Triazolopyrimidine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11207325-B2
Application number	US-202016863631-A
Country	US
Kind code	B2
Filing date	Apr 30, 2020
Priority date	Dec 23, 2014
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder:wherein R1, R2, R3, R4, R5, and n are as defined herein.

First claim

What is claimed is:

1. A method for treating a disease or disorder mediated by Embryonic Ectoderm Development (EED) or Polycomb Repressive Complex 2 (PRC2), wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (IA), or a pharmaceutically acceptable salt thereof:

wherein:
R 1 and R 2 are independently H or halogen;
R 3 is independently selected from: halogen, phenyl, and a 5- to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O and S(O) p ; wherein said phenyl and heteroaryl are substituted with 0-3 R 3A ;
each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 6 alkyl substituted with 0-1 R 3B ), C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, R 3C , —OR 3c , —C(═O)R 3D , NR 3E R 3F , —C(═O)NR 3E R 3F , —NHC(═O)R 3D , —S(═O) 2 R 3D , —S(═O) 2 NR 3E R 3F , —NHS(═O) 2 (C 1 -C 4 alkyl), and —CR 3C R 3E R 3G ;
R 3B is independently selected from: OH, NR e R f , C 1 -C 4 alkoxy, —C(═O)NR e R f , —S(═O) 2 (C 1 -C 4 alkyl), —NHC(═O)(C 1 -C 4 alkyl), and a 5- to 6-membered heterocycloalkyl comprising carbon atoms and 1-2 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycloalkyl is substituted with 0-2 R c ;
each R 3C is independently selected from: C 3 -C 6 cycloalkyl, phenyl, and a 4- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein each moiety is substituted with 0-2 R c ;
each R 3D is independently selected from: C 1 -C 4 alkyl and R 3C ;
R 3E and R 3G are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
each R 3F is independently selected from: H and C 1 -C 4 alkyl substituted with 0-1 R d ;
R 4 is independently selected from: H, halogen and C 1 -C 4 alkyl;
R 5 is independently selected from OH and C 1 -C 4 alkyl;
each R a is independently selected from: H, →O, C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)H, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, and benzyl;
R b is independently selected from: halogen, OH and C 1 -C 4 alkoxy;
each R c is independently selected from: ═O, halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy;
R d is independently selected from: OH and NR e R f ;
R e and R f are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
each p is independently selected from 0, 1 and 2; and
m and n are, at each occurrence, independently selected from 0 and 1,

and wherein the disease or disorder is diffused large B cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast carcinoma, bile duct and gallbladder cancers, bladder carcinoma, neuroblastoma, schwannoma, glioma, glioblastoma, astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancers, parathyroid tumors, uterine tumors, and soft tissue sarcoma.

2. The method of claim 1 , wherein:
each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 4 alkyl substituted with 0-1 R 3B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, R 3C , —C(═O)R 3D , NR 3E R 3F , —C(═O)NR 3E R 3F , —S(═O) 2 R 3D , —S(═O) 2 NHR 3F , —NHS(═O) 2 (C 1 -C 4 alkyl), —O—C 3 -C 6 cycloalkyl, and

R a is independently selected from: H, →O, C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)H, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), and C 3 -C 6 cycloalkyl;
R 4 is H;
m is independently selected from 0 and 1; and
n is 0.

3. The method of claim 1 , wherein:
R 1 is independently H or F;
R 2 is H; and
R 3 is independently selected from: phenyl, and a 6-membered heteroaryl comprising carbon atoms and 1-2 heteroatoms selected from N and NR a ; wherein said phenyl and heteroaryl are substituted with 0-3 R 3A .

4. The method of claim 3 , wherein:
R 3 is independently selected from: phenyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl; wherein each moiety is substituted with 0-3 R 3A .

5. The method of claim 4 , wherein:
R 3 is independently selected from:

6. The method of claim 4 , wherein:
R 3 is independently selected from:

each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 4 alkyl substituted with 0-1 R 3B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), —C(═O)N(C 1 -C 4 alkyl) 2 , —C(═O)N(C 1 -C 4 alkyl)(CH 2 ) 2 N(C 1 -C 4 alkyl) 2 , —CH 2 NHC(═O)(C 1 -C 4 alkyl), —S(═O) 2 R 3D , —S(═O) 2 NH(C 1 -C 4 alkyl substituted with 0-1 OH), —NHS(═O) 2 (C 1 -C 4 alkyl), NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , C 3 -C 6 cycloalkyl,

R 3B is independently selected from: OH, NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkoxy, —C(═O)N(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl),

R 3D is independently selected from: C 1 -C 4 alkyl and 1H-piperidin-4-yl; and
each R a is independently selected from: H, C 1 -C 4 alkyl, —C(═O)H, —C(═O)(C 1 -C 4 alkyl), and —CO 2 (C 1 -C 4 alkyl).

7. The method of claim 6 , wherein:
R 3 is independently selected from:

each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 4 alkyl substituted with 0-1 R 3B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), —C(═O)N(C 1 -C 4 alkyl) 2 , —C(═O)N(C 1 -C 4 alkyl)(CH 2 ) 2 N(C 1 -C 4 alkyl) 2 , —CH 2 NHC(═O)(C 1 -C 4 alkyl), —S(═O) 2 (C 1 -C 4 alkyl), NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , C 3 -C 6 cycloalkyl,

R 3B is independently sleeted from: OH, N(C 1 -C 4 alkyl), C 1 -C 4 alkoxy, —C(═O)N(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl),

and
each R a is independently selected from: H, C 1 -C 4 alkyl, —C(═O)H, —C(═O)(C 1 -C 4 alkyl), and —CO 2 (C 1 -C 4 alkyl).

8. The method of claim 7 , wherein:
each R 3A is independently selected from: F, Cl, CH 3 , —CH 2 OH, CH 2 F, CHF 2 , CF 3 , CN, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCHF 2 , —C(═O)N(CH 3 ) 2 , —CH 2 NHC(═O)CH 3 , —S(═O) 2 CH 3 , NH 2 , cyclopropyl,

9. The method of claim 1 , wherein said compound, or a pharmaceutically acceptable salt thereof, is of Formula (IA-1):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently H or F; and

Assignees

• Novartis Ag

Inventors

• Chan Ho Man
• Gu Xiang-Ju Justin
• Huang Ying
• Li Ling
• Mi Yuan
• Qi Wei
• Sendzik Martin
• Sun Yongfeng
• Wang Long
• Yu Zhengtian
• Zhang Hailong
• Zhang Ji Yue (Jeff)
• Zhang Man
• Zhang Qiong
• Zhao Kehao

Classifications

• A61K45/06

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61P43/00

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

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title