# US 2014/0155382 A1 · Anti-viral compounds

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- Number: US 2014/0155382 A1
- Document ID: US20140155382A1
- Status: Published application
- Kind: A1
- Application number: 14/087,480
- Filed: 2013-11-22
- Published: 2014-06-05
- Earliest claimed: 2009-04-15
- Assignees: AbbVie Inc.
- Applicants: Abbvie Inc.
- Inventors: David A. DEGOEY; Allan C. KRUEGER; Charles W. HUTCHINS; Warren M. KATI; William A. CARROLL
- Web page: https://patentgrep.com/patent/US20140155382A1

## CPC

- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- 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 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 207/22: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 209/52: condensed with a ring other than six-membered
- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 263/06: with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
- C07D 277/06: with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07K 5/06034: {the side chain containing 2 to 4 carbon atoms}
- C07K 5/06043: {Leu-amino acid}
- C07K 5/0606: {the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr}
- C07K 5/06069: {Ser-amino acid}
- C07K 5/06078: {and aromatic or cycloaliphatic}
- C07K 5/06139: {with the first amino acid being heterocyclic}
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

## Claims

### Claim 1

A compound of Formula I, or a pharmaceutically acceptable salt thereof,
wherein:
A and B are each independently phenyl, and are each independently optionally substituted with one or more RA;
D is C3-C10carbocycle or 3- to 10-membered heterocycle, and is optionally substituted with one or more RA; or D is selected from C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or more substituents selected from halogen, RT, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, —C(O)ORS, nitro, phosphonoxy, phosphono, oxo, thioxo, formyl or cyano; or D is hydrogen or RA;
X is C(RC) and is optionally substituted with RA or RF;
one of L1 and L2 is a bond and the other is —(CH2)—, wherein the —(CH2)— is optionally substituted with one or more substituents selected from halogen, RT, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, C(O)ORS, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano;
L3 is bond;
Y is selected from -T′-C(R1R2)N(R5)-T-RD, -T′-C(R3R4)C(R6R7)-T-RD, -LK-T-RD, or -LK-E;
R1 and R2 are each independently RC, and R5 is RB; or R1 is RC, and R2 and R5, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocyclic ring which is optionally substituted with one or more RA;
R3, R4, R6, and R7 are each independently RC; or R3 and R6 are each independently RC, and R4 and R7, taken together with the atoms to which they are attached, form a 3- to 12-membered carbocyclic or heterocyclic ring which is optionally substituted with one or more RA;
Z is selected from -T′-C(R8R9)N(R12)-T-RD, -T′-C(R10R11)C(R13R14)-T-RD, -LK-T-RD, or -LK-E;
R8 and R9 are each independently RC, and R12 is RB; or R8 is RC, and R9 and R12, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocyclic ring which is optionally substituted with one or more RA;
R10, R11, R13, and R14 are each independently RC; or R10 and R13 are each independently RC, and R11 and R14, taken together with the atoms to which they are attached, form a 3- to 12-membered carbocyclic or heterocyclic ring which is optionally substituted with one or more RA;
LK is independently selected at each occurrence from a bond, -LS-N(RB)C(O)-LS′- -LS-C(O)N(RB)-LS′-; or C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL; or C3-C12carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more RA;
E is independently selected at each occurrence from C3-C12carbocycle or 3- to 12-membered heterocycle, and is independently optionally substituted at each occurrence with one or more RA;
T and T′ are each independently selected at each occurrence from a bond, -LS-, -LS-M-LS′-, -LS-M-LS′-M′-LS″-, wherein M and M′ are each independently selected at each occurrence from a bond, —O—, —S—, —N(RB)—, —C(O)—, —S(O)2—, —S(O)—, —OS(O)—, —OS(O)2—, —S(O)2O—, —S(O)O—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(RB)—, —N(RB)C(O)—, —N(RB)C(O)O—, —OC(O)N(RB)—, —N(RB)S(O)—, —N(RB)S(O)2—, S(O)N(RB)—, —S(O)2N(RB)—, —C(O)N(RB)C(O)—, —N(RB)C(O)N(RB′)—, N(RB)SO2N(RB′)—, —N(RB)S(O)N(RB′)—, C3-C12carbocycle, or 3- to 12-membered heterocycle, and wherein said C3-C12carbocycle and 3- to 12-membered heterocycle are each independently optionally substituted at each occurrence with one or more RA;
RA is independently selected at each occurrence from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -LA, or -LS-RE, wherein two adjacent RA, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form a carbocycle or a heterocycle;
RB and RB′ are each independently selected at each occurrence from hydrogen or RE;
RC is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, or RE;
RD is each independently selected at each occurrence from hydrogen or RA;
RE is independently selected at each occurrence from —O—RS, —S—RS, —C(O)RS, —OC(O)RS, —C(O)ORS, —N(RSRS′), —S(O)RS, —SO2RS, —C(O)N(RSRS′), —N(RS)C(O)RS′, —N(RS)C(O)N(RS′RS″), —N(RS)SO2RS′, —SO2N(RSRS′), —N(RS)SO2N(RS′RS″), —N(RS)S(O)N(RS′RS″), —OS(O)—RS, —OS(O)2—RS, —S(O)2ORS, —S(O)ORS, —OC(O)ORS, —N(RS)C(O)ORS′, —OC(O)N(RSRS′), —N(RS)S(O)—RS′, —S(O)N(RSRS′), —C(O)N(RS)C(O)—RS′; C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C10-carbocyclyl, or 3- to 10-membered heterocyclyl, wherein said C3-C10carbocyclyl and 3- to 10-membered heterocyclyl are each independently optionally substituted at each occurrence with one or more substituents selected from halogen, RT, —O—RB, —S—RB, —N(RBRB′), —OC(O)RB, —C(O)ORB, nitro, phosphonoxy, phosphono, oxo, thioxo, formyl or cyano;
RF is independently selected at each occurrence from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered heterocyclyl or (3- or 6-membered heterocyclyl)C1-C6alkyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano;
RL is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—RS, —S—RS, —C(O)RS, —OC(O)RS, —C(O)ORS, —N(RSRS′), —S(O)RS, —SO2RS, —C(O)N(RSRS′), or —N(RS)C(O)RS′; or C3-C6carbocycle 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl, or C2-C6haloalkynyl; wherein two adjacent RL, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle;
LA is independently selected at each occurrence from C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, RT, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, C(O)ORS, nitro, phosphonoxy, phosphono, oxo, thioxo, formyl or cyano;
LS, LS′ and LS″ are each independently selected at each occurrence from a bond; or C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, RT, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, —C(O)ORS, nitro, phosphonoxy, phosphono, oxo, thioxo, formyl or cyano;
RS, RS′ and RS″ are each independently selected at each occurrence from hydrogen or RT;
RT is independently selected at each occurrence from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered heterocyclyl, or (3- or 6-membered heterocyclyl)C1-C6alkyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, RF, —O—RB, —S—RB, —N(RBRB′), —OC(O)RB, —C(O)ORB, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein:
X is CH;
T is independently selected at each occurrence from —C(O)-LS′-M′-LS″- or —N(RB)C(O)-LS′-M′-LS″-; and
LS′ is independently C1-C6alkylene, and is independently optionally substituted at each occurrence with one or more substituents selected from halogen, RT, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, C(O)ORS, nitro, phosphonoxy, phosphono, oxo, thioxo, formyl or cyano.

