Selective PI3k inhibitors

Abstract

Provided herein are inhibitors of PI3Kα, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the PI3Kα inhibitory compounds for the treatment of diseases or disorders.

Description

WSGR Ref: 69354-705.601SELECTIVE PI3K INHIBITORSCROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 694 ,098, filed on September 12, 2024, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] The PI3Ka enzyme is a kinase and one of the most frequently mutated kinases found in cancer cells. PI3Ka is closely associated with cell growth and proliferation, and its acquired functional mutations serve as driving factors in tumor formation, making it a significant target for cancer treatment.BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are inhibitors of PI3Ka, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said inhibitory compounds for the treatment of cancer and neoplastic disease.

[0004] One embodiment provides a compound having the structure of Formula (I), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof :wherein,Y is selected from CH, or N;Z is selected from CR10Rn, NR10, or C(O);Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;WSGR Ref: 69354-705.601R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; orR10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Y is CH, Z isNH, Al is O, and A2, A3 and A4 are C, then R

[0005] One embodiment provides a compound having the structure of Formula (I-A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof :wherein,Y is selected from CH, or N;Z is selected from CR10Rn, NR10, or C(O);Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;WSGR Ref: 69354-705.601R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; or R10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Y is CH, Z isNH, Al is O, and A2, A3 and A4 are C, then R

[0006] One embodiment provides a compound having the structure of Formula (II), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;WSGR Ref: 69354-705.601A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; and each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Al is O, and A2, A3 and A4 are C, then R is not

[0007] One embodiment provides a compound having the structure of Formula (II-A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;WSGR Ref: 69354-705.601A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; and each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Al is O, and A2, A3 and A4 are C, then R is not

[0008] One embodiment provides a compound having the structure of Formula (III), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;WSGR Ref: 69354-705.601A2, A3, and A4 are each independently selected from C, or N;Z is selected from CR10Rn, NR10, or C(O);R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; or R10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl.

[0009] One embodiment provides a compound having the structure of Formula (III-A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;Z is selected from CR10Rn, NR10, or C(O);WSGR Ref: 69354-705.601R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; or R10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl.

[0010] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I)-(III), Formula (I-A)-(III-A), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0011] One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I)-(III), Formula (I-A)-(III-A), or pharmaceutically acceptable salt or solvate thereof.

[0012] One embodiment provides a method of inhibiting PI3Ka protein activity comprising contacting the PI3Ka protein with a compound of Formula (I)-(III) or Formula (I-A)-(III-A), wherein the PI3Ka protein is contacted in an in vitro setting.

[0013] One embodiment provides a method of inhibiting PI3Ka protein activity comprising contacting the PI3Ka protein with a compound of Formula (I)-(III) or Formula (I-A)-(III-A), wherein the PI3Ka protein is contacted in an in vivo setting.WSGR Ref: 69354-705.601INCORPORATION BY REFERENCE

[0014] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub- combinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features.Definitions

[0016] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0017] " Amino" refers to the -NH2radical.

[0018] "Cyano" refers to the -CN radical.

[0019] "Nitro" refers to the -NO2radical.

[0020] " Oxa" refers to the -O- radical.

[0021] " Oxo" refers to the =0 radical.

[0022] " Thioxo" refers to the =S radical.

[0023] " Imino" refers to the =N-H radical.

[0024] " Oximo" refers to the =N-0H radical.

[0025] "Hydrazino" refers to the =N-NH2radical.

[0026] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atomsWSGR Ref: 69354-705.601(e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C C 13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (w-propyl), 1 - methylethyl (z o-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1 , 1 -dimethyl ethyl (tert-butyl), 1 -pentyl ( / / -pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, oxo or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, oxo or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3group.

[0027] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.WSGR Ref: 69354-705.601

[0028] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-1 -enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta-1, 4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0029] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(0)N(Ra)2, -N(Ra)C(0)0Ra, -0C(0)-N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionallyWSGR Ref: 69354-705.601 substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0030] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ^-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-C8alkylene). In other embodiments, an alkylene comprisesone to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprisesone to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprisesone to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprisesone to two carbon atoms (e.g., Ci-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SR , -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy,WSGR Ref: 69354-705.601 methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0031] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atom s (e.g., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substitutedby one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, - N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0032] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon andWSGR Ref: 69354-705.601 hydrogen, containing at least one carbon -carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SR , -OC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, - N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0033] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, ie., it contains a cyclic, delocalized (4n+2) 71-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meantto include aryl radicals optionally substituted by one or more substituentsWSGR Ref: 69354-705.601 independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), eachRbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0034] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0035] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0036] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0037] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described aboveWSGR Ref: 69354-705.601 for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0038] "Carbocyclyl" refers to a stable non -aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, spiro, or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (z.e., containing single C-C bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (z.e., bicyclo[2.2. l]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.WSGR Ref: 69354-705.601

[0039] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0040] "Carbocyclylalkynyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0041] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0042] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0043] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluorom ethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0044] "Heterocyclyl" refers to a stable 3 - to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused, spiro, or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb- OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-WSGR Ref: 69354-705.601C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), eachRbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0045] "A-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An A-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1 -morpholinyl, 1- piperidinyl, 1 -piperazinyl, 1 -pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0046] " C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2 -morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3 -pyrrolidinyl, and the like.

[0047] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen -containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.WSGR Ref: 69354-705.601

[0048] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0049] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 -benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyrimidinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10, 10a-octahydrobenzo[h]quinazolinyl, l -phenyl-UT-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5, 6, 7, 8 -tetrahydroquinazolinyl,WSGR Ref: 69354-705.6015.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (z.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)2F, -Rb-S(O)2Cl, -Rb-S(O)tORa(where t is 1 or 2), -Rb- S(O)tN(Ra)2(where t is 1 or 2), -Rb-S-Ra, -Rb-P(O)RaRa, -Rb-P(O)(ORa)2, -Rb-P(O)Ra(ORa), - B(ORa)2, and -Si(Ra)3, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, alkenyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a directbond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0050] "7V-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An 7V-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.WSGR Ref: 69354-705.601

[0051] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0052] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen -containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0053] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0054] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (A)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans .) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0055] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:WSGR Ref: 69354-705.601

[0056] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one embodiment, the compound is deuterated in at least one position. Such deuterated forms are referred to herein as deuteroisotopes. Deuterated analogs can be made by the procedure described in, for example, U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. PatentNos. 5,846,514 and 6,334,997, deuterium substitution can, in some instances, improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0057] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0058] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N, 160,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0059] In certain embodiments, the compounds disclosed herein have some or all theJH atoms replaced with2H atoms. The methods of synthesis for deuterium -containing compounds areWSGR Ref: 69354-705.601 known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0060] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1- 2), 9-32.

[0061] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium -containing compounds. Large numbers of deuterium -containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0062] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3(CD3I), are readily available and may be employed to transfer a deuterium - substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

[0063] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4is illustrated, by way of example only, in the reaction schemes below.

[0064] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon -carbon linkages and to perform a reductive substitution of aryl carbon -halogen bonds as illustrated, by way of example only, in the reaction schemes below.WSGR Ref: 69354-705.601

[0065] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeableJH hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0066] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the PI3Ka inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0067] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates,WSGR Ref: 69354-705.601 dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0068] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic b ase or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hy drab amine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, poly amine resins and the like. See Berge et al., supra.

[0069] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.WSGR Ref: 69354-705.601

[0070] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non -human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0071] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.PI3Ka Protein and Function

[0072] Phosphoinositide kinases (PIKs) are lipid kinases that phosphorylate the inositol ring of phosphoinositides. Depending on the phosphorylation site, PIKs are categorized into three families: phosphoinositide 3 -kinases (PI3Ks), phosphoinositide 4-kinases (PIP4Ks) and phosphoinositide 5 -kinases (PIP5Ks). PI3Ks are further grouped into classes I, II or III, depending on their structure, regulation, and substrate selectivity. Class I PI3Ks are composed of two subgroups, IA and IB. The class IAPI3K subgroup consists of three catalytic subunits: pl 10a, pl 10P, and pl 105 that form heterodimers with one of five regulatory domains: p85y, p85p, p85a, p55a, and p50a.

