Multibinding inhibitors of HMG-CoA reductase

A compound of formula II:

• L′—X′—L′ II
• wherein each L′ is a ligand independently selected from the group consisting of:
• (a) a ligand of formula IIA:
• wherein
• A1 is selected from the group consisting of:
• where Ra is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• R21 is selected from the group consisting of hydrogen, lower alkyl, hydroxy and a covalent bond attaching the ligand to a linker;
• R22, R23 and R24 are independently selected from the group consisting of hydrogen and a covalent bond attaching the ligand to a linker;
• and
• e and f represent optional double bonds;
• provided that one of R21, R22, R23 or R24 is a covalent bond linking the ligand to a linker;
• (b) a ligand of formula IIB:
• wherein
• A1 is as defined above;
• R25 is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl and a covalent bond attaching the ligand to a linker;
• and
• R26 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and a covalent bond attaching the ligand to a linker;
• provided that one of R25 or R26 is a covalent bond linking the ligand to a linker;
• (c) a ligand of formula IIC:
• wherein
• A1 is as defined above;
• R27 is selected from the group consisting of hydrogen and a covalent bond attaching the ligand to a linker;
• and
• R28 is selected from the group consisting of amino, substituted amino and a covalent bond attaching the ligand to a linker;
• provided that one of R27 or R28 is a covalent bond linking the ligand to a linker;
• and
• (d) a ligand of formula IID:
• wherein
• A1 is as defined above;
• and
• R29 is a covalent bond attaching the ligand to a linker;
• X′ is a linker of the formula:
• —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
• wherein
• m is an integer of from 0 to 20;
• Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— and a covalent bond where R is as defined below;
• Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, and a covalent bond;
• Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —P(O)(OR′)—O—, —S(O)nCR′R″—, —S(O)n—NR′—, —S—S— and a covalent bond;
• where n is 0, 1 or 2;
• and
• R, R′ R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• and further wherein the distance between ligands is at least 10 Å;
• and pharmaceutically-acceptable salts thereof.

A compound of formula III:

• wherein
• each A1 is independently selected from the group consisting of:
• where Ra is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• and
• X″ is a linker of the formula:
• —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
• wherein
• m is an integer of from 0 to 20;
• Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— and a covalent bond where R is as defined below;
• Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, and a covalent bond;
• Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, -P(O)(OR′)—O—, -S(O)nCR′R″—, —S(O)n—NR′—, —S—S— and a covalent bond;
• where n is 0, 1 or 2;
• and
• R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• and further wherein the distance between ligands is at least 10 Å;
• and pharmaceutically acceptable salts thereof.

A compound of formula IV:

• wherein
• each A1 is independently selected from the group consisting of:
• where Ra is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• and
• X″ is a linker of the formula:
• —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
• wherein
• m is an integer of from 0 to 20;
• Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— and a covalent bond where R is as defined below;
• Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, and a covalent bond;
• Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —P(O)(OR′)—O—, —S(O)nCR′R″—, —S(O)C—NR′—, —S—S— and a covalent bond;
• where n is 0, 1 or 2;
• and
• R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• and further wherein the distance between ligands is at least 10 Å;
• and pharmaceutically acceptable salts thereof.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula I:

