1-deoxy analogs of 1,25-dihydroxyvitamin d3 compounds

A compound having Formula II, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

• wherein each independently is a single bond or a double bond;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring, with the proviso that when between carbon-23 and carbon-24 is a double bond, then R5 is absent;
• R7 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, aryl and heteroaryl, with C1-6 alkyl and C2-6alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, halo, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl), and with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, SC2-4alkenyl NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl)CN, C(O)OH, C(O)OC1-4alkyl, C(O)OC2-4alkenyl, C(O)NHC1-4alkyl, C(O)NHC2-4alkenyl, NHC(O)C1-4alkyl, NHC(O)C2-4alkenyl, OC(O)C1-4alkyl, OC(O)C2-4alkenyl, SOC1-4alkyl, SOC2-4alkenyl, SO2C1-4alkyl, SO2C2-4alkenyl, SO2NHC1-4alkyl, SO2NHC2-4alkenyl and SO2NH2;
• and
• R8 is selected from the group consisting of C1-6alkyl, C2-6alkenyl, cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl, aryl, heteroaryl, aryl-C1-6alkyl, aryl-C2-6alkenyl, heteroaryl-C1-6alkyl, and heteroaryl-C2-6alkenyl with C1-6alkyl and C2-6alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, halo, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), and N(C2-4alkenyl)(C1-4alkyl), and with cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl aryl, heteroaryl, aryl-C1-6alkyl, aryl-C2-6alkenyl, heteroaryl-C1-6alkyl, heteroaryl-C2-6alkenyl being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, SC2-4alkenyl, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl), CN, C(O)OH, C(O)OC1-4alkyl, C(O)OC2-4alkenyl, C(O)NHC1-4alkyl, C(O)NHC2-4alkenyl, NHC(O)C1-4alkyl, NHC(O)C2-4alkenyl, OC(O)C1-4alkyl, OC(O)C2-4alkenyl, SOC1-4alkyl, SOC2-4alkenyl SO2C1-4alkyl, SO2C2-4alkenyl, SO2NHC1-4alkyl, SO2NHC2-4alkenyl and SO2NH2.

A compound having Formula III, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

• wherein is a single bond or a double bond;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring;
• R7 is selected from the group consisting of O, NH, N(C1-6alkyl), and NC(O)R9;
• R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo, OH, OCF3, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), and CN;
• and,
• R9 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo.

A pharmaceutical composition comprising an admixture of a pharmaceutically-acceptable excipient and a compound:

• (i) having Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein each ——— independently is a single bond or a double bond;
• n is 0, 1 or 2;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring, with the proviso that when ——— between carbon-23 and carbon-24 is a double bond, then R5 is absent;
• R7 is selected from the group consisting of O, NH, N(C1-6alkyl), and NC(O)R9;
• R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo, OH, OCF3, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), and CN;
• and
• R9 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo;
• with the proviso that when n is 0, then R7 is O;
• and
• with the proviso that when each ——— is a single bond, n is 1, R1 is OH, R2 and R3 together form ═CH2, R4 is C1alkyl, R5 and R6 are each H, and R8 is methyl, then R7 is selected from the group consisting of NH, N(C1-6alkyl), and NC(O)R9;
• or
• (ii) having Formula II, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein each ——— independently is a single bond or a double bond;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring, with the proviso that when ——— between carbon-23 and carbon-24 is a double bond, then R5 is absent;
• R7 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, aryl and heteroaryl, with C1-6alkyl and C2-6alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, halo, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl), and with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, SC2-4alkenyl NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl)CN, C(O)OH, C(O)OC1-4alkyl, C(O)OC2-4alkenyl, C(O)NHC1-4alkyl, C(O)NHC2-4alkenyl, NHC(O)C1-4alkyl, NHC(O)C2-4alkenyl, OC(O)C1-4alkyl, OC(O)C2-4alkenyl, SOC1-4alkyl, SOC2-4alkenyl, SO2C1-4alkyl, SO2C2-4alkenyl, SO2NHC1-4alkyl, SO2NHC2-4alkenyl and SO2NH2;
• and
• R8 is selected from the group consisting of C1-6alkyl, C2-6alkenyl, cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl, aryl, heteroaryl, aryl-C1-6alkyl, aryl-C2-6alkenyl, heteroaryl-C1-6alkyl, and heteroaryl-C2-6alkenyl with C1-6alkyl and C2-6alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, halo, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), and N(C2-4alkenyl)(C1-4alkyl), and with cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl aryl, heteroaryl, aryl-C1-6alkyl, aryl-C2-6alkenyl, heteroaryl-C1-6alkyl, heteroaryl-C2-6alkenyl being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, SC2-4alkenyl, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl), CN, C(O)OH, C(O)OC1-4alkyl, C(O)OC2-4alkenyl, C(O)NHC1-4alkyl, C(O)NHC2-4alkenyl, NHC(O)C1-4alkyl, NHC(O)C2-4alkenyl, OC(O)C1-4alkyl, OC(O)C2-4alkenyl, SOC1-4alkyl, SOC2-4alkenyl SO2C1-4alkyl, SO2C2-4alkenyl, SO2NHC1-4alkyl, SO2NHC2-4alkenyl and SO2NH2;
• or
• (iii) having Formula III, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein ——— is a single bond or a double bond;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring;
• R7 is selected from the group consisting of O, NH, N(C1-6alkyl), and NC(O)R9;
• R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo, OH, OCF3, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), and CN;
• and,
• R9 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo.

