Benzimidazole derivatives and aza-benzimidazole derivatives as Janus kinase 2 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-12522583-B2
Application number	US-201917291904-A
Country	US
Kind code	B2
Filing date	Nov 7, 2019
Priority date	Nov 7, 2018
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase (e.g., Janus kinase (JAK), e.g., Janus kinase 2 (JAK2)) inhibitors. Also provided are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits (e.g., for treating a disease (e.g., proliferative disease) in a subject in need thereof).

First claim

What is claimed is:

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein:
Y is —NR A R B ;
each instance of R a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two instances of R a are joined to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;
R A is —C(═O)R a , —C(═O)OR a , or —C(═O)N(R a ) 2 ;
R B is hydrogen or substituted or unsubstituted alkyl;
each instance of R C is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of X is independently C or N, provided that:
only 0, 1, or 2, or 3 instances of X are N; and

is a 9-membered bicyclic heteroaryl ring;
when attached to a carbon atom, each instance of R D is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
when attached to a nitrogen atom, each instance of R D is independently hydrogen, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
m is 0, 1, 2, 3, or 4, as valency permits;
R F is hydrogen, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , or substituted or unsubstituted alkyl;
each instance of R H is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and
n is 0, 1, 2, 3, 4, or 5;
provided that:
a) when

then R A is —C(═O)R a ,

and
b) when

2 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein each instance of R C is hydrogen.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein

4 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein at least one instance of R D attached to a carbon atom is hydrogen, halogen, or substituted or unsubstituted alkyl.

5 . The compound of claim 4 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein at least one instance of R D attached to a carbon atom is halogen or substituted or unsubstituted C 1-3 alkyl.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein at least one instance of R D attached to a nitrogen atom is hydrogen or substituted or unsubstituted alkyl.

7 . The compound of claim 6 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein at least one instance of R D attached to a nitrogen atom is substituted or unsubstituted C 1-3 alkyl.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein R F is hydrogen.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein

10 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein: at least one instance of R H is halogen or substituted or unsubstituted alkyl; and n is 1, 2, 3, 4, or 5.

11 . The compound of claim 10 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein at least one instance of R H is halogen or —CF 3 .

12 . The compound of claim 10 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein at least one instance of R H is -(substituted or unsubstituted, C 1-3 alkylene)-(substituted or unsubstituted piperazinyl).

13 . The compound of claim 10 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein n is 2.

14 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein the compound is of the formula:

15 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof, wherein the compound is of the formula:

16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17 . A pharmaceutical composition comprising:
a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, tautomer, or stereoisomer thereof; and a pharmaceutically acceptable excipient.

18 . A method of treating a cancer selected from brain cancer, pancreatic cancer, leukemia, lymphoma, essential thrombocythemia, myelofibrosis, myeloproliferative neoplasm, myeloid malignancy, or polycythemia vera in a subject in need t

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Gray Nathanael S
• Zhang Tinghu
• Liu Yao
• Weinstock David
• Li Loretta Sze-Mun

Classifications

• C07D473/28

  Oxygen atom · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title