[0073] Phosphoinositide 3 -kinase alpha (PI3Ka) is a heterodimer composed of a p85 regulatory subunit and a pl 10a catalytic subunit. In response to growth factor stimulation and the subsequent activation of receptor tyrosine kinases (RTKs), PI3Ka is recruited to the membrane via interaction of the p85 subunit with phosphotyrosine -containing motifs on the activated receptor. The pl 10a catalytic subunit of PI3Ka then catalyzes the phosphorylation of phosphatidylinositol 3,4,5 trisphosphate (PIP3). PIP3 recruits multiple effectors, including kinases and regulators of G protein signaling which play critical roles in regulating growth, survival, proliferation, and metabolism.WSGR Ref: 69354-705.601

[0074] PI3K pathway hyperactivation is one of the most frequent events in human cancers, commonly resulting from PIK3CA mutations, RTK mutation or amplification, or loss of the PI3K antagonist PTEN. The PIK3CA and PIK3R1 genes encoding the pl 10a and p85a subunits of PI3Ka are both often mutated in human cancers. Oncogenic transformation by p85a mutations is driven by the activation of pl 10a (encoded by PIK3CA). The initial discovery of PIK3CA mutations in colon cancers (found in about 32% of 234 studied colon tumors) led to the examination of PIK3CA mutations in additional cancer types (Samuels et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304:554). Subsequent studies showed that large numbers of mutations in PIK3CA were present in breast cancer, and it is now appreciated that mutations of PIK3CA are found in about 25-40% of all human breast cancers. The discovery of PIK3CA mutations in breast cancer provided a molecular explanation for the frequent PI3K pathway activation observed in breast cancer (see Page et al. Elevated phosphorylation of AKT and Stat3 in prostate, breast, and cervical cancer cells. Int J Oncol. 2000; 17:23-28). A high frequency of mutations of PIK3CA have also been reported in certain types of endometrial cancer (about 36%), brain tumors (about 27%), skin cancer (about 27%), ovarian cancer (about 12%), gastric cancer (about 25%), and head and neck cancer (about 21%), among others (Samuels et al. Oncogenic mutations of PIK3CA in human cancers. Current topics in microbiology and immunology 2010; 347:21 -41). The prevalence of these mutations in tumorigenesis suggests that PIK3CA is one of the most commonly mutated oncogenes in human cancers.

[0075] The majority of mutations found in PIK3CA lead to amino acid substitutions, although more complex insertions and deletions can also occur. For pl 10a (encoded by PIK3CA) the most frequent mutations are located at two hot spots located at the helical-nSH2 interface (E542K, E545K) and the C-terminus of the kinase domain (Hl 047R). For example, a study of PIK3CA mutations in breast cancer revealed that the most frequent mutations identified were H1047R (35%), E545K (17%), and E542K (11%), comprising 63% of all PIK3CA mutations detected (Martinez-Saez et al. Frequency and spectrum oiPIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020; 22:45). The high frequency of PIK3CA mutations have important clinical implications, and targeting specific PI3Ka mutants (e.g., H1047R, E545K, E542K, etc.) with novel therapeutics could have a substantial impact on eliminating the morbidity and mortality of human cancer.Prior Art Small Molecules Inhibitors of PI3Ka

[0076] The PI3K pathway is an intracellular signaling pathway that has regulatory roles in cell survival, proliferation, and differentiation, and a critical role in tumorigenesis. MultipleWSGR Ref: 69354-705.601 inhibitors targeting PI3K, and its isoforms, have been developed for the treatment of cancer, including buparlisib (BKM120), pictilisib (GDC-0941), PX-866, pilaralisib (SAR245408; XL147), copanlisib (BAY 80-6946), BEZ235, GSK2126458, Gedatolisib (PF-05212384; PKI- 587), Apitolisib (GDC-0980), and PQR309 (Janku, F. Phosphoinositide 3 -kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients. Cancer treatment reviews 2017; 59:93-101). Selective inhibitors of specific PI3K isoforms, such as PI3Ka, have also been developed and include alpelisib (BYL719), and MLN 1117. Other compounds suitable as PI3K inhibitors are disclosed in WO2022265993; WO2024097636; W02024077036; WO2023220131; and WO2023018636.

[0077] Despite the initial enthusiasm for and significant investment in the development of PI3K inhibitors for treatment in tumorigenesis, PI3K inhibitors have thus far not yielded comparable clinical activity observed with other approved targeted therapies. One of the clinical obstacles to PI3K inhibitor efficacy include drug-related toxicity. For example, PI3Ka inhibitors are frequently associated with hyperglycemia and rash. Drug resistance is also a hurdle to PI3K inhibitors and can often be attributed to RTK-induced activation of PI3K / AKT / TOR, resulting in AKT-mediated phosphorylation of FOXO proteins which transcriptionally repress the RTKs that activate PI3Ks. Moreover, increased insulin production often occurs upon inhibition of PI3K, thus long-term use of PI3K inhibitors would be expected to induce insulin resistance and potentially type II diabetes.

[0078] In view of the considerable challenges faced by PI3K inhibitors (e.g., toxicity, drug resistance, increased insulin production), there is a serious unmet clinical need for PI3K inhibitors that can not only maintain efficacy against tumors, but also maintain normal cellular homeostasis. PI3K inhibitors that specifically target mutants of pl 10a (e.g., H1047R, E545K, E542K) could spare endogenous pl 10a and downstream effectors, thus maintaining normal homeostasis, limiting toxicity, and permitting higher doses and more complete target inhibition.Novel Compounds Inhibiting PI3Ka

[0079] In one aspect, provided herein are selective PI3Ka inhibitory compounds.

[0080] One embodiment provides a compound having the structure of Formula (I), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof :WSGR Ref: 69354-705.601wherein,Y is selected from CH, or N;Z is selected from CR10Rn, NR10, or C(O);Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; orR10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl;WSGR Ref: 69354-705.601

[0081] with the provision that if Y is CH, Z isNH, Al is O, and A2, A3 and A4 are C, then R

[0082] One embodiment provides a compound having the structure of Formula (I-A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof :wherein,Y is selected from CH, or N;Z is selected from CR10Rn, NR10, or C(O);Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;WSGR Ref: 69354-705.601R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; orR10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Y is CH, Z isNH, Al is O, and A2, A3 and A4 are C, then R

[0083] One embodiment provides a compound having the structure of Formula (II), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; andWSGR Ref: 69354-705.601 each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Al is O, and A2, A3 and A4 are C, then R is not

[0084] One embodiment provides a compound having the structure of Formula (II-A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; andWSGR Ref: 69354-705.601 each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Al is O, and A2, A3 and A4 are C, then R is not

[0085] One embodiment provides a compound having the structure of Formula (III), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;Z is selected from CR10Rn, NR10, or C(O);R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring;WSGR Ref: 69354-705.601 each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; or R10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl.

[0086] One embodiment provides a compound having the structure of Formula (III-A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;Z is selected from CR10Rn, NR10, or C(O);R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;WSGR Ref: 69354-705.601R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; orR10and R11are both optionally substituted alkyl and join to form a ring; and R12is independently hydrogen or optionally substituted alkyl.

[0087] One embodiment provides a PI3Ka inhibitory compound, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1 .Table 1WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGR Ref: 69354-705.601

[0088] Another embodiment provides a PI3Ka inhibitor compound, or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2.WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGR Ref: 69354-705.601Preparation of Compounds

[0089] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature."Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical andFluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDHInc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservicelnc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pf al tz& Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0090] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., AcademicWSGR Ref: 69354-705.601Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley -Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley -VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley -VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley -Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0091] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0092] General synthetic schemes:Scheme A: Synthesis of amine intermediateWSGR Ref: 69354-705.601VIII IX

[0093] The synthesis of Intermediate IX can be accomplished as described in Scheme A. BenzofuranII can be prepared from phenol I through alkylation and cyclization with methyl 2- bromacetate and a base, such as DBU. Reduction of II with a reducing agent, such as LiAlH4, can afford alcohol III, which can be oxidized to aldehyde IV with IBX. Nucleophilic addition to aldehyde IV can afford alcohol V. Alcohol V can be oxidized with IBX to afford ketone VI, that can be reacted with ammonium hydroxide to provide oxime VII. Reduction of oxime VII with a reducing agent, such as zinc / acetic acid, will provide amine VIII. The isomers of amine VIII can be separated via chiral methods to afford amine Intermediate IX.

[0094] Scheme B: Synthesis of amine compounds

[0095] Compounds listed in Table 1 can be synthesized according to Scheme B, where amine Intermediate IX can be reacted with an electrophilic compound X, such as 2 -chloropyridine, in the presence of a base, such as diisopropylethylamine, to give the amine compounds.

