Bicyclic azaheterocyclobenzylamines as pi3k inhibitors

Patent metadata

Field	Value
Publication number	US-2016264580-A1
Application number	US-201615065409-A
Country	US
Kind code	A1
Filing date	Mar 9, 2016
Priority date	Apr 2, 2012
Publication date	Sep 15, 2016
Grant date	—

Abstract

The present invention provides bicyclic azaheterocyclobenzylamines of Formula I:

wherein the variables are defined herein, 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.

First claim

1 - 28 . (canceled)

29 . A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:
V is C(═O), S(═O) 2 , or CH 2 ;
T is C(═O), S(═O) 2 , CH 2 , or CH(CH 3 );
Q is C(═O), S(═O) 2 , CH 2 , CH(CH 3 ), CH(CH 2 CH 3 ), or CH 2 CH 2 ;
U is O or NR 3d ;
provided that when T is C(═O) or S(═O) 2 , then Q is CH 2 or CH(CH 3 );
further provided that when Q is C(═O) or S(═O) 2 , then T is CH 2 , and U is NR 3d ;
R 1 is C 1-3 alkyl;
R 3b is H, Cy, —(C 1-3 alkylene)-Cy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C(═O)R b , C(═O)NR c R d , C(═O)OR a , S(═O) 2 R b , or S(═O) 2 NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted by 1, 2, 3, or 4 independently selected R 13b groups;
R 3d is H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy-C 1-4 alkyl, or C 1-4 haloalkoxy-C 1-4 alkyl;
R 4 is H, halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
R 5 is halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, or cyclopropyl;
R 6 is H;
R 8 is H, halo, —OH, —CN, C 1-6 alkyl, or C 1-6 haloalkyl;
R 10 is H or C 1-4 alkyl;
each R 11 is independently selected from halo, OH, NO 2 , CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, carbamyl, C 1-3 alkylcarbamyl, and di(C 1-3 alkyl)carbamyl;
each R 13b is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 S(═O)R b1 , NR c1 S(═O) 2 NR c1 R c1 , S(═O)R b1 , 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 are each optionally substituted with 1, 2, or 3 independently selected R 11 groups;
each Cy is independently selected from C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl, wherein said C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R 13b groups;
each R a , R c , and R d is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and Cy; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 independently selected R 13b groups;
each R b is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and Cy; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 independently selected R 13b groups; or
each R a1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R 11 groups; and
each R b1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R 11 groups; or
each Cy 2 is independently selected from C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and 9-10-membered bicyclic heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 11 groups.

30 . A compound of claim 29 , having Formula IV:

or a pharmaceutically acceptable salt thereof.

31 . A compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein V is C(═O) or CH 2 .

32 . (canceled)

33 . A compound of claim 29 , having Formula XXIII:

or a pharmaceutically acceptable salt thereof.

34 . (canceled)

35 . A compound of claim 29 , having Formula IVb:

or a pharmaceutically acceptable salt thereof.

36 . A compound of claim 29 , having Formula XXIV:

or a pharmaceutically acceptable salt thereof.

37 . A compound of claim 36 , wherein R a is methyl.

38 . A compound of claim 29 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl; R 4 is C 1-4 alkyl, halo or CN; R 5 is halo; R 6 is H; R 3b is H, Cy, —(C 1-3 alkylene)-Cy, C 1-6 alkyl, C 1-6 haloalkyl, C(═O)R b , C(═O)NR c R d , C(═O)OR a , or S(═O) 2 R b , wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R 13b groups; each R a , R b , R c , and R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and Cy; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 13b groups; each Cy is independently selected from monocyclic C 3-7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl, wherein said monocyclic C 3-7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R 13b groups; each R 13b is independently selected from CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , C(═O)OR a1 , NR c1 C(═O)R b1 , S(═O) 2 R b1 , and S(═O) 2 NR c1 R d1 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 11 groups; each R 11 is independently selected from OH, CN, C 1-3 alkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, carbamyl, C 1-3 alkylcarbamyl, and di(C 1-3 alkyl)carbamyl; each R a1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; and each R b1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

39 . A compound of claim 29 , having Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:
V is C(═O) or CH 2 ;
R 1 is methyl;
R 4 is methyl, F or CN;
R 5 is Cl;
R 6 is H;
R 3b is H, Cy, —(C 1-3 alkylene)-Cy, C 1-6 alkyl, C 1-6 haloalkyl, C(═O)R b , C(═O)NR c R d , C(═O)OR a , or S(═O) 2 R b , wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R 13b groups;
each R a , R b , R c , and R d is independently selected from C 1-6 alkyl and Cy; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 13b groups;
each Cy is independently selected from monocyclic C 3-7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 membered heteroaryl, wherein said monocyclic C 3-7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl, phenyl, and monocyclic 5-6 member

Assignees

• Incyte Corp
• Incyte Holdings Corp

Inventors

• Combs Andrew P
• Sparks Richard B
• Maduskuie Jr Thomas P

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title