IP Library › Granted Patent US 9,193,721

Granted Patent B2

US 9,193,721 · App. 13/085,643 · Granted Nov 24, 2015

Fused derivatives as PI3Kδ inhibitors

Inventors: Andrew P. Combs (Kennett Square, PA); Richard B. Sparks (Wilmington, DE); Eddy W. Yue (Landenberg, PA)

Assignees: Incyte Holdings Corporation; Incyte Corporation

C07D471/04 C07D473/26

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,193,721
App. No.: 13/085,643
Granted: Nov 24, 2015
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides fused derivatives 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 (191)

1. A compound of Formula Ia:

or a pharmaceutically acceptable salt thereof; wherein:

V is CR 2 or N;

X is CR 3 or N;

Y is CR 4 or N;

provided that at least two of V, X, and Y are other than N;

W is CH;

Z is O, S, or NR A ;

Cy is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups;

each R C is 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, 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, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl are 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, 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 g )NR c2 R d2 , NR c2 C(═NR g )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 1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, OH, CN, NR 11 R 12 , C 1-6 alkoxy, C 1-6 haloalkoxy, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R 11 and R 12 is independently selected from H and C 1-6 alkyl;

or any R 11 and R 12 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl;

R 2 , R 3 , R 4 , or R 5 are each independently selected from H, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

Ar is heteroaryl, substituted with n independently selected R D groups;

each R D is 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 A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each Cy 1 is, independently, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R a , R c , and R d is 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 (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 ;

each R b is independently selected from 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 any 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 ;

each R e , R f , and R g is independently selected from H, C 1-6 alkyl, CN, 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 ;

each R a1 , R c1 , and R d1 is 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 OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R b1 is independently selected from 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 OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

or any 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 OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, amino sulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, amino carbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R a2 , R c2 , and R d2 is 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 ;

each R b2 is independently selected from 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 any 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 ;

each R a5 , R c5 , and R d5 is 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, thio, C 1-6 alkylthio, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R b5 is independently selected from 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, thio, C 1-6 alkylthio, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

or any 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;

n is 0, 1, 2, 3, 4, or 5; and

r is 0 or 1.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is NR A .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is heterocycloalkyl, optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is heteroaryl, optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is a phenyl ring, which is optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R C is independently halo.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar is a moiety of formula:

wherein n is 0 or 1.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

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

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

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , and R 5 are independently selected from H, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, halo, C 1-6 alkyl, and C 1-6 haloalkyl.

12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof,

wherein:

Z is NH;

Cy is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups;

each R C is 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 , 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, and C 1-6 haloalkyl are 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, 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 g )NR c2 R d2 , NR c2 C(═NR g )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 ;

Ar is a bicyclic azaheteroaryl group, substituted with n independently selected R D groups; wherein n is 0, 1, 2, 3, or 4;

each R D is independently selected from NR c1 R d1 ;

R 1 is C 1-6 alkyl; and

R 2 , R 3 , R 4 , and R 5 are independently selected from H, OH, halo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 -alkyl)amino, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 -alkyl)carbamyl, C 1-6 alkylcarbonylamino, C 1-6 alkylthio, C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl.

13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof,

wherein:

Z is NH;

Cy is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups;

each R C is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR 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 , 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 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from hydroxy, C 1-6 alkoxy, and C 1-6 haloalkoxy;

Ar is a moiety of formula:

R 1 is C 1-6 alkyl; and

R 2 , R 3 , R 4 , and R 5 are each independently selected from H, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

14. A compound of claim 1 , or a pharmaceutically acceptable salt thereof,

wherein:

Z is NH;

Cy is aryl, optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups;

each R C is independently selected from halo;

Ar is a moiety of formula:

R 1 is C 1-6 alkyl; and

R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

15. A compound of claim 1 , or a pharmaceutically acceptable salt thereof,

wherein:

Z is NH;

Cy is phenyl, 5-membered or 6-membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups;

each R C is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, CN, OR a , C(O)R b , and S(O) 2 R b ; wherein said C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, CN, and OR a2 ;

each R a is selected from H, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

wherein said C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, and OR a5 ;

each R b is independently selected from C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, and OR a5 ;

each R a2 and R a5 is independently selected from H and C 1-4 alkyl;

Ar is a moiety of formula:

R 1 is C 1-6 alkyl; and

R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

16. A compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

Cy is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups;

each R 11 and R 12 is independently selected from H and C 1-6 alkyl;

R 2 , R 4 , or R 5 are each independently selected from H, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

Ar is heteroaryl, substituted with n independently selected R D groups;

each R a , R c , and R d is 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 ;

each R e , R f , and R g is independently selected from H, C 1-6 alkyl, CN, 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 ;

or any 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 OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, amino carbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

n is 0, 1, 2, 3, 4, or 5; and

r is 0 or 1.

17. The compound of claim 1 , having Formula IIIa:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 , having Formula IVa:

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 , selected from:

N-{1-[8-Chloro-5-(3-fluorophenyl)imidazo[1,2-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

N-{1-[8-Chloro-5-(3-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine; and

N-{1-[8-chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

or a pharmaceutically acceptable salt of any of the aforementioned.