A method

• for treating diseases which benefit from a modulation of the levels of 1α,25-dihydroxyvitamin D3, or
• for treating diseases which benefit from an inhibition of the catabolism of 1α,25-dihydroxyvitamin D3, or
• for inhibiting cell proliferation in an animal, or
• for inhibiting CYP24 activity in a cell or animal, or
• for modulating the levels of 1α,25-dihydroxyvitamin D3 in a cell or animal, or
• for inhibiting the catabolism of 1α,25-dihydroxyvitamin D3 in a cell o animal,
• comprising administering to a cell or animal in need thereof an effective amount of a compound:
• (i) having Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein each ——— independently is a single bond or a double bond;
• n is 0, 1 or 2;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring, with the proviso that when ——— between carbon-23 and carbon-24 is a double bond, then R5 is absent;
• R7 is selected from the group consisting of O, NH, N(C1-6alkyl), and NC(O)R9;
• R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo, OH, OCF3, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), and CN;
• and
• R9 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo;
• with the proviso that when n is 0, then R7 is O;
• and
• with the proviso that when each ——— is a single bond, n is 1, R1 is OH, R2 and R3 together form ═CH2, R4 is C1alkyl, R5 and R6 are each H, and R8 is methyl, then R7 is selected from the group consisting of NH, N(C1-6alkyl), and NC(O)R9;
• or
• (ii) having Formula II, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein each ——— independently is a single bond or a double bond;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring, with the proviso that when ——— between carbon-23 and carbon-24 is a double bond, then R5 is absent;
• R7 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, aryl and heteroaryl, with C1-6alkyl and C2-6alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, halo, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl), and with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, SC2-4alkenyl NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl)CN, C(O)OH, C(O)OC1-4alkyl, C(O)OC2-4alkenyl, C(O)NHC1-4alkyl, C(O)NHC2-4alkenyl, NHC(O)C1-4alkyl, NHC(O)C2-4alkenyl, OC(O)C1-4alkyl, OC(O)C2-4alkenyl, SOC1-4alkyl, SOC2-4alkenyl, SO2C1-4alkyl, SO2C2-4alkenyl, SO2NHC1-4alkyl, SO2NHC2-4alkenyl and SO2NH2;
• and
• R8 is selected from the group consisting of C1-6alkyl, C2-6alkenyl, cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl, aryl, heteroaryl, aryl-C1-6alkyl, aryl-C2-6alkenyl, heteroaryl-C1-6alkyl, and heteroaryl-C2-6alkenyl with C1-6alkyl and C2-6alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, halo, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), and N(C2-4alkenyl)(C1-4alkyl), and with cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl aryl, heteroaryl, aryl-C1-6alkyl, aryl-C2-6alkenyl, heteroaryl-C1-6alkyl, heteroaryl-C2-6alkenyl being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, SC2-4alkenyl, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl), CN, C(O)OH, C(O)OC1-4alkyl, C(O)OC2-4alkenyl, C(O)NHC1-4alkyl, C(O)NHC2-4alkenyl, NHC(O)C1-4alkyl, NHC(O)C2-4alkenyl, OC(O)C1-4alkyl, OC(O)C2-4alkenyl, SOC1-4alkyl, SOC2-4alkenyl SO2C1-4alkyl, SO2C2-4alkenyl, SO2NHC1-4alkyl, SO2NHC2-4alkenyl and SO2NH2;
• or
• (iii) having Formula III, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein ——— is a single bond or a double bond;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring;
• R7 is selected from the group consisting of O, NH, N(C1-6alkyl), and NC(O)R9;
• R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo, OH, OCF3, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), and CN;
• and,
• R9 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo.

