# US 9,434,762 B2 · Macrocyclic cysteine protease inhibitors and compositions thereof

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- Number: US 9,434,762 B2
- Document ID: US9434762B2
- Status: Granted
- Kind: B2
- Application number: 14/206,051
- Filed: 2014-03-12
- Published: 2014-07-10
- Granted: 2016-09-06
- Earliest claimed: 2006-10-18
- Assignees: University of Canterbury; Lincoln University; Douglas Pharmaceuticals Limited
- Applicants: Lincoln University; Canterprise Limited; Douglas Pharmaceuticals 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/US9434762B2

## 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 1

A compound of Formula I or a pharmaceutically acceptable salt 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 2 (depends on 1)

A compound as claimed in claim 1, wherein the compound has the following stereochemistry:

### Claim 3 (depends on 1)

A compound as claimed in claim 1, wherein R60, R61, R62 and R63 are each hydrogen.

### Claim 4 (depends on 1)

A compound as claimed in claim 1, wherein R2 is a side chain of a natural alpha-amino acid.

### Claim 5 (depends on 1)

A compound as claimed in claim 1, wherein R2 is a side chain of L-leucine or L-valine.

### Claim 6 (depends on 1)

A compound as claimed in claim 1, wherein A is —C(═O)R5.

### Claim 7 (depends on 6)

A compound as claimed in claim 6, wherein R5 is optionally substituted arylalkoxy, optionally substituted aryl or heteroaryl.

### Claim 8 (depends on 7)

A compound as claimed in claim 7, wherein R5 is benzyloxy.

### Claim 9 (depends on 7)

A compound as claimed in claim 7, wherein R5 is 2-pyrrolyl.

### Claim 10 (depends on 1)

A compound as claimed in claim 1, wherein A is —S(═O)2R6.

### Claim 11 (depends on 10)

A compound as claimed in claim 10, wherein R6 is optionally substituted C1-C6 alkyl or optionally substituted aryl.

### Claim 12 (depends on 11)

A compound as claimed in claim 11, wherein R6 is methyl.

### Claim 13 (depends on 11)

A compound as claimed in claim 11, wherein R6 is 4-fluorophenyl.

### Claim 14 (depends on 1)

A compound as claimed in claim 1, wherein R3 is —CH2OH or —CHO.

### Claim 15 (depends on 1)

A compound as claimed in claim 1, wherein R4 is —O-propyl-, —O-butyl-, —O-pentyl-, —O—(CH2)4OCH2— or —O—(CH2)4SCH2—.

### Claim 16

A compound selected from the group consisting of:
and the pharmaceutically acceptable salts.

### Claim 17

A compound selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.

### Claim 18 (depends on 1)

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 1 to the mammal.

### Claim 19 (depends on 18)

A method as claimed in claim 18, wherein the cysteine protease is a calpain.

### Claim 20 (depends on 19)

A method as claimed in claim 19, 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 21 (depends on 1)

A method for the treatment or prophylaxis of cataracts in a mammal comprising the step of administering a compound as claimed in claim 1 to the mammal.

### Claim 22 (depends on 1)

A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.