# US 8,785,378 B2 · Macrocyclic peptides as inhibitors of viral replication

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- Number: US 8,785,378 B2
- Document ID: US8785378B2
- Status: Granted
- Kind: B2
- Application number: 12/955,413
- Filed: 2010-11-29
- Published: 2011-03-24
- Granted: 2014-07-22
- Earliest claimed: 2006-07-13
- Assignees: Achillion Pharmaceuticals, Inc.
- Applicants: Avinash Phadke; Xiangzhu Wang; Suoming Zhang; Atul Agarwal
- Inventors: Avinash Phadke; Xiangzhu Wang; Suoming Zhang; Atul Agarwal
- Web page: https://patentgrep.com/patent/US8785378B2

## CPC

- A61K 38/05: Dipeptides
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 5/02: containing at least one abnormal peptide link
- C07K 5/06078: {and aromatic or cycloaliphatic}
- C07K 5/06139: {with the first amino acid being heterocyclic}
- C07K 5/06165: {and Pro-amino acid; Derivatives thereof}
- C07K 5/06191: {containing heteroatoms different from O, S, or N}
- C07K 5/0808: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- C07K 5/12: Cyclic peptides {with only normal peptide bonds in the ring}
- 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)
- 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
- 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)

## Abstract

The invention provides 4-amino-4-oxobutanoyl peptide compounds of Formula I and the pharmaceutically salts and hydrates thereof. The variables R1-R9, R16, R18, R19, n, M, n, M, and Z are defined herein. Certain compounds of Formula I are useful as antiviral agents. Certain 4-amino-4-oxobutanoyl peptide compounds disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more 4-amino-4-oxobutanoyl peptide compounds and one or more pharmaceutically acceptable carriers. Such pharmaceutical compositions may contain 4-amino-4-oxobutanoyl peptide compound as the only active agent or may contain a combination of 4-amino-4-oxobutanoyl peptide containing peptides compound and one or more other pharmaceutically active agents. The invention also provides methods for treating viral infections, including Hepatitis C infections, in mammals.

## Claims

### Claim 1

A compound of the formula:
or a pharmaceutically acceptable salt thereof, where
R1 is —(C═O)R12, or —(C═O)OR12, and
R2 is hydrogen, or
R1 and R2 are joined to form a 5- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently chosen from N, O, and S which ring is optionally fused to a phenyl or 5- or 6-membered heteroaryl to form a bicyclic ring system, each of which 5- to 7-membered heterocycloalkyl ring or bicyclic ring system is optionally substituted;
R3, R4, R6, and R8 are independently hydrogen or methyl;
R5 is a C7-C11 saturated or unsaturated hydrocarbon chain that is (i) covalently bound to R7, where R7 is a methylene group or R5 is a C7-C11 saturated or unsaturated hydrocarbon chain that is (ii) covalently bound to an optionally substituted cycloalkyl ring formed by R7 and R8 being joined to from a 3- to 7-membered optionally substituted cycloalkyl ring; and R6 is hydrogen, C1-C6alkyl, or (C3-C7cycloalkyl)C0-C2alkyl;
R9 is hydroxyl, amino, —COOH, —NR10R11, —OR12, —SR12, —NR10(S═O)R11, or —NR10SO2R11,
R10, R11, and R12 are independently at each occurrence
hydrogen, or
C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (aryl)C0-C2alkyl, (C3-C7cycloalkyl)C0-C2alkyl, (C3-C7cycloalkenyl)C0-C2alkyl, (heterocycloalkyl)C0-C2alkyl, or (5- to 10-membered heteroaryl)C0-C2alkyl, each of which substituted with 0 to 3 substituents independently chosen from halogen, hydroxyl, oxo, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, and trifluoromethoxy;
n is 0, 1, or 2;
M is hydrogen; halogen, hydroxyl, C1-C2alkyl, or C1-C2alkoxy;
Y is O, —O(C═O)(NR20)—, or —O(C═O)—;
Z is
R21 represents from 0 to 3 groups independently chosen from halogen, hydroxyl, amino, cyano, —CONH2, —COOH, C1-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, C1-C4alkylthio, mono- and di-C1-C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
R22 is hydrogen, halogen, hydroxyl, amino, cyano, —CONH2, —COOH, C1-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, C1-C4alkylthio, mono- and di-C1-C4alkylamino, C1-C4alkylester, C1-C2haloalkyl, and C1-C2haloalkoxy, or
R22 is (C3-C7cycloalkyl)C0-C2alkyl, (phenyl)C0-C2alkyl, (phenyl)C0-C2alkoxy, (5- or 6-membered heteroaryl)C0-C2alkyl, (5- or 6-membered heteroaryl)C0-C2alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl)C0-C2alkyl, or 9- or 10 membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently chosen from
(i) halogen, hydroxyl, amino, cyano, nitro, —COOH, —CONH2, CH3(C═O)NH—, C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxyalkyl, mono- and di-C1-C4alkylamino, —NR8SO2R11, —C(O)OR11, —NR8COR11, —NR8C(O)OR11, trifluoromethyl, trifluoromethoxy, and
(ii) phenyl and 5- or 6-membered heteroaryl, each of which is substituted with 0 or 1 or more of halogen, hydroxyl, C1-C4alkyl, C1-C2alkoxy; and
R16 represents 0 to 4 substituents is independently chosen at from halogen, C1-C2alkyl, and C1-C2alkoxy;
R18 and R19 are independently hydrogen, hydroxyl, halogen, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, or C1-C2haloalkoxy; and
R20 is hydrogen, C1-C2alkyl, C1-C2haloalkyl, or C1-C2haloalkoxy.

