IP Library Granted Patent US 10,428,087
Granted Patent B2
US 10,428,087 · App. 15/959,942 · Granted Oct 1, 2019

Pyrimidinones as PI3K inhibitors

Inventors: Yun-Long Li (Chadds Ford, PA); Brian W. Metcalf (Moraga, CA); Andrew P. Combs (Kennett Square, PA)
Assignees: Incyte Corporation; Incyte Holdings Corporation
C07D519/00C07D471/04C07D487/04C07D513/04
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Quick Facts
Patent No.
US 10,428,087
App. No.
15/959,942
Granted
Oct 1, 2019
Kind
B2
Abstract

The present invention provides pyrimidinones that modulate the activity of phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

Claims (123)

1. A compound of Formula If:

or pharmaceutically acceptable salt thereof, wherein:

A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;

R 1 is OR A , SR A , S(O)R A , S(O) 2 R A , NR A R B , NR c C(O)NR A R B , NR C C(O)OR A , NR C C(═NR E )NR A R B , NR C S(O) 2 R A , NR C S(O) 2 NR C R A , heterocycloalkyl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from —(C 1-4 alkyl) r -Cy 1 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, 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 , C(═NR e )NR c1 R d1 , NR c1 C(═NR e )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 , 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 ;

R 2a is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, 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 , C(═NR e )NR c2 R d2 , NR c2 C(═NR e )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 , 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 ;

R 3 , R 4 , R 5 , and R 6 are independently selected from H, halo, CN, NO 2 , 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 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O) 2 NR c3 R d3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e )NR c3 R d3 , NR c3 C(═NR e )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 ;

R A is heteroaryl, heterocycloalkyl, heteroarylalkyl, or heterocycloalkylalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from —(C 1-4 alkyl) r -Cy 1 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, 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 , C(═NR e )NR c1 R d1 , NR c1 C(═NR e )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 , 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 ;

R B and R C are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

R E is H, CN, NO 2 , OR a5 , SR b5 , S(O) 2 R b5 , C(O)R b5 , S(O) 2 NR c5 R d5 , or C(O)NR c5 R d5 ;

Cy 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, 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 , C(═NR e )NR c1 R d1 , NR c1 C(═NR e )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 , 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 ;

R a , R b , R c , and R d are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

or R c and R d together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or a heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

R a1 , R b1 , R c1 , and R d1 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

or R c1 and R d1 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or a heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

R a2 , R b2 , R c2 , and R d2 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

or R c2 and R d2 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or a heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

R a3 , R b3 , R c3 , and R d3 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

or R c3 and R d3 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or a heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR a5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

R e and R f are independently selected from H, CN, NO 2 , OR a5 , SR b5 , S(O) 2 R b5 , C(O)R b5 , S(O) 2 NR c5 R d5 , and C(O)NR c5 R d5 ;

R a5 , R b5 , R c5 , and R d5 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

or R c5 and R d5 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 haloalkyl, and C 1-6 haloalkoxy; and

r is 0 or 1;

provided that:

a) when A is 3-fluorophenyl; R 2a is H; R 3 is methyl; and R 4 , R 5 , and R 6 are H; then, R 1 is other than 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl; and

b) when A is 1,3-dioxolan-2-yl; R 2a , R 3 , R 4 , and R 6 are H; then, R 1 is other than 1-(tert-butoxycarbonyl)piperidin-4-yl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR c )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, or C 1-6 haloalkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is phenyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is pyridyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, or C 1-6 haloalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl optionally substituted with 1 or 2 substituents independently selected from halo, C 1-6 alkyl, or C 1-6 haloalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is purinyl optionally substituted with —(C 1-4 alkyl) r -Cy 1 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, 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 , C(═NR e )NR c1 R d1 , NR c1 C(═NR e )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 , 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 , or S(O) 2 NR c1 R d1 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is NR A R B .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is purinyl optionally substituted with 1 or 2 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , NR c5 C(═NR f )NR c5 R d5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is:

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B and R c are independently selected from H and C 1-6 alkyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a is methyl or ethyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is halo, CN, NO 2 , 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 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O) 2 NR c3 R d3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e )NR c3 R d3 , NR c3 C(═NR e )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 .

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H or C 1-6 alkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , and R 6 are each H.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula Ih:

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula Ii:

wherein R 8 and R 9 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR f )NR c5 R d5 , NR c5 C(═NR f )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 .