### Claim 3 (depends on 1)

The compound or salt of claim 1, wherein:
Y is —N(RB)C(O)C(R1R2)N(R5)-T-RD;
Z is —N(RB)C(O)C(R8R9)N(R12)-T-RD;
T is independently selected at each occurrence from —C(O)-LS′-M′-LS″-; and
D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 10-membered bicycles, and is optionally substituted with one or more RM, where RM is halogen, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano, or -LS-RE.

### Claim 4 (depends on 3)

The compound or salt of claim 3, wherein T is independently selected at each occurrence from —C(O)-LS′-N(RB)C(O)-LS″- or —C(O)-LS′-N(RB)C(O)O-LS″-.

### Claim 5 (depends on 3)

The compound or salt of claim 3, wherein RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.

### Claim 6 (depends on 1)

The compound or salt of claim 1, wherein:
D is hydrogen or RA;
Y is selected from -T′-C(R1R2)N(R5)-T-RD;
R1 is RC, and R2 and R5, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more RA;
Z is selected from -T′-C(R8R9)N(R12)-T-RD;
R8 is RC, and R9 and R12, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more RA; and
LS, LS′, and LS″ are each independently selected at each occurrence from a bond; or C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL.

### Claim 7 (depends on 6)

The compound or salt of claim 6, wherein:
D is hydrogen;
X is C(H) and is optionally substituted with RA;
one of L1 and L2 is a bond and the other is —(CH2)—;
T and T′ are each independently selected at each occurrence from a bond, -LS-, -LS-M-LS′-, -LS-M-LS′-M′-LS″-, wherein M and M′ are each independently selected at each occurrence from a —C(O)—, —N(RB)C(O)—, C3-C12carbocycle, or 3- to 12-membered heterocycle, and wherein said C3-C12carbocycle and 3- to 12-membered heterocycle are each independently optionally substituted at each occurrence with one or more RA;
RA is independently selected at each occurrence from -LS-RE, wherein two adjacent RA, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form a carbocycle or a heterocycle;
RB is independently selected at each occurrence from hydrogen;
RC is independently selected at each occurrence from hydrogen;
RE is independently selected at each occurrence from —O—RS or C1-C6alkyl;
LS, LS′, and LS″ are each independently selected at each occurrence from a bond or C1-C6alkylene; and
RS is independently selected at each occurrence from C1-C6alkyl.

### Claim 8 (depends on 7)

The compound or salt of claim 7, wherein:
Y is
Z is
T is independently selected at each occurrence from -LS-M-LS′-M′-LS″-, wherein M is —C(O)—, and M′ is —NHC(O)— or —NMeC(O)—;
LS and LS″ are bonds; and
LS′ are each independently selected at each occurrence from a C1-C6alkylene selected

### Claim 9 (depends on 8)

The compound or salt of claim 8, wherein:
T-RD is selected from

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a compound or salt of claim 1.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10, further comprising a HCV protease inhibitor, a HCV polymerase inhibitor, or another anti-HCV agent.

### Claim 12 (depends on 1)

A method of treating HCV infection, comprising administering to an HCV patient a compound or salt of claim 1.

### Claim 13 (depends on 1)

A process of making a compound of claim 1, comprising a step described in one of the schemes described hereinabove.