Compounds containing fused tricyclic rings as PI3k inhibitors

Abstract

Novel PI3K inhibitors of the general Formula (1) are described along with methods of their preparation and their use in the treatment of diseases associated with the elevation or activation of the PI3K pathway, wherein R1 to R7 and Z are defined as described.

Description

COMPOUNDS CONTAINING FUSED TRICYCLIC RINGS AS PI3K INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 657,426, filed June 7, 2024, the disclosure of which is incorporated by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION

[0002] Phosphatidylinositol lipids (PIs) and their various phosphorylated subspecies are second messengers involved in a wide array of cellular vesicle trafficking and signal transduction processes. Phosphoinositide 3’ kinases (PI3Ks) are a family of enzymes responsible for phosphorylation of the 3’ hydroxyl position of the inositol ring of PIs. PI3Ks are subdivided into 3 classes according to their structure and substrates. Class II PI3Ks (PI3K-C2α, PI3K-C2β, PI3K-C2γ) and Class III PI3Ks (vps34) are monomeric enzymes primarily associated with endocytosis and autophagy (Posor et al., Biochim Biophys Acta 2015, 1851, 794; Backer, Biochem J.2016, 473, 2251). The Class I PI3Ks are heterodimeric, consisting of a catalytic kinase subunit (p110α, β, γ, δ) and one of several regulatory subunits that determine binding partners and subcellular localization. Class I PI3Ks are activated upon interaction with receptor tyrosine kinases (RTKs), Ras-related GTPases, G-protein coupled receptors, and / or related adaptor proteins, and in their active form convert phosphatidylinositol 4,5-diphosphate (PIP2) to phosphatidyl 3,4,5- triphosphate (PIP3) (Fruman et al., Cell 2017, 170, 605).

[0003] High local concentrations of PIP3 promote the recruitment and activation of downstream signaling partners, including AKT and mTOR. Activation of the AKT / mTOR pathways are implicated in several growth-related roles and pathologies including glucose regulation, cell survival, angiogenesis, and proliferation (Porta et al., Front Oncol.2014, 4, 1), indicating a role for Class I PI3Ks as a critical upstream regulator of these functions.

[0004] Class I PI3Ks are further subdivided into 4 isoforms (α, β, γ, and δ) based on the identity of their catalytic (p110α, p110β, p110γ, or p110δ) and regulatory (p85α or its various splice variants, p85β, p55γ, or p101) subunits, giving rise to distinct roles in cellular physiology (Vanhaesebroeck et al., J Mol Med (Berl).2016, 94, 5). PI3Kγ and PI3Kδ are mostly expressed in leukocytes and play an important role in pro-inflammatory pathways (Hawkins et. al., Biochimica et Biophysica Acta 2015, 1851, 882; Okkenhaug et al., Science 2002, 297, 1031; Ali et al., Nature 2004, 431, 1007). PI3Kα and β are more ubiquitously expressed and share similar but not identical roles. For example, PI3Kα has a nonredundant role in angiogenesis (Soler et al., J ExpMed.2013, 210, 1937), while PI3Kβ is known to serve a specific function in platelet aggregation (Liu et. al., Nat Rev Drug Discov.2009, 8, 627; Jackson et al., Nat Med.2005, 11, 507).

[0005] Elevation or constitutive activation of the PI3K pathway is one of the most frequent events in human cancers. The PI3K pathway is overactivated through a variety of mechanisms, including activating mutation of PI3K isoforms, up-regulation of PI3K isoforms, loss or inactivation of the tumor suppressor PTEN, or hyperactivation of tyrosine kinase growth factor receptors or other upstream signaling partners (Yang et al., Mol Cancer 2019, 18, 1). Mutations in the gene coding for PI3Kα or mutations which lead to upregulation of PI3Kα have been found to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers (Goncalves et al., N Eng J Med.2018, 379,2052). In particular, PIK3CA, the gene encoding the p110α subunit of PI3Kα, is frequently mutated or amplified in a variety of tumor types. Missense mutations occur in all domains of p110α, but cluster in two ‘hot spots’, the most common being E542K and E545K in the helical domain, and H1047R in the kinase domain. Helical domain mutations reduce inhibition of p110α by p85 or facilitate direct interaction of p110α with insulin receptor substrate 1 (IRS1)37, whereas kinase domain mutations increase interaction of p110α with lipid membranes, concomitantly upregulating signaling events. (Thorpe et al., Nat Rev Cancer 2015, 15, 7).