### Claim 2 (depends on 1)

A compound or salt of claim 1, wherein
R1 and R2 are joined to form a pyrrolidine, piperidine, or piperazine ring, or a piperazine ring fused to a phenyl, each of which is optionally substituted with 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, CONH2, —COOH, C1-C2alkyl, and C1-C2alkoxy.

### Claim 3 (depends on 1)

A compound of claim 1 in which R1 is
C1-C4O(C═O)—, C1-C4(C═O)—

### Claim 4 (depends on 3)

A compound or salt of claim 3, wherein R2 is hydrogen.

### Claim 5 (depends on 1)

A compound or salt of claim 1, wherein
R5 is a C7-C11 saturated or unsaturated hydrocarbon chain that is covalently bound to R7, where R7 is a methylene group.

### Claim 6 (depends on 5)

A compound or salt of claim 5, of the formula
where D is an alkyl or alkenyl group having 6 to 10 carbon atoms.

### Claim 7 (depends on 6)

A compound or salt of claim 6, of the formula

### Claim 8 (depends on 1)

A compound or salt of claim 1, wherein
R5 is a C7-C11 saturated or unsaturated hydrocarbon chain that is covalently bound to an optionally substituted cycloalkyl ring formed by R7 and R8 being joined to from a 3- to 7-membered optionally substituted cycloalkyl ring.

### Claim 9 (depends on 8)

A compound or salt of claim 8, of the formula
where D is an alkyl or alkenyl group having 6 to 10 carbon atoms;
Y is O and n is 0.

### Claim 10 (depends on 9)

A compound or salt of claim 9, of the formula

### Claim 11 (depends on 1)

A compound or salt of claim 1, wherein
R9 is hydroxyl-OR12 or —NR10SO2R11.

### Claim 12 (depends on 11)

A compound or salt of claim 11 wherein R9 is —NR10SO2R11,
where R10 is hydrogen or methyl and R11 is cyclopropyl.

### Claim 13 (depends on 11)

A compound or salt of claim 11, wherein
R9 is hydroxyl, —OR12, or —NR10SO2R11 where R10, R11, and R12 are independently hydrogen or C1-C6alkyl.

### Claim 14 (depends on 1)

A compound or salt of claim 1, wherein
R10, R11, and R12 are independently
hydrogen, or
C1-C6alkyl- or (C3-C7cycloalkyl)C0-C2alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxyl, oxo, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, and trifluoromethoxy.

### Claim 15 (depends on 1)

A compound or salt of claim 1 wherein n is 0 and Y is O.

### Claim 16 (depends on 1)

A compound or salt of claim 1, wherein
R21 represents a substituent at the 7-position of the quinoline, and 0 to 2 additional substituents independently chosen from halogen, hydroxyl, amino, cyano, —CONH2, —COOH, C1-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy; and
R22 is (phenyl)C0-C2alkyl or (pyridyl)C0-C2alkyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from halogen, hydroxyl, amino, cyano, —COOH, —CONH2, C1-C4alkyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, trifluoromethyl, and trifluoromethoxy.

### Claim 17 (depends on 16)

A compound or salt of claim 16, wherein
R21 is a methoxy or ethoxy substituent at the 7-position of the quinoline and R22 is phenyl or pyridyl.

### Claim 18 (depends on 1)

A compound or salt of claim 1, of the formula
wherein
R1 and R2 are joined to form a pyrrolidine, piperidine, or piperazine ring or a piperazine ring fused to a phenyl, each of which is optionally substituted with 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, CONH2, C1-C4alkyl(C═O)—COOH, C1-C2alkyl, and C1-C2alkoxy;
R3, R4, R6, and R8 are independently chosen from hydrogen, C1-C4alkyl, and (C3-C7cycloalkyl)C0-C2alkyl;
R9 is hydroxyl, amino, —COOH, NR10R11, —OR12, —NR10SO2R11, (C═O)OR10, or —CONR10R11;
R10, R11, and R12 are independently hydrogen, or
C1-C6alkyl, C2-C6alkenyl, C2C6alkynyl, (C3-C7cycloalkyl)C0-C2alkyl, (heterocycloalkyl)C0-C2alkyl, (phenyl)C0-C2alkyl, or (5- to 6-membered monocyclic heteroaryl)C0-C2alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxyl, oxo, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, and trifluoromethoxy;
R16 is 0 to 2 substituents independently chosen from halogen, C1-C2alkyl, and C1-C2alkoxy;
M is hydrogen or methyl; and
Z is a quinoline of the formula
wherein
R21 represents a substituent at the 7-position of the quinoline, and 0 to 2 additional substituents independently chosen from halogen, hydroxyl, amino, cyano, —CONH2, —COOH, C1-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy; and
R22 is (phenyl)C0-C2alkyl or (pyridyl)C0-C2alkyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from halogen, hydroxyl, amino, cyano, —COOH, —CONH2, C1-C4alkyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, trifluoromethyl, and trifluoromethoxy.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or salts claim 1 and at least one pharmaceutically acceptable carrier.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19 additionally comprising a second active agent.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20 wherein second active agent is ribavarin.

### Claim 22 (depends on 19)

The pharmaceutical composition of claim 19 additionally comprising at least one interferon or Peg-interferon alpha conjugate.

### Claim 23 (depends on 19)

The pharmaceutical composition of claim 19, wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a pill, a capsule, a syrup, ophthalmic solution, or a transdermal patch.

### Claim 24 (depends on 1)

A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is
(2R,6S,16aS,Z)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid;
(2R,6R,13aS,14aR,16aS,Z)-ethyl 2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aR,14aS,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide; or
(2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide.