c) —(CH2)e-E-(CH2)r—, wherein E is —O—, —C(O)—, phenylene, —NR22— or —S(O)0-2—, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
• d) —(C2-C6)alkenylene-;
• e) —(CH2)f—V—(CH2)g—, wherein V is C3-C6cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
• and
• f)
• wherein M is —O—, —S—, —S(O)— or —S(O)2—;
• X, Y and Z are each independently selected from the group consisting of —CH2—, —CH (C1-C6)alkyl- and —C(di-(C1-C6)alkyl )-;
• R8 is selected from the group consisting of H and alkyl;
• R10 and R11 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of (C1-C6)alkyl, —OR19, —O(CO)R19, —O(CO)OR21, —O(CH2)1-5OR19, —O(CO)NR19R20, —NR19R20, —NR19(CO)R20, —NR19(CO)OR21, —NR19(CO)NR20R25, —NR19SO2R21, —COOR19, —CONR19R20, —COR19, —SO2NR19R20, S(O)0-2R21, —O(CH2)1-10—COOR19, —O(CH2)1-10CONR19R20, —(C1-C6 alkylene)-COOR19, —CH═CH—COOR19, —CF3, —CN, —NO2 and halo;
• R15 and R17 are each independently selected from the group consisting of —OR19, —OC(O)R19, —OC(O)OR21, —OC(O)NR19R20;
• R16 and R18 are each independently selected from the group consisting of H, (C1-C6)alkyl and aryl;
• or R15 and R16 together are ═O, or R17and R18 together are ═O;
• d is 1, 2 or 3;
• h is 0, 1, 2, 3 or 4;
• s is 0 or 1;
• t is 1 or 1;
• m, n and p are each independently selected from 0-4;
• provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
• provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;
• and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
• v is 0 or 1;
• j and k are each independently 1-5, provided that the sum of j, k and v is 1-5;
• Q is a bond, —(CH2)q—, wherein q is 1-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group
• wherein R12 is
• R13 and R14 are each independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)-, —C(di-(C1-C6) alkyl), —CH═CH— and —C(C1-C6 alkyl)═CH—;
• or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a —CH═CH— or a —CH═C(C1-C6 alkyl)- group;
• a and b are each independently 0, 1, 2 or 3, provided both are not zero;
• provided that when R13 is —CH═CH— or —C(C1-C6 alkyl)═CH—, a is 1;
• provided that when R14 is —CH═CH— or —C(C1-C6 alkyl)═CH—, b is 1;
• provided that when a is 2 or 3, the R13's can be the same or different;
• and provided that when b is 2 or 3, the R14's can be the same or different;
• and when Q is a bond and L is
• then Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
• R19 and R20 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
• R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
• R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, —C(O)R19 or —COOR19;
• R23 and R24 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, —COOH, NO2, —NR19R20, —OH and halo;
• and
• R25 is H, —OH or (C1-C6)alkoxy.