Hepatitis C virus inhibitors

Patent metadata

Field	Value
Publication number	US-9643999-B2
Application number	US-201314064619-A
Country	US
Kind code	B2
Filing date	Oct 28, 2013
Priority date	Nov 2, 2012
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

Hepatitis C virus inhibitors having the general formula (I)

are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.

First claim

What is claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2;
is a single or double bond;
R 1 is selected from

wherein R 1 is attached to the parent molecular moiety through any substitutable carbon atom in the group;
m is 0, 1, or 2;
n is 1, 2, 3, 4, 5, or 6;
z is 0, 1, 2, 3, 4, 5, or 6;
one of X 1 and X 3 is N and the other is selected from CH and CR a ;
X 2 is selected from CH and CR a ;
X 2′ is selected from CH and CR a ;
X 3′ is selected from N, CH, and CR a ;
X 4 is selected from CH and CR a ;
one of X 5 , X 6 , X 7 , and X 8 is N and the others are selected from CH and CR a′ ;
X 9 is selected from CR a , CH, and N;
each R a and R a′ are independently selected from alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, halo, haloalkyl, imidazolyl, oxazolyl, substituted pyrazolyl, thiazolyl, and —NR q R q′ , wherein the imidazolyl, the oxazolyl, and the thiazolyl are optionally substituted with one or two groups independently selected from alkoxy, alkyl, halo, and haloalkyl; and wherein the substituted pyrazolyl is substituted with one or two groups independently selected from alkoxy, alkyl, halo, and haloalkyl; and wherein two adjacent R a groups, together with the carbon atoms to which they are attached, can optionally form a furanyl ring; provided that at least one R a is other than alkoxy, alkyl, halo, or haloalkyl;
R x is selected from methyl and ethyl;
R y and R z are independently selected from hydrogen and hydroxy; provided that when is a double bond, R y and R z are each hydrogen;
R 2 is selected from hydrogen, alkyl, halo, haloalkoxy, haloalkyl, and hydroxyalkyl;
R 3 is selected from alkoxycarbonyl, alkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylcarbonyl, cycloalkyloxycarbonyl, deuteroalkoxycarbonyl, deuterohaloalkoxycarbonyl, haloalkoxycarbonyl, and
one of R q and R q′ is selected from hydrogen and alkyl and the other is selected from alkylcarbonyl and phenylcarbonyl.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m and p are 1.

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein is a double bond.

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R y and R z are hydrogen.

5. A compound of claim 1 wherein R 2 is selected from hydrogen and alkyl.

6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
m and p are 1;
is a double bond;
R y and R z are hydrogen;
and R 2 is selected from hydrogen and alkyl.

7. A compound selected from
methyl 1-(((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl)oxy)-6-methoxyisoquinoline-4-carboxylate;
methyl 1-(((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl)oxy)-6-methoxyisoquinoline-4-carboxylate;
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2-(1H-imidazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-7-ethyl-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate;
1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-(1H-imidazol-1-yl)-7-methoxyquinolin-2-yl)oxy)-7-ethyl-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,

Assignees

• Bristol Myers Squibb Co

Inventors

• Sun Li-Qiang
• Zhao Qian
• Renduchintala Kishore V
• Sarkunam Kandhasamy
• Nagalakshmi Pulicharla
• Gillis Eric P
• Scola Paul Michael

Classifications

• A61K38/208

  IL-12 · CPC title

• A61K38/204

  IL-6 · CPC title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• C07K5/0804

  and aliphatic · CPC title

• A61K38/00

  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) · CPC title