# US 8,771,665 B2 · Inhibitors of hepatitis C virus polymerase

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- Number: US 8,771,665 B2
- Document ID: US8771665B2
- Status: Granted
- Kind: B2
- Application number: 13/328,036
- Filed: 2011-12-16
- Published: 2012-07-19
- Granted: 2014-07-08
- Earliest claimed: 2010-12-17
- Assignees: Cocrystal Discovery, Inc.
- Applicants: Sam S K Lee; Wang Shen; Xiaoling Zheng; Irina C. Jacobson
- Inventors: Sam S K Lee; Wang Shen; Xiaoling Zheng; Irina C. Jacobson
- Web page: https://patentgrep.com/patent/US8771665B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/4436: containing a heterocyclic ring having sulfur as a ring hetero atom
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/497: containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 38/21: Interferons {[IFN]}
- A61K 38/212: {IFN-alpha}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/14: for RNA viruses
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The present invention provides, among other things, compounds represented by the general Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, R1A, R1B, R2, and R3 are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.

## Claims

### Claim 1

A compound according to Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
one of X and Y is —CH— and the other is —N—;
R1A and R1B are each selected from the group consisting of independently hydrogen, —C1-4alkyl, —C1-4alkyl-C3-7cycloalkyl, —C0-3alkyl-C5-7heterocycloalkyl, —C1-4hydroxyalkyl, —C1-4haloalkyl, —C1-4alkyl-O—C1-4alkyl, —S(O)2C1-4alkyl, —S(O)2—RP, —S(O)2C5-7aryl-C0-3alkyl, —C1-4alkyl-S(O)2RL, —C2-4alkyl-NRMRN, —C1-4alkyl-RO, —C0-3alkyl-RP, —C0-3alkyl-C(O)C1-4alkyl, —C0-3alkyl-C(O)—C1-4hydroxyalkyl, —C0-3alkyl-C(O)—O—C0-4alkyl-RO, —C0-3alkyl-C(O)—C0-4alkyl-RP, —C(O)O—C1-4alkyl, —C0-3alkyl-C(O)O—C0-4alkyl-RO, —C0-3alkyl-C(O)O—C0-4alkyl-RP, —C0-4alkyl-C(O)OH and, —C0-3alkyl-C(O)—C0-4alkyl-NRMRN;
wherein:
RL is selected from the group consisting of —C1-4alkyl, —C3-5cycloalkyl and, —NRMRN;
RM and RN are independently hydrogen or, —C1-4alkyl; or RM and RN together with the atoms to which they are attached can form a 4- to 6-membered ring;
RO is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, in each case monocyclic or bicyclic, and optionally substituted with (a) one to three moieties independently selected from —C1-4alkyl, halogen, —NRMRN, and —C1-4haloalkyl, or (b) a 6-membered aryl or 5-6 membered heteroaryl, optionally substituted with one to three moieties independently selected from —C1-4alkyl, halogen, and —NRMRN; and
RP is a 5- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with a hydroxyl;
provided that at least one of R1A and R1B is hydrogen;
R2 is selected from the group consisting of —C5-6cycloalkyl, —C5-6cycloalkyl-C1-3alkyl optionally substituted with a halogen, —C5-6cycloalkenyl, —C5-6cycloalkenyl-C1-3alkyl optionally substituted with a halogen and —C1-4alkyl-C3-5cycloalkyl;
R3 is —RA—RB or halo;
wherein RA is ethynyl, or phenyl optionally substituted with one or two halogens, and
wherein RB selected from the group consisting of is hydrogen, —C1-6alkyl, —C0-3alkyl-NRMRN, —NHC1-3alkyl-RQ, —N(RU)C(O)—RQ, —C(O)NURQ, carboxyl, —C2-6alkenyl, —C2-6alkynyl, —C0-3alkyl-C3-6cycloalkyl, —C1-4alkoxy, -methyl-(C1-4alkoxy)1-2, —C0-3alkyl-NRSRT, —C3-7cycloalkyl-C0-3alkyl-RQ, —C0-4alkyl-RQ, —C2-6alkynylRQ and, —C2-4alkenyl-RQ;
wherein RQ is a 5 to 9-membered monocyclic heteroaryl or 5 to 9-membered bicyclic heteroaryl or 3 to 7-membered cycloalkyl or 3 to 7-membered heterocycloalkyl, and, optionally substituted with one or two —C1-3alkyl or —NRMRN;
RS and RT are each independently hydrogen or —C1-4alkyl, or one of RS and RT is hydrogen and the other is —C(O)-5- to 9-membered aryl or heteroaryl; and
RU is hydrogen or —C1-4alkyl;
provided that, if RA is phenyl, then RB appears at the para or meta position relative to the thiophene moiety; and
R4 is selected from the group consisting of hydrogen, —C1-4alkyl, —C1-4alkyl-OC(O)O—C1-4alkyl, —C1-4alkyl-OC(O)—C1-4alkyl, —C1-4alkyl-OC(O)O—C3-6cycloalkyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C0-3alkyl-C5-6aryl and, —C1-4alkyl-NRURV;
wherein RU and RV are independently hydrogen or —C1-4alkyl.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein RA is ethynyl.

### Claim 3 (depends on 2)

A compound according to claim 2, wherein RB selected from the group consisting of is —C1-6alkyl, —C3-6cycloalkyl, —C1-4-alkoxy, -methyl-(C1-4-alkoxy)1-2.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein RA is phenyl.

### Claim 5 (depends on 4)

A compound according to claim 4, wherein RB appears at the para position relative to the thiophene moiety.

### Claim 6 (depends on 5)

A compound according to claim 5, wherein RB is —NHC(O)—RQ.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein R2 is —C5-6cycloalkyl-C1-3alkyl.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein:
R1A and R1B are each selected from the group consisting of independently hydrogen, —C1-4alkyl, —C1-3alkyl-C3-6cycloalkyl, —C1-4hydroxyalkyl, —C2-4alkyl-NRMRN, —C1-4alkyl ester and, —C1-3alkyl-C6-10aryl; and
RM and RN are independently hydrogen or, —C1-4alkyl; or RM and RN together with the atoms to which they are attached can form a 4- to 6-membered ring;
provided that at least one of R1A and R1B is hydrogen.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein X is —N— and R1B is hydrogen.

### Claim 10 (depends on 9)

A compound according to claim 9, wherein R1A is each selected from the group consisting of —C1-4alkyl, —C1-3alkyl-C3-6cycloalkyl, —C1-4hydroxyalkyl and, —C2-4alkyl-NRMRN.

### Claim 11 (depends on 1)

A compound according to claim 1, wherein R2 is —C5-6cycloalkyl-C1-3alkyl.

### Claim 12 (depends on 1)

A compound according to claim 1, wherein R4 is hydrogen.

### Claim 13 (depends on 1)

A composition comprising a compound according to claim 1, and at least one pharmaceutically acceptable carrier or excipient.