2,3,5-trisubstituted pyrazolo[1,5-A]pyrimidine compounds

Patent metadata

Field	Value
Publication number	US-12410170-B2
Application number	US-202017615550-A
Country	US
Kind code	B2
Filing date	Jun 3, 2020
Priority date	Jun 4, 2019
Publication date	Sep 9, 2025
Grant date	Sep 9, 2025

Abstract

Compounds that inhibit PI3Kγ, and compositions containing the compound(s) and methods for synthesizing the compounds, are described herein. Also described are the use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by PI3Kγ.

First claim

What is claimed is:

1. A compound represented by Formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,
X is C(R 2 ) or N;
R 1a and R 1b are each a member independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —Y 1 , —X 1 —C(O) 2 R a , —X 1 —OR a , —X 1 —NR a R b , —X 1 —CONR a R b , —X 1 —N(R a )SO 2 R a , —X 1 —SO 2 R a , —X 1 —SO 2 NR a R b , —X 1 —SO 3 R a , —X 1 —CN, —X 1 —Y 1 and —X 1 —Y 1 —Y 1a wherein each X 1 is a bond or C 1-6 alkylene and is optionally further substituted with from 1 to 3 substituents independently selected from the group consisting of OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl and CO 2 H, and each Y 1 and Y 1a is independently selected from the group consisting of C 3-10 cycloalkyl, 4- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and aryl, wherein each heterocycloalkyl and heteroaryl have 1 to 3 heteroatom ring vertices selected from O, N and S; and each Y 1 and Y 1a is optionally further substituted with one to four substituents independently selected from the group consisting of halogen, oxo, CN, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , CO—C 1-8 alkyl, COO—C 1-8 alkyl, and CO 2 H;
R 2 is a member selected from the group consisting of halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —Y 2 , —X 2 —C(O) 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —CONR a R b , —X 2 —SO 2 R a , —X 2 —N(R a )SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a , —O—X 2 —Y 2 and —X 2 —Y 2 wherein each X 2 is a bond or C 1-6 alkylene and is optionally further substituted with from 1 to 3 substituents independently selected from the group consisting of OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl and CO 2 H, and each Y 2 is selected from the group consisting of C 3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein each heterocycloalkyl and heteroaryl have 1 to 3 heteroatom ring vertices selected from O, N and S; and each Y 2 is optionally further substituted with one to four substituents independently selected from the group consisting of halogen, oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, and CO 2 H;
R 3 is a member selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl and —X 3 —Y 3 wherein each X 3 is a bond, C 1-6 alkylene or C 1-6 haloalkylene and is optionally further substituted with OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H, and each Y 3 is selected from the group consisting of C 3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein each heterocycloalkyl and heteroaryl have 1 to 3 heteroatom ring vertices selected from O, N and S; and each Y 3 is optionally further substituted with one to four substituents independently selected from the group consisting of halogen, oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, and CO 2 H;
R 4a and R 4b are each a member independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl;
each R a is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, C 1-6 alkylene-SO 3 H, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-3 alkyl, C 1-3 alkylC 3-6 cycloalkyl, phenyl and 3- to 7-membered heterocycloalkyl having from one to three heteroatom ring vertices selected from O, N and S; and each R a is optionally further substituted with one or two members independently selected from halogen, OH, C 1-4 alkoxy, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl and CO 2 H; and
each R b is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H, each of which is optionally further substituted with one or two members independently selected from OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl and CO 2 H.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
X is C(R 2 ) or N;
R 1a and R 1b are each a member independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —Y 1 , —X 1 —C(O) 2 R a , —X 1 —OR a , —X 1 —NR a R b , —X 1 —CONR a R b , —X 1 —N(R a )SO 2 R a , —X 1 —SO 2 R a , —X 1 —SO 2 NR a R b , —X 1 —SO 3 R a , —X 1 —CN, —X 1 —Y 1 and —X 1 —Y 1 —Y 1a wherein each X 1 is a bond or C 1-6 alkylene and is optionally further substituted with OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H, and each Y 1 and Y 1a is independently selected from the group consisting of C 3-10 cycloalkyl, 4- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and aryl, each of which is optionally further substituted with one to four substituents independently selected from the group consisting of halogen, oxo, CN, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , CO—C 1-8 alkyl, COO—C 1-8 alkyl, and CO 2 H;
R 2 is a member selected from the group consisting of halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —Y 2 , —X 2 —C(O) 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —CONR a R b , —X 2 —SO 2 R a , —X 2 —N(R a )SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a , —O—X 2 —Y 2 and —X 2 —Y 2 wherein each X 2 is a bond or C 1-6 alkylene and is optionally further substituted with OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H, and each Y 2 is selected from the group consisting of C 3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of which is optionally further substituted with one to four substituents independently selected from the group consisting of halogen, oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, and CO 2 H;
R 3 is a member selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-3 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl and —X 3 —Y 3 wherein each X 3 is a bond, C 1-6 alkylene or C 1-6 haloalkylene and is optionally further substituted with OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H, and each Y 3 is selected from the group consisting of C 3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of which is optionally further substituted with one to four substituents independently selected from the group consisting of halogen, oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, and CO 2 H;
R 4a and R 4b are each a member independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 al

Assignees

• Arcus Biosciences Inc

Inventors

• Beatty Joel Worley
• Drew Samuel Lawrie
• Fournier Jeremy Thomas Andre
• Jeffrey Jenna Leigh
• Lawson Kenneth Victor
• Leleti Manmohan Reddy
• Mailyan Artur Karenovich
• Mata Guillaume
• Miles Dillon Harding
• Powers Jay Patrick
• Sharif Ehesan Ui
• Thomas-Tran Rhiannon
• Yan Xuelei

Classifications

• A61N2005/0636

  Irradiating the whole body · CPC title

• A61N5/06

  using light · CPC title

• A61K45/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

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