A method of increasing the efficacy of a vitamin D receptor agonist comprising co-administering an effective amount of the vitamin D receptor agonist and a compound:

• (i) having Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein each ——— independently is a single bond or a double bond;
• n is 0, 1 or 2;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring, with the proviso that when ——— between carbon-23 and carbon-24 is a double bond, then R5 is absent;
• R7 is selected from the group consisting of O, NH, N(C1-6alkyl), and NC(O)R9;
• R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo, OH, OCF3, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), and CN;
• and
• R9 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo;
• with the proviso that when n is 0, then R7 is O;
• and
• with the proviso that when each ——— is a single bond, n is 1, R1 is OH, R2 and R3 together form ═CH2, R4 is C1alkyl, R5 and R6 are each H, and R8 is methyl, then R7 is selected from the group consisting of NH, N(C1-6alkyl), and NC(O)R9;
• or
• (ii) having Formula II, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein each ——— independently is a single bond or a double bond;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring, with the proviso that when ——— between carbon-23 and carbon-24 is a double bond, then R5 is absent;
• R7 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, aryl and heteroaryl, with C1-6alkyl and C2-6alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, halo, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl), and with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, SC2-4alkenyl NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl)CN, C(O)OH, C(O)OC1-4alkyl, C(O)OC2-4alkenyl, C(O)NHC1-4alkyl, C(O)NHC2-4alkenyl, NHC(O)C1-4alkyl, NHC(O)C2-4alkenyl, OC(O)C1-4alkyl, OC(O)C2-4alkenyl, SOC1-4alkyl, SOC2-4alkenyl, SO2C1-4alkyl, SO2C2-4alkenyl, SO2NHC1-4alkyl, SO2NHC2-4alkenyl and SO2NH2;
• and
• R8 is selected from the group consisting of C1-6alkyl, C2-6alkenyl, cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl, aryl, heteroaryl, aryl-C1-6alkyl, aryl-C2-6alkenyl, heteroaryl-C1-6alkyl, and heteroaryl-C2-6alkenyl with C1-6alkyl and C2-6alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, halo, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), and N(C2-4alkenyl)(C1-4alkyl), and with cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl aryl, heteroaryl, aryl-C1-6alkyl, aryl-C2-6alkenyl, heteroaryl-C1-6alkyl, heteroaryl-C2-6alkenyl being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, SC2-4alkenyl, NH2, NHC1-4alkyl, NHC2-4alkenyl, N(C1-4alkyl)(C1-4alkyl), N(C2-4alkenyl)(C1-4alkyl), CN, C(O)OH, C(O)OC1-4alkyl, C(O)OC2-4alkenyl, C(O)NHC1-4alkyl, C(O)NHC2-4alkenyl, NHC(O)C1-4alkyl, NHC(O)C2-4alkenyl, OC(O)C1-4alkyl, OC(O)C2-4alkenyl, SOC1-4alkyl, SOC2-4alkenyl SO2C1-4alkyl, SO2C2-4alkenyl, SO2NHC1-4alkyl, SO2NHC2-4alkenyl and SO2NH2;
• or
• (iii) having Formula III, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
• wherein ——— is a single bond or a double bond;
• R1 is selected from the group consisting of OH, OC1-6alkyl, and halo;
• R2 and R3 are each independently H or halo, or together form ═CH2;
• R4 is C1-6alkyl;
• R5 and R6 are each independently H, halo, C1-4alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-6cycloalkyl ring;
• R7 is selected from the group consisting of O, NH, N(C1-6alkyl), and NC(O)R9;
• R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo, OH, OCF3, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), and CN;
• and,
• R9 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, halo.