# US 2013/0157987 A1 · 1-deoxy analogs of 1,25-dihydroxyvitamin d3 compounds

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- Number: US 2013/0157987 A1
- Document ID: US20130157987A1
- Status: Published application
- Kind: A1
- Application number: 13/521,980
- Filed: 2011-01-13
- Published: 2013-06-20
- Earliest claimed: 2010-01-13
- Assignees: The Johns Hopkins University; Cytochroma Inc.
- Inventors: Gary H. Posner; Lindsey C. Hess; Alvin S. Kalinda; Rachel D. Slack; Uttam Saha; P. Martin Petkovich
- Web page: https://patentgrep.com/patent/US20130157987A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/593: 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 3/12: for electrolyte homeostasis
- A61P 5/18: of the parathyroid hormones
- A61P 5/20: for decreasing, blocking or antagonising the activity of PTH
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 31/06: for tuberculosis
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 401/00: Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
- C07C 2601/14: The ring being saturated
- C07C 2602/24: the ring system containing nine carbon atoms, e.g. perhydroindane
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

This present disclosure is directed to novel prodrugs of activated vitamin D3 compounds. The prodrugs can be designed to have one or more beneficial properties, such as selective inhibition of the enzyme CYP24, low calcemic activity, and anti-proliferative activity. Specifically, these prodrugs are 1-deoxy prohormones of active Vitamin D analogs, e.g. analogs of calcitriol. This disclosure is also directed to pharmaceutical and diagnostic compositions containing the prodrugs of the invention, and to their medical use, particularly as prodrugs in the treatment and/or prevention of diseases.

## Claims

### Claim 1

A compound 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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein
n is 0 or 1;
R1 is OH or halo;
R2 and R3 are either both H or together form ═CH2;
R4 is C1-4alkyl;
R5 and R6 are each independently H, halo, or C1-2alkyl, 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, and N(C1-6alkyl); and
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, and halo.

### Claim 3 (depends on 2)

The compound of claim 2, wherein
R1 is OH or F;
R2 and R3 together form ═CH2;
R4 is CH3;
R5 and R6 are each independently H, halo, or CH3, with the proviso that when between carbon-23 and carbon-24 is a double bond, then R5 is absent;
R7 is O or NH; and
R8 is selected from the group consisting of C1-4alkyl, aryl and heteroaryl, wherein each of 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, and halo.

### Claim 4 (depends on 3)

The compound of claim 3, wherein
R1 is OH; and,
R5 and R6 are each independently H, CH3, Cl, or F, with the proviso that when between carbon-23 and carbon-24 is a double bond, then R5 is absent; and
R8 is selected from the group consisting of C1-4alkyl and aryl, wherein aryl is either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2, and halo.

### Claim 5 (depends on 4)

The compound of claim 4, selected from the group consisting of:

### Claim 6 (depends on 1)

The compound of claim 1 having a relative stereochemistry as shown below:

### Claim 7 (depends on 6)

The compound of claim 6 selected from the group consisting of:

### Claim 8

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.

### Claim 9 (depends on 8)

The compound of claim 8, wherein
R1 is OH or halo;
R2 and R3 are either both H or together form ═CH2;
R4 is C1-4alkyl;
R5 and R6 are each independently H, halo, or C1-2alkyl, 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, C1-4alkyl, C2-5alkenyl, aryl and heteroaryl, with C1-4alkyl and C2-4alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, and halo, 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, and halo; and
R8 is selected from the group consisting of C1-4alkyl, C2-4alkenyl, cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl, aryl, heteroaryl, with C1-4alkyl and C2-4alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, and halo, and with cyclo(C3-C6)alkyl, cyclo(C5-C6)alkenyl aryl, and heteroaryl, being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, OH, CF3, OCF3, and halo.

### Claim 10 (depends on 9)

The compound of claim 9, wherein
R1 is OH or F;
R2 and R3 together form ═CH2;
R4 is CH3;
R5 and R6 are each independently H, halo, or CH3, 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, C1-4alkyl, C2-5alkenyl, aryl and heteroaryl, with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, CF3, OCF3, and halo; and
R8 is selected from the group consisting of C1-4alkyl, aryl, and heteroaryl, with aryl, and heteroaryl, being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, CF3, OCF3, and halo.

### Claim 11 (depends on 10)

The compound of claim 10, wherein
R1 is OH;
R5 and R6 are each H, 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, C1-4alkyl, C2-5alkenyl, aryl and heteroaryl, with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, CF3, OCF3, and halo; and
R8 is selected from the group consisting of C1-4alkyl, aryl, and heteroaryl, with aryl, and heteroaryl, being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, CF3, OCF3, and halo.

### Claim 12 (depends on 11)

The compound of claim 11, wherein R7 is selected from the group consisting of H, C2-5alkenyl, aryl and heteroaryl; and R8 is C1-4alkyl or aryl.

### Claim 13 (depends on 12)

The compound of claim 12 wherein the compound is:

### Claim 14 (depends on 8)

The compound of claim 8 having a relative stereochemistry as shown below:

### Claim 15 (depends on 14)

The compound of claim 14 wherein the compound is:

### Claim 16

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.

### Claim 17 (depends on 16)

The compound of claim 16, wherein
R1 is OH or halo;
R2 and R3 are either both H or together form ═CH2;
R4 is C1-4alkyl;
R5 and R6 are each independently H, halo, or C1-2alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C3-4cycloalkyl ring;
R7 is selected from the group consisting of O, NH, and N(C1-6alkyl); and
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, and halo.

### Claim 18 (depends on 17)

The compound of claim 17, wherein
R1 is OH or F;
R2 and R3 together form ═CH2;
R4 is CH3;
R5 and R6 are each independently H, halo, or CH3, or can be taken, together with the carbon atom to which they are bound, to form a C3-4cycloalkyl ring;
R7 is O or NH; and
R8 is selected from the group consisting of C1-4alkyl, aryl and heteroaryl, wherein each of 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, and halo.

### Claim 19 (depends on 18)

The compound of claim 18 selected from the group consisting of:

### Claim 20 (depends on 16)

The compound of claim 16 having a relative stereochemistry as shown below:

### Claim 21 (depends on 20)

The compound of claim 20 selected from the group consisting of:

### Claim 22

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.

### Claim 23

(canceled)

### Claim 24

(canceled)

### Claim 25

(canceled)

### Claim 26

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.

### Claim 27

(canceled)

### Claim 28

(canceled)

### Claim 29

(canceled)

### Claim 30

(canceled)

### Claim 31

(canceled)

### Claim 32

(canceled)

### Claim 33

(canceled)

### Claim 34

(canceled)

### Claim 35

(canceled)

### Claim 36

(canceled)

### Claim 37

(canceled)

### Claim 38

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.

### Claim 39

(canceled)

### Claim 40

(canceled)

### Claim 41

A compound selected from the group consisting of:

### Claim 42 (depends on 41)

A method for treating diseases which benefit from a modulation of the levels of 1α,25-dihydroxyvitamin D3 comprising administering an effective amount of a compound of claim 41 to a cell or animal in need thereof.