Bicyclic azaheterocyclobenzylamines as PI3K inhibitors

Patent metadata

Field	Value
Publication number	US-9309251-B2
Application number	US-201313854789-A
Country	US
Kind code	B2
Filing date	Apr 1, 2013
Priority date	Apr 2, 2012
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

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

What is claimed is:

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:
V is CH 2 ;
T is CH 2 , or CH(CH 3 );
Q is CH 2 , CH(CH 3 ), or CH(CH 2 CH 3 );
U is O;
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 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 d1 , 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.

2. A compound of claim 1 , having Formula IV:

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 , having Formula IVa:

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 , 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.

5. A compound of claim 1 , having Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:
V is 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 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 or 2 independently selected R 11 groups;
each R 11 is independently selected from OH and 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.

6. A compound of claim 1 , having Formula XXI:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl;
R 3a is methyl or ethyl;
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;
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Assignees

• Incyte Corp
• Incyte Holdings Corp

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

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

• C07C53/18

  containing fluorine · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title