[0006] The development of inhibitors for the PI3K pathway has been challenging due to the inability to achieve dosing sufficient for tumor suppression without adverse events. To date PI3K inhibitors in the clinic (alpelisib, buparlisib, copanlisib, duvelisib, idelalisib, pictilisib, taselisib, and others) have caused dose-dependent adverse events such as hyperglycemia, rash, fatigue, diarrhea, etc. (Jiang et al., Mol Biol Rep.2020, 47, 4587) which are known on-target toxicities. Hyperglycemia is a result of the body not producing enough insulin or aberrant utilization. The pancreas regulates insulin release in response to changes in blood glucose levels, resulting in either glucose uptake by muscle and fat cells when insulin levels are high or gluconeogenesis by the liver when insulin levels are low. Tissue cellular response to insulin requires PI3K signaling through the ubiquitously expressed p110α sub-unit. As a result, pan-PI3K inhibition of the target disrupts glucose metabolism in tissues, leading to insulin resistance (Hopkins et al., Nature 2018, 560, 499). To mitigate adverse events, selective PI3K isoform inhibitors were developed. The severity of the adverse event is dependent on the select isoform, for example PI3Kα inhibitors are associated with hyperglycemia and rash due to the p110α sub-unit role in insulin response (Rugo et al., The Breast 2022, 61, 156). Similarly, use of a selective PI3Kδ inhibitor (idelalisib),where the p110δ sub-unit is highly expressed in immune cells, causes severe diarrhea and colitis. Inhibition with a dual inhibitor (taselisib), a potent PI3Kδ inhibitor possessing modest PI3Kα inhibition led to gastrointestinal (GI) side effects, but a highly selective and potent PI3Kδ inhibitor (umbralisib) reported no GI related adverse events (Gadkar et al., CPT Pharmacometrics Syst Pharmacol.2021, 11, 616). Such amelioration of adverse events with highly isoform selective and potent inhibitors demonstrates that a strategy to mitigate toxicity by developing mutant selective isoform inhibitors is promising for decreasing the severity of toxicity. Furthermore, selective inhibition of the mutant PI3Kα isoform over wild type may suppress cancer signaling while having minimal effect on PI3K signaling in healthy cells bearing just wild type PI3Kα, leading to a reduction in the toxicities associated with nonselective PI3K inhibition (Castel et al., Nat Cancer 20212, 587).

[0007] There is currently an interest in developing PI3K inhibitors for cancer therapy (WO 2023 / 081209, WO 2023 / 078401, WO 2023 / 060262, WO 2023 / 056407, WO 2021 / 202964, WO 2023 / 159155). However, there is a continued need for novel potent and selective PI3K inhibitors, either as single agents or as combination therapies, in the treatment of cancer. SUMMARY OF THE INVENTION

[0008] An aspect of the invention is a compound of Formula (1)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein:Z is heteroaryl or heterocyclyl, wherein the heteroaryl or heterocyclyl is substituted or unsubstituted, such as a substituted or unsubstituted 5- to 6- membered heteroaromatic ring containing up to 4 nitrogen ring atoms (which includes the nitrogen atom depicted in Formula (1)) or a substituted or unsubstituted 5- to 7-membered heterocyclic ring containing up to 2 nitrogen ring atoms (which includes the nitrogen atom depicted in Formula (1)); R1is aryl, heteroaryl or heterocyclyl, where each of the aryl, heteroaryl and heterocyclyl is unsubstituted or substituted, with the proviso that when R1is aryl or heteroaryl, a carboxylic acid or ester thereof is not a substituent at a position ortho to the point of attachment of the aryl or heteroaryl ring to the nitrogen atom of N-R3; R2 is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF3, CFH2 or CF2H, where the C1-C4 alkyl and C3-C7 cycloalkyl is unsubstituted or substituted, and where R2is not H, the carbon atom attached to R2is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer; R3is H or C1-C4alkyl, where the C1-C4alkyl is unsubstituted or substituted; R4is H, F, Cl, C1-C4alkyl, C3-C7cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4alkyl and C3-C7cycloalkyl is unsubstituted or substituted; R6is H, F, Cl, C1-C4alkyl, C3-C7cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4alkyl and C3-C7 cycloalkyl is unsubstituted or substituted; each R7is independently H, F, Cl, C1-C4alkyl, C3-C7cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4alkyl and C3-C7cycloalkyl is unsubstituted or substituted; and R5is heteroaryl or a non-aromatic N-linked heterocyclic ring , where the heteroaryl and the heterocyclic ring are substituted or unsubstituted, and where the heterocyclic ring optionally contains one or more additional ring atoms selected from N, O, Si and S, and is optionally part of a bridged, fused or spiro ring system. In particular embodiments, the N-linked heterocyclic ring is a substituted or unsubstituted azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2- oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane.