[0096] Scheme C: Synthesis of diamine compoundsWSGR Ref: 69354-705.601

[0097] Compounds listed in Table 1 can also be synthesized according to Scheme C, where amine Intermediate IX can be reacted with an electrophilic compound XI, such as 4,6- dichloropyrimidine, in the presence of a base, such as diisopropylethylamine, to give Intermediate XII. Intermediate XII can be further reacted with an amine XIII, such as methylamine, to give diamine compounds.Pharmaceutical Compositions

[0098] In certain embodiments, the PI3Ka inhibitory compound described herein is administered as a pure chemical. In other embodiments, the PI3Ka inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science andPractice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0099] Provided herein is a pharmaceutical composition comprising at least one PI3Ka inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0100] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I)-(III) or Formula (I-A)-(III-A), or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof.

[0101] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I)-(III) or Formula (I-A)-(III-A), or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0102] In certain embodiments, the PI3Ka inhibitory compound as described by Formula (I)-(III) or Formula (I-A)-(III-A), or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, orWSGR Ref: 69354-705.601 less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0103] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof.

[0104] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0105] In certain embodiments, the PI3Ka inhibitory compound as described by Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0106] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. See, e.g., Remington: The Science andPractice of Pharmacy (Gennaro, 21stEd. Mack Pub . Co. , Easton, PA (2005)).

[0107] In some embodiments, the PI3Ka inhibitory compound as described by Formula (I)-(III) or Formula (I-A)-(III-A), or Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil -based formulation, such as sesame oil, or the like.

[0108] The dose of the composition comprising at least one PI3Ka inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0109] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency ofWSGR Ref: 69354-705.601 administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g, an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0110] Oral doses typically range from about 0.01 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0111] One embodiment provides a compound of Formula (I)-(III) or Formula (I-A)-(III-A), or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0112] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I)-(III) or Formula (I-A)-(III-A), or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0113] One embodiment provides a use of a compound of Formula (I)-(III) or Formula (I-A)-(III-A), or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

[0114] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I)-(III) or Formula (I-A)-(III- A), or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I)-(III) or Formula (I-A)-(III-A), or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0115] One embodiment provides a compound of Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0116] One embodiment provides a compound of Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer.WSGR Ref: 69354-705.601

[0117] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0118] One embodiment provides a use of a compound of Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

[0119] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0120] One embodiment provides a method of inhibiting PI3Ka protein activity comprising contacting the PI3Ka protein with a compound of Formula (I)-(III) or Formula (I-A)-(III-A), or Table 1, or a deuteroisotope thereof. Another embodiment provides the method of inhibiting PI3Ka protein activity, wherein the PI3Ka protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting PI3Ka protein activity, wherein the PI3Ka protein is contacted in an in vitro setting.

[0121] Other embodiments and uses will be apparent to one skilled in the art considering the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.EXAMPLESI. Chemical Synthesis

[0122] In some embodiments, the PI3Ka inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrile°C degrees CelsiusSHchemical shift in parts per million downfield from tetramethyl silaneDCM dichloromethane (CH2Q2)DIAD diisopropyl azodicarboxylateDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateWSGR Ref: 69354-705.601EtOAc ethyl acetateESI electrospray ionizationEt ethyl g gram(s) h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometry n micro m multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterMS mass spectrometry nm nanometer(s)NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum etherRT room temperature s singlet (spectral) t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP Triphenylphosphine

[0123] Intermediate 1 : (R)-l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-l-amineWSGR Ref: 69354-705.601Step 1. Methyl 5, 7-difluoro-3 -methyl- l-benzofuran-2 -carboxylateTo a stirred mixture of l-(3,5-difluoro-2-hydroxyphenyl)ethanone (40 g, 232.38 mmol) and methyl 2-bromoacetate (52.98 g, 348.56 mmol) in DMF (400 mL) was added potassium carbonate (64.14 g, 464.76 mmol) in portions at room temperature. The resulting mixture was stirred at 80 °C for another 2 h. Then l,8-diazabicyclo[5.4.0]undec-7- ene (35.32 g, 232.38 mmol) was added drop wise to the above mixture at room temperature. The resulting mixture was stirred at 80 °C for another 2 h. After the reaction was completed, the reaction mixture was allowed to cool to ambient temperature and then quenched with water (3000 mL x 1). The resulting mixture was extracted by ethyl acetate (2000 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10:1) to afford methyl 5,7-difluoro-3-methyl-l- benzofuran-2-carboxylate (13.0 g, 25%) as a white solid. MS ESI calculated for CnH8F2O3 [M+H]+227.04, observed 227.00. !HNMR(400 MHz, DMSO-t / 6) 8 7.61-7.48 (m, 2H), 3.91 (s, 3H), 2.50 (s, 3H).Step 2. (5,7-difluoro-3-methyl-l-benzofuran-2-yl)methanolTo a stirred mixture of methyl 5,7-difluoro-3-methyl-l-benzofuran-2-carboxylate (13.0 g, 57.52 mmol) in tetrahydrofuran (130mL) was added lithium aluminum hydride (1.31 g, 34.49 mmol) in portions at -50 °C. The resulting mixture was stirred at -50 °C for another 2 h. After the reaction was completed, the reaction mixture was allowed to warm to 0 °C and quenched by adding ice water (400 mL) and warmed to ambient temperature. The resulting mixture was extracted with ethyl acetate (400 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (6:1) to afford (5, 7-difluoro-3 -methyl- 1 -benzo furan-2-yl)methanol (10.0 g, 87%) as a white solid. 'H NMR (400 MHz, DMSO-t / 6) 6 7.39-7.19 (m, 2H), 5.45 (t, J= 6.0 Hz, 1H), 4.56 (d, = 6.0 Hz, 2H), 2.20 (s, 3H).Step 3. 5,7-difluoro-3-methyl-l-benzofuran-2-carbaldehydeTo a stirred mixture of (5, 7-difluoro-3 -methyl- 1 -benzofuran -2 -yl)m ethanol (10.0 g, 50.50 mmol) in acetonitrile (200 mL) was added 2-iodoxybenzoic acid (14.13 g, 50.50 mmol) in portions at 0 °C. The resulting mixture was heated and stirred at 80 °C for 2 h. After theWSGR Ref: 69354-705.601 reaction was completed, the mixture was cooled to ambient temperature. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (3 x 200 mL). The filtrate was concentrated under reduced pressure to afford 5,7-difluoro-3-methyl-l- benzofuran-2-carbaldehyde (7.3 g, 73%) as a white solid. MS ESI calculated for CIOH6F202 [M+H]+ 197.03, observed 197.00. !HNMR(400 MHz, DMSO-<6) 8 10.05 (s, 1H), 7.68-7.57 (m, 2H), 2.59 (s, 3H).Step 4. l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethanolTo a stirred mixture of 5,7-difluoro-3-methyl-l-benzofuran-2-carbaldehyde (7.3 g, 37.23 mmol) and potassium carbonate (10.28 g, 74.46 mmol) in N, A-dimethylformamide (100 mL) was added (trifluoromethyl)trimethylsilane (7.37 g, 74.46 mmol) dropwise at 0 °C. The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched by adding water (500 mL) upon completion. The resulting mixture was extracted with ethyl acetate (500 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5:1) to afford 1 -(5,7- difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethanol (8.1 g, 82%) as a yellow solid. MS ESI calculated for CIIH7F5O2[M-H]- 265.04, observed 264.90. 'H NMR (400 MHz, DMSO-t / 6) 6 7.42-7.25 (m, 2H), 7.20 (s, 1H), 5.57 (q, J= 7.2 Hz, 1H), 2.29 (s, 3H).Step 5. l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethanoneTo a stirred mixture of l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethanol (8.1 g, 30.41 mmol) in acetonitrile (100 mL) was added 2-iodoxybenzoic acid(12.78 g, 45.65 mmol) in portions at ambient temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with acetonitrile (300 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (6 / 1) to afford l-(5,7-difluoro-3-methyl-l-benzofuran-2- yl)-2,2,2-trifluoroethanone (5.5 g, 68%) as a white solid. 'H NMR (400 MHz, DMSO-t / e) 8 7.90-7.60 (m, 2H), 2.64 (s, 3H).Step 6. l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethanamineTo a stirred mixture of 1 -(5, 7-difluoro-3 -methyl- 1 -benzofuran -2-yl)-2, 2, 2-trifluoroethanone (5.5 g, 20.84 mmol) and sodium acetate trihydrate (28.25 g, 207.78 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (10.04 g, 145.50 mmol) in portions at ambient temperature. The resulting mixture was stirred at 80 °C for another 16 h. The reaction mixture was allowed to cool to ambient temperature. The resulting mixture was concentrated underWSGR Ref: 69354-705.601 reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 :1) to afford (£)-A-[l-(5,7-difluoro-3-methyl-l- benzofuran-2-yl)-2,2,2-trifluoroethylidene]hydroxylamine as a yellow solid (4.50 g). MS ESI calculated for CIIH6F5NO2[M-H]' 278.03, observed 278.25.Step 7. l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-l-amine To a stirred mixture of (£)-A-[l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethylidene]hydroxylamine (4.50 g, 16.13 mmol) and zinc (5.24 g, 80.65 mmol) in ethanol (25 mL) and water (25 mL) was added ammonium chloride (1.74 g, 32.26 mmol) in portions at ambient temperature. The resulting mixture was stirred at 70 °C for another 16 h. After the reaction was completed, the reaction mixture was allowed to cool to ambient temperature and filtered; the filter cake was washed with ethyl acetate (100 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 :l)to afford 1 -(5,7- difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethanamine (3.0g, 54%) as a white solid. JH NMR (400 MHz, DMSO-t / 6) 87.51-7.16 (m, 2H), 4.99-4.93 (m, 1H), 2.62 (d, J = 7.2 Hz, 2H), 2.25 (s, 3H).Step 8. (R)-l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-l-amine l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethanamine (3 g) was resolved by Prep-chiral-HPLC with the following conditions (Column: CHIRALPAKIF3 ); Mobile Phase A: Hex (0.2% Diethanolamine): (ethanol: dichloromethane = 1 : 1) = 90: 10; Flow rate: 1.0 mL / min; to afford (R)-l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-l-amine (1.3 g, 43%) as a white solid.XH NMR (400 MHz, DMSO-t / 6) 6 7.51-7.16 (m, 2H), 4.99-4.93 (m, 1H), 2.62 (d, J= 7.2 Hz, 2H), 2.25 (s, 3H).

