Subtype-selective NMDA receptor ligands and the use thereof

A compound having the Formula (II):

• 123
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1-R4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN)2, guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
• R5 is hydrogen, lower alkyl, acyl or aryl;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• R6 is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• p is 0, 1, 2 or 3;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, carbonylamido, hydrazino, oximo, amidino, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (IIa):

• 124
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1-R4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN)2, guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
• R5 is hydrogen, lower alkyl, acyl or aryl;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• R6 is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• p is 0, 1, 2 or 3;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, carbonylamido, hydrazino, oximo, amidino, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (III):

• 125
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
• X is a bond, (CH2)m, carbonyl, oxygen, or NR;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R;
• optionally substituted cycloalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R is hydrogen, alkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
• R1 is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• m is 0, 1, 2, or 3;
• and
• p is 0, 1, 2, 3 or 4.
• with the proviso, that when W is adamantyl or when p is other than zero, or when the piperidine ring is substituted in the 3-position with W—X, then Y may also be optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• wherein
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having Formula IIIa:

• 126
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• Y is CH3, CN, CO2R, carboxamido, an optionally substituted cycloalkyl group or an optionally substituted heterocycloalkyl group;
• R is alkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• m is 0, 1, 2, 3;
• with the proviso, that when W is adamantyl, then Y may also be optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• wherein
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.

A compound having the Formula IIIb:

• 127
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• Y is CH3, CN, CO2R, carboxamido, an optionally substituted cycloalkyl group or an optionally substituted heterocycloalkyl group;
• R is alkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• m is 0, 1, 2, or 3;
• with the proviso, that when W is adamantyl, then Y may also be optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• wherein
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.

A compound having the Formula IIIc:

• 128
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• Y is CH3, CN, CO2R, carboxamido, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, an amino group, an amido group, a ureidoalkyl group, a guanidinoalkyl group, or O—N═CR1R2, where R1 and R2 are independently aryl or lower alkyl;
• R is alkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• m is 0, 1, 2, or 3;
• with the proviso, that when W is adamantyl, then Y may also be optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• wherein
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.

A compound having the Formula IIId:

• 129
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• X is a bond, (CH2)m, oxygen, or NR;
• Y1 is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R1 is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• m is 0, 1, 2, or 3;
• with the proviso that when W is an adamantyl group, then Y may further be an optionally substituted aralkyl group, or an optionally substituted aryl group.

A compound having the Formula IIIe:

• 130
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• Y1 is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R1 is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• m is 0, 1, 2, or 3;
• with the proviso that when W is an adamantyl group, then Y may further be an optionally substituted aralkyl group, or an optionally substituted aryl group.

A compound having the Formula IIIf:

• 131
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• Y1 is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R1 is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• m is 0, 1, 2, or 3;
• with the proviso that when W is an adamantyl group, then Y1 may further be an optionally substituted aralkyl group, or an optionally substituted aryl group.

A compound having the Formula IIIg:

• 132
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• Y1 is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R1 is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• m is 0, 1, 2, or 3;
• with the proviso that when W is an adamantyl group, then Y may further be an optionally substituted aralkyl group, or an optionally substituted aryl group.

A compound having the Formula IIIh:

• 133
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• Y is optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• Y1 is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• Z is (CH2)m, oxygen, sulfur, or NR;
• m is 0, 1, 2, or 3;
• and
• n is 1, 2, 3, 4, 5, or 6.

A compound having the Formula (IIIi):

• 134
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1-R5 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
• n is 1, 2, 3, 4, 5, or 6;
• Y is optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydrogen, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.

A compound having Formula (IIIj):

• 135
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1-R5 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
• n is 1, 2, 3, 4, 5, or 6;
• Y is optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydrogen, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.

A compound having the Formula (IIIk):

• 136
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1-R5 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
• n is 1, 2, 3, 4, 5, or 6;
• Y is optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydrogen, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.

A compound having the Formula (IIIl):

• 137
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is optionally substituted aryl;
• Y is optionally substituted aryl, optionally substituted aryloxy, an optionally substituted aryloxy group, SAr, COAr, hydrogen, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• Q is hydrogen, alkyl, aryl, aralkyl, a heterocyclic group, a heterocyclic substituted alkyl group, an aryl group, or an aralkyl group;
• X is a bond, (CH2)m, oxygen, or sulfur;
• m is 0, 1, 2, or 3;
• n is 1, 2, 3, 4, 5, or 6;
• and
• p is 0 or 1.

A compound having the Formula (IIIm):

• 138
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is optionally substituted aryl;
• X is a bond, (CH2)m, oxygen, sulfur, or NR;
• R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R1 is hydrogen, hydroxy, aryl, or aralkyl;
• m is 0, 1, 2, or 3;
• n is 1, 2, 3, 4, 5, or 6;
• =single or double bond;
• and
• =carbon ring or heterocyclic ring, with the proviso that said carbon ring is not part of a naphthyl group.

A compound having the Formula (IIIn):

• 139
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group or an optionally substituted aryl group;
• X is a bond, (CH2)m;
• Y is CH3, CN, CO2R;
• an optionally substituted aryl group, an optionally substituted aryloxy group, SAr, COAr, hydroxy, ≡—Y1, ═—Y1, a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;
• Y1 is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group
• R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• m is 0, 1, 2, or 3.

