# US 8,541,424 B2 · Anti-viral compounds

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- Number: US 8,541,424 B2
- Document ID: US8541424B2
- Status: Granted
- Kind: B2
- Application number: 12/644,427
- Filed: 2009-12-22
- Published: 2010-07-01
- Granted: 2013-09-24
- Earliest claimed: 2008-12-23
- Assignees: Abbott Laboratories
- Applicants: David A. DeGoey; Pamela L. Donner; Warren M. Kati; Charles W. Hutchins; Mark A. Matulenko; Tammie K. Jinkerson; Ryan G. Keddy
- Inventors: David A. DeGoey; Pamela L. Donner; Warren M. Kati; Charles W. Hutchins; Mark A. Matulenko; Tammie K. Jinkerson; Ryan G. Keddy
- Web page: https://patentgrep.com/patent/US8541424B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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:
A1 is C3-C14carbocyclyl or 3- to 14-membered heterocyclyl, and is substituted with —X1—R7, wherein said C3-C14carbocyclyl and 3- to 14-membered heterocyclyl are optionally substituted with one or more RA;
X1 is selected from a bond, -LS-, —O—, —S—, or —N(RB)—;
R7 is selected from C5-C10carbocyclyl, or 5- to 10-membered heterocyclyl, wherein at each occurrence said C5-C10carbocyclyl and 5- to 10-membered heterocyclyl are each independently optionally substituted with one or more RA;
Z1 is selected from a bond, —C(RCRC′)—, —O—, —S—, or —N(RB)—;
W1 and W2 are each N;
R1 is selected from hydrogen or RA;
R3 and R4, taken together with the carbon atoms to which they are attached, form
R9, R10, and R11 are each independently selected from hydrogen or RA;
A2 is C3-C14carbocyclyl or 3- to 14-membered heterocyclyl, and is optionally substituted with one or more RA;
R2 is —N(RB)C(O)C(R5R6)N(R8)-T-RD,
or -LK-B;
R5 is RC;
R6 is RC′, and R8 is RB; or R6 and R8, taken together with the atoms to which they are attached, form a 3- to 10-membered heterocyclic ring which is optionally substituted with one or more RA;
LK is 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, RS (except hydrogen), —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, —C(O)ORS, nitro, phosphate, oxo, thioxo, formyl or cyano; or —N(RB)C(O)— or —C(O)N(RB)—;
B is C3-C10carbocycle or 3- to 10-membered heterocycle, and is optionally substituted with one or more RA;
T is 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 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′)—, C5-C10carbocycle, or 5- to 10-membered heterocycle, and wherein at each occurrence T is independently optionally substituted with one or more RA;
RA is independently selected at each occurrence from halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl, cyano, LA, or -LS-RE;
RB and RB′ are each independently selected at each occurrence from hydrogen; or 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, phosphate, oxo, thioxo, formyl or cyano;
RC and RC′ are each independently selected at each occurrence from hydrogen; halogen; hydroxy; mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo; formyl; cyano; or C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C3-C6carbocyclyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;
RD, RD′ and RD″ are each independently selected at each occurrence from hydrogen or RA;
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, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, —C(O)ORS, nitro, phosphate, 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, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, —C(O)ORS, nitro, phosphate, thioxo, formyl or cyano;
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′, C3-C10carbocyclyl, 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 C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, RS (except hydrogen), halogen, —O—RB, —S—RB, —N(RBRB′), —OC(O)RB, —C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano; and
RS, RS′ and RS″ are each independently selected at each occurrence from hydrogen; or 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, —O—RB, —S—RB, —N(RBRB′), —OC(O)RB, —C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein:
A1 is C5-C6carbocyclyl or 5- to 6-membered heterocyclyl, which is optionally substituted with one or more RA, and A1 is substituted with —X1—R7;
R7 is C5-C6carbocyclyl or 5- to 6-membered heterocyclyl, and is optionally substituted with one or more RA; and
A2 is C5-C10carbocyclyl or 5- to 10-membered heterocyclyl, and is optionally substituted with one or more RA.

### Claim 3 (depends on 2)

The compound or salt of claim 2, wherein A2 is C5-C6carbocyclyl or 5- to 6-membered heterocyclyl, and is optionally substituted with one or more RA.

### Claim 4 (depends on 2)

The compound or salt of claim 2, wherein R7 is phenyl, and is optionally substituted with one or more RA.

### Claim 5 (depends on 2)

The compound or salt of claim 2, wherein A1 is phenyl, and is optionally substituted with one or more RA.