[0124] Intermediate 2: terLButyl (6-bromopyrimidin-4-yl)(tert-butoxycarbonyl)carbamateTo a solution of 6-bromopyrimidin-4-amine (150 mg, 0.867 mmol) and Boc2O (284 mg, 1.301 mmol) in DCM (3 mL) was added DIPEA (338 mg, 2.601 mmol), DMAP (11 mg, 0.087 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for another 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (10 / 1) concentrated under reduced pressure to afford terLbutyl N- (6-bromopyrimidin-4-yl)-A-(tert-butoxycarbonyl)carbamate (170 mg, 52%) as a white solid.WSGR Ref: 69354-705.601

[0125] Example 1 : (R)-N4-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)pyrimidine-4,6-diamineStep 1. te / 7-Butyl A-(6-{[(lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethyl]amino}pyrimidin-4-yl)carbamateTo a stirred mixture of tert-butyl A-(6-bromopyrimidin-4-yl)-A-(tert- butoxycarbonyl)carbamate (169 mg, 0.452 mmol) and (1 A)-l-(5,7-difluoro-3-methyl-l- benzofuran-2-yl)-2,2,2-trifluoroethanamine (100 mg, 0.377 mmol) in toluene (4 mL) was added (DiMeH4eptCl)Pd(cinnamyl)Cl (CAS: 2138491-47-9) (40 mg, 0.034 mmol) and sodium benzenolate (88 mg, 0.758 mmol) at ambient temperature. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. After the reaction completion, the mixture was allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (5 / 1). The fractions containing the desired product were collected and concentrated under reduced pressure to afford tert-butyl A-(6-{[(lA)-l- (5, 7-difluoro-3 -methyl- 1 -benzofuran -2-yl)-2, 2, 2-trifluoroethyl]amino }pyrimidin-4- yl)carbamate (146 mg, 85%) as a yellow oil. MS ESI calculated for C18H16F5N7O [M+H]+459.14 observed 459.10.Step 2. (R)-N4-(l -(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)pyrimidine-4,6- diamineTo a solution of tert-butyl A-(6-{[(lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethyl]amino}pyrimidin-4-yl)carbamate (150 mg, 0.327 mmol) and hydrochloric acid (gas) in 1 ,4-dioxane (6 mL) in 1 ,4-dioxane (3 mL) was stirred at ambient temperature for 16 h. After the reaction was completed, the reaction mixture was basified to pH 8 with ammonium in methanol. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM Cl 8-1, 20-40 pm, 120 g; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 30% to 50% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. The fractions containing the desired product were collected, concentrated, and lyophilized to afford (R)-N4-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)pyrimidine-4,6-diamine (52.6 mg, 45%). MS ESI calculated for C15H11F5N4O [M+H]+ 359.09 observed 359.10. !H NMR (400 MHz, DMSO-t / 6) 8 8.01-7.99WSGR Ref: 69354-705.601(m, 2H), 7.41-7.34 (m, 2H), 6.62-6.53 (m, 1H), 6.33 (s, 2H), 5.72 (s, 1H), 2.29 (s, 3H).19F NMR (400 MHz, DMSO-t / 6) 6 -71.62 (3F), -116.36 (IF), -132.95 (IF).

[0126] Example 2: (R)-6-bromo-N-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)pyrimidin-4-amineTo a stirred mixture of (lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethanamine (lOO mg, 0.377 mmol) and 4,6-dibromopyrimidine (215 mg, 0.905 mmol) in toluene (4 mL) was added (DiMeIHeptCl)Pd(cinnamyl)Cl (44 mg, 0.038 mmol) and K3PO4 (160 mg, 0.754 mmol) at ambient temperature. The resulting mixture was stirred at 120 °C for 24 h. After the reaction was completed, the mixture was allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5 / 1). The mixture was further purified by reverse phase flash chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (plus 10 mmol / L NH4HCO3); Eluent B: ACN; Gradient: 45% to 65% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm; desired fractions were collected and concentrated under reduced pressure to afford 6-bromo-A-[(lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethyl]pyrimidin-4-amine (32.3 mg, 20%). MS ESI calculated for Ci5H9BrF5N3O [M+H]+ 421 .98, 423.98 observed 422.00, 424.00. 'HNMR (400 MHz, DMSO-t / 6) 8 9.10 (d, J = 9.2 Hz, 1H), 8.41 (s, 1H), 7.45-7.39 (m, 2H), 7.04 (s, 1H), 6.61-6.57 (m, 1H), 2.32 (s, 3H). 19F NMR (400 MHz, DMSO-t / 6) 6 -71.62 (3F), -116.10 (IF), -132.87 (IF).

