Tricyclic compounds as HPK1 inhibitor and the use thereof

Patent metadata

Field	Value
Publication number	US-12459958-B2
Application number	US-202017627885-A
Country	US
Kind code	B2
Filing date	Jul 17, 2020
Priority date	Jul 17, 2019
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

Disclosed herein is a tricyclic compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.

First claim

What is claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein
X 1 is CH or N;
X 2 is N;
R 1 and R 2 are each hydrogen
n is 0;
R 3 is —CONR 3a R 3b ,
R 4 , at each of its occurrences, is independently halogen or —C 1-8 alkyl,
R 3a and R 3b are each independently hydrogen or —C 1-8 alkyl, said —C 1-8 alkyl is optionally substituted with at least one substituent R 3e , wherein R 3e is selected from —OR 3f or heterocyclyl, wherein the heterocyclyl is a 5-, 6- or 7-membered heterocyclyl comprising 1 heteroatom selected from nitrogen or oxygen; or
R 3a and R 3b , together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from nitrogen and oxygen as ring member(s), said ring is optionally substituted with at least one substituent R 3e , wherein R 3e is each independently selected from oxo, —C 1-8 alkyl, —OR 3f , —NR 3f R 3g or heterocyclyl, said —C 1-8 alkyl or heterocyclyl is optionally substituted by at least one halogen;
R 3f and R 3g are each independently hydrogen or —C 1-8 alkyl;
L 1 is a single bond
R 6 is —C 1-8 alkyl,
p is 0;
X 3 and X 4 are each CH 2 ;
L 2 is a single bond;
L 3 is CH 2 ;
R 51 is hydrogen or —C 1-8 alkyl; and
m is 0.

2. The compound according to claim 1 , wherein:
R 3a and R 3b are each independently hydrogen or —C 1-8 alkyl, said —C 1-8 alkyl is optionally substituted with at least one substituent R 3e ;
R 3e is selected from —OR 3f or heterocyclyl, wherein the heterocyclyl is a 5-, 6- or 7-membered heterocyclyl comprising 1 heteroatom selected from nitrogen or oxygen.

3. The compound according to claim 1 , wherein:
R 3a is —C 1-8 alkyl;
R 3b is —C 1-8 alkyl optionally substituted with at least one substituent R 3e ; and
R 3e is selected from —OR 3f or heterocyclyl, wherein the heterocyclyl is a 5-, 6- or 7-membered heterocyclyl comprising 1 heteroatom selected from nitrogen or oxygen.

4. The compound according to claim 3 , wherein:
R 3a is methyl, ethyl, propyl, 2-methylpropyl, butyl, pentyl or hexyl; and
R 3b is methyl, ethyl, propyl, 2-methylpropyl, butyl, pentyl or hexyl, each optionally substituted with at least one substituent R 3e .

5. The compound according to claim 1 , wherein:
R 3 is —CONR 3a R 3b ;
R 3a and R 3b , together with the nitrogen atom to which they are attached, form a 4- to 12-membered ring comprising 1 or 2 additional nitrogen or oxygen heteroatoms as ring member(s), said ring is optionally substituted with at least one substituent R 3e ; and
R 3e is each independently selected from —C 1-8 alkyl, —OR 3f , or heterocyclyl, said —C 1-8 alkyl or heterocyclyl is optionally substituted by at least one halogen.

6. The compound according to claim 5 , wherein:
a)
R 3a and R 3b , together with the nitrogen atom to which they are attached, form a monocyclic 3- to 8-membered ring comprising 1 or 2 additional nitrogen or oxygen heteroatoms as ring member(s), said ring is optionally substituted with at least one substituent R 3e ;
or

b)
R 3a and R 3b , together with the nitrogen atom to which they are attached, form a bicyclic spiro 7- to 12-membered ring comprising 1 or 2 additional nitrogen or oxygen heteroatoms as ring member(s), said ring is optionally substituted with at least one substituent R 3e .

7. The compound according to claim 6 , wherein:
a) R 3a and R 3b , together with the nitrogen atom to which they are attached, form a monocyclic 3- to 8-membered ring selected from azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is further substituted with a heterocyclyl group;
b) R 3a and R 3b , together with the nitrogen atom to which they are attached, form a bicyclic spiro 7- to 12-membered ring comprising 1 or 2 additional nitrogen or oxygen heteroatoms as ring member(s) selected from 4-membered/3-membered, 4-membered/4-membered, 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl; or
c) R 3a and R 3b , together with the nitrogen atom to which they are attached, form a bicyclic spiro 7- to 12-membered ring selected from 2,3-dihydrospiro [indene-1,2′-pyrrolidine], 1,3-dihydrospiro [indene-2,2′-pyrrolidine], azaspiro [2.4] heptane, 2-oxa-6-azaspiro [3.3] heptane, azaspiro [3.4] octane, 2-oxa-6-azaspiro [3.4] octane, azaspiro [3.4] octane, azaspiro [3.4] octane, 1,7-dioxaspiro [4.5]decane, 2-oxa-7-aza-spiro [4.4] nonane, 7-oxa-spiro [3.5] nonyl or 5-oxa-spiro [2.4] heptyl.

8. The compound according to claim 1 , wherein R 3 is selected from

9. The compound according to claim 1 , wherein n is 1 and R 4 is —C 1-8 alkyl.

10. The compound according to claim 1 , wherein the

moiety is

11. The compound according to claim 10 , wherein the

is selected from the following:

12. The compound according to claim 11 , wherein:
a) R 6 and R 51 are each independently —C 1-8 alkyl; or
b) R 6 and R 51 are each independently methyl, ethyl, propyl, butyl, pentyl or hexyl.

13. A compound according to claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Assignees

• Beigene Ltd
• Beone Medicines I Gmbh

Inventors

• Li Jing
• Wang Zhiwei
• Xu Sanjia

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D519/00 Primary

  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