21. The compound of claim 1 ,

or a pharmaceutically acceptable salt thereof; wherein:

A is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a ;

R 1 is NR A R B or heteroaryl; wherein said hetereoaryl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a1 ;

R 2a is C 1-6 alkyl;

R 3 , R 4 , R 5 , and R 6 are independently selected from H, halo, CN, NO 2 , OR a3 , and C 1-6 alkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo;

R A is heteroaryl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, CN, OR a1 , and NR c1 R d1 ;

R B is H;

each R a is independently selected from H and C 1-6 alkyl;

each R a1 , R c1 , and R d1 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo; and

each R a3 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo.

22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein:

A is phenyl, 5-membered heteroaryl or 6-membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a ;

R 1 is NR A R B or

R 2a is C 1-6 alkyl;

R 3 , R 4 , R 5 , and R 6 are independently selected from H, halo, CN, NO 2 , OR a3 , and C 1-6 alkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo;

R A is selected from:

R B is H;

each R a is independently selected from H and C 1-6 alkyl; and

each R a3 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo.

23. The compound of claim 1 , selected from:

2-[1-(6-amino-9H-purin-9-yl)ethyl]-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one;

6-methyl-3-phenyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(5-fluoropyridin-3-yl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3-fluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3,5-difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(2-fluoropyridin-3-yl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one; and

6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-3-(1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one;

or a pharmaceutically acceptable salt of any of the aforementioned.

24. The compound of claim 1 , selected from:

6-Methyl-3-phenyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one;

6-Methyl-3-(3-methylphenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-6-methyl-3-(3-methylphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3-Chlorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3-chlorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(4-Chlorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(4-chlorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(2-Chlorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(2-chlorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(2-Fluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(2-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;

4-{6-Methyl-4-oxo-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-3-yl}benzonitrile;

4-(2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)benzonitrile;

6-Methyl-3-(2-methylphenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

6-Methyl-3-(4-methylphenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3-Methoxyphenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(2,3-Difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(2,5-Difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3,4-Difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3,5-Difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3-Fluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3,5-Difluorophenyl)-6-ethyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3,5-difluorophenyl)-6-ethyl-4H-pyrido[1,2-a]pyrimidin-4-one;

6-Ethyl-3-(4-fluorophenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(3,5-Difluorophenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3,5-difluorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one;

3-(6-Chloro-5-methylpyridin-3-yl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(6-chloro-5-methylpyridin-3-yl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;

3-{6-Methyl-4-oxo-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-3-yl}benzonitrile; and

3-(2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)benzonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned.

25. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

26. A method of inhibiting an activity of a PI3Kδ kinase comprising contacting the PI3Kδ kinase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

27. The method of claim 26 , wherein said compound is a selective inhibitor for PI3Kδ over one or more of PI3Kα, PI3Kβ, and PI3Kγ.

28. A method of treating a disease selected from B cell lymphoma, rheumatoid arthritis, myasthenia gravis, Sjöegren's syndrome, multiple sclerosis, glomerulonephritis, lupus, and inflammation related to rheumatoid arthritis, glomerulonephritis, or lupus, in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

29. The method of claim 28 , wherein the disease is rheumatoid arthritis.

30. The method of claim 28 , wherein the disease is B cell lymphoma.

31. The method of claim 30 , wherein the B cell lymphoma is diffuse large B cell lymphoma.

32. The method of claim 28 , wherein the disease is myasthenia gravis.

33. The method of claim 28 , wherein the disease is Sjöegren's syndrome.

34. The method of claim 28 , wherein the disease is multiple sclerosis.

35. The method of claim 28 , wherein the disease is glomerulonephritis.

36. The method of claim 28 , wherein the disease is lupus.

37. The method of claim 28 , wherein the disease is inflammation related to rheumatoid arthritis.

38. The method of claim 28 , wherein the disease is inflammation related to glomerulonephritis.

39. The method of claim 28 , wherein the disease is inflammation related to lupus.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 30, 2018
From: LI, YUN-LONG; METCALF, BRIAN W.; COMBS, ANDREW P.
To: INCYTE CORPORATION
Reel/Frame 045937/0737 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 30, 2018
From: INCYTE CORPORATION
To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION
Reel/Frame 045937/0814 →
Continuity (6)
Continuation 15221163 · Jul 27, 2016
Continuation 14146169 · Jan 2, 2014
Continuation 12824924 · Jun 28, 2010
Provisional Application 61259765 · Nov 10, 2009
Provisional Application 61221160 · Jun 29, 2009
Related Publication 20180362546A1 · Dec 20, 2018
Cited By (2)
US 12,201,636 US 12,226,418