Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of Their Use and Manufacture

A compound of Formula 1(a):

• or a single stereoisomer or mixture of isomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, where
• R1 is phenyl optionally substituted with one, two, or three R6 groups;
• or
• R1 is heteroaryl optionally substituted with one, two, or three R7;
• R2 is —NR3R4;
• R3 is hydrogen, alkyl, or alkoxycarbonylalkyl;
• and R4 is optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• or
• R3 and R4 together with the nitrogen to which they are attached form HET optionally substituted on any substitutable atom of the ring with R10, R10a, R10b, R10c, R10d, R10e, and R10f;
• HET is
• (a) a saturated or partially unsaturated, but non-aromatic, monocyclic 5- to 8-membered ring optionally containing an additional one or two ring heteroatoms which are independently oxygen, sulfur, or nitrogen where the remaining ring atoms are carbon;
• or
• (b) a partially unsaturated, but not aromatic, monocyclic 5- to 8-membered ring optionally containing an additional one or two ring heteroatoms which are independently oxygen, sulfur, or nitrogen and the remaining ring atoms are carbon and which ring is fused to a benzo ring;
• or
• (c) a fused, bridged, or spirocyclic, bicyclic 7- to 11-membered ring optionally containing an additional one or two heteroatoms which are independently oxygen, sulfur, or nitrogen and the remaining ring atoms are carbon and where each ring of the 7- to 1-membered ring is saturated or partially unsaturated but not fully aromatic;
• or
• (d) a fused, bridged, or spirocyclic, bicyclic 7- to 11-membered ring optionally containing an additional one or two ring heteroatoms which are independently oxygen, sulfur, or nitrogen and the remaining ring atoms are carbon where each ring of the bicyclic 7- to 11-membered ring is saturated or partially unsaturated but not fully aromatic, and where the bicyclic 7- to 11-membered ring is fused to a benzo ring;
• R5a and R5c are independently hydrogen or alkyl;
• R5h is hydrogen or halo;
• R5b is hydrogen, amino, or halo;
• R5d, R5e, R5f, and R5g are hydrogen;
• each R6, when R6 is present, is independently nitro;
• cyano;
• halo;
• alkyl;
• alkenyl;
• alkynyl;
• halo;
• haloalkyl;
• —OR8a;
• —NR8R8a;
• —C(O)NR8R8a;
• —NR8C(O)OR9;
• —NR8C(O)R9;
• —NR8S(O)2R8a;
• —NR8C(O)NR8aR9;
• carboxy, —C(O)OR9;
• alkylcarbonyl;
• alkyl substituted with one or two —C(O)NR8R8a;
• heteroaryl optionally substituted with 1, 2, or 3 R14;
• or optionally substituted heterocycloalkyl;
• each R7, when R7 is present, is independently oxo;
• nitro;
• cyano;
• alkyl;
• alkenyl;
• alkynyl;
• halo;
• haloalkyl;
• hydroxyalkyl;
• alkoxyalkyl;
• —OR8a;
• —SR13;
• —S(O)R13;
• —S(O)2R13;
• —NR8R8a;
• —C(O)NR8R8a;
• —NR8C(O)OR9;
• —NR8C(O)R9;
• —NR8S(O)2R8a;
• —NR8C(O)NR8aR9;
• carboxy;
• —C(O)OR9;
• alkylcarbonyl;
• —S(O)2NR8R9;
• alkyl substituted with one or two —NR8R8a;
• alkyl substituted with one or two —NR8C(O)R8a;
• optionally substituted cycloalkyl;
• optionally substituted cycloalkylalkyl;
• optionally substituted heterocycloalkyl;
• optionally substituted heterocycloalkylalkyl;
• optionally substituted heteroaryl;
• or optionally substituted heteroarylalkyl;
• R8 is hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, or haloalkyl;
• R8a is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyanoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R9 is alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, or optionally substituted heterocycloalkylalkyl;
• R10, R10a, R10b, R10c, R10d, R10e, and R10f of are independently hydrogen;
• halo;
• alkyl;
• haloalkyl;
• haloalkenyl;
• hydroxyalkyl;
• alkylthio;
• alkylsulfonyl;
• hydroxy;
• alkoxy;
• haloalkoxy;
• cyano;
• alkoxycarbonyl;
• carboxy;
• amino;
• alkylamino;
• dialkylamino;
• —C(O)R12;
• —C(O)NR11R11a;
• optionally substituted cycloalkyl;
• optionally substituted cycloalkylalkyl;
• optionally substituted phenyl;
• optionally substituted phenylalkyl;
• optionally substituted phenyloxy;
• optionally substituted phenyloxyalkyl;
• optionally substituted heterocycloalkyl;
• optionally substituted heterocycloalkylalkyl;
• optionally substituted heteroaryl;
• or optionally substituted heteroarylalkyl;
• or two of R10, R10a, R10b, R10c, R10d, R10e, and R10f when attached to the same carbon form oxo, imino, or thiono;
• R11 hydrogen, alkyl, or alkenyl;
• R11a hydrogen, alkyl, or alkenyl;
• R12 is alkyl, or optionally substituted heteroaryl;
• R13 is alkyl or haloalkyl;
• and
• each R14, when R14 is present, is independently amino, alkylamino, dialkylamino, acylamino, halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or optionally substituted phenyl.