# US 8,772,275 B2 · Mediators of hedgehog signaling pathways, compositions and uses related thereto

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,772,275 B2
- Document ID: US8772275B2
- Status: Granted
- Kind: B2
- Application number: 13/712,525
- Filed: 2012-12-12
- Published: 2013-07-25
- Granted: 2014-07-08
- Earliest claimed: 2001-07-27
- Assignees: Curis, Inc.
- Applicants: Curis, Inc.
- Inventors: Lee L. Rubin; Oivin Guicherit; Stephen Price; Edward Andrew Boyd
- Web page: https://patentgrep.com/patent/US8772275B2

## CPC

- C07D 263/57: Aryl or substituted aryl radicals
- A61K 31/395: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/428: condensed with carbocyclic rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/14: for baldness or alopecia
- A61P 19/00: Drugs for skeletal disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 235/18: with aryl radicals directly attached in position 2
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.

## Claims

### Claim 1

A compound of the formula (II):
wherein, as valence and stability permit,
X represents —N(R8)—;
Z represents —NH— or a direct bond;
Y represents —C(═O)—, —C(═S)— or SO2;
A represents —NH—;
G represents a phenyl or pyridyl ring fused to the ring to which it is attached;
R1 represents a substituted or unsubstituted benzene ring, cyclopentyl ring, cyclohexyl ring or heterocyclyl ring selected from substituted or unsubstituted thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, benzodioxane, benzodioxole, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam, azetidinone, pyrrolidinone, sultam or sultone rings, wherein the optional substituents on the R1 ring are selected from nitro, halogen, cyano, lower alkyl, acylamino, alkoxy or alkylamino groups or a cycloalkyl, heterocyclyl, aryl or heteroaryl ring fused to the benzene or heterocyclyl ring;
R2 represents from 0-4 substituents on the ring to which it is attached, where the substituents are selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl group, thiocarbonyl, ketone, aldehyde, amino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, J-R8, J-OH, J-lower alkyl, J-lower alkenyl, J-R8, J-SH, J-NH2, protected forms of the above, or any two R2, when occurring more than once in a cyclic or polycyclic structure, taken together form a 4- to 8-membered cycloalkyl, aryl, or heteroaryl;
R3 represents a substituent on the ring to which it is attached, the substituent being at a position on the ring which is para to where the X group is attached, and the substituent being selected from halogen, hydroxyl, alkoxy, amino, alkylamino, cyano, nitro, lower alkyl, and acyl,
R8, independently for each occurrence, represents H, lower alkyl or cycloalkyl; and
J represents, independently for each occurrence, a chain having from 0-8 units selected from CK2, NK, O, and S, wherein K represents, independently for each occurrence, H or lower alkyl;
provided that, when J is CK2, R1 is not a cyclohexyl ring; and
provided that, when R8 is H, Z is a direct bond and Y is —C(═O)—, R1 is not a disubstituted pyridine ring;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X—Y—Z includes an amide, urea, or sulfonamide.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is optionally substituted with from 1-5 substituents.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the substituents on R1 are selected from nitro, halogen, cyano, lower alkyl, acylamino, alkoxy, or alkylamino groups, or a benzene, 2,5-dioxacyclohexyl or 2,4-dioxacyclopentyl ring fused to the benzene or heterocyclyl ring.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 represents from 1-4 substituents as defined.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R2 represents from 1-4 substituents selected from halogen, cyano, nitro, alkoxy, amino, acylamino, a cycloalkyl, heterocyclyl, aryl, or heteroaryl fused to G, and lower alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 represents a substituted or unsubstituted benzene ring, cyclopentyl ring, cyclohexyl ring, thiophene ring, furan ring, isobenzofuran ring, pyridine ring, benzodioxane ring, or benzodioxole ring.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R1 represents a substituted or unsubstituted benzene ring or pyridine ring.

### Claim 9 (depends on 1)

The compound of claim 1, which is a compound selected from the following:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising one or more compounds according to claim 1 formulated together with one or more pharmaceutically acceptable carriers and/or diluents.