# US 2014/0154208 A1 · Novel [N-Me-4-hydroxyleucine]-9-Cyclosporin Analogues for Treatment and Prevention of Hepatitis C Infection

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- Number: US 2014/0154208 A1
- Document ID: US20140154208A1
- Status: Published application
- Kind: A1
- Application number: 14/092,171
- Filed: 2013-11-27
- Published: 2014-06-05
- Earliest claimed: 2012-11-28
- Assignees: Enanta Pharmaceuticals, Inc.
- Applicants: Enanta Pharmaceuticals, Inc.
- Inventors: Yat Sun Or; In Jong Kim; Jiang Long; Lijuan Jiang; Sheng Sean Liu; Guoqiang Wang
- Web page: https://patentgrep.com/patent/US20140154208A1

## CPC

- C07K 7/645: {Cyclosporins; Related peptides}
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/21: Interferons {[IFN]}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 7/64: Cyclic peptides containing only normal peptide links
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to novel cyclosporine analogues having antiviral activity against HCV and useful in the treatment of HCV infections. More particularly, the invention relates to novel cyclosporine analogue compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.

## Claims

### Claim 1

A compound represented by the formula (I) or (II):
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein R1 is selected from:
a) R11, wherein R11 is selected from:
1) Hydrogen;
2) Deuterium;
3) C1-C8 alkyl;
4) Substituted C1-C8 alkyl;
5) C2-C8 alkenyl;
6) Substituted C2-C8 alkenyl;
7) C2-C8 alkynyl;
8) Substituted C2-C8 alkynyl;
9) C3-C12 cycloalkyl;
10) Substituted C3-C12 cycloalkyl;
11) Aryl;
12) Substituted aryl;
13) Heterocycloalkyl;
14) Substituted heterocycloalkyl;
15) Heteroaryl; and
16) Substituted heteroaryl;
b) —C(O)N(R12)(R13), wherein R12 and R13 are independently selected from R11 and R11 is as previously defined or R12 and R13 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl;
c) R14, wherein R14 is selected from:
1)-M-R11, wherein R11 is as previously defined and M is selected from:
i. C1-C8 alkylene;
ii. Substituted C1-C8 alkylene;
iii. C2-C8 alkenylene;
iv. Substituted C2-C8 alkenylene;
v. C2-C8 alkynylene;
vi. Substituted C2-C8 alkynylene;
vii. C3-C12 cycloalkylene;
viii. Substituted C3-C12 cycloalkylene;
2) -M-NR15R18, wherein R15 and R18 are each independently R11; or R15 and R18 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl, and M is as previously defined;
3) -M-S(O)mRii, wherein m=0, 1, or 2; M and R11 are as previously defined;
4) -M-OR11, wherein M and R11 are as previously defined;
5) -M-C(O)R16, wherein M is as previously defined and R16 is selected from
i. C1-C8 alkyl;
ii. Substituted C1-C8 alkyl;
iii. C2-C8 alkenyl;
iv. Substituted C2-C8 alkenyl;
v. C2-C8 alkynyl;
vi. Substituted C2-C8 alkynyl;
vii. C3-C12 cycloalkyl; and
viii. Substituted C3-C12 cycloalkyl;
6) -M-OC(O)R16, wherein M and R16 are as previously defined;
7) -M-OC(O)OR16, wherein M and R16 are as previously defined;
8) -M-NR17C(O)R16, wherein R17 is R11, M and R16 are as previously defined;
9) -MNR17C(O)OR16, wherein R17, M and R16 are as previously defined;
10) -M-C(O)NR17R11, wherein R17, M and R11 are as previously defined;
11) -M-C(O)N(R17)—OR11, wherein R17, M and R11 are as previously defined;
12) -M-OC(O)NR17R11, wherein R17, M and R11 are as previously defined;
13) -M-NR17C(O)NR16R18, wherein M, R16, R17 and R18 are as previously defined or R16 and R17 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl;
14) -M-C(S)SR11, wherein M and R11 are as previously defined;
15) -M-OC(S)SR16, wherein M and R16 are as previously defined;
16) -M-NR17C(O)SR16, wherein M, R17 and R16 are as previously defined;
17) -M-SC(O)NR17R18, wherein M, R18 and R17 are as previously defined or R17 and R18 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl;
18) -M-CH═N—OR11, wherein M and R11 are as previously defined;
19) -M-CH═N—NR17R18, wherein M, R18 and R17 are as previously defined or R17 and R18 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl;
W is absent, or —O—, or —S(O)m—, where m=0, or 1, or 2;
R2, R3 and R4 are independently selected from: hydrogen or methyl.

### Claim 2 (depends on 1)

A compound according to claim 1 which is represented by the formula (III) or (IV):
wherein, R1, R3, R4, W are as defined in claim 1.

### Claim 3 (depends on 1)

A compound according to claim 1 which is represented by the formula (V) or (VI):
wherein, R1, R3, R4 are as defined in claim 1.

### Claim 4 (depends on 1)

A compound according to claim 1 represented by Formula VII or Formula VIII, wherein R1 for each compound is set forth in Table 1:
TABLE 1
Exam-
ple
R1
1
2
3
4
5
6
7
8
Ac
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 6 (depends on 5)

A method treating a viral infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition according to claim 5.

### Claim 7 (depends on 6)

The method according to claim 6, wherein said viral infection is selected from HCV, HBV, HAV and HIV infection.

### Claim 8 (depends on 6)

The method of claim 6, further comprising co-administering one or more additional anti-viral agents.

### Claim 9 (depends on 6)

The method of claim 6, wherein said one or more additional anti-viral agents are selected from peg-interferon, ribavirin, viral-enzyme targeted compounds, viral-genome-targeted therapies, immunomodulatory agents and Toll-receptor agonists.

### Claim 10 (depends on 9)

The method of claim 9, wherein said one or more additional anti-viral agents are selected from peg-interferon, viral-enzyme targeted compounds, viral-genome-targeted therapy, immunomodulatory agents and toll-receptor agonist and combinations thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein said viral-genome-targeted therapy is selected from RNA interference and RNAi.

### Claim 12 (depends on 11)

The method of claim 11, wherein said immunomodulatory agent is selected from ribavarin and interferon.