Bicyclic fused pyrazole derivatives for the treatment of RSV

Patent metadata

Field	Value
Publication number	US-10906899-B2
Application number	US-201716099969-A
Country	US
Kind code	B2
Filing date	May 10, 2017
Priority date	May 10, 2016
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

Abstract

Disclosed herein are compounds and compositions for treating or inhibiting RSV and related members of the pneumovirus and paramyxovirus families such as human metapneumovirus, mumps virus, human parainfluenzaviruses, and Nipah and hendra virus, and methods of treatment or prevention thereof.

First claim

What is claimed is:

1. A method of inhibiting RSV, comprising administering to a patient in need thereof, an effective amount of a compound of Formula 1b:

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof, wherein:
R 0 is a monocyclic or bicyclic heteroaryl-alkyl having at least three carbon atoms and to three heteroatoms selected from the group consisting of O, S, and N, wherein said heteroaryl is substituted with Cl, F, or methoxy;
R 1 and R b together form a double bond;
R 2 is phenyl-alkyl, wherein the phenyl is optionally substituted with methoxy;
R 3 is a monocyclic or bicyclic heteroaryl having one to three heteroatoms selected from the group consisting of O, S, and N, wherein the heteroaryl is optionally substituted with alkoxy, alkyl, oxycycloalkyl, Cl, or F;
R 4 and R 5 together form a carbonyl;
R 6 and R 8 together form a double bond;
R 7 is alkyl or aryl optionally substituted with —R c or —OR c ; and
R a is selected from the group consisting of —R c , —OR c , —N(R c ) 2 , —SR c , —SO 2 R c , —SO 2 N(R c ) 2 ; —C(O)R c , OC(O)R c , —COOR c , —C(O)N(R c ) 2 , —OC(O)N(R c ) 2 , —N(R c )C(O), —N(R c )C(O)N(R c ) 2 , —F, —Cl, —Br, —I, —CN, and —NO 2 ;
wherein R c is selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, a monocyclic or bicyclic heterocyclyl having from two to eight carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N, C 6-12 aryl, a monocyclic or bicyclic heteroaryl having from three to twelve carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N, C 1-8 alkyl-C 3-8 cycloalkyl, a monocyclic or bicyclic heterocyclyl-alkyl having from three to sixteen carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N, C 1-8 alkyl-C 6-12 aryl, and a monocyclic or bicyclic heteroaryl-alkyl having from four to twenty carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N.

2. The method according to claim 1 , wherein R 7 is C 6 aryl.

3. The method according to claim 1 , wherein R 7 has the formula:

4. The method according to claim 1 , wherein R 7 has the formula:

5. The method according to claim 1 , wherein R 3 is a monocyclic or bicyclic heteroaryl having from three to twelve carbon atoms.

6. The method according to claim 1 , wherein R a is hydrogen.

7. The method according to claim 1 , wherein R 7 is C 1-8 alkyl.

8. The method according to claim 1 , wherein R 7 is methyl.

9. The method according to claim 1 , wherein R 2 is an unsubstituted phenyl-alkyl.

10. The method according to claim 1 , wherein R 0 is CH 2 -heteroaryl.

11. The method according to claim 1 , wherein R 0 is CH 2 -furan-2-yl.

12. The method according to claim 1 , wherein R 3 has the formula:

13. The method according to claim 1 , wherein R 3 has the formula:

14. A method of treating an RSV infection, comprising administering to a patient in need thereof an effective amount of a compound of Formula 1b:

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof, wherein:
R 0 is a monocyclic or bicyclic heteroaryl-alkyl having at least three carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N, wherein said heteroaryl is substituted with Cl, F, or methoxy,
R 1 and R b together form a double bond;
R 2 is a phenyl-alkyl, wherein the phenyl is optionally substituted with methoxy;
R 3 is a monocyclic or bicyclic heteroaryl having one to three heteroatoms selected from the group consisting of O, S, and N, wherein the heteroaryl is optionally substituted with alkoxy, alkyl, oxycycloalkyl, Cl, or F;
R 4 and R 5 together form a carbonyl;
R 6 and W together form a double bond;
R 7 is alkyl or aryl optionally substituted with —R c or —OR c ; and
R a is selected from the group consisting of —R c , —OR c ′, —N(R c ) 2 , —SR c , —SO 2 R c , —SO 2 N(R c ) 2 —C(O)R c , OC(O)R c , —COOR c , —C(O)N(R c ) 2 , —OC(O)N(R c ) 2 , —N(R c )C(O), —N(R c )C(O)N(R c ) 2 , —F, —Cl, —Br, —I, —CN, and —NO 2 ;
wherein R c is selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, a monocyclic or bicyclic heterocyclyl having from two to eight carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N, C 6-12 aryl, a monocyclic or bicyclic heteroaryl having from three to twelve carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N, C 1-8 alkyl-C 3-8 cycloalkyl, a monocyclic or bicyclic heterocyclyl-alkyl having from three to sixteen carbon atoms and one to three heteroatoms selected from the group consisting of 0, S, and N, C 1-8 alkyl-C 6-12 aryl, and a monocyclic or bicyclic heteroaryl-alkyl having from four to twenty carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N.

15. The method of treating an RSV infection according to claim 14 wherein the compound is administered via a route of administration selected from the group consisting of buccal, oral, intravenous, inhalation, intradermal, intramuscular, topical, subcutaneous, rectal, vaginal, parenteral, pulmonary, intranasal, and ophthalmic.

16. A compound of Formula 1b:

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof, wherein:
R 0 is a monocyclic or bicyclic heteroaryl-alkyl having at least three carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N, wherein said heteroaryl is substituted with Cl, F, or methoxy,
R 1 and R b together form a double bond;
R 2 is a phenyl-alkyl, wherein the phenyl is optionally substituted with methoxy;
R 3 is a monocyclic or bicyclic heteroaryl having one to three heteroatoms selected from the group consisting of O, S, and N, wherein the heteroaryl is optionally substituted with alkoxy, alkyl, oxycycloalkyl, Cl, or F;
R 4 and R 5 together form a carbonyl;
R 6 and W together form a double bond;
R 7 is alkyl or aryl optionally substituted with —R c or —OR c ; and
R a is selected from the group consisting of —R c , —OR c ′, —N(R c ) 2 , —SR c , —SO 2 R c , —SO 2 N(R c ) 2 —C(O)R c , OC(O)R c , —COOR c , —C(O)N(R c ) 2 , —OC(O)N(R c ) 2 , —N(R c )C(O), —N(R c )C(O)N(R c ) 2 , —F, —Cl, —Br, —I, —CN, and —NO 2 ;
wherein R c is selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, a monocyclic or bicyclic heterocyclyl having from two to eight carbon atoms and one to three heteroatoms selected from the group consisting of O, S, and N, C 6-12 aryl, a monocyclic or bicyclic heteroaryl

Assignees

• Univ Georgia State Res Found
• Aviragen Therapeutics Inc

Inventors

• Plemper Richard K
• Lee Eddy
• Vernachio John
• Bourque Elyse

Classifications

• C12N2760/18511

  Pneumovirus, e.g. human respiratory syncytial virus · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P31/12

  Antivirals · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title