[0009] In an exemplary embodiment of the compound of Formula (1), R1is selected from the following:wherein: R8is selected from the following:; where each A is independently C1-C4alkyl, fluoroalkyl, C3-C7cycloalkyl, N(Ra)2, (CH2)0-5-NRa-C(O)- C3-C7cycloalkyl, (CH2)1-5-O-C1-C3cycloalkyl, (CH2)1-5-O-(CH2)1-5-C1-C3fluoroalkyl, (CH2)0-5-aryl, (CH2)0-5-heteroaryl, (CH2)0-5-heterocyclyl, (CH2)0-5-NRa-(CH2)0-5-heteroaryl or (CH2)0-5-NRa-(CH2)1-5- N-heterocyclyl, where the alkyl, fluoroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl aresubstituted or unsubstituted, or alternatively, A and A together with the attached -P(=O)- moiety may form a substituted or unsubstituted heterocyclyl ring; each B is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, (CH2)1-5-NRa-C(O)-C3-C7 cycloalkyl, (CH2)0-5- aryl, (CH2)0-5-heteroaryl, (CH2)0-5-heterocyclyl, (CH2)1-5-NRa-(CH2)0-5-heteroaryl or (CH2)1-5-NRa- (CH2)2-5-N-heterocyclyl, O-C1-5-alkyl, O-C0-5-cycloalkyl, O-C0-5-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, B and B together with the attached -[O or NH]-P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring, or alternatively, A and B together with the attached -P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring; each Ra is independently H, C1-C4 alkyl, C(O)C1-C3 alkyl or C(O)-(CH2)1-5-O-C1-C3 alkyl, where the alkyl is substituted or unsubstituted, or alternatively, Raand A together with the attached - S(=O)2- moiety may form a substituted or unsubstituted heterocyclic ring, or R8and R9together form a substituted or unsubstituted heterocyclic ring (such as a 5- or 6- membered heterocyclic ring) containing one or more sulfur atoms (which includes the sulfoxide (SO) and sulfone (SO2) forms), nitrogen atoms (which includes the oxidized forms) and oxygen atoms; R9 is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2 or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted, or R9and R8together form a heterocyclic ring as described herein; each R10is independently H, C1-C4alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted; R11is H, C1-C4alkyl, C3-C7cycloalkyl, CF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted; and each X1, X2, X3 and X4 is independently CH, N or substituted C.

[0010] In an exemplary embodiment of the compound of Formula (1), R1iswherein R8, R9, X2, X3and X4are defined as described herein. In a particular embodiment, X2is C- CN.

[0011] In an exemplary embodiment of the compound of Formula (1), R1 iswherein R8, X2, X3and X4are defined as described herein. In a particular embodiment, X2is C-CN.

[0012] In an exemplary embodiment of the compound of Formula (1), R1iswherein R8, X2, X3and X4are defined as described herein. In a particular embodiment, X2is C-CN.

[0013] In an exemplary embodiment of the compound of Formula (1), R1is selected from the following:wherein R10and R11are defined as described herein.

