Fused pyrazine derivatives as A2A / A2B inhibitors

Patent metadata

Field	Value
Publication number	US-11999740-B2
Application number	US-202117500140-A
Country	US
Kind code	B2
Filing date	Oct 13, 2021
Priority date	Jul 5, 2018
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

Abstract

This application relates to compounds of Formula (I):or pharmaceutically acceptable salts thereof, which modulate the activity of adenosine receptors, such as subtypes A2A and A2B receptors, and are useful in the treatment of diseases related to the activity of adenosine receptors including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.

First claim

What is claimed is:

1. A method of inhibiting an activity of an adenosine receptor, comprising contacting the receptor with a compound of Formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy 1 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 7 substituents;
each R 7 is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a7 , SR a7 , NHOR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)NR c7 (OR a7 ), C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 NR c7 R d7 , NR c7 C(O)R b7 NR c7 C(O)OR a7 , NR c7 C(O)NR c7 R d7 , C(═NR c7 )R b7 , C(═NOH)R b7 , C(═NCN)R b7 , C(═NR e7 )NR c7 R d7 , NR c7 C(═NR e7 )NR c7 R d7 , NR c7 C(═NOH)NR c7 R d7 , NR c7 C(═NCN)NR c7 R d7 , NR c7 C(═NR e7 )R b7 , NR c7 S(O)NR c7 R d7 , NR c7 S(O)R b7 , NR c7 S(O) 2 R b7 , NR c7 S(O)(═NR e7 )R b7 NR c7 S(O) 2 NR c7 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , S(O) 2 NR c7 R d7 , OS(O)(═NR e7 )R b7 , OS(O) 2 R b7 , SF 5 , P(O)R f7 R g7 , OP(O)(OR h7 )(OR i7 ), P(O)(OR h7 )(OR i7 ), and BR j7 R k7 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 7 are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents;
each R a7 , R b7 , R c7 , and R d7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a7 , R b7 , R c7 and R d7 are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents;
or, any R c7 and R d7 , attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents;
each R e7 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, and C 2-6 alkynyl;
each R f7 and R g7 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;
each R h7 and R i7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;
each R j7 and R k7 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
or any R j7 and R k7 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl;
each R 7A is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-5 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkylcarbonyloxy, aminocarbonyloxy, C 1-6 alkylaminocarbonyloxy, di(C 1-6 alkyl)aminocarbonyloxy, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;
R 2 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a2 , SR a2 , NHOR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)NR c2 (OR a2 ), C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 NR c2 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 c2 )R b2 , C(═NOH)R b2 , C(═NCN)R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 C(═NOH)NR c2 R d2 , NR c2 C(═NCN)NR c2 R d2 , NR c2 C(═NR e2 )R b2 , NR c2 S(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O)(═NR e2 )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 , S(O) 2 NR c2 R d2 , OS(O)(═NR e2 )R b2 , OS(O) 2 R b2 , SF 5 , P(O)R f2 R g2 , OP(O)(OR h2 )(OR i2 ), P(O)(OR h2 )(OR i2 ), and BR j2 R k2 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 2A substituents;
R 4 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)NR c4 (OR a4 ), C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 NR c4 NR c4 R d4 NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C(═NR e4 )R b4 , C(═NOH)R b4 , C(═NCN)R b4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , NR c4 C(═NOH)NR c4 R d4 , NR c4 C(═NCN)NR c4 R d4 , NR c4 C(═NR e4 )R b4 , NR c4 S(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O)(═NR e4 )R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , S(O) 2 NR c4 R d4 , OS(O)(═NR e4 )R b4 , OS(O) 2 R b4 , SF 5 , P(O)R f4 R g4 , OP(O)(OR h4 )(OR i4 ), P(O)(OR h4 )(OR i4 ), and BR j4 R k4 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 memb

Assignees

• Incyte Corp

Inventors

• Wang xiaozhao
• Carlsen Peter Niels
• Gan Pei
• Hoang Gia
• Li Yong
• Qi Chao
• Wu Liangxing
• Yao Wenqing
• Zhu Wenyu

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title