[0127] Example 14: (R)-N-(l-(6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl)-2,2,2- trifluoroethyl)-6-(methylsulfonyl)-lH-benzo[d]imidazol-2-amineStep 1. Methyl 6,8-difluoro-3-methylimidazo[l,2-a]pyridine-2-carboxylate.To a stirred solution of 3,5-difluoropyridin-2-amine (10 g, 76.86 mmol) in anhydrous EtOH (50 mL) was added methyl 3-bromo-2-oxobutanoate (29.98 g, 153.73 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. Upon completion, theWSGR Ref: 69354-705.601 mixture was concentrated and mixed with saturated NaHCO3aqueous solution (50 mL). The resulting mixture was extracted with ethyl acetate (5 x 50 mL), and the combined organic phase was washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give crude product methyl 6,8-difluoro-3-methylimidazo[l,2-a]pyridine-2-carboxylate (1.4 g, 8.1% yield). MS ESI calculated for CI0H8F2N2O2[M+H]+, 227.06, found 226.95.1H NMR (400 MHz, DMSO-t / 6) 8 8.61-8.59 (m, 1H), 7.63-7.58 (m, 1H), 3.86 (s, 3H), 2.73 (s, 3H).Step 2. {6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl}methanol.To a stirred solution of methyl 6, 8-difluoro-3-methylimidazo[l,2-a]pyridine-2 -carboxylate (1.4 g, 6.19 mmol) in anhydrous THF (30 mL) was added lithium borohydride (2.0 Min THF) (31 mL, 62.00 mmol) at 0 °C. The reaction mixture was then stirred at 40 °C for 2 hours, then quenched with water (10 mL) at 0 °C. The aqueous layer was extracted with DCM (three times, 30 mL each), and the combined organic phase was washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give crude product that was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM Cl 8 -I, 20 - 40 pm, 120 g; Eluent A: Water (plus 10 mmol / L NH4HCO3); Eluent B: ACN; Detector: 220 / 254 nm; desired fractions were collected and concentrated under reduced pressure to afford {6,8- difluoro-3-methylimidazo[l, 2 -a]pyridin-2-yl {methanol (580 mg, 47.3% yield). MS ESI calculated for C9H8F2N2O [M+H ]+, 199.06, found 199.10. TI NMR (400 MHz, DMSO-t / 6) 6 8.48-8.43 (m, 1H), 7.45-7.41 (m, 1H), 5.12 (s, 1H), 4.58 (s, 2H), 2.47 (s, 3H).Step 3. 6,8-difluoro-3-methylimidazo[l,2-a]pyridine-2-carbaldehyde.To a stirred mixture of {6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl{methanol (580 mg, 2.927 mmol) in CH3CN (8 mL) was added IBX (2048 mg, 7.317 mmol) in portions at ambient temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 hours. The mixture was then allowed to cool down to room temperature. After filtration, the filter cake was washed with DCM (3 x 10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PEZEA (1 / 1 ) to afford 6,8-difluoro-3-methylimidazo[l,2-a]pyridine-2-carbaldehyde (400 mg, 69.7% yield) as an off-white solid. MS ESI calculated for C9H6F2N2O [M+H]+, 197.04, found 197.05. 'H NMR (400 MHz, DMSO-t / 6) 6 10.13 (s, 1H), 7.87 - 7.81 (m, 1H), 7.71 - 7.67 (m, 1H), 2.75 (s, 3H).Step 4. (5)-A-[(lZ)-{6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl{methylidene]-2- methylpropane-2-sulfinamide.WSGR Ref: 69354-705.601To a stirred mixture of 6,8-difluoro-3-methylimidazo[ l ,2-a]pyridine-2-carbaldehyde (400 mg, 2.039 mmol) and (5)-2-methylpropane-2-sulfinamide (370 mg, 3.059 mmol) in THF (8 mL) was added tetrakis(propan-2-yloxy)titanium (1738 mg, 6. 117 mmol) dropwise at ambient temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 2 hours. The mixture was then allowed to cool down to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford (5)-A-[(lZ)-{6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2- yl}methylidene]-2-methylpropane-2-sulfinamide (500 mg, 81.9% yield) as an off-white solid. MS ESI calculated for CI3HI5F2N3OS [M+H]+, 300.09, found 300.00.Step 5. (£)-A-[(lA)-l-{6,8-difhioro-3-methylimidazo[l,2-a]pyridin-2-yl}-2,2,2- trifluoroethyl]-2-methylpropane-2-sulfinamide.To a stirred solution of (5)-A-[(lZ)-{6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2- yl}methylidene]-2-methylpropane-2-sulfinamide (500 mg, 1.670 mmol) in anhydrous THF (10 mL), there was added TBAF (655 mg, 2.505 mmol) and trimethyl(trifluoromethyl)silane (950 mg, 6.680 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 90 minutes. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PEZEA (1 / 1) to afford (5)-A-[(lA)-l-{6,8-difluoro-3- methylimidazo[l,2-a]pyridin-2-yl}-2,2,2-trifhioroethyl]-2-methylpropane-2-sulfinamide (80 mg, 13.0% yield) as a white solid. MS ESI calculated for CI4HI6F5N3OS [M+H]+, 370.09, found 370.15. 'HNMR (400 MHz, DMSO-t / 6) 88.63-8.49 (m, 1H), 7.62-7.56 (m, 1H), 5.63- 5.61 (m, 1H), 2.55 (s, 3H), 1.17 (d, J = .2 Hz, 9H).Step 6. (A)-l-(6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl)-2,2,2-trifluoroethan-l-amine. To a stirred solution of (5)-A-[(lA)-l-{6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl}- 2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide (80 mg, 0.217 mmol) in anhydrous dioxane (1 mL), there was added HC1 in 1,4-dioxane (4.0 M) (1 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was then concentrated under reduced pressure and purified by reverse phase flash chromatography with the following conditions: Column: WelFlash TM Cl 8 -I, 20 - 40 pm, 120 g; Eluent A: Water (plus 10 mmol / L NH4HCO3); Eluent B: ACN; Detector: 220 / 254 nm; desired fractions were collected and concentrated under reduced pressure to afford ( / )- ! -(6,8- difluoro-3-methylimidazo[l,2-a]pyridin-2-yl)-2,2,2-trifluoroethan-l-amine (35 mg, 60.9% yield) as a white solid. MS ESI calculated for CI0H8F5N3[M+H]+, 266.06, found 266.00. Step 7. A-[(lA)-l-{6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl}-2,2,2-trifluoroethyl]-6- methanesulfonyl-l-{[2-(trimethylsilyl)ethoxy]methyl} -1,3 -benzodiazol -2-amine.WSGR Ref: 69354-705.601To a stirred mixture of (R)-l -(6, 8-difluoro-3-m ethylimidazofl ,2-a]py ridin -2-yl )-2, 2,2- trifluoroethan-1 -amine (18 mg, 0.068 mmol) and 2-chloro-6-methanesulfonyl-l-{[2- (trimethylsilyl)ethoxy]methyl}-l,3-benzodiazole (29.40 mg, 0.082 mmol) in dioxane (1 mL) there was added Pd-PEPPSI-IPentCl (4.61 mg, 0.007 mmol) and CS2CO3 (44.23 mg, 0.136 mmol) in portions at ambient temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 hours, then allowed to cool to ambient temperature. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TMC18-I, 20- 40 pm, 120 g; Eluent A: Water (plus 10 mmol / L NH4HCO3); Eluent B: ACN; Detector: 220 / 254 nm; desired fractions were collected and concentrated under reduced pressure to afford A-[(17?)-l-{6,8-difhioro-3-methylimidazo[l,2-a]pyridin-2-yl}-2,2,2-trifluoroethyl]-6- methanesulfonyl- l-{[2-(trimethylsilyl)ethoxy]methyl} -1,3 -benzodiazol -2-amine (19 mg, 47.5% yield) as a yellow solid. MS ESI calculated for C24H28F5N5O3SSi [M+H]+, 590.16, found 590.15.Step 8. N-[(lR)-l-{6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl}-2,2,2-trifluoroethyl]-5- methanesulfonyl-3H-l,3-benzodiazol-2-amine.To a stirred mixture of A-[(17?)-l-{6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl}-2,2,2- trifluoroethyl]-5-methan esulfonyl -N-{ [2-(trimethylsilyl)ethoxy ]methyl} -377-1, 3 -benzodiazol- 2-amine (19 mg, 0.032 mmol) in DCM (1 mL) there was added BBr3(1 M in DCM, 1 mL) dropwise at ambient temperature. The resulting mixture was stirred at the same temperature for 1 hour, and then quenched with ice water. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: Water (plus 10 mmol / L ammonium bicarbonate); Eluent B: ACN; Detector: 220 / 254 nm; desired fractions were collected, concentrated and lyophilized to afford A-[(17?)- l-{6,8-difluoro-3-methylimidazo[l,2-a]pyridin-2-yl}-2,2,2-trifluoroethyl]-5-methanesulfonyl- 377-1, 3-benzodiazol-2-amine (11.5 mg, 77.7% yield) as an off-white solid. MS ESI calculated for C18H14F5N5O2S [M+H]+, 460.08, found 460.05. 'H NMR (500 MHz, DMSO-t / 6) 8 10.95 (s, 1H), 8.56 (dd, .7 = 4.4, 2.0 Hz, 1H), 8.38 (s, 1H), 7.76 (s, 1H), 7.62-7.58 (m, 1H), 7.53-7.37 (m, 2H), 6.26-6.12 (m, 1H), 3.12 (s, 3H), 2.60 (s, 3H).19F NMR (376 MHz, DMSO-t / 6) 6 - 72.77 (3F), -128.19 (IF), -138.98 (IF).