### Claim 6 (depends on 2)

The compound or salt of claim 2, wherein A2 is phenyl, and is optionally substituted with one or more RA.

### Claim 7 (depends on 2)

The compound or salt of claim 2, wherein A1, A2 and R7 are phenyl, and are each independently optionally substituted with one or more RA.

### Claim 8 (depends on 2)

The compound or salt of claim 2, wherein Z1 is —N(RB)—.

### Claim 9 (depends on 2)

The compound or salt of claim 2, wherein:
Z1 is —N(RB)—; and
X1 is —CH2—, —O—, or —S—.

### Claim 10 (depends on 9)

The compound or salt of claim 9, wherein
A1 is phenyl, and is optionally substituted with one or more RA;
R7 is phenyl, and is optionally substituted with one or more RA;
R1 is hydrogen;
R9, R10, and R11 are each independently selected from hydrogen; halogen; or C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, or C3-C6carbocyclyC1-C6alkyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano.

### Claim 11 (depends on 1)

The compound or salt of claim 1, wherein R2 is —N(RB)C(O)C(R5R6)N(R8)-T-RD.

### Claim 12 (depends on 11)

The compound or salt of claim 11, wherein R5 is RC, and R6 and R8 taken together with the atoms to which they are attached form a 5- to 6-membered heterocyclic ring which is optionally substituted with one or more RA.

### Claim 13 (depends on 11)

The compound or salt of claim 11, wherein:
R5 is H;
R6 and R8, taken together with the atoms to which they are attached, form
each of which is independently optionally substituted with one or more RA;
n is 0, 1 or 2; and
m is 1 or 2.

### Claim 14 (depends on 13)

The compound or salt of claim 13, wherein:
-T-RD is —C(O)-LS′-R12 or —C(O)-LS′-M′-LS″-R12; and
R12 is hydrogen; 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, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, —C(O)ORS, nitro, phosphate, oxo, thioxo, formyl or cyano; or C3-C10carbocyclyl or 3- to 10-membered heterocyclyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, -D-RB, —S—RB, —N(RBRB′), OC(O)RB, —C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano.

### Claim 15 (depends on 1)

The compound or salt of claim 1, wherein R2 is

### Claim 16 (depends on 15)

The compound or salt of claim 15, wherein R5 is RC, and R6 and R8, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring which is optionally substituted with one or more RA.

### Claim 17 (depends on 15)

The compound or salt of claim 15, wherein:
R5 is H;
R6 and R8, taken together with the atoms to which they are attached, form
which is optionally substituted with one or more RA;
n is 0, 1 or 2; and
m is 1 or 2.

### Claim 18 (depends on 17)

The compound or salt of claim 17, wherein:
-T-RD″ is —C(O)-LS′-R12 or —C(O)-LS′-M′-LS″-R12; and
R12 is hydrogen; 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, —O—RS, —S—RS, —N(RSRS′), —OC(O)RS, —C(O)ORS, nitro, phosphate, oxo, thioxo, formyl or cyano; or C3-C10carbocyclyl or 3- to 10-membered heterocyclyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, —O—RB, —S—RB, —N(RBRB′), OC(O)RB, —C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano.

### Claim 19 (depends on 1)

The compound or salt of claim 1, wherein R2 is

### Claim 20 (depends on 1)

The compound or salt of claim 1, wherein R2 is -LK-B.

### Claim 21 (depends on 20)

The compound or salt of claim 20, wherein B is C3-C10carbocycle or 3- to 10-membered heterocycle and is optionally substituted with one or more RA.

### Claim 22 (depends on 20)

The compound or salt of claim 20 wherein B is
and is optionally substituted with one or more RA.

### Claim 23 (depends on 20)

The compound or salt of claim 20, wherein:
n is 0, 1, 2, 3, or 4;
m is 0, 1, 2, or 3;
V is —C(O)— or —S(O)2—;
R12 is —RS, —ORS, or —N(RSRS′).

### Claim 24 (depends on 1)

A pharmaceutical composition comprising a compound or salt according to claim 1.

### Claim 25 (depends on 1)

A process of making a compound according to claim 1, comprising the step of:
coupling a compound of Formula IV
to a compound of Formula V
wherein T1 is a carboxylic acid, an activated derivative, or an activated ester, T2 is an amine or a substituted amine, and A1, A2, Z1, W1, W2, R1, R2, R3, and R4 are as defined in claim 1.