Pyrazolo[1,5-A]pyrimidines for antiviral treatment

Patent metadata

Field	Value
Publication number	US-9238039-B2
Application number	US-201313905410-A
Country	US
Kind code	B2
Filing date	May 30, 2013
Priority date	Jun 24, 2010
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

The invention provides compounds of Formula I or Formula II:

or a pharmaceutically acceptable salt or ester, thereof, as described herein. The compounds and compositions thereof are useful for treating Pneumovirinae virus infections. The compounds, compositions, and methods provided are particularly useful for the treatment of Human respiratory syncytial virus infections.

First claim

What is claimed is:

1. A compound of Formula I or Formula II:

or a pharmaceutically acceptable salt, thereof;

wherein:
A is —(C(R 4 ) 2 ) n — wherein any one C(R 4 ) 2 of said —(C(R 4 ) 2 ) n — may be optionally replaced with —O—, —S—, —S(O) p —, NH or NR a ;
n is 3, 4, 5 or 6;
each p is 1 or 2;
Ar is a monocyclic heterocyclyl group having 3 to 7 ring atoms or a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S, or a C 6 -C 20 aryl group, wherein the monocyclic heterocyclyl group having 3 to 7 ring atoms, the bicyclic heterocyclyl group having 7 to 12 ring atoms, or the C 6 -C 20 aryl group is optionally substituted with 1 to 5 R 6 ;
X is —C(R 13 )(R 14 )—, —N(CH 2 R 14 )— or X is absent;
Y is N or CR 7 ;
each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 or R 8 is independently H, oxo, OR 11 , NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)R 11 , NR 11 C(O)NR 11 R 12 , N 3 , CN, NO 2 , SR 11 , S(O) p R a , NR 11 S(O) p R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O) p (OR 11 ), —SO 2 NR 11 R 12 , —NR 11 S(O) p (OR 11 ), —NR 11 SO p NR 11 R 12 , NR 11 C(═NR 11 )NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )carbocyclylalkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S;
two R 4 on adjacent carbon atoms, when taken together, may form a double bond between the two carbons to which they are attached or may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
four R 4 on adjacent carbon atoms, when taken together, may form an optionally substituted C 6 aryl ring;
two R 4 on the same carbon atom, when taken together, may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
two R 6 on adjacent carbon atoms, when taken together, may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
any R 6 adjacent to the obligate carbonyl group of said Ar, when taken together with R 3 , may form a bond or a—(C(R 5 ) 2 ) m — group wherein m is 1 or 2;
any R 6 adjacent to the obligate carbonyl group of said Ar, when taken together with R 2 , may form a bond;
each R a is independently (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )carbocyclylalkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, or a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S, wherein any (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl or (C 2 -C 8 )alkynyl of R a is optionally substituted with one or more OH, NH 2 , CO 2 H, a monocyclic heterocyclyl group having 3 to 7 ring atoms, or a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S, and wherein any aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )carbocyclylalkyl, monocyclic heterocyclyl group, or bicyclic heterocyclyl group of R a is optionally substituted with one or more substituents selected from OH, NH 2 , CO 2 H, (C 1 -C 8 )alkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, and a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S;
each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R a , —S(O) p R a , aryl(C 1 -C 8 )alkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S—, —S(O) p —, —NH—, —NR a —or —C(O)—;
R 13 is H or (C 1 -C 8 )alkyl;
R 14 is H, (C 1 -C 8 )alkyl, NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 12 , NR 11 S(O) p R a , —NR 11 S(O) p (OR 11 ) or NR 11 SO p NR 11 R 12 ; and
wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, monocyclic heterocyclyl group having 3 to 7 ring atoms, bicyclic heterocyclyl group having 7 to 12 ring atoms, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl of each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 or R 12 is, independently, optionally substituted with one or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .

2. The compound of claim 1 which is a compound of Formula I.

3. The compound of claim 1 wherein each R 3 is H.

4. The compound of claim 1 which is a compound of Formula VII or a compound of Formula VIII:

or a pharmaceutically acceptable salt or ester, thereof.

5. The compound of claim 4 which is a compound of Formula VII.

6. The compound of claim 1 wherein R 2 is H.

7. The compound of claim 1 wherein R 7 is H, halogen or (C 1 -C 8 )alkyl.

8. The compound of claim 1 wherein n is 3 or 4.

9. The compound of claim 1 wherein each R 4 is independently H or optionally substituted (C 1 -C 8 )alkyl, or four R 4 on adjacent carbon atoms, when taken together, may form an optionally substituted C 6 aryl ring.

10. The compound of claim 1 wherein A is —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH 2 —O—CH 2 —, —CH 2 —CH(CH 3 )—CH 2 —, —CH 2 —CH(CF 3 )—CH 2 —, —CH 2 —CH 2 —CH(CH 3 )— or the structure:

11. The compound of claim 1 wherein A is —(CH 2 ) 3 —.

12. The compound of claim 1 wherein X is —CR 13 (NR 11 C(O)OR 11 )—, —CR 13 (NR 11 R 12 )—, —CR 13 (NR 11 S(O) p R a )— or X is absent.

13. The compound of claim 1 wherein X is absent.

14. The compound of claim 1 wherein R 1 is H, OR 11 , NR 11 R 12 , CN, (C 1 -C 8 )alkyl, C 6 -C 20 aryl, (C 3 -C 7 )cycloalkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, a bicyclic heterocyclyl group havi

Assignees

• Gilead Sciences Inc

Inventors

• Babaoglu Kerim
• Boojamra Constantine G
• Eisenberg Eugene J
• Hui Hon Chung
• Mackman Richard L
• Parrish Jay P
• Sangi Michael
• Saunders Oliver L
• Siegel Dustin
• Sperandio David
• Yang Hai

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title