# US 8,785,489 B2 · Heteroaryl substituted indole compounds useful as MMP-13 inhibitors

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- Number: US 8,785,489 B2
- Document ID: US8785489B2
- Status: Granted
- Kind: B2
- Application number: 13/123,048
- Filed: 2009-10-13
- Published: 2011-11-10
- Granted: 2014-07-22
- Earliest claimed: 2008-10-17
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Asitha Abeywardane; Bennett Farmer; Neil Alexander Farrow; Donghong Amy Gao; Alexander Heim-Riether; Lana Louise Smith Keenan; Ingo Andreas Mugge; Steven John Taylor; Zhaoming Xiong; Yang Yu; Qiang Zhang
- Inventors: Asitha Abeywardane; Bennett Farmer; Neil Alexander Farrow; Donghong Amy Gao; Alexander Heim-Riether; Lana Louise Smith Keenan; Ingo Andreas Mugge; Steven John Taylor; Zhaoming Xiong; Yang Yu; Qiang Zhang
- Web page: https://patentgrep.com/patent/US8785489B2

## CPC

- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/497: containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/04: specific for metastasis
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are compounds and compositions of the formula I as described herein which are inhibitors of MMP-13. Also disclosed are methods of using and making compounds of the formula I.

## Claims

### Claim 1

A compound of the formula (I):
Het is a ring chosen from phenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl and pyridazinyl each optionally substituted by one to three C1-5 alkyl, C1-5 alkoxy, C1-5 acyl, C1-5 acylamino, amino, cyano, hydroxyl or halogen;
X is —N(R3)—;
Y is N or CH;
Z is H or F;
R1 is chosen from C1-5 alkoxyC1-5 alkyl, C1-5 alkoxycarbonyl-(CH2)n—, —C(O)NR4R5 and Ar1;
R2 is chosen from Ar2—(CH2)n—, heterocycle and C1-5 alkyl;
R3 is chosen from hydrogen and C1-5 alkyl;
each R4 and R5 is independently chosen from hydrogen, C1-5 acyl, C1-5 alkyl, C1-5 alkoxy, hydroxyl, carbocycle-(CH2)n—, heteroaryl and heterocycle-(CH2)n—;
Ar1 is chosen from carbocycle, heteroaryl and heterocycle wherein Ar1 is optionally substituted by one to three C1-5 alkyl, C1-5 alkoxy, C1-5 acyl, C1-5 acylamino, amino, cyano, hydroxyl or halogen;
Ar2 is chosen from carbocycle, heteroaryl and heterocycle wherein Ar2 is optionally substituted by one to three heteroaryl, C1-5 alkyl, C1-5 alkoxy-(CH2)n—, C1-5 alkoxycarbonyl-(CH2)n—, carboxy-(CH2)n—, C1-5 acyl, C1-5 acylamino, amino, cyano, hydroxyl, sulfonyl, sulfoxide, thio, oxo or halogen;
each n is independently 0-2;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the compound is represented by formula (II)
wherein
R1 is chosen from C1-5 alkoxy C1-5 alkyl, C1-5 alkoxycarbonyl-(CH2)n— and Ar1;
R2 is chosen from Ar2—(CH2)n—, heterocycle and C1-5 alkyl;
R3 is chosen from hydrogen and C1-5 alkyl;
Ar1 is chosen from phenyl, oxazolyl, 4,5-dihydro-oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl wherein Ar1 is optionally substituted by one to three C1-5 alkyl, C1-5 alkoxy, C1-5 acyl, C1-5 acylamino, amino, cyano, hydroxyl or halogen;
Ar2 is chosen from phenyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, thiophenyl, triazolyl, thiadiazolyl, isothiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl wherein Ar2 is optionally substituted by one to three C1-5 alkyl, C1-5 alkoxy-(CH2)n—, C1-5 alkoxycarbonyl-(CH2)n—, carboxy-(CH2)n—, C1-5 acyl, C1-5 acylamino, amino, cyano, hydroxyl, oxo or halogen.

### Claim 3 (depends on 2)

The compound according to claim 2 and wherein
R2 is chosen from Ar2—(CH2)n—;
Ar2 is chosen from phenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl wherein Ar2 is optionally substituted by one to three C1-5 alkyl, C1-5 alkoxy-(CH2)n—, C1-5 alkoxycarbonyl-(CH2)n—, carboxy-(CH2)n—, C1-5 acyl, C1-5 acylamino, amino, cyano, hydroxyl, oxo or halogen.

### Claim 4 (depends on 3)

The compound according to claim 3 and wherein
Het is a ring chosen from pyrazolyl, imidazolyl and pyridinyl each optionally substituted by one to three C1-5 alkyl, C1-5 alkoxy, C1-5 acyl, C1-5 acylamino, amino, cyano, hydroxyl or halogen;
Ar1 is chosen from phenyl, oxazolyl, 4,5-dihydro-oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridinyl and pyrimidinyl wherein Ar1 is optionally substituted by one to two C1-5 alkyl or halogen;
Ar2 is chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl wherein Ar2 is optionally substituted by one to three C1-5 alkyl, C1-5 alkoxy, C1-5 alkoxycarbonyl, carboxy, or halogen.

### Claim 5 (depends on 3)

The compound according to claim 3 and wherein
Het is a ring chosen from pyrazolyl, imidazolyl and pyridinyl each optionally substituted by C1-5 alkyl, C1-5 alkoxy or halogen;
R1 is chosen from C1-2 alkoxyC1-2 alkyl, C1-2 alkoxycarbonyl and Ar1;
R2 is chosen from Ar2-CH2—;
Ar1 is chosen from phenyl, 4,5-dihydro-oxazolyl, oxadiazolyl, pyrazolyl, pyridinyl and pyrimidinyl wherein Ar1 is optionally substituted by one to two C1-3 alkyl or halogen;
Ar2 is chosen from phenyl and pyridinyl wherein Ar2 is optionally substituted by one to two C1-5 alkyl, C1-5 alkoxy, C1-5 alkoxycarbonyl, hydroxyl, oxo, carboxy, or halogen.

### Claim 6 (depends on 1)

The compound according to claim 1 and wherein
Y is CH;
Het is chosen from
R2 is chosen from
R1 is chosen from

### Claim 7 (depends on 1)

The compound according to claim 1 and wherein
R2 is hydrogen or C1-3 alkyl;
R1 is chosen from C1-5 alkoxyC1-5 alkyl, C1-5 alkoxycarbonyl- and

### Claim 8 (depends on 7)

The compound according to claim 7 and wherein
R1 is C1-5 alkoxycarbonyl-.

### Claim 9

A compound chosen from
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers and/or adjuvants.

### Claim 11 (depends on 1)

A method of treating a disease chosen from rheumatoid arthritis, osteoarthritis, osteoporosis, peridontitis, atherosclerosis, congestive heart failure and multiple sclerosis comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.