[0128] Example 79: (R)-N-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-7-amineWSGR Ref: 69354-705.601Step 1. A-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)imidazo[l,2- a]pyridin-7-amine.A mixture of 7-bromoimidazo[l,2-a]pyridine(37 mg, 0.188 mmol), sodium phenoxide (43.60 mg, 0.376 mmol), (lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethanamine (49.80 mg, 0.188 mmol) and (DiMeIHeptCl)Pd(cinnamyl)Cl (21.92 mg, 0.019 mmol) [CAS: 2138491-47-9] in toluene (1 mL) was stirred at 100 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, the reaction mixture was allowed to cool down to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford A-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)imidazo[l,2-a]pyri din-7 -amine (25 mg, 34.7% yield) as a white solid. MS ESI calculated for CI8HI2F5N3O [M+H]+, 382.09 found 382.05, 70% ee. Prep-Chiral HPLC further purified the crude product with the following conditions (Column: CHIRAL ART Amylose- SA, 2 x 25 cm, five pm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH: DCM =1 / 1; Flow rate: 20 mL / min; Wave Length: 220 / 254 nm). Desired fractions were collected and concentrated to afford (A)-A-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-7-amine (15.7 mg, 62.8% yield) as a white solid. MS ESI calculated for CI8HI2F5N3O [M+H]+, 382.09 found 382.05. TI NMR (400 MHz, DMSO-t / 6) <5 8.22 (d, J= 7.2 Hz, 1H), 7.57 - 7.56 (m, 1H), 7.41 - 7.35 (m, 2H), 7.28 - 7.21 (m, 2H), 6.80 (d, .7= 2.0 Hz, 1H), 6.73 (dd, J = 7.2, 2.0 Hz, 1H), 6.20 - 6.16 (m, 1H), 2.38 (s, 3H).19F NMR (376 MHz, DMSO-d6) 5 -71.42 (3F), -116.33 (IF), -132.84 (IF).

[0129] Example 100: (R)-5-((l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)amino)pyrimidine-2-carbonitrileTo a stirred mixture of (A)-l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-l- amine (50 mg, 0.189 mmol) and 5-bromopyrimidine-2-carbonitrile (50 mg, 0.272 mmol) in toluene (1 mL) there was added sodium phenoxide (44 mg, 0.380 mmol) andWSGR Ref: 69354-705.601(DiMeIHeptCl)Pd(cinnamyl)Cl (22 mg, 0.019 mmol) [CAS: 2138491-47-9] at ambient temperature under nitrogen atmosphere. The mixture was stirred at 100 °C for two hours and then allowed to cool down to ambient temperature The mixture was concentrated under reduced pressure and the residue was purified by PLC (PE / EA = 5 / 1) to afford a crude product that was further purified by reverse phase flash chromatography with the following conditions: Column: WelFlash TM C18-I, 20 - 40 pm, 120 g; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Detector: 220 / 254 nm). The desired fractions were collected and concentrated under reduced pressure to afford 5-((l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2, 2, 2-trifluoroethyl)amino)pyrimidine-2 -carbonitrile (6.1 mg, 8.8%) as an off-white solid. MS ESI calculated for C16H9F5N4O [M-H] -367-07;found 366.95, 67% ee. 'HNMR (300 MHz, DMSO) 5 8.66 (s, 2H), 8.35 (d, = 9.6 Hz, 1H), 7.49 - 7.35 (m, 2H), 6.46 - 6.36 (m, 1H), 2.37 (s, 3H).19F NMR (282 MHz, DMSO-d6) 5 -71 .88 (3F), -116.05 (IF), -132.67 (IF).

[0130] Example 166: (R)-N4-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-6- methylpyridine-2,4-diamineStep 1. tert-butyl A-(4-bromo-6-methylpyridin-2-yl)carbamate.To a stirred solution of 4-bromo-6-methylpyridin-2 -amine (500 mg, 2.673 mmol) and BOC2O (875 mg, 4.010 mmol) in DCM (10 mL) was added TEA (812 mg, 8.019 mmol) and DMAP (32.66 mg, 0.267 mmol) at ambient temperature. Then, the mixture was stirred at 40 °C for another three hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (5 / 1) to afford tert-butyl A-(4-bromo-6-methylpyridin-2-yl)carbamate (300 mg, 39.1%) as a colorless oil. MS ESI calculated for CnHi5BrN2O2 [M+H]+, 287.03, 289.03 found 287.00, 289.00.1HNMR (400 MHz, DMSO-t / 6) 89.98 (s, 1H), 7.85 (d, J= 1.6 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 2.36 (s, 3H), 1.46 (s, 9H).Step 2. tert-butyl A-(4-{[(lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethyl]amino}-6-methylpyridin-2-yl)carbamate.To a stirred solution of (lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethanamine (100 mg, 0.377 mmol) and tert-butyl A-(4-bromo-6-methylpyridin-2- yl)carbamate (130 mg, 0.452 mmol) in toluene (2 mL) were added sodium benzenolate (88WSGR Ref: 69354-705.601 mg, 0.754 mmol) and (DiMeIHeptCl)Pd(cinnamyl)Cl (44 mg, 0.038 mmol) [CAS: 2138491- 47-9] at room temperature under nitrogen atmosphere. Then, the reaction mixture was heated to 100 °C and stirred for another 4 hours. The reaction mixture was cooled down to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (5 / 1) to afford tert-butyl N- (4-{[(lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethyl]amino}-6- methylpyridin-2-yl)carbamate (140 mg, 78.8%) as a colorless oil. MS ESI calculated for C22H22F5N3O3 [M+H]+, 472.16 found 472.15.Step 3. N4-[(l R)- 1 -(5, 7-difluoro-3 -methyl- 1 -benzofuran -2 -yl)-2, 2, 2-trifluoroethyl]-6- methylpyridine-2,4-diamine.A mixture of tert-butyl A-(4-{[(lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethyl]amino}-6-methylpyridin-2-yl)carbamate (lOO mg, 0.212 mmol) and HCl in 1,4- dioxane (4.0 M, 2 mL) was stirred at room temperature for 8 hours. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30x 150 mm; Mobile Phase A: water (plus 10 mmol / L NH4HCO3), Mobile Phase B: CH3CN; Wavelength: 254 / 220 nm). The desired fractions were concentrated and lyophilized to afford N4-[(lA)-l-(5,7-difluoro-3- methyl-l-benzofuran-2-yl)-2,2,2-trifluoroethyl]-6-methylpyridine-2,4-diamine (26.6 mg, 33.8%) as a white solid. MS ESI calculated for Ci7Hi4F5N3O [M+H]+, 372.11 found 372.10. JH NMR (400 MHz, DMSO-t / 6) 87.41-7.34 (m, 2H), 7.08 (d, J= 4.8 Hz, 1H), 6.07 (d, J= 1.6 Hz, 1H), 5.95-5.83 (m, 1H), 5.69 (d, J= 1 .6 Hz, 1H), 5.37 (s, 2H), 2.34 (s, 3H), 2.08 (s, 3H). 19F NMR (376 MHz, DMSO-t / 6) 6 -71.46 (3F), -116.41 (IF), -132.89 (IF).

[0131] Example 214: (R)-(2-((l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)amino)- lH-benzo[d]imidazol-6-yl)dimethylphosphine oxideStep 1. (3,4-diaminophenyl)dimethylphosphine oxide.A mixture of 4-bromobenzene-l,2-diamine (1 g, 5.346 mmol), dimethylphosphine oxide (1 .25 g, 16.038 mmol), Pd2(dba)3 (489.59 mg, 0.535 mmol), XantPhos (618.73 mg, 1.069 mmol) and K3PO4 (3.40 g, 16.038 mmol) in DMF (20 mL) was stirred at 140 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled down to ambient temperature tooWSGR Ref: 69354-705.601 and filtered through membranes. The filtrate was used directly in the next step without further purification. MS ESI calculated for C8HI3N2OP [M+H]+, 185.08 found 184.95.Step 2. (R)- 1 -(2-amino-5 -(dimethy Iphosphory l)pheny l)-3 -( 1 -(5 ,7-difluoro-3 - methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)thiourea.To (3,4-aminophenyl)dimethylphosphine oxide in 2 mL DMF was added CH3CN (2.5 mL), and the resulting mixture was stirred at 70 °C. Then (A)-5,7-difluoro-3-methyl-2-(2,2,2- trifluoro-l-isothiocyanatoethyl)benzofuran (125 mg, 0.407 mmol) was added dropwise to the mixture. After stirring at 70 °C for an additional hour, the reaction mixture was cooled to room temperature and quenched with water (10 mL). The resulting mixture was then extracted with ethyl acetate (EtOAc) (3 x 8 mL). The combined organic layers were washed with brine (1 x 15 mL) and dried over anhydrous sodium sulfate (Na2SO4). After filtration, the filtrate was concentrated under reduced pressure. The crude product was usedin the next step without further purification. MS ESI calculated for C2OHI9F5N302PS [M+H]+, 492.09 found 492.15. Step 3. (R)-(2-((l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)amino)-lH- benzo[d]imidazol-6-yl)dimethylphosphine oxide.A solution of (A)-l-(2-amino-5-(dimethylphosphoryl)phenyl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)thiourea (100 mg, 0.203 mmol), (diacetoxyiodo)benzene (98.32 mg, 0.304 mmol) and DIPEA (131.50 mg, 1.015 mmol) in CH3CN (2 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by PLC (PE / EA / EtOH = 4 / 1 / 3) to afford a crude product. The crude product was further purified by reverse flash chromatography with the following conditions: Column: Spherical Cl 8, 20-40 pm, 120 g; Mobile Phase A: Water (plus 0.1% NH4HCO3), Mobile Phase B: ACN; Detector: 220 / 254 nm. The fractions containing the desired product were collected and concentrated under reduced pressure to afford (A)-(2-((l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)amino)-17 / -benzo[tZ]imidazol-6-yl)dimethylphosphine oxide (36.2 mg, 38.9% yield) as a white solid. MS ESI calculated for C2oHi7F5N302P [M+H]+, 458.10 found 458.15. JH NMR (400 MHz, DMSO) 5 10.94 (br, 1H), 8.56 (t, J= 9.2 Hz, 1H), 7.62 (dd, J= 12.0, 4.0 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.36 - 7.29 (m, 2H), 6.38 - 6.31 (m, 1H), 2.36 (s, 3H), 1.62 (s, 3H), 1.59 (s, 3H).19F NMR (376 MHz, DMSO) 5 -71.99 (3F), -116.21 (IF), -132.96 (IF).31P NMR (162 MHz, DMSO) 5 32.80 (IP).