[0014] In an exemplary embodiment of the compound of Formula (1), R1is selected from the following:X2, X3and X4are defined as described herein; Y is O, NR11or C(R4)2; and each R4, R10and R10is independently defined as described herein. In a particular embodiment, X2is C-CN.

[0015] In an exemplary embodiment of the compound of Formula (1), R5 as a N-linked non-aromatic heterocyclyl ring is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7- azaspiro[4.4]nonane or 2-azaadamantane.

[0016] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is not part of a bridged, fused or spiro ring system.

[0017] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is part of a bridged, fused or spiro ring system.

[0018] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, does not contain additional atoms selected from N, O, Si and S, and is not part of a bridged, fused or spiro ring system.

[0019] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, does not contain additional atoms selected from N, O, Si and S, and is part of a bridged, fused or spiro ring system.

[0020] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is not part of a bridged, fused or spiro ring system.

[0021] In an exemplary embodiment of the compound of Formula (1), R5 as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is part of a bridged, fused or spiro ring system.

[0022] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is not part of a bridged, fused or spiro ring system.

[0023] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is part of a bridged, fused or spiro ring system.

[0024] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is not part of a bridged, fused or spiro ring system.

[0025] In an exemplary embodiment of the compound of Formula (1), R5as a N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is part of a bridged, fused or spiro ring system.

[0026] In an exemplary embodiment of the compound of Formula (1), R5is heteroaryl.

[0027] In an exemplary embodiment of the compound of Formula (1), R5is a 5-membered heteroaromatic ring.

[0028] In an exemplary embodiment of the compound of Formula (1), R5is a 5-membered heterocyclyl ring.

[0029] In an exemplary embodiment of Formula (1), C1-C4alkyl is preferably methyl.

[0030] In an exemplary embodiment of Formula (1), halogen is preferably F.

[0031] In an exemplary embodiment of Formula (1), halogen is preferably Cl.

[0032] In an exemplary embodiment of the compound of Formula (1), Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

[0033] In an exemplary embodiment of the compound of Formula (1), R1is a substituted or unsubstituted heteroaryl.

[0034] In an exemplary embodiment of the compound of Formula (1), R1is selected fromwhere X2, X3, X4, A and B are as defined.

[0035] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand R8is selected fromwhere X2, X3, X4, A, B and Raare as defined.

[0036] In an exemplary embodiment of the compound of Formula (1), R1is selected fromwhere X2, X3, X4and B are as defined.

[0037] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F or CHF2.

[0038] In an exemplary embodiment of the compound of Formula (1), R3is H.

[0039] In an exemplary embodiment of the compound of Formula (1), R4 is H or F or Cl.

[0040] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F; and R3is H.

[0041] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F; R3is H; and R4 is H or F or Cl.

[0042] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F; R3is H; and R6is CH3or F or Cl.

[0043] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F; R3is H; and R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1,4-dioxa-7-azaspiro[4.4]nonane or 2- azaadamantane.

[0044] In an exemplary embodiment of the compound of Formula (1), R1is selected fromwhere X2, X3, X4, A, B and Raare as defined; R3is H; and R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7- azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane.

[0045] In an exemplary embodiment of the compound of Formula (1), R1is selected fromwhere X2, X3, X4, A, B and Raare as defined; R2is CH3or CH2F; R3is H; and R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2- oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane.

[0046] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand R8 is selected fromwhere X2, X3, X4, A, B and Raare as defined; R2is CH3or CH2F; R3is H; R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2- oxa-7-azaspiro[3.5]nonane, 1,4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane, and each R7is independently H or F or Cl.

[0047] In an exemplary embodiment of the compound of Formula (1), R1is selected fromwhere X2, X3, X4, A, B and Raare as defined; R2is CH3or CH2F; R3is H; R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2- oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane; each R7isindependently H or F; and Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4- triazole, 1,2,3-triazole, or tetrazole.

[0048] In an exemplary embodiment of the compound of Formula (1), R1 is selected fromwhere X2, X3, X4, A, B and Raare as defined; R2is CH3or CH2F; R3is H; R4is H or F or Cl; R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1,4-dioxa-7-azaspiro[4.4]nonane or 2- azaadamantane; R6is CH3; each R7is H or F; and Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

[0049] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand at least one of X1, X2, X3and X4is N.