• (L)p(X)q I
• wherein each L is a ligand independently selected from the group consisting of:
• (a) a ligand of formula IA:
• wherein
• A1 is selected from the group consisting of:
• where Ra is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• R1 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, heterocyclic, amino, substituted amino, thioalkoxy, substituted thioalkoxy and thioaryloxy;
• R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—ORd where Rd is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker;
• or R2 together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
• substituted alkoxy, aryl, heterocyclic, amino, substituted amino, thioalkoxy, substituted thioalkoxy and thioaryloxy;
• R2 is selected from the group consisting of hydrogen, alkyl, substituted alky, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—ORd where Rd is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker;
• or R2 together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
• R3 is selected from the group consisting of hydrogen, alky, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—ORd where Rd is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker;
• or R3 together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
• R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—ORd where Rd is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker;
• or R4 together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
• R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—ORd where Rd is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker;
• or R2 together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
• and
• a, b, c and d represent optional double bonds, provided that when a or c is a double bond, b is not a double bond;
• and when b or d is a double bond, c is not a double bond;
• and
• W1 is —CH2CH2—;
• provided that one of R2, R3, R4 or R5 is a covalent bond linking the ligand to a linker;
• (b) a ligand of formula IB:
• wherein
• A2 is selected from the group consisting of:
• where Ra, Rb and Rc are independently selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted amino, heterocyclic, heteroaryl and a covalent bond attaching the ligand to a linker;
• R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted amino, heterocyclic, heteroaryl, alkoxycarbonyl, cyano, carboxyl and a covalent bond attaching the ligand to a linker;
• R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, akenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl and aralkoxy;
• W2 is —CH2CH2—, —CH═CH— or —C≡C—;
• provided that one of R6 or R7 is a covalent bond linking the ligand to a linker;
• (c) a ligand of formula IC:
• wherein
• A1 is as defined above;
• R10 is selected from the group consisting of cycloalkyl and aryl;
• one of R11 and R12 is —C(O)NR14R15 where R14 and R15 are independently selected from the group consisting of hydrogen, alkyl, aryl and a covalent bond attaching the ligand to a linker;
• and the other of R11 and R12 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and a covalent bond attaching the ligand to a linker;
• R13 is selected from the group consisting of alkyl, cycloalkyl and trifluoromethyl;
• W3 is —CH2—, —CH2CH2—, —CH2CH2CH2— or —CH2CH(CH3)—;
• provided that one of R11, R12, R14 or R15 is a covalent bond linking the ligand to a linker;
• and
• (d) a ligand of formula ID:
• R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—ORd where Rd is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker;
• or R3 together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
• R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—ORd where Rd is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker;
• or R4 together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
• R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—ORd where Rd is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker;
• or R2 together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
• and
• a, b, c and d represent optional double bonds, provided that when a or c is a double bond, b is not a double bond;
• and when b or d is a double bond, c is not a double bond;
• and
• W1 is —CH2CH2—;
• provided that one of R2, R3, R4 or R5 is a covalent bond linking the ligand to a linker;
• (b) a ligand of formula IB:
• wherein
• A2 is selected from the group consisting of:
• where Ra, Rb and Rc are independently selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted amino, heterocyclic, heteroaryl and a covalent bond attaching the ligand to a linker;
• R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted amino, heterocyclic, heteroaryl, alkoxycarbonyl, cyano, carboxyl and a covalent bond attaching the ligand to a linker;
• R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, akenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl and aralkoxy;
• W2 is —CH2CH2—, —CH═CH— or —C≡C—;
• provided that one of R6 or R7 is a covalent bond linking the ligand to a linker;
• (c) a ligand of formula IC:
• wherein
• A1 is as defined above;
• R10 is selected from the group consisting of cycloalkyl and aryl;
• one of R11 and R12 is —C(O)NR14R15 where R14 and R15 are independently selected from the group consisting of hydrogen, alkyl, aryl and a covalent bond attaching the ligand to a linker;
• and the other of R11 and R12 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and a covalent bond attaching the ligand to a linker;
• R13 is selected from the group consisting of alkyl, cycloalkyl and trifluoromethyl;
• W3 is —CH2—, —CH2CH2—, —CH2CH2CH2— or —CH2CH(CH3)—;
• provided that one of R11, R12, R14 or R15 is a covalent bond linking the ligand to a linker;
• and
• (d) a ligand of formula ID:
• wherein
• A1 is as defined above;
• one of R16 and R17 is aryl;
• and the other of R16 and R17 is selected from the group consisting of alkyl, cycloalkyl and aralkyl;
• R18 and R19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, halo, aryloxy, aralkoxy and a covalent bond attaching the ligand to a linker;
• and
• W4 is —CH2—, —CH2CH2—, —CH2CH2CH2— or —CH═CH—;
• provided that one of R18 or R19 is a covalent bond linking the ligand to a linker;
• each X is independently a linker of the formula:
• —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
• wherein
• m is an integer of from 0 to 20;
• Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— and a covalent bond where R is as defined below;
• Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, and a covalent bond;
• Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —P(O)(OR′)—O—, —S(O)nCR′R″—, —S(O)n—NR′—, —S—S— and a covalent bond;
• where n is 0, 1 or 2;
• and
• R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• p is an integer of from 2 to 10;
• q is an integer of from 1 to 20, provided that q is less than p;
• and further wherein the distance between ligands is at least 10 Å;
• and pharmaceutically-acceptable salts thereof.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula II:

• L′—X′—L′ II
• wherein each L′ is a ligand independently selected from the group consisting of:
• (a) a ligand of formula IIA:
• wherein
• A1 is selected from the group consisting of:
• where Ra is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• R21 is selected from the group consisting of hydrogen, lower alkyl, hydroxy and a covalent bond attaching the ligand to a linker;
• R22, R23 and R24 are independently selected from the group consisting of hydrogen and a covalent bond attaching the ligand to a linker;
• and
• e and f represent optional double bonds;
• provided that one of R21, R22, R23 or R24 is a covalent bond linking the ligand to a linker;
• (b) a ligand of formula IIB:
• wherein
• A1 is as defined above;
• R25 is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl and a covalent bond attaching the ligand to a linker;
• and
• R26 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and a covalent bond attaching the ligand to a linker;
• provided that one of R25 or R26 is a covalent bond linking the ligand to a linker;
• (c) a ligand of formula IIC:
• wherein
• A1 is as defined above;
• R27 is selected from the group consisting of hydrogen and a covalent bond attaching the ligand to a linker;
• and
• R28 is selected from the group consisting of amino, substituted amino and a covalent bond attaching the ligand to a linker;
• provided that one of R27 or R28 is a covalent bond linking the ligand to a linker;
• and
• (d) a ligand of formula IID:
• wherein
• A1 is as defined above;
• and
• R29 is a covalent bond attaching the ligand to a linker;
• X′ is a linker of the formula:
• —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
• wherein
• m is an integer of from 0 to 20;
• Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— and a covalent bond where R is as defined below;
• Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, and a covalent bond;
• Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —P(O)(OR′)—O—, —S(O)nCR′R″—, —S(O)n—NR′—, —S—S— and a covalent bond;
• where n is 0, 1 or 2;
• and
• R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• and further wherein the distance between ligands is at least 10 Å;
• and pharmaceutically-acceptable salts thereof.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula III:

• wherein
• each A1 is independently selected from the group consisting of:
• where Ra is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• and
• X″ is a linker of the formula:
• —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
• wherein
• m is an integer of from 0 to 20;
• Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— and a covalent bond where R is as defined below;
• Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, and a covalent bond;
• Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —P(O)(OR′)—O—, —S(O)nCR′R″—, —S(O)n—NR′—, —S—S— and a covalent bond;
• where n is 0, 1 or 2;
• and
• R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• and further wherein the distance between ligands is at least 10 Å;
• and pharmaceutically-acceptable salts thereof.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula IV:

• wherein
• each A1 is independently selected from the group consisting of:
• where Ra is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
• and
• X″ is a linker of the formula:
• —Xa—Z—(Ya—Z)m—Yb—Z—Xa—
• wherein
• m is an integer of from 0 to 20;
• Xa at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— and a covalent bond where R is as defined below;
• Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, and a covalent bond;
• Ya and Yb at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —P(O)(OR′)—O—, —S(O)nCR′R″—, —S(O)n—NR′—, —S—S— and a covalent bond;
• where n is 0, 1 or 2;
• and
• R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
• and further wherein the distance between ligands is at least 10 Å;
• and
• pharmaceutically-acceptable salts thereof.