[0132] Example 215: Dimethyl (R)-(2-((l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)amino)-lH-benzo[d]imidazol-6-yl)phosphonateWSGR Ref: 69354-705.601Step 1. (A)-5,7-difluoro-3-methyl-2-(2,2,2-trifluoro-l-isothiocyanatoethyl)benzofuran. To a stirred mixture of (lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethanamine (2 g, 7.54 mmol) and sodium bicarbonate (6.34 g, 75.42 mmol) in dichloromethane (20 mL) and water (20 mL), thiophosgene (1.30 g, 11.31 mmol) was added dropwise at ambient temperature under a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 4 hours, extracted with ethyl acetate (3 x 50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9 / 1) to afford (A)-5,7-difluoro-3-methyl-2-(2,2,2- trifluoro-l-isothiocyanatoethyl)benzofuran (2.2 g, 94.8% yield) as a white oil. MS ESI calculated for CI2H6F5NOS [M-H]-, 306.01, found 305.95.Step 2. (R)- 1 -(2 -amino-5 -bromoph enyl)-3-(l -(5, 7-difluoro-3 -methylbenzofuran -2 -yl)-2, 2,2- triflu oro ethy 1 )th i ourea .4-bromobenzene-l,2-diamine (121.6 mg, 0.650 mmol) and (A)-5,7-difluoro-3-methyl-2- (2,2,2-trifluoro-l-isothiocyanatoethyl)benzofuran (100 mg, 0.325 mmol) were mixed in CH3CN (2 mL) at ambient temperature. The resulting mixture was stirred at 70 °C for 4 hours. The reaction mixture was cooled to ambient temperature and quenched with water (30 mL). The resulting solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous sodium sulfate (Na2SO4). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5 / 1) to afford (R)-l-(2- amino-5-bromophenyl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)thiourea (120 mg, 74.6% yield) as a white solid. MS ESI calculated for Ci8Hi3BrF5N3OS [M-H]+: 491.99, 493.99; found: 491.90, 493.90.Step 3. (A)-6-bromo-A-(l -(5, 7-difluoro-3 -methylbenzofuran -2 -yl)-2, 2, 2-trifluoroethyl)- 1H- benzo[t / ]imidazol-2-amine.A solution of (A)-l-(2-amino-5-bromophenyl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)thiourea (120 mg, 0.243 mmol), (diacetoxyiodo)benzene (117.30 mg,WSGR Ref: 69354-705.6010.364 mmol), and DIEA (156.89 mg, 1.215 mmol) in CH3CN (2 mL) was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to afford the crude product that was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford (A)-6-bromo-A-(l -(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-l / 7-benzo[t / ]imidazol-2-amine (80 mg, 71.6% yield) as a white solid. MS ESI calculated for CisHnBrFsNsO [M+H]+, 460.00, 462.00, found 460.00, 462.05.Step 4. dimethyl 2-{[(lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethyl]amino}-3J7-l,3-benzodiazol-5-ylphosphonate.To a stirred mixture of (A)-6-bromo-A-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)-17 / -benzo[t / ]imidazol-2-amine (80 mg, 0.174 mmol) and dimethyl phosphite (38.26 mg, 0.348 mmol) in dioxane (2 mL) were added CataCXium A Pd G3 (18.99 mg, 0.026 mmol) and K3PO4 (73.80 mg, 0.348 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for an additional 16 hours. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM Cl 8 -I, 20 - 40 pm, 120 g; Eluent A: Water (plus 10 mmol / L ammonium bicarbonate); Eluent B: ACN; Detector: 220 / 254 nm; desired fractions were collected and concentrated under reduced pressure to afford dimethyl 2-{[(lA)-l-(5,7-difluoro-3-methyl-l-benzofuran-2-yl)-2,2,2- trifluoroethyl]amino}-3J / -l,3-benzodiazol-5-ylphosphonate (25.6 mg, 30. l%yield) as an off- white solid. MS ESI calculated for C2OHI7F5N304P [M+H]+, 490.09, found 490. 10. iH NMR (400 MHz, DMSC s) 8 10.97 (br, 1H), 8.70-8.65 (m, 1H), 7.61-7.56 (m, 1H), 7.48-7.24 (m, 4H), 6.47-6.27 (m, 1H), 3.70-3.50 (m, 6H), 2.37 (d, J= 3.2 Hz, 3H).19F NMR (376 MHz, DMSO-t / 6) 6 -71.93 (3F), -116.20 (IF), -132.96 (IF).II. Biological Evaluation

[0133] Example 1 : Cellular Viability Assay

[0134] Cells were seeded in a 96 well plate (Corning 3904) in 90 pL growth media at the following cell densities: SK-BR-3 and MCF7 at 2000 cells / well and T47D at 1500 cells / well. Cells were allowed to settle and then incubated overnight at 37 °C. with 5% CO2. The following day, compounds were serially diluted from a 10 mM top dose for a 9 -point 3 -fold dilution curve in DMSO. Compounds were transferred using Tecan D300e digital dispenser for a final volume of 100 pL and 0.1% DMSO. Compounds and cells were incubated together for 120WSGR Ref: 69354-705.601 hours at 37 °C. with 5% CO2. The CellTiter-Glo® 2.0 Assay determines the number of viable cells in culture by quantifying ATP, which indicates the presence of metabolically active cells. Luminescence readout is directly proportional to the number of viable cells in culture.CellTiter-Glo reagent (Promega, G9243) and cell plates were allowed to equilibrate to room temperature for at least 15 min, then 100 pL of CellTiter-Glo was added to each well for a 1 :1 ratio of reagent to media. Samples were placed on a shaker for 2 min prior to a 30 min incubation at room temperature protected from light. Luminescence was read on a Perkin Elmer Envision plate reader 2105 and used to calculate IC50values within the Dotmatics Knowledge Solutions Studies curve fitting environment (Dotmatics, Bishops Stortford, UK, CM23) and are presented in Table 3.Table 3WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGRRef: 69354-705.601WSGR Ref: 69354-705.601“A” for EC50less than 0.1 pM;“B” for EC50less than 1.0 pM, but greater (>) than 0.1 pM; and “C” for EC50less than 10 pM, but greater (>) than 1.0 pM. “D” for EC50greater than 10 pM.III. Preparation of Pharmaceutical Dosage Forms

[0135] Example 1 : Oral capsule

[0136] The active ingredient is a compound of Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1 - 1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[0137] Example 2: Solution for injection

[0138] The active ingredient is a compound of Table 1, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq / mL.

