Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
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.
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;
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.
7. A compound of claim 1 , wherein said compound is selected from:
tert-Butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate;
1-[1-(7-Chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
tert-Butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate;
1-{1-[4-(1-Acetylazetidin-3-yl)-7-chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-[1-(7-Chloro-4-cyclobutyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-[1-(7-Chloro-4-cyclopentyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-[1-(7-Chloro-4-cyclohexyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-{1-[7-Chloro-4-(4-methoxycyclohexyl)-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-[1-(7-Chloro-4,6-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-[1-(7-Chloro-4-isopropyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]acetonitrile;
3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-3-oxopropanenitrile;
1-{1-[7-Chloro-6-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-{1-[7-Chloro-6-methyl-4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-N-(2-methylphenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxamide;
1-[1-(4-Benzoyl-7-chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-(1-{7-Chloro-4-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-{1-[7-Chloro-4-(cyclopropylsulfonyl)-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-[1-(4-Acetyl-7-chloro-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-[1-(7-Chloro-6-methyl-4-propionyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-{1-[7-Chloro-4-(methoxyacetyl)-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-[1-(7-Chloro-4-isobutyryl-6-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
2-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-1,3-thiazole-5-carbonitrile; and
1-[1-(7-Chloro-6-methyl-4-pyrazin-2-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
or a pharmaceutically acceptable salt of any of the aforementioned.
8. A compound of claim 1 , selected from:
tert-Butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate;
1-{1-[4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-{1-[4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-{1-[(3S)-7-Chloro-6-fluoro-3-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-{1-[7-Chloro-6-fluoro-2-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutanecarboxylic acid;
3-[(2S)-9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutanecarboxamide;
4-(1-Acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(2-hydroxyethyl)azetidin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
4-(1-Acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
2-{3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidin-1-yl}acetamide;
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(2-hydroxy-2-methylpropyl)azetidin-3-yl]-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
(2S)-9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(2-hydroxyethyl)azetidin-3-yl]-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-4-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(2-hydroxyethyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(2-hydroxy-2-methylpropyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
N-{3-[9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}acetamide;
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-ethyl-4-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-N,N-dimethylazetidine-1-carboxamide;
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-N,N-dimethylazetidine-1-sulfonamide;
1-(1-{7-chloro-6-fluoro-2-methyl-4-[1-(methylsulfonyl)azetidin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-{1-[7-chloro-6-fluoro-2-methyl-4-(1-propionylazetidin-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
(2R)-1-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]propan-2-ol;
methyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate;
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-sulfonamide;
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxamide;
(2S)-1-{3-[(2S)-9-[(1S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidin-1-yl}propan-2-ol;
(2S)-1-{3-[(2S)-9-[(1S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidin-1-yl}propan-2-ol;
2-{3-[(2S)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidin-1-yl}acetamide;
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(1-propionylazetidin-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(methylsulfonyl)azetidin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-N-isopropylazetidine-1-carboxamide;
ethyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate;
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-4-[1-(methylsulfonyl)azetidin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-4-(1-propionylazetidin-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-N-ethylazetidine-1-carboxamide;
ethyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate;
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-N-isopropylazetidine-1-carboxamide;
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-[1-(2-hydroxyethyl)azetidin-3-yl]-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-N,N-dimethylazetidine-1-sulfonamide;
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(cyanomethyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile;
2-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]acetamide;
9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-4-(2-methoxyethyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile; and
3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]-N-methylcyclobutanecarboxamide;
or a pharmaceutically acceptable salt of any of the aforementioned.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
10. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
11. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 alkyl, halo or CN.
12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, F, or CN.
13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is halo.
14. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is chloro.
15. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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.
16. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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 are each optionally substituted with 1, 2, or 3 independently selected R 13b groups.
17. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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.
18. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 13b is independently selected from CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , C(═O)R b1 , or C(═O)OR a1 .
19. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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.
20. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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.
21. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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.
22. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from OH and carbamyl.
23. A compound of claim 1 , having Formula XXII:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl;
R 3a 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.
24. 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.
25. 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.
26. A method of treating chronic lymphocytic 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.
27. A method of treating follicular B-cell Non-Hodgkin 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.
28. A method of treating small lymphocytic 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.
29. A method of treating Non-Hodgkin 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.