Pyrazolopyrimidine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-2022017521-A1
Application number	US-202117394006-A
Country	US
Kind code	A1
Filing date	Aug 4, 2021
Priority date	Sep 25, 2018
Publication date	Jan 20, 2022
Grant date	—

Abstract

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting ALK2 activity and/or FGFR activity, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with ALK2 activity and/or FGFR activity, such as cancer.

First claim

What is claimed is:

1 .- 53 . (canceled)

54 . A method of treating myeloproliferative diseases in a patient, wherein said method comprises administering to the patient a therapeutically effective amount of a compound of Formula I,

or a pharmaceutically acceptable salt thereof, and ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from Cy 1 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NOR a )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;
Cy 1 is selected from C 4-8 cycloalkyl 4-12 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl; wherein the 4-12 membered heterocycloalkyl and 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S: wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-12 membered heterocycloalkyi is optionally substituted by oxo to form a carbonyl group; and wherein the C 4-8 cycloalkyl, 4-12 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;
Cy is 4-12 membered heterocycloalkyl; wherein the 4-12 membered heterocycloalkyl has at least one ring-forming carbon atom and 1,2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of 4-12 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; wherein when the 4-12 membered heterocycloalkyl of Cy has a fused aromatic ring, the 4-12 membered heterocycloalkyi is directly attached to the pyrazolopyrimidine core structure through a ring-forming atom of the saturated or partially saturated ring; and wherein the 4-12 membered heterocycloalkyi is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 20 ;
R 2 is selected from H. D, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy,
each R 10 is independently selected from C 1-6 alkyl. C 2-6 alkenyl. C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl. 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene. 4-10 membered heterocycloalkyl-C 1-3 alkylene. C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene. halo, D, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 , R d1 , NR c1 ,C(O)R b1 , NR c1 C(O)OR a1 , NR c1 , C(O)NR c1 , R d1 , C(═NR e1 )R b1 , C(═NOR a1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl. 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1 , 2 , 3 , or 4 substituents independently selected from R 11 ;
or two R 10 substituents taken together with the carbon atom to which they are attached form a spiro 4-7-membered heterocycloalkyl ring, or a spiro C 3-6 cycloalkyl ring; wherein each spiro 4-7-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2 or 3, ring-forming heteroatoms independently selected from N, O, and S; wherein a ring-forming carbon atom of each spiro 4-7-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group; and wherein the spiro 4-7-membered heterocycloalkyl ring and spiro C 3-6 cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
each R 11 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl. C 3-10 cycloalkyl-C 1-3 alkylene. 4-10 membered heterocycloalkyl-C 1-3 alkylene. C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , and S(O) 2 NR c3 R d3 , wherein said C 1-6 alkyl, C 2-6 alkenyl. C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ;
each R 12 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaiyl, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d3 , C(O)OR a5 NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 S(O)R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyryl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl C 1-3 alkylene, and 5-10 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R 20 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene, halo, D, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(═NR e2 )R b2 , C(═NOR a2 )R b2 , C(═NR c2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalky, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalky-C 1-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R 21 ;
each R 21 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl. C 3-10 cycloalkyl-C 1-3 alkylene. 4-10 membered heterocycloalkyl-C 1-3 alkylene. C 6-10 aryl-C 1-3

Assignees

• Incyte Corp

Inventors

• Vechorkin Oleg
• Nguyen Minh
• Qi Chao
• Wang Anlai
• Wu Liangxing
• Yao Wenqing
• Zhao Peng

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/02 Primary

  in which the condensed system contains two hetero rings · CPC title