[0139] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WSGR Ref: 69354-705.601CLAIMSWe claim:

1. A compound having the structure of Formula (I), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Y is selected from CH, or N;Z is selected from CR10Rn, NR10, or C(O);Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; or R10and R11are both optionally substituted alkyl and join to form a ring; andWSGR Ref: 69354-705.601R12is independently hydrogen or optionally substituted alkyl; with the provision that if Y is CH, Z isNH, Al is O, and A2, A3 and A4 are C, then R2. A compound having the structure of Formula (I -A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Y is selected from CH, or N;Z is selected from CR10Rn, NR10, or C(O);Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;R7is optionally substituted alkyl;WSGR Ref: 69354-705.601 each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; or R10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Y is CH, Z is NH, Al is O, and A2, A3 and A4 are C, then R3. A compound having the structure of Formula (II), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;WSGR Ref: 69354-705.601R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; and each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Al is O, and A2, A3 and A4 are C, then R is not4. A compound having the structure of Formula (II- A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;WSGR Ref: 69354-705.601R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; and each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring; andR12is independently hydrogen or optionally substituted alkyl; with the provision that if Al is O, and A2, A3 and A4 are C, then R is not5. A compound having the structure of Formula (III), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;Z is selected from CR10Rn, NR10, or C(O);R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted tricyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionallyWSGR Ref: 69354-705.601 substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-O-;R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; or R10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl.

6. A compound having the structure of Formula (III- A), or a deuteroisotope, or pharmaceutically acceptable salt or solvate thereof:wherein,Al is selected from CR12, CH, N, NH, O, or S;A2, A3, and A4 are each independently selected from C, or N;Z is selected from CR10Rn, NR10, or C(O);R is selected from optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, or -SO2R7;R1is selected from optionally substituted alkyl, or optionally substituted carbocyclylalkyl;R2is selected from hydrogen, deuterium, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, -SO2NH2, - S(O)(NH)R7, -SO2R7, -PO(R8)2, -COR7, -CONH2, or -CON(R9)2; each R3-R6is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted alkoxy, (optionally substituted carbocyclyl)-O-, or (optionally substituted carbocyclylalkyl)-©-;WSGR Ref: 69354-705.601R7is optionally substituted alkyl; each R8is independently optionally substituted alkyl; or two R8join to form a ring; each R9is independently hydrogen or optionally substituted alkyl; or two R9to form a ring;R10and R11are independently hydrogen, deuterium, or optionally substituted alkyl; or R10and R11are both optionally substituted alkyl and join to form a ring; andR12is independently hydrogen or optionally substituted alkyl.

7. The compound of any one of claims 1 -6, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Al is O; A2 is C; A3 is C; and A4 is C.

8. The compound of any one of claims 1 -6, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Al is S; A2 is C; A3 is C; and A4 is C.

9. The compound of any one of claims 1 -6, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Al is NH; A2 is C; A3 is C; and A4 is C.

10. The compound of any one of claims 1 -6, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Al is CH; A2 is N; A3 is C; and A4 is C.

11. The compound of any one of claims 1 -6, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Al is N; A2 is N; A3 is C; and A4 is C.

12. The compound of any one of claims 1 -6, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Al is N; A2 is C; A3 is C; and A4 is N.

13. The compound of any one of claims 1 -6, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Al is N; A2 is C; A3 is N; and A4 is C.

14. The compound of any one of claims 1 -13, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted carbocyclyl.

15. The compound of any one of claims 1 -13, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted aryl.

16. The compound of claim 15, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.

17. The compound of any one of claims 1 -13, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted monocyclic heteroaryl.

18. The compound of claim 17, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted monocyclic heteroaryl is selected from the group consisting of optionally substituted pyrimidine, optionally substituted pyridine, optionally substituted py ridazine, optionally substituted triazine, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted pyrazole, optionallyWSGR Ref: 69354-705.601 substituted thiophene, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted furan, optionally substituted oxazole, optionally substituted isoxazole, optionally substituted oxadiazole, optionally substituted triazole, and optionally substituted thiadiazole.

19. The compound of claim 18, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is optionally substituted pyrimidine.

20. The compound of claim 18, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is optionally substituted pyridine.

21. The compound of claim 18, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is optionally substituted pyridazine.

22. The compound of claim 18, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is optionally substituted triazine.

23. The compound of claim 18, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridazinone, optionally substituted pyrimidinone, optionally substituted pyridinone, or optionally substituted pyrazinone.

24. The compound of claim 23, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted pyridazinone, optionally substituted pyrimidinone, optionally substituted pyridinone, or optionally substituted pyrazinone, is an optionally substituted pyridazinone, optionally substituted pyrimidinone, optionally substituted pyridinone, or optionally substituted pyrazinone selected from the group of consisting of25. The compound of claim 24, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted pyridazinone, optionally substituted pyrimidinone, optionally substituted pyridinone, or optionally substituted pyrazinone, is selected from the group of consisting ofWSGR Ref: 69354-705.60126. The compound of any one of claims 1-13, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted heterocyclyl.

27. The compound of claim 26, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted spirocylic heterocyclyl.

28. The compound of any one of claims 1-13, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted bicyclic heteroaryl.

29. The compound of claim 28, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted bicyclic heteroaryl is an optionally substituted benzoimidazole, pyrrolo[3,2-b]pyridine, imidazo[l,2-a]pyridine, pyrazolo[l,5- a]pyridine, [l,2,4]triazolo[4,3-a]pyridine, imidazo[4,5-c]pyridine, [l,2,4]triazolo[l,5- a]pyridine, quinoxaline, benzo[d]thiazole, quinoline, indole, imidazo[4,5-b]pyridine, imidazo[l,5-a]pyridine, indazole, pyrrolo[2,3-b]pyridine, thieno[3,4-d]imidazole, purine, thieno[2,3-d]imidazole, pyrrolo[3,2-c]pyridine, pyrazolo[4,3-c]pyridine, thiazolo[4,5- b]pyridine, thiazolo[5,4-b]pyridine, pyrrolo[3,2-d]pyrimidine, imidazo[l,2-a]pyrimidine, imidazo[l,2-b]pyridazine, imidazo[4,5-c]pyridazine, imidazo[4,5-b]pyrazine.

30. The compound of any one of claims 1-13, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted tricyclic heteroaryl.

31. The compound of claim 30, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted tricyclic heteroaryl is an optionally substituted phosphorous-containing tricyclic heteroaryl.

32. The compound of any one of claims 1-13, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -SO2R7.

33. The compound of any one of claims 6-32, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is selected from CR10Rn.

34. The compound of any one of claims 6-32, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is selected from NR10.

35. The compound of any one of claims 6-32, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is selected from C(O).

36. The compound of any one of claims 1 -35, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from optionally substituted alkyl.WSGR Ref: 69354-705.60137. The compound of any one of claims 1 -35, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from optionally substituted carbocyclylalkyl.

38. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen or deuterium.

39. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is halogen.

40. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CN.

41. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted alkyl.

42. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted carbocyclyl.

43. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted carbocyclylalkyl.

44. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -SO2NH2.

45. The compound of any one of claims 1-37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -S(O)(NH)R7.

46. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -SO2R7.

47. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -PO(R8)2.

48. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -COR7.

49. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CONH2.

50. The compound of any one of claims 1 -37, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CON(R9)2.

51. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3-R6is independently selected from hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted carbocyclylalkyl.WSGR Ref: 69354-705.60152. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3-R6is independently selected from hydrogen, deuterium, halogen, or optionally substituted alkyl.

53. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3-R6is independently selected from hydrogen, deuterium, or halogen.

54. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is halogen.

55. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is halogen.

56. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is F.

57. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is F.

58. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R3and R5are F.

59. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R2and R6are hydrogen or deuterium.

60. The compound of any one of claims 1 -50, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R3and R5are F; and R2and R6are hydrogen or deuterium.

61. A compound, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, as described in Table 1.

62. A compound, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, as described in Table 2.

63. A pharmaceutical composition comprising a compound, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1 -62 and a pharmaceutically acceptable excipient.

64. A method of preparing a pharmaceutical composition comprising mixing a compound, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-62, and a pharmaceutically acceptable carrier.

65. A compound of any one of claims 1 -62, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.WSGR Ref: 69354-705.60166. A compound of any one of claims 1 -62, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer.

67. Use of a compound of any one of claims 1 -62, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

68. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1 -62, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof.

69. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-62, or a deuteroisotope, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

70. A method of inhibiting PI3Ka protein activity, comprising contacting the PI3Ka protein with a compound of any one of claims 1-62, wherein the PI3Ka protein is contacted in an in vitro setting.

71. A method of inhibiting PI3Ka protein activity, comprising contacting the PI3Ka protein with a compound of any one of claims 1-62, wherein the PI3Ka protein is contacted in an in vivo setting.

Images