Anti-viral compounds
View Patent ↗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.
1. A compound of Formula II, or a pharmaceutically acceptable salt thereof,
wherein:
X 1 and X 2 are each independently selected from a bond, -L S -, —O—, —S—, or —N(R B )—, and at least one of X 1 and X 2 is selected from —CH 2 —, —O—, —S—, or —N(R B )—;
R 7 and R 8 are each independently selected from hydrogen, -L A , C 5 -C 10 carbocyclyl, or 5- to 10-membered heterocyclyl, wherein at each occurrence said C 5 -C 10 carbocyclyl and 5- to 10-membered heterocyclyl are each independently optionally substituted with one or more R A ;
Z 1 and Z 2 are each independently selected from a bond, —C(R C R C′ )—, —O—, —S—, or —N(R B )—;
W 1 , W 2 , W 3 , W 4 , W 5 , and W 7 are each N, and W 6 and W 8 are each independently C(R D ), wherein R D is independently selected at each occurrence from hydrogen or R A ;
R 1 , R 2 , R 9 , R 11 , R 12 , R 14 , R 15 , and R 16 are each independently selected at each occurrence from hydrogen or R A ;
m and n are each independently selected from 0, 1, 2, or 3;
T is selected from a bond, -L S -, -L S -M-L S′ -, -L S -M-L S′ -M′-L S″ -, wherein M and M′ are each independently selected from a 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 5 -C 10 carbocycle, or 5- to 10-membered heterocycle, and wherein T is optionally substituted with one or more R A ;
R A is independently selected at each occurrence from halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl, cyano, -L A , 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, C 2 -C 6 alkynyl, C 3 -C 6 -carbocyclyl, C 3 -C 6 carbocyclylC 1 -C 6 alkyl, 3- to 6-membered heterocyclyl, or (3- or 6-membered heterocyclyl)C 1 -C 6 alkyl, 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;
R C and R C′ are each independently selected at each occurrence from hydrogen; halogen; hydroxy; mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo; formyl; cyano; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 6 carbocyclyl, 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;
L A is independently selected at each occurrence from 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, —O—R S , —S—R S , —N(R S R S′ ), —OC(O)R S , —C(O)OR S , nitro, phosphate, oxo, thioxo, formyl or cyano;
L S , L S′ and L S″ are each independently selected at each occurrence from a 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 substituents selected from halogen, —O—R S , —S—R S , —N(R S R S′ ), —OC(O)R S , —C(O)OR S , nitro, phosphate, oxo, thioxo, formyl or cyano;
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′ ), —C(O)N(R S )C(O)—R S′ , C 3 -C 6 carbocyclyl, or 3- to 6-membered heterocyclyl, and said C 3 -C 6 carbocyclyl and 3- to 6-membered heterocyclyl are each independently optionally substituted at each occurrence with one or more substituents selected from R S (except hydrogen), halogen, —O—R B , —S—R B , —N(R B R B′ ), —OC(O)OR B , —C(O)OR B , nitro, phosphate, oxo, thioxo, formyl or cyano; and
R S , R S′ and R S″ are each independently selected at each occurrence from hydrogen; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 carbocyclyl, C 3 -C 6 carbocyclylC 1 -C 6 alkyl, 3- to 6-membered heterocyclyl, or (3- or 6-membered heterocyclyl)C 1 -C 6 alkyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —O—R B , —S—R B , —N(R B R B′ ), —OC(O)R B , —C(O)OR B , nitro, phosphate, oxo, thioxo, formyl or cyano.
2. The compound or salt of claim 1 , wherein:
at least one of X 1 and X 2 is selected from —CH 2 —, —O—, or —S—;
at least one of R 7 and R 8 is selected from C 5 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl, wherein said C 5 -C 6 carbocyclyl and 5- to 6-membered heterocyclyl are optionally substituted with one or more R A ; and
Z 1 and Z 2 are each independently —N(R B )—.
3. The compound or salt of claim 2 , wherein:
X 1 and X 2 are each independently selected from —CH 2 —, —O—, or —S—;
R 7 and R 8 are each independently selected from C 5 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl, wherein at each occurrence said C 5 -C 6 carbocyclyl and 5- to 6-membered heterocyclyl are each optionally substituted with one or more R A ; and
Z 1 and Z 2 are each independently —N(R B )—.
4. The compound or salt of claim 1 , wherein:
R 1 and R 2 are hydrogen;
R 7 and R 8 are phenyl, and are each independently optionally substituted with one or more R A ; and
R 9 , R 11 , R 12 , R 14 , and R D are each independently selected at each occurrence from hydrogen; halogen; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 carbocyclyl, or C 3 -C 6 carbocyclyC 1 -C 6 alkyl, 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.
