C17-aryl substituted betulinic acid analogs

Patent metadata

Field	Value
Publication number	US-10047118-B2
Application number	US-201515523453-A
Country	US
Kind code	B2
Filing date	Nov 12, 2015
Priority date	Nov 14, 2014
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, betulinic acid derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula I:

These compounds are useful for the treatment of HIV and AIDS.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein R 1 is isopropenyl or isopropyl;
X is selected from the group of phenyl, heteroaryl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, C 4-9 spirocycloalkyl, C 4-9 spirocycloalkenyl, C 4-8 oxacycloalkyl, C 6-8 dioxacycloalkenyl, C 6-9 oxaspirocycloalkyl and C 6-9 oxaspirocycloalkenyl ring;
wherein X is substituted with A, wherein A is at least one member selected from the group of —H, -halo, -hydroxyl, —C 1-6 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkyl, —CN, —COOR 2 , —CONR 2 R 2 , —NR 8 R 9 , and —C 1-6 alkyl-Q,
Q is selected from the group of aryl, heteroaryl, substituted heteroaryl, —OR 2 , —COORS, —NR 2 R 2 , —SO 2 R 7 , —CONHSO 2 R 3 , and —CONHSO 2 NR 2 R 2 ;
R 2 is —H, —C 1-6 alkyl, -alkylsubstituted C 1-6 alkyl or benzyl;
Y is selected from the group of —COOR 2 , —C(O)NR 2 SO 2 R 3 , —C(O )NHSO 2 NR 2 R 2 , —NR 2 SO 2 R 2 , —SO 2 NR 2 R 2 , —C 3-6 cycloalkyl-COOR 2 ,—C 2-6 alkenyl-COOR 2 , —C 2-6 alkynyl-COOR 2 , —C 1-6 alkyl-COOR 2 , -alkylsubstituted-C 1-6 alkyl —COOR 2 , —CF 2 —COOR 2 , —NHC(O)(CH 2 )n—COOR 2 , —SO 2 NR 2 C(O)R 2 , -tetrazole, and —CONHOH,
wherein n=1-6;
W is absent or is .C≡C. ;
Z is a heteroaryl group, wherein Z can be substituted with —H, —C 1-6 alkyl, —C 1-6 substituted alkyl, —C 1-6 alkyl-Q 1 , —CONR 10 R 11 , and —COOR 2 ;
Q 1 is selected from the group of heteroaryl, substituted heteroaryl, halogen, —CF 3 , —OR 2 , —COOR 2 , —NR 4 R 5 , —CONR 10 R 11 and —SO 2 R 7 ;
R 3 is —H, —C 1-6 alkyl, -alkylsubstituted C 1-6 alkyl or benzyl;
R 4 is selected from the group of —H, —C 1-6 alkyl, —C 1-6 alkyl-C(OR 3 ) 2 —C 3-6 cycloalkyl, —C 1-6 substituted alkyl, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 1-6 alkyl-Q 1 , —C 1-6 alkyl-C 3-6 cycloalkyl-Q 1 , aryl, heteroaryl, substituted heteroaryl, —COR 6 , —COCOR 6 , —SO 2 R 7 , and —SO 2 NR 2 R 2 ;
R 5 is selected from the group of —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, —C 1-6 alkylsubstituted alkyl, —C 1-6 alkyl-NR 8 R 9 , —COR 10 , —COR 6 , —COCOR 6 , —SO 2 R 7 and —SO 2 NR 2 R 2 ;
or R 4 and R 5 are taken together with the adjacent N to form a cycle selected from the group of:

with the proviso that only one of R 4 or R 5 can be selected from the group of —COR 6 , —COCOR 6 , —SO 2 R 7 and —SO 2 NR 2 R 2 ;
R 6 is selected from the group of —H, —C 1-6 alkyl, —C 1-6 alkyl-substitutedalkyl, —C 3-6 cycloalkyl, —C 3-6 substitutedcycloalkyl-Q 2 , —C 1-6 alkyl-Q 2 , —C 1-6 alkyl-substitutedalkyl-Q 2, —C 3-6 cycloalkyl-Q 2 , aryl-Q 2 , —NR 2 R 2 , and —OR 3 ;
Q 2 is selected from the group of aryl, heteroaryl, substituted heteroaryl, —OR 2 , —COOR 2 , —NR 8 R 9 , SO 2 R 7 , —CONHSO 2 R 3 , and —CONHSO 2 NR 2 R 2 ;
R 7 is selected from the group of —H, —C 1-6 alkyl, —C 1-6 substituted alkyl, —C 3-6 cycloalkyl, —CF 3 , aryl, and heteroaryl;
R 8 and R 9 are independently selected from the group of —H, —C 1-6 alkyl, —C 1-6 substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, —C 1-6 alkyl-Q 2 , and —COOR 3 , or R 8 and R 9 are taken together with the adjacent N to form a cycle selected from the group of:

with the proviso that only one of R 8 or R 9 can be —COOR 3 ;
R 10 is selected from the group of —H, —C 1-6 alkyl, —NR 2 R 2 , and —COOR 3 ;
R 11 is selected from the group of —H, —C 1-6 alkyl, —C 1-6 alkyl-OH; —C 1-6 alkyl, —C 1-6 substituted alkyl,—C 3-6 cycloalkyl, —COR 7 , —COONR 2 R 2 , —SOR 7 , and —SONR 2 R 2 ; and
R 12 is selected from the group of —H, —C 1-6 alkyl, —COOR 3 , and aryl.

2. A compound or salt as claimed in claim 1 , wherein X is phenyl.

3. A compound or salt as claimed in claim 2 , wherein Y is —COOH.

4. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

5. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

6. A composition which comprises a compound or salt as claimed in claim 1 , together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

7. A composition which comprises a compound or salt as claimed in claim 4 , together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

Assignees

• Viiv Healthcare Uk No 5 Ltd

Inventors

• Chen Jie
• Chen Yan
• Meanwell Nicholas A
• Regueiro-Ren Alicia
• Sin Ny
• Sit Sing-Yuen

Classifications

• A61P31/18

  for HIV · CPC title

• C07J63/008 Primary

  Expansion of ring D by one atom, e.g. D homo steroids · CPC title