# US 8,785,377 B2 · Tetrazolyl macrocyclic hepatitis C serine protease inhibitors

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- Number: US 8,785,377 B2
- Document ID: US8785377B2
- Status: Granted
- Kind: B2
- Application number: 12/016,659
- Filed: 2008-01-18
- Published: 2009-05-21
- Granted: 2014-07-22
- Earliest claimed: 2006-08-04
- Assignees: Enanta Pharmaceuticals, Inc.
- Applicants: Ying Sun; Dong Liu; Yat Sun Or; Zhe Wang
- Inventors: Ying Sun; Dong Liu; Yat Sun Or; Zhe Wang
- Web page: https://patentgrep.com/patent/US8785377B2

## CPC

- C07K 5/0804: {and aliphatic}
- A61K 31/13: Amines {(A61K31/04 takes precedence)}
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 38/212: {IFN-alpha}
- A61K 38/215: {IFN-beta}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- C07D 487/04: Ortho-condensed systems
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to compounds of Formula I, II, III or IV, or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising a compound of the present invention.

## Claims

### Claim 1

A compound represented by Formula I, II, III or IV:
or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of R1, —(C═O)—O—R1, —(C═O)—R2, —C(═O)—NH—R2, —S(O)2—R1, and —S(O)2NHR2;
R1 is selected from the group consisting of:
(i) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; and
(iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
R2 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
G is selected from the group consisting of —NHS(O)2—R3 and —NH(SO2)NR4R5;
R3 is selected from the group consisting of:
(i) heteroaryl; substituted heteroaryl; and
(ii) heterocycloalkyl or substituted heterocycloalkyl;
R4 and R5 are independently selected from:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
L is selected from the group consisting of —CH2—, —O—, —S—, and —S(O)2—;
X is selected from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl;
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; and
(v) —W—R6, where W is absent, or selected from —O—, —S—, —NH—, —N(Me)—, —C(O)NH—, and —C(O)N(Me)-; R6 is selected from the group consisting of:
(a) hydrogen;
(b) aryl; substituted aryl; heteroaryl; substituted heteroaryl
(c) heterocyclic or substituted heterocyclic; and
(d) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
denotes a carbon-carbon single or double bond
j=0, 1, 2, 3, or 4;
k=1, 2, or 3;
m=0, 1, or 2; and
n=1, 2 or 3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is represented by Formula V, VI, VII or VIII:
or a pharmaceutically acceptable salt thereof, where A, G and X are as defined in claim 1.

### Claim 3

A compound represented by Formula IX, or a pharmaceutically acceptable salt thereof, where A, Q and G are delineated in Table 1,
TABLE 1
(IX)
Example #
A
Q
G
26
27
28
29
30
65
66
67
69
73
74
75
80
82
83
84
88
89
91
92
93
94

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

### Claim 5 (depends on 4)

A method of treating a hepatitis C viral infection in a subject, comprising administering to the subject an inhibitory amount of a pharmaceutical composition according to claim 4.

### Claim 6 (depends on 1)

A method of inhibiting the replication of hepatitis C virus, the method comprising contacting a hepatitis C virus with an effective amount of a compound of claim 1.

### Claim 7 (depends on 5)

The method of claim 5 further comprising administering concurrently an additional anti-hepatitis C virus agent.

### Claim 8 (depends on 7)

The method of claim 7, wherein said additional anti-hepatitis C virus agent is selected from the group consisting of: α-interferon, β-interferon, ribavarin, and adamantine.

### Claim 9 (depends on 7)

The method of claim 7, wherein said additional anti-hepatitis C virus agent is an inhibitor of hepatitis C virus helicase, polymerase, metalloprotease, or IRES.

### Claim 10 (depends on 4)

The pharmaceutical composition of claim 4, further comprising an agent selected from interferon, ribavirin, amantadine, another HCV protease inhibitor, an HCV polymerase inhibitor, an HCV helicase inhibitor, or an internal ribosome entry site inhibitor.

### Claim 11 (depends on 4)

The pharmaceutical composition of claim 4, further comprising pegylated interferon.

### Claim 12 (depends on 4)

The pharmaceutical composition of claim 4, further comprising another anti-viral, anti-bacterial, anti-fungal or anti-cancer agent, or an immune modulator.

### Claim 13 (depends on 4)

The pharmaceutical composition of claim 4, further comprising a cytochrome P450 monooxygenase inhibitor.

### Claim 14 (depends on 5)

The method of claim 5, further comprising administering concurrently a cytochrome P450 inhibitor.

### Claim 15 (depends on 13)

The composition of claim 13, wherein the cytochrome P450 inhibitor is an inhibitor of CYP3A4, CYP2C19, CYP2D6, CYP1A2, CYP2C9, or CYP2E1.

### Claim 16 (depends on 13)

The composition of claim 13, wherein the cytochrome P450 inhibitor is ritonavir, ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporin, or clomethiazole.

### Claim 17 (depends on 13)

The composition of claim 13, wherein the cytochrome P450 inhibitor is an inhibitor of CYP3A4.

### Claim 18 (depends on 13)

The composition of claim 13, wherein the cytochrome P450 inhibitor is ritonavir.