Substituted eneoxindoles and uses thereof

Patent metadata

Field	Value
Publication number	US-12037342-B2
Application number	US-202217820374-A
Country	US
Kind code	B2
Filing date	Aug 17, 2022
Priority date	May 23, 2019
Publication date	Jul 16, 2024
Grant date	Jul 16, 2024

Abstract

The present disclosure relates generally to certain ene-oxindole compounds, pharmaceutical compositions comprising thereof. Also disclosed are methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by hematopoietic progenitor kinase 1 (HPK1) inhibitors, such as HBV, HIV, cancer, and/or a hyper-proliferative disease.

First claim

What is claimed:

1. A method of treating a disease or disorder associated with increased hematopoietic progenitor kinase 1 (HPK1) activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a (i)-compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
A is N or CR 1 ;
each R 1 , R 2 , and R 3 is independently H, halogen, -CN, -N(R 13 ) 2 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, or —SO 2 R 13 , wherein the C 2 -C 3 alkynyl is unsubstituted or substituted with 1, 2, or 3 R 9 groups;
one of B and E is and the other is J;
J is H, —CN, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl; wherein the C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl is unsubstituted or substituted with 1, 2, or 3 R 10 groups;
is a group of formula

wherein
W is NR 4 or S;
X is N or CR 5 ;
Y is N or CR 6 ;
Z is N or CR 7 ;
X 1 is NH;
R 4 is H;
each R 5 , R 6 , and R 7 is independently H, halogen, —CN, -CON(R 8 ) 2 , -NR 13 C(O)R 13 ,—SO 2 N(R 13 ) 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -N(R 13 ) 2 , C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 4-6 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, or 4-6 membered heterocyclyl is unsubstituted or substituted with 1, 2, or 3 R 11 groups;
or wherein R 5 and R 6 , or R 6 and R 7 together with atoms to which they are attached form a phenyl or a 5-6 membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 11 groups;
each R 8 is independently H or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is unsubstituted or substituted with 1, 2, or 3 R 12 groups; or
wherein two R 8 groups together with the nitrogen they are attached to form a 4-6 membered heterocyclic ring having 1 or 2 heteroatoms selected from the group consisting of N, O, or S, wherein the 4-6 membered heterocyclic ring is unsubstituted or substituted with 1, 2, or 3 R 12 groups;
each R 9 is independently —OR 13 , C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl;
each R 10 and R 11 is independently selected from the group consisting of —OR 13 , halogen, CN, —N(R 8 ) 2 , —CON(R 8 ) 2 , —N(R 13 )COR 13 , —S(O) 2 R 13 , C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, and 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S;
each R 12 is independently —OR 13 , C 1 -C 3 alkyl, or —N(R 13 ) 2 ; wherein the C 1 -C 3 alkyl is unsubstituted or substituted with 1, 2, or 3 groups independently selected from —OR 13 and —N(R 13 ) 2 , each R 13 is independently H or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is unsubstituted or substituted with 1, 2, or 3 R 22 groups;
each R 22 is independently selected from the group consisting of halogen, —OH, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 wherein each C 1 -C 3 alkyl is same or different, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl with 1, 2, or 3 heteroatoms selected from N, O, and S, C 6 -C 10 aryl, and 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; and
is a group of formula:

wherein L 1 is N or CR 19 ;
n is 0, 1 or 2;
m is 0, 1, or 2;
p is 0,1, 2, 3, 4, 5, or 6;
R 19 is H, —OR 13 , halogen, CN, —N(R 13 ) 2 , or C 1 -C 3 alkyl;
each R 20 is independently —OR 13 , halogen, CN, —N(R 13 ) 2 , or C 1 -C 3 alkyl; and
each R 21 is independently —OR 13 , oxo, halogen, CN, —N(R 13 ) 2 , or C 1 -C 3 alkyl;
or two R 21 groups on same or adjoining atoms are joined together to form a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring having 1 or 2 heteroatoms selected from N, O, and S;
and (ii) a therapeutically effective amount of one or more additional therapeutic agents.

2. The method of claim 1 , wherein the compound is of a Formula I-Z:

3. The method of claim 1 , wherein the compound is of a Formula I-E:

4. The method of claim 1 , wherein is

5. The method of claim 1 , wherein is

6. The method of claim 1 , wherein is

7. The method of claim 1 , wherein the compound is of a Formula II-Z:

8. The method of claim 1 , wherein the compound is of a Formula Ha-Z:

9. The method of claim 1 , wherein each R 5 , R 6 , and R 7 is independently H, halogen, —CN, —CON(R 8 ) 2 , —NR 13 C(O)R 13 , —SO 2 N(R 13 ) 2 , C 1 -C 3 alkyl, 5-6 membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S, or C 3 -C 6 cycloalkyl; wherein the C 1 -C 3 alkyl or the C 3 -C 6 cycloalkyl is unsubstituted or substituted with 1, 2, or 3 R 11 groups.

10. The method of claim 1 , wherein R 5 is H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl.

11. The method of claim 1 , wherein R 6 is H, halogen, CN, C 1 -C 3 alkyl, or CON(R 8 ) 2 .

12. The method of claim 1 , wherein R 7 is H or C 1 -C 3 alkyl.

13. The method of claim 1 , wherein each R 5 , R 6 , and R 7 is H.

14. The method of claim 1 , wherein:
X is CR 5 ;
Y is CR 6 , and
wherein R 5 and R 6 together with atoms to which they are attached form a phenyl or 5-6 membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 11 groups.

15. The method of claim 1 , wherein
Y is CR 6 ;
Z is CR 7 , and
wherein R 6 and R 7 together with atoms to which they are attached form a phenyl or 5-6 membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S; wherein the phenyl or the 5-6 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 11 groups.

16. The method of claim 1 , wherein R 11 is selected from the group consisting of (i) CN, (ii) —N(R 8 ) 2 , (iii) —N(R 13 )COR 13 , and (iv) 4-6 membered heterocyclyl having 1, 2, or 3, heteroatoms independently selected from N, O, and S;
wherein each R 13 is independently H or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is unsubstituted or substituted with 1, 2, or 3 R 22 groups; and
each R 22 is independently selected from the gr

Assignees

• Gilead Sciences Inc

Inventors

• Aktoudianakis Evangelos
• Chandrasekhar Jayaraman
• Codelli Julian A
• Conway John H
• Elbel Kristyna M
• Kalla Rao V
• Metobo Samuel E
• Mitchell Scott A
• Perry Thao D
• Simonovich Scott P
• Ziebenhaus Christopher A

Classifications

• 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

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title