5. A compound of Formula III, or a pharmaceutically acceptable salt thereof,
wherein:
X 1 and X 2 are each independently selected from a bond, -L S -, —O—, —S—, or —N(R B )—, and at least one of X 1 and X 2 is selected from —CH 2 —, —O—, —S—, or —N(R B )—;
R 7 and R 8 are each independently selected from hydrogen, -L A , C 5 -C 10 carbocyclyl, or 5- to 10-membered heterocyclyl, wherein at each occurrence said C 5 -C 10 carbocyclyl and 5- to 10-membered heterocyclyl are each independently optionally substituted with one or more R A ;
Z 1 and Z 2 are each independently selected from a bond, —C(R C R C′ )—, —O—, —S—, or —N(R B )—;
W 1 , W 2 , W 3 , W 4 , W 5 , and W 7 are each N, and W 6 and W 8 are each independently C(R D ), wherein R D is independently selected at each occurrence from hydrogen or R A ;
R 1 , R 2 , R 9 , R 11 , R 12 , R 14 , R 15 , and R 16 are each independently selected at each occurrence from hydrogen or R A ;
m and n are each independently selected from 0, 1, 2, or 3;
T is selected from a bond, -L S -, -L S -M-L S′ -, -L S -M-L S′ -M′-L S″ -, wherein M and M′ are each independently selected from a 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 5 -C 10 carbocycle, or 5- to 10-membered heterocycle, and wherein T is optionally substituted with one or more R A ;
R A is independently selected at each occurrence from halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl, cyano, -L A , 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, C 2 -C 6 alkynyl, C 3 -C 6 carbocyclyl, C 3 -C 6 carbocyclylC 1 -C 6 alkyl, 3- to 6-membered heterocyclyl, or (3- or 6-membered heterocyclyl)C 1 -C 6 alkyl, 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;
R C and R C′ are each independently selected at each occurrence from hydrogen; halogen; hydroxy; mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo; formyl; cyano; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 6 carbocyclyl, 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;
L A is independently selected at each occurrence from 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, —O—R S , —S—R S , —N(R S R S′ ), —OC(O)R S , —C(O)OR S , nitro, phosphate, oxo, thioxo, formyl or cyano;
L S , L S′ and L S″ are each independently selected at each occurrence from a 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 substituents selected from halogen, —O—R S , —S—R S , —N(R S R S′ ), —OC(O)R S , —C(O)OR S , nitro, phosphate, oxo, thioxo, formyl or cyano;
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′ ), —C(O)N(R S )C(O)—R S′ , C 3 -C 6 carbocyclyl, or 3- to 6-membered heterocyclyl, and said C 3 -C 6 carbocyclyl and 3- to 6-membered heterocyclyl are each independently optionally substituted at each occurrence with one or more substituents selected from R S (except hydrogen), halogen, —O—R B , —S—R B , —N(R B R B′ ), —OC(O)R B , —C(O)OR B , nitro, phosphate, oxo, thioxo, formyl or cyano; and
R S , R S′ and R S″ are each independently selected at each occurrence from hydrogen; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 carbocyclyl, C 3 -C 6 carbocyclylC 1 -C 6 alkyl, 3- to 6-membered heterocyclyl, or (3- to 6-membered heterocyclyl)C 1 -C 6 alkyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —O—R B , —S—R B , —N(R B R B′ ), —OC(O)R B , —C(O)OR B , nitro, phosphate, oxo, thioxo, formyl or cyano.
6. The compound or salt of claim 5 , wherein:
at least one of X 1 and X 2 is selected from —CH 2 —, —O—, or —S—;
at least one of R 7 and R 8 is selected from C 5 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl, wherein said C 5 -C 6 carbocyclyl and 5- to 6-membered heterocyclyl are optionally substituted with one or more R A ; and
Z 1 and Z 2 are each independently —N(R B )—.
7. The compound or salt of claim 5 , wherein:
X 1 and X 2 are each independently selected from —CH 2 —, —O—, or —S—;
R 7 and R 8 are each independently selected from C 5 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl, wherein at each occurrence said C 5 -C 6 carbocyclyl and 5- to 6-membered heterocyclyl are each optionally substituted with one or more R A ; and
Z 1 and Z 2 are each independently —N(R B )—.
8. The compound or salt of claim 5 , wherein:
R 1 and R 2 are hydrogen;
R 7 and R 8 are phenyl, and are each independently optionally substituted with one or more R A ; and
R 9 , R 11 , R 12 , R 14 , and R D are each independently selected at each occurrence from hydrogen; halogen; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 carbocyclyl, or C 3 -C 6 carbocyclyC 1 -C 6 alkyl, 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.
9. A pharmaceutical composition comprising a compound or salt of claim 1 or 5 .
10. A process of making a compound of claim 1 or 5 , comprising the step of:
coupling a compound of Formula IV
to a compound of Formula V
wherein T 1 is a carboxylic acid, an activated derivative, or an activated ester and T 2 is an amine or a substituted amine, and A 1 , A 2 , Z 1 , Z 2 , W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in claim 1 or 5 .