# US 7,405,209 B2 · Protease inhibitors

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- Number: US 7,405,209 B2
- Document ID: US7405209B2
- Status: Granted
- Kind: B2
- Application number: 11/152,745
- Filed: 2005-06-14
- Published: 2005-11-17
- Granted: 2008-07-29
- Earliest claimed: 1998-12-23
- Assignees: SmithKline Beecham Corporation
- Inventors: Robert Wells Marquis, Jr.; Yu Ru; Daniel Frank Veber; Maxwell David Cummings; Scott Kevin Thompson; Dennis Shinji Yamashita
- Web page: https://patentgrep.com/patent/US7405209B2

## CPC

- C07D 405/14: containing three or more hetero rings
- A61P 19/00: Drugs for skeletal disorders
- C07D 223/12: Nitrogen atoms not forming part of a nitro radical
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07K 5/06139: {with the first amino acid being heterocyclic}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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)

## Abstract

The present invention provides 4-amino-azepan-3-one protease inhibitors and pharmaceutically acceptable salts, hydrates and solvates thereof which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, novel intermediates of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia of malignancy; and metabolic bone disease, comprising inhibiting said bone loss or excessive cartilage or matrix degradation by administering to a patient in need thereof a compound of the present invention.

## Claims

### Claim 1

A compound of Formula (I)
wherein:
R5 is benzofuranyl, or thieno[3,2,b]thiophenyl, all of which may be substituted or unsubstituted by C1-3alkyl;
R′″ is hydrogen or C1-6alkyl;
R3 is C1-6alkyl, phenylC1-6alkyl, or naphthylC1-6alkyl;
R9 is pyridinyl, 1-oxy-pyridinyl, phenyl, halogen substituted phenyl, C1-6alkyl substituted phenyl, C1-6alkoxy substituted phenyl, cyanophenyl, imidazolyl, or C1-6alkyl substituted imidazolyl, or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R3 is selected from the group consisting of: methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, and naphthalen-2-ylmethyl.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R3 is isobutyl.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R5 is thieno[3,2-b]thiophen-2-yl.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R′″ is H.

### Claim 6 (depends on 1)

A compound according to claim 1 wherein R9 is selected from the group consisting of:
3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-cyanophenyl;
pyridin-2-yl pyridin-3-yl, 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl;
1H-imidazol-2-yl, 1H-imidazol-4-yl, 1-methyl-1H-imidazol-2-yl, and 1-methyl-1H-imidazol-4-yl.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein:
R3 is isobutyl;
R5 is selected from the group consisting of: 3-methyl-benzofuran-2-yl or thieno[3,2-b]thiophen-2-yl; and
R9 is selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl.

### Claim 8 (depends on 1)

A compound according to claim 1 wherein R5 is benzofuran-2-yl.

### Claim 9 (depends on 1)

A compound according to claim 1 wherein R9 is pyridin-2-yl.

### Claim 10

A compound of Formula II
R5 is benzofuranyl, benzo[b]thiophenyl, or thieno[3,2,b]thiophenyl;
R′″ is hydrogen or C1-6alkyl;
R3 is C1-6alkyl, phenylC1-6alkyl, or naphthylC1-6alkyl;
R9 is pyridinyl, 1-oxy-pyridinyl, phenyl, halogen substituted phenyl, C1-6alkyl substituted phenyl, C1-6alkoxy substituted phenyl, cyanophenyl, imidazolyl, or C1-6alkyl substituted imidazolyl.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

### Claim 12 (depends on 1)

A method of treating osteoporosis by administering to a patient in need thereof an effective amount of a compound according to claim 1.

### Claim 13 (depends on 1)

A method of treating periodontitis by administering to a patient in need thereof an effective amount of a compound according to claim 1.

### Claim 14 (depends on 1)

A method of treating gingivitis by administering to a patient in need thereof an effective amount of a compound according to claim 1.

### Claim 15 (depends on 1)

A method of treating osteoarthritis by administering to a patient in need thereof an effective amount of a compound according to claim 1.

### Claim 16 (depends on 1)

A method of treating rheumatoid arthritis by administering to a patient in need thereof an effective amount of a compound according to claim 1.