# US 2014/0194362 A1 · Macrocyclic Cysteine Protease Inhibitors and Compositions Thereof

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- Number: US 2014/0194362 A1
- Document ID: US20140194362A1
- Status: Published application
- Kind: A1
- Application number: 14/206,051
- Filed: 2014-03-12
- Published: 2014-07-10
- Earliest claimed: 2006-10-18
- Assignees: Lincoln University; Douglas Pharmaceuticals Limited; Canterprise Limited
- Applicants: Lincoln University; Douglas Pharmaceuticals Limited; Canterprise Limited
- Inventors: Andrew David Abell; James Morriss Coxon; Matthew Alan Jones; Stephen Brian McNabb; Axel Thomas Neffe; Steven Geoffrey Aitken; Blair Gibb Stuart; Janna Marie Nikkel; Joanna Kimberley Duncan; Mutita Klanchantra; James David Morton; Roy Bickerstaffe; Lucinda Jane Goodricke Robertson; Hannah Yun Young Lee; Matthew Stewart Muir
- Web page: https://patentgrep.com/patent/US20140194362A1

## CPC

- C07K 5/0808: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 27/12: for cataracts
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- C07K 14/8125: {Alpha-1-antitrypsin}
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a novel class of macrocyclic compounds, which are useful as cysteine protease inhibitors. Also provided are novel intermediates and methods of preparing the compounds. The invention also provides pharmaceutical compositions comprising the compounds. The compounds and compositions are useful in methods of treating or preventing one or more diseases associated with cysteine protease activity, particularly those associated with calpain activity.

## Claims

### Claim at position 1

1-64. (canceled)

### Claim 65

A compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate or prodrug derivative thereof:
wherein;
A is —C(═O)R5 or —S(═O)2R6;
wherein R5 is optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted arylalkoxy or optionally substituted heteroarylalkoxy; and
R6 is optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted arylalkoxy or optionally substituted heteroarylalkoxy;
R2 is a side chain of a natural or non-natural alpha-amino acid;
R3 is —CH2OH, —CH2OR7, —CH2N3, —CH2NR8R9, —CH(OH)R10, —CHO, —CH(OH)C(═O)NR11R12, —C(═O)C(═O)NR11R12, or —C(═O)R13;
wherein R7 is C1-C6 alkyl, aryl or arylalkyl;
R8 is hydrogen, C1-C6 alkyl, aryl or arylalkyl;
R9 is hydrogen, C1-C6 alkyl, aryl or arylalkyl;
R10 is C1-C6 alkyl, alkoxy, thioalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl or cyano;
R11 and R12 are each independently selected from hydrogen, C1-C6 alkyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R11 and R12 taken together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl; and
R13 is C1-C6 alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R4 is —O—R20— which is attached to the 1,4-phenylene ring through the oxygen atom;
wherein R20 is optionally substituted straight chain —(C3-C6)-alkyl- or optionally substituted straight chain —(C3-C6)-alkenyl-; wherein any one methylene group within the straight chain —(C3-C6)-alkyl- or straight chain —(C3-C6)-alkenyl-, except the methylene group adjacent to the oxygen atom to which R20 is attached, may be replaced by an oxygen, nitrogen or sulfur heteroatom or a —S(═O)— or —S(═O)2— group; and wherein any two carbon atoms, or a carbon atom and a nitrogen heteroatom, if present, of the straight chain —(C3-C6)-alkyl- or straight chain —(C3-C6)-alkenyl- may be linked to one another through a chain of 1 to 4 atoms to form a fused ring selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; and
R60, R61, R62 and R63 are each independently selected from hydrogen, halogen, —NH2, —NO2, —OH, C1-C6 alkyl and C1-C6 alkoxy.

### Claim 66 (depends on 65)

A compound as claimed in claim 65, wherein the compound has the following stereochemistry:

### Claim 67 (depends on 65)

A compound as claimed in claim 65, wherein R60, R61, R62 and R63 are each hydrogen.

### Claim 68 (depends on 65)

A compound as claimed in claim 65, wherein R2 is a side chain of a natural alpha-amino acid.

### Claim 69 (depends on 65)

A compound as claimed in claim 65, wherein R2 is a side chain of L-leucine or L-valine.

### Claim 70 (depends on 65)

A compound as claimed in claim 65, wherein A is —C(═O)R5.

### Claim 71 (depends on 70)

A compound as claimed in claim 70, wherein R5 is optionally substituted arylalkoxy, optionally substituted aryl or heteroaryl.

### Claim 72 (depends on 71)

A compound as claimed in claim 71, wherein R5 is benzyloxy.

### Claim 73 (depends on 71)

A compound as claimed in claim 71, wherein R5 is 2-pyrrolyl.

### Claim 74 (depends on 65)

A compound as claimed in claim 65, wherein A is —S(═O)2R6.

### Claim 75 (depends on 74)

A compound as claimed in claim 74, wherein R6 is optionally substituted C1-C6 alkyl or optionally substituted aryl.

### Claim 76 (depends on 75)

A compound as claimed in claim 75, wherein R6 is methyl.

### Claim 77 (depends on 75)

A compound as claimed in claim 75, wherein R6 is 4-fluorophenyl.

### Claim 78 (depends on 65)

A compound as claimed in claim 65, wherein R3 is —CH2OH or —CHO.

### Claim 79 (depends on 65)

A compound as claimed in claim 65, wherein R4 is —O-propyl-, —O-butyl-, —O-pentyl-, —O—(CH2)4OCH2— or —O—(CH2)4SCH2—.

### Claim 80

A compound selected from the group consisting of:
and the pharmaceutically acceptable salts, solvates, hydrates or prodrug derivatives thereof.

### Claim 81

A compound selected from the group consisting of:
and the pharmaceutically acceptable salts, solvates, hydrates or prodrug derivatives thereof.

### Claim 82 (depends on 65)

A method for the treatment or prophylaxis of a disease or disorder resulting from excessive cysteine protease activity in a mammal comprising the step of administering a compound as claimed in claim 65 to the mammal.

### Claim 83 (depends on 82)

A method as claimed in claim 82, wherein the cysteine protease is a calpain.

### Claim 84 (depends on 83)

A method as claimed in claim 83, wherein the disease or disorder is selected from the group consisting of: inflammatory and immunological diseases; cardiovascular and cerebrovascular diseases; disorders of the central or peripheral nervous system; osteoporosis; muscular dystrophies; cachexia; proliferative diseases; loss of hearing; ocular disorders; organ transplants; auto-immune and viral diseases; and cancer.

### Claim 85 (depends on 65)

A method for the treatment or prophylaxis of cataracts in a mammal comprising the step of administering a compound as claimed in claim 65 to the mammal.

### Claim 86 (depends on 65)

A pharmaceutical composition comprising a compound as claimed in claim 65 and a pharmaceutically acceptable carrier, diluent or excipient.