A compound having the Formula (IIIo):

• 140
• or a pharmaceutically acceptable salt thereof;
• wherein
• Y is hydrogen, hydroxy, CH3, CN, CO2R, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
• and
• n is 0, 1, 2, 3, 4, 5 or 6.

A compound having the Formula (IV):

• 141
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1-R5 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (V):

• 142
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1-R4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (VI):

• 143
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
• X is a bond, (CH2)m, oxygen, or NR;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
• R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R1 is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• m is 0, 1, 2, or 3;
• and
• p is 0, 1 or 2.

A compound having the Formula (VII):

• 144
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
• X is a bond, (CH2)m, oxygen, or NR;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
• R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R1 is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• m is 0, 1, 2, or 3;
• and
• p is 0, 1 or 2.

A compound having the Formula (VIII):

• 145
• or a pharmaceutically acceptable salt thereof;
• wherein
• W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
• X is a bond, (CH2)m, oxygen, or NR;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;
• R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;
• R1 is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• m is 0, 1, 2, or 3;
• and
• p is 0, 1 or 2.

A compound having the Formula (IX):

• 146
• or a pharmaceutically acceptable salt thereof;
• wherein
• one of K and L is nitrogen and the other is CH;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (X):

• 147
• or a pharmaceutically acceptable salt thereof;
• wherein
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (XI):

• 148
• or a pharmaceutically acceptable salt thereof;
• wherein
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (XII):

• 149
• or a pharmaceutically acceptable salt thereof;
• wherein
• A and B are one or more substituents which are independently hydrogen, halo, alkoxy, trifluoromethylthio, cyano, carboxy or hydroxy;
• R1 is alkyl, alkenyl, aralkyl, cycloalkyl-alkyl, dialkylaminoalkyl, or hydroxyalkyl;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (XIII):

• 150
• or a pharmaceutically acceptable salt thereof;
• wherein
• R is hydrogen, C2-C6 acyl, C1-C6 alkyl, aryl, C1-C6 alkoxycarbonyl, C7-C10 aralkyl, C2-C6 alkenyl, C3-C15 dialkylaminoalkyl, C1-C6 hydroxyalkyl, C2-C6 alkynyl, C3-C15 trialkylsilyl, C4-C10 alkylcycloalkyl, or C3-C6 cycloalkyl;
• A and B are independently selected from the group consisting of a halogen such as chloro, fluoro, bromo, iodo, trifluoromethyl, azido, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C5-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
• Z represents a group selected from
• 151
• wherein R1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, aralkyl, C4-C15 dialkylaminoalkyl, heterocycloalkyl, C2-C6 acyl, aroyl, or aralkanoyl, and R3 is C1-C6 alkyl, C2-C6 alkenyl, phenyl, aralkyl or C3-C15 dialkylaminoalkyl;
• and
• f and g are independently integers selected from 0 (A or B is hydrogen, respectively), 1, 2, 3, or 4;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (XIV):

• 152
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1 is carboxy or an alkylester or amide thereof;
• alkyl carboxy or an alkyl ester or amide thereof;
• hydroxy or hydroxymethyl group;
• p is 0, 1 or 2;
• the dotted line represents a single or double bond;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound having the Formula (XV):

• 153
• or a pharmaceutically acceptable salt thereof;
• wherein
• R1-R4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN)2, guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;
• E is (CRaRb)r—Gs—(CRcRd)t, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy;
• G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO2 or O2C), carbonyl (CO), or NRe, wherein Re is hydrogen, alkyl or aryl;
• r and t are independently 0, 1, 2, 3, 4, or 5;
• and s is 0 or 1;
• R6 is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;
• p is 0, 1, 2, or 3;
• Y is hydrogen, hydroxy, CH3, CN, CO2R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y1, ═—Y1 (which may be cis or trans, throughout) carbonylamido, hydrazino, oximo, amidino, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;
• and
• Y1 is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.

A compound of the Formula XVI:

• 154
• or a pharmaceutically acceptable salt thereof;
• wherein
• Ar1 is optionally substituted aryl or optionally substituted heteroaryl;
• X is O, NR1 or (CH2)n wherein n is 0, 1, 2, 3 or 4 and R1 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms;
• U is hydroxy or hydrogen;
• Y is (CH2)m wherein m is 1, 2 or 3;
• Z is (CHR2)z wherein z is 0, 1, 2, 3, or 4 and R2 is hydroxy, hydrogen or a lower alkyl group having 1 to 6 carbon atoms;
• and
• A and B are each hydrogen or together are (CH2)w wherein w is 0, 1, 2, 3 or 4.

A compound of the Formula XVII:

• 155
• or a pharmaceutically acceptable salt thereof;
• wherein
• Ar1 is optionally substituted aryl or optionally substituted heteroaryl;
• X is O, NR, or (CH2)n wherein n is 0, 1, 2, 3, or 4 and R1 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms;
• U is hydroxy or hydrogen;
• Z is (CHR2)z wherein z is 0, 1, 2, 3 or 4 and R2 is hydroxy, hydrogen or a lower alkyl group having 1 to 6 carbon atoms;
• Q is —CH═CH═ or —C≡C—;
• R3 is hydrogen, hydroxy or hydroxy substituted lower alkyl having 1 to 6 carbon atoms;
• and
• Y is hydrogen, hydroxy, optionally substituted aryl or optionally substituted heteroaryl.