IP Library Granted Patent US 9,006,387
Granted Patent B2
US 9,006,387 · App. 14/180,886 · Granted Apr 14, 2015

Anti-viral compounds

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Quick Facts
Patent No.
US 9,006,387
App. No.
14/180,886
Granted
Apr 14, 2015
Kind
B2
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 (39)

1. A method of treating HCV infection, comprising administering to an HCV patient a compound of Formula I or a pharmaceutically acceptable salt thereof,

wherein:

X is

wherein the nitrogen ring atom is directly linked to -L 3 -D, and wherein X is optionally substituted with one or more R A ;

L 1 , L 2 and L 3 are bond;

A and B are each independently

and are each independently optionally substituted with one or more R A ;

D is C 3 -C 12 carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R A ;

Y is —N(R B )C(O)C(R 1 R 2 )N(R 5 )-T-R D or —N(R B )C(O)C(R 3 R 4 )C(R 6 R 7 )-T-R D ;

Z is —N(R B )C(O)C(R 8 R 9 )N(R 12 )-T-R D or —N(R B )C(O)C(R 10 R 11 )C(R 13 R 14 )-T-R D ;

R 1 is R C , and R 2 and R 5 , 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 R A ;

R 3 and R 6 are each independently R C , and R 4 and R 7 , taken together with the atoms to which they are attached, form a 3- to 12-membered carbocycle or heterocycle which is optionally substituted with one or more R A ;

R 8 is R C , and R 9 and R 12 , 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 R A ;

R 10 and R 13 are each independently R C , and R 11 and R 14 , taken together with the atoms to which they are attached, form a 3- to 12-membered carbocycle or heterocycle which is optionally substituted with one or more R A ;

T is each independently selected at each occurrence from bond, -L S -, -L S -M-L S ′-, or -L S -M-L S ′-M′-L S ″-, wherein M and M′ are each independently selected at each occurrence from bond, —O—, —S—, —N(R B )—, —C(O)—, —S(O) 2 —, —S(O)—, —OS(O)—, —OS(O) 2 —, —S(O) 2 O—, —S(O)O—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R B )—, —N(R B )C(O)—, —N(R B )C(O)O—, —OC(O)N(R B )—, —N(R B )S(O)—, —N(R B )S(O) 2 —, —S(O)N(R B )—, —S(O) 2 N(R B )—, —C(O)N(R B )C(O)—, —N(R B )C(O)N(R B ′)—, —N(R B )SO 2 N(R B ′)—, —N(R B )S(O)N(R B ′)—, C 3 -C 12 carbocycle or 3- to 12-membered heterocycle, and wherein said C 3 -C 12 carbocycle and 3- to 12-membered heterocycle are each independently optionally substituted at each occurrence with one or more R A ;

R D is each independently selected at each occurrence from hydrogen or R A ;

R A is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E ;

R B and R B ′ are each independently selected at each occurrence from hydrogen; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, 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 or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R B or R B ′ 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl or C 2 -C 6 haloalkynyl;

R C is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, 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 or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R C 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl or C 2 -C 6 haloalkynyl;

R E is independently selected at each occurrence from —O—R S , —S—R S , —C(O)R S , —OC(O)R S , —C(O)OR S , —N(R S R S ′), —S(O)R S , —SO 2 R S , —C(O)N(R S R S ′), —N(R S )C(O)R S ′, —N(R S )C(O)N(R S ′R S ″), —N(R S )SO 2 R S ′, —SO 2 N(R S R S ′), —N(R S )SO 2 N(R S ′R S ″), —N(R S )S(O)N(R S ′R S ″), —OS(O)—R S , —OS(O) 2 —R S , —S(O) 2 OR S , —S(O)OR S , —OC(O)OR S , —N(R S )C(O)OR S ′, —OC(O)N(R S R S ′), —N(R S )S(O)—R S ′, —S(O)N(R S R S ′) or —C(O)N(R S )C(O)—R S ′; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, 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 C 3 -C 6 carbocycle 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl or C 2 -C 6 haloalkynyl;

R L is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—R S , —S—R S , —C(O)R S , —OC(O)R S , —C(O)OR S , —N(R S R S ′), —S(O)R S , —SO 2 R S , —C(O)N(R S R S ′) or —N(R S )C(O)R S ′; or C 3 -C 6 carbocycle 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl or C 2 -C 6 haloalkynyl;

L S , L S ′ and L S ″ are each independently selected at each occurrence from bond; or C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, each of which is independently optionally substituted at each occurrence with one or more R L ; and

R S , R S ′ and R S ″ are each independently selected at each occurrence from hydrogen; C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, 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 or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R S , R S ′ or R S ′ 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl or C 2 -C 6 haloalkynyl.

2. The method of claim 1 , wherein:

T is independently selected at each occurrence from —C(O)-L S ′-M′-L S ″- or —N(R B )C(O)-L S ′-M′-L S ″-; and

L S ′ is each independently C 1 -C 6 alkylene, and is independently optionally substituted at each occurrence with one or more R L .

3. The method of claim 1 , wherein:

Y is —N(R B )C(O)C(R 1 R 2 )N(R 5 )-T-R D ;

Z is —N(R B )C(O)C(R 8 R 9 )N(R 12 )-T-R D ;

T is independently selected at each occurrence from —C(O)-L S ′-M′-L S ″-; and

D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 10-membered bicycles, and is substituted with one or more R A .

4. The method of claim 3 , wherein T is independently selected at each occurrence from —C(O)-L S ′-N(R B )C(O)-L S ″- or —C(O)-L S ′-N(R B )C(O)O-L S ″-; and R 2 and R 5 , taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R A ; and R 9 and R 12 , taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R A .

5. The method of claim 1 , wherein R A is independently selected at each occurrence from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, 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.

6. The method of claim 5 , wherein L S , L S ′ and L S ″ are each independently selected at each occurrence from bond; or C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.

7. The method of claim 4 , wherein R A is independently selected at each occurrence from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, 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.

8. The method of claim 7 , wherein L S , L S ′ and L S ″ are each independently selected at each occurrence from bond; or C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.

9. A method of claim 1 , wherein said compound is dimethyl (2S,2'S)-1,1′-((2S,2'S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 6, 2015
From: GAO, YI
To: ABBOTT LABORATORIES
Reel/Frame 034906/0171 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 28, 2015
From: ABBOTT LABORATORIES
To: ABBVIE INC.
Reel/Frame 034828/0598 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 28, 2015
From: DEGOEY, DAVID A.; KATI, WARREN M.; HUTCHINS, CHARLES W.; DONNER, PAMELA L.; KRUEGER, ALLAN C.; RANDOLPH, JOHN T.; MOTTER, CHRISTOPHER E.; NELSON, LISSA T.; PATEL, SACHIN V.; MATULENKO, MARK A.; KEDDY, RYAN G.; JINKERSON, TAMMIE K.; SOLTWEDEL, TODD N.; HUTCHINSON, DOUGLAS K.; FLENTGE, CHARLES A.; WAGNER, ROLF; MARING, CLARENCE J.; TUFANO, MICHAEL D.; BETEBENNER, DAVID A.; ROCKWAY, TODD W.
To: ABBOTT LABORATORIES
Reel/Frame 034828/0641 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 28, 2015
From: LIU, DACHUN; PRATT, JOHN K.; LAVIN, MICHAEL J.; SARRIS, KATHY; WOLLER, KEVIN R.; WAGAW, SEBLE H.; CALIFANO, JEAN C.; LI, WENKE; CASPI, DANIEL D.; BELLIZZI, MARY E.
To: ABBOTT LABORATORIES
Reel/Frame 034829/0086 →