20. The compound according to claim 1 , selected from:

N-{1-[5-(4-Acetylpiperazin-1-yl)-8-chloroimidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

N-(1-{8-chloro-5-[4-(methylsulfonyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

tert-Butyl 4-{8-chloro-6-[1-(9H-purin-6-ylamino)ethyl]imidazo[1,5-a]pyridin-5-yl}piperazine-1-carboxylate;

N-(1-{8-Chloro-5-[4-(cyclopropylcarbonyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

N-(1-{8-chloro-5-[4-(methoxyacetyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

N-[1-(8-Chloro-5-piperazin-1-ylimidazo[1,5-a]pyridin-6-yl)ethyl]-9H-purin-6-amine dihydrochloride;

3-(4-{ 8-Chloro-6-[1-(9H-purin-6-ylamino)ethyl]imidazo[1,5-a]pyridin-5-yl}piperazin-1-yl)-3-oxopropanenitrile;

N-[1-(8-Chloro-5-{4-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperazin-1-yl}imidazo[1,5-a]pyridin-6-yl)ethyl]-9H-purin-6-amine;

N-(1-{8-Chloro-5-[4-(2-methoxyethyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

(4-{8-Chloro-6-[1-(9H-purin-6-ylamino)ethyl]imidazo[1,5-a]pyridin-5-yl}piperazin-1-yl)acetonitrile;

N-(1-{8-Chloro-5-[4-(4,4,4-trifluorobutyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

N-{1-[8-Chloro-5-(4-cyclobutylpiperazin-1-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

N-(1-{8-Chloro-5-[4-(tetrahydrofuran-2-ylmethyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

N-(1-{8-Chloro-5-[4-(cyclopropylmethyl)piperazin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

N-{1-[8-Chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridin-6-yl]propyl}-9H-purin-6-amine;

N-{1-[8-Chloro-5-(3,5-difluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

N-{1-[8-Chloro-5-(3,5-difluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]propyl}-9H-purin-6-amine;

N-(1-{8-Chloro-5-[(3R)-3-methoxypyrrolidin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

N-(1-{8-Chloro-5-[(3S)-3-methoxypyrrolidin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine;

(3R)-1-{8-Chloro-6-[1-(9H-purin-6-ylamino)ethyl]imidazo[1,5-a]pyridin-5-yl}pyrrolidin-3-ol;

(3S)-1-{8-Chloro-6-[1-(9H-purin-6-ylamino)ethyl]imidazo[1,5-a]pyridin-5-yl}pyrrolidin-3-ol;

N-{1-[8-Chloro-5-(diethylamino)-3-methylimidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

N-{1-[4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

N-{1-[4-fluoro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine; and

N-{1-[4-chloro-7-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

or a pharmaceutically acceptable salt of any of the aforementioned.

21. A compound according to claim 1 , selected from:

N-{1-[8-Fluoro-5-(3-fluorophenyl)imidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

N-{1-[5-(4-Acetylpiperazin-1-yl)-8-bromoimidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

5-(4-Acetylpiperazin-1-yl)-6-[1-(9H-purin-6-ylamino)ethyl]imidazo[1,5-a]pyridine-8-carbonitrile; and

N-{1-[5-(4-Acetylpiperazin-1-yl)-8-methylimidazo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine;

or a pharmaceutically acceptable salt of any of the aforementioned.

22. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

23. A method of inhibiting an activity of a PI3K kinase, comprising contacting the kinase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

24. The method of claim 23 , wherein the PI3K is selected from the group consisting of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ.

25. The method of claim 23 , wherein said compound is a selective inhibitor for PI3Kδ over one or more of PI3Kγ, PI3Kβ, and PI3Kγ.

26. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein:

Cy is phenyl, 5-membered or 6-membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups;

each R a is selected from H, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

each R a2 and R a5 is independently selected from H and C 1-4 alkyl;

Ar is a moiety of formula:

R 1 is C 1-6 alkyl; and

R 2 , R 4 , and R 5 are each independently selected from H, halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

27. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein:

Cy is phenyl, 5-membered or 6-membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R C groups;

each R a is selected from H, C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; wherein said C 1-6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, and OR a5 ;

each R a2 and R a5 is independently selected from H and C 1-4 alkyl;

Ar is a moiety of formula:

R 1 is C 1-6 alkyl; and

R 2 , R 3 , and R 5 are each independently selected from H, halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

28. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:

Cy is phenyl, 5-membered or 6-membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R c groups;

each R a2 and R a5 is independently selected from H and C 1-4 alkyl;

Ar is a moiety of formula:

R 1 is C 1-6 alkyl; and

R 3 , R 4 , and R 5 are each independently selected from H, halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

29. A method of treating arthritis in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

30. A method of treating myasthenia gravis in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

31. A method of treating Sjöegren's syndrome in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

32. A method of treating multiple sclerosis in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

33. A method of treating rheumatoid arthritis in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

34. A method of treating glomerulonephritis in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

35. A method of treating 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, wherein said treating refers to inhibiting or ameliorating.

36. A method of treating diffuse large B cell lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

37. A method of treating acute myeloblastic leukemia in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

38. A method of treating B cell lymphoma in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

39. A method of treating chronic myeloid leukemia in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said treating refers to inhibiting or ameliorating.

Assignments (3)

CORRECTIVE ASSIGNMENT TO CORRECT THE OMMISSION OF SECOND RECEIVING PARTY NAME PREVIOUSLY RECORDED AT REEL: 035292 FRAME: 0004. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Jul 2, 2015

From: INCYTE CORPORATION

To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION

Reel/Frame 036054/0696 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2015

From: INCYTE CORPORATION

To: INCYTE HOLDINGS CORPORATION AND INCYTE CORPORATION

Reel/Frame 035924/0004 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 30, 2011

From: COMBS, ANDREW P.; SPARKS, RICHARD B.; YUE, EDDY W.

To: INCYTE CORPORATION

Reel/Frame 026527/0792 →

Continuity (3)

Provisional Application 61324143 · Apr 14, 2010

Provisional Application 61425085 · Dec 20, 2010

Related Publication 20110281884A1 · Nov 17, 2011