Pyrazolopyridine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11795166-B2
Application number	US-202117143567-A
Country	US
Kind code	B2
Filing date	Jan 7, 2021
Priority date	Sep 9, 2016
Publication date	Oct 24, 2023
Grant date	Oct 24, 2023

Abstract

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.

First claim

What is claimed is:

1. A method for treating a cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein said cancer is selected from breast cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, uterine cancer, renal cancer, hepatic cancer, gastric cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma; and wherein:
R 1 is Cy 1 ;
Cy 1 is selected from C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl 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 4-10 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C 3-10 cycloalkyl, 4-10 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 A is C 6-10 aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 20 ;
R 2 is selected from H, 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, CN, SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)OR a7 , NR c7 S(O)R b7 , NR c7 S(O) 2 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 , and S(O) 2 NR c7 R d7 ; 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 30 ;
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, 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 )NR 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 3-7-membered heterocycloalkyl ring, or a spiro C 3-6 cycloalkyl ring; wherein each spiro 3-7-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 3-7-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group; and wherein the spiro 3-7-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, 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 , S(O) 2 R b3 , 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 heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , 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 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl 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, 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 e2 )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 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 21 ;
or two adjacent R 20 substituents on the Cy A ring, taken together with the atoms to which they are attached, form a fused C 3-7 cycloalkyl ring; wherein a ring-forming ca

Assignees

• Incyte Corp

Inventors

• Vechorkin Oleg
• Pan Jun
• Liu Kai
• Sokolsky Alexander
• Wang Anlai
• Ye Hai Fen
• Yao Wenqing

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  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

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title