Substituted 4,5,6,7-tetrahydropyrazolo[1,5-A]pyrazine derivatives as casein kinase 1 D/E inhibitors

Patent metadata

Field	Value
Publication number	US-9598423-B2
Application number	US-201415034217-A
Country	US
Kind code	B2
Filing date	Nov 14, 2014
Priority date	Nov 14, 2013
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The invention provides compounds of Formula (I):

and pharmaceutically acceptable salts thereof. The compounds of Formula (I) inhibit protein kinase activity thereby making them useful as anticancer agents.

First claim

What is claimed is:

1. A compound according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X is independently O or NH;
R 1 is independently carbocyclyl substituted with 1-5 R 5 , or heterocyclyl comprising carbon atoms and 1 to 3 heteroatoms selected from N, NR 4 , O, S, and substituted with 1-5 R 5 ;
R 2 is independently aryl substituted with 1-8 R 7 or heteroaryl comprising carbon atoms and 1 to 4 heteroatoms selected from N, NR 6 , O, S, and substituted with 1-8 R 7 ;
R 3a , R 3b , R 3c , R 3d , R 3e and R 3f are independently H, CN, C 1-4 alkyl substituted with 1-3 R 8 , —C(═O)OR b , —C(═O)NR a R a , —C(═O)R b , —NR a C(═O)R b , —NR a C(═O)OR b , —(CH 2 ) r -carbocyclyl substituted with 1-3 R 8 , or —(CH 2 ) r -heterocyclyl substituted with 1-3 R 8 ;
alternatively, R 3a and R 3b , or R 3c and R 3d , or R 3e and R 3f , together with the carbon atom to which they are both attached form a spiral carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, each substituted with 1-5 R 8 ;
alternatively, R 3a and R 3c or R 3b and R 3d together form a heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and substituted with 1-5 R 8 ;
R 4 is independently H, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r CN, —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 R c , (CH 2 ) r -carbocyclyl substituted with 0-3 R e , or —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 5 , at each occurrence, is independently H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, ═O, CN, NO 2 , —OR b , —(CH 2 ) r CN, —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 R c , (CH 2 ) r -carbocyclyl substituted with 0-3 R e , or —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 6 is independently H, —C(═O)R b , —CO(═O)R b , —S(O) p R c , C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-6 carbocyclyl substituted with 0-5 R e , or —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R 7 , at each occurrence, is independently H, F, Cl, Br, —(CR d R d ) r CN, NO 2 , —(CR d R d ) r OR b , —S(O) p R c , —C(═O)R b , —(CR d R d ) r NR a R a , —(CR d R d ) r C(═O)NR a R a , —NR a C(═O)R b , —NR a C(═O)OR b , —OC(═O)NR a R a , —NR a C(═O)NR a R a , —(CR d R d ) r C(═O)OR b , —S(O) 2 NR a R a , —NR a S(O) 2 NR a R a , —NR a S(O) 2 R e , C 1-6 alkyl substituted with 0-5 R e , —(CR d R d ) r —C 3-6 carbocyclyl substituted with 0-5 R e , or —(CR d R d ) r -heterocyclyl substituted with 0-5 R e ;
R 8 , at each occurrence, is independently H, F, Cl, Br, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , —(CH 2 ) r -heterocyclyl substituted with 0-5 R e , CO 2 H, —(CH 2 ) r OR b , or —(CH 2 ) r NR a R a ;
R a , at each occurrence, is independently H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , or —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , or —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, or heterocyclyl;
R d , at each occurrence, is independently H or C 1-4 alkyl substituted with 0-5 R e ;
R e , at each occurrence, is independently F, Cl, Br, CN, NO 2 , ═O, C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, —(CH 2 ) r -aryl, —(CH 2 ) r -heterocyclyl, CO 2 H, —(CH 2 ) r OR f , SR f , or —(CH 2 ) r NR f R f ;
R f , at each occurrence, is independently H, C 1-5 alkyl optionally substituted with F, Cl, Br, C 3-6 cycloalkyl, or phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl;
p, at each occurrence, is independently zero, 1, or 2; and
r, at each occurrence, is independently zero, 1, 2, 3, or 4.

2. The compound according to claim 1 , having Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently aryl substituted with 1-4 R 5 , or 5- to 12-membered heteroaryl comprising carbon atoms and 1 to 3 heteroatoms selected from N, NR 4 , O, S, and substituted with 1-4 R 5 ;
R 2 is independently aryl substituted with 1-8 R 7 or heteroaryl comprising carbon atoms and 1 to 4 heteroatoms selected from N, NR 6 , O, S, and substituted with 1-8 R 7 ;
R 3a , R 3b , R 6c , and R 3d are independently H, CN, C 1-4 alkyl substituted with 1-3 R 8 , —C(═O)OR b , —C(═O)NR a R a , —C(═O)R b , —NR a C(═O)R b , —NR a C(═O)OR b , —(CH 2 ) r -carbocyclyl substituted with 1-3 R 8 , or —(CH 2 ) r -heterocyclyl substituted with 1-3 R 8 ;
alternatively, R 3a and R 3b , or R 3c and R 3d , or R 3e and R 3f , together with the carbon atom to which they are both attached form a spiral carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, each substituted with 0-5 R e ;
alternatively, R 3a and R 3c or R 3b and R 3d together form a heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and substituted with 0-5 R e ;
R 4 is independently H or C 1-4 alkyl substituted with 0-3 R e ;
R 5 , at each occurrence, is independently H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, ═O, CN, NO 2 , —OR b , —(CH 2 ) r CN, —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 R e , (CH 2 ) r -carbocyclyl substituted with 0-3 R e , or —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 6 is independently H, —C(═O)R b , —CO(═O)R b , —S(O) p R c , C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-6 carbocyclyl substituted with 0-5 R e , or —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R 7 , at each occurrence, is independently H, F, Cl, Br, —(CR d R d ) r CN, NO 2 , —(CR d R d ) r OR b , —S(O) p R c , —C(═O)R b , —(CR d R d ) r NR a R a , —(CR d R d ) r C(═O)NR a R a , —NR a C(═O)R b , —NR a C(═O)OR b , —OC(═O)NR a R a , —NR a C(═O)NR a R a , —(CR d R

Assignees

• Bristol Myers Squibb Co

Inventors

• Velaparthi Upender
• Darne Chetan Padmakar
• Liu Peiying
• Wittman Mark D
• Pearce Bradley C
• Araujo Erika M V
• Dasgupta Bireshwar
• Nair Jalathi Surendran
• Janakiraman Sakthi Kumaran
• Rachamreddy Chandrasekhar Reddy
• Mettu Mallikarjuna Rao
• Karuppiah Arul Mozhi Selvan Subbiah
• Reddy Bandreddy Subba
• Nagalakshmi Pulicharla
• Bora Rajesh Onkardas
• Maheshwarappa Shilpa Holehatti
• Kumaravel Selvakumar
• Mullick Dibakar
• Sistla Ramesh

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title