[0050] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand at least two of X1, X2, X3and X4is N.

[0051] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand at least three of X1, X2, X3and X4is N.

[0052] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand X1is N.

[0053] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand X2is N.

[0054] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand X3is N.

[0055] In an exemplary embodiment of the compound of Formula (1), R1is selected fromand X4is N.

[0056] In an exemplary embodiment of the compound of Formula (1), none of X1, X2, X3and X4is N.

[0057] In an exemplary embodiment, the compound of Formula (1) is a compound of Formula (2)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: R5and Z are as defined in the compound of Formula (1); each X1, X2, X3and X4is independently CH, N or substituted C; R8is selected from; where A, B and Raare defined as described herein; the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer, and the listing of substituents within brackets indicates individual compounds containing one of each of the substituents.

[0058] In an exemplary embodiment of the compound of Formula (2), R8is selected fromwhere A, B and Raare defined as described herein.

[0059] In an exemplary embodiment of the compound of Formula (2), R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2- oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane.

[0060] In an exemplary embodiment of the compound of Formula (2), R8is selected from:where A, B and Raare defined as described herein; and R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7- azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane.

[0061] In an exemplary embodiment of the compound of Formula (2), R8is selected fromwhere A, B and Raare defined as described herein; R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane; and Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

[0062] In an exemplary embodiment of the compound of Formula (2), at least one of X1, X2, X3and X4is N.

[0063] In an exemplary embodiment of the compound of Formula (2), at least two of X1, X2, X3and X4is N.

[0064] In an exemplary embodiment of the compound of Formula (2), at least three of X1, X2, X3and X4is N.

[0065] In an exemplary embodiment of the compound of Formula (2), X1is N.

[0066] In an exemplary embodiment of the compound of Formula (2), X2is N.

[0067] In an exemplary embodiment of the compound of Formula (2), X3is N.

[0068] In an exemplary embodiment of the compound of Formula (2), X4is N.

[0069] In an exemplary embodiment of the compound of Formula (2), none of X1, X2, X3and X4is N.

[0070] In an exemplary embodiment, the compound of Formula (1) is a compound of Formula (3)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: R5and Z are as defined in the compound of Formula (1); each X2, X3and X4is independently CH, N or substituted C; R8is selected from; where A, B and Raare defined as described herein; R9is H, C1-C4alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted, orR8and R9together form a substituted or unsubstituted heterocyclic ring (such as a 5- or 6- membered heterocyclic ring) containing one or more sulfur atoms (which includes the sulfoxide (SO) and sulfone (SO2) forms), nitrogen atoms (which includes the oxidized forms) and oxygen atoms; the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer, and the listing of substituents within brackets indicates individual compounds containing one of each of the substituents.

[0071] In an exemplary embodiment of the compound of Formula (3), R8is selected from:where A, B and Raare defined as described herein.

[0072] In an exemplary embodiment of the compound of Formula (3), R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2- oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane.

[0073] In an exemplary embodiment of the compound of Formula (3), R8and R9together form a heterocyclic ring with the result that themoiety is selected fromY is O, NR11or C(R4)2; and X2, X3, X4, R4, R10and R11are defined as described herein.

[0074] In an exemplary embodiment of the compound of Formula (3), R8is selected fromwhere A, B and Raare defined as described herein; R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2-azaadamantane; and Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

[0075] In an exemplary embodiment of the compound of Formula (3), at least one of X2, X3and X4is N.

[0076] In an exemplary embodiment of the compound of Formula (3), at least two of X2, X3and X4is N.

[0077] In an exemplary embodiment of the compound of Formula (3), all three of X1, X2, X3 and X4 is N.

[0078] In an exemplary embodiment of the compound of Formula (3), X2is N.

[0079] In an exemplary embodiment of the compound of Formula (3), X3is N.

[0080] In an exemplary embodiment of the compound of Formula (3), X4is N.

[0081] In an exemplary embodiment of the compound of Formula (3), none of X2, X3and X4is N.

[0082] In an exemplary embodiment, the compound of Formula (1) is a compound of Formula (4)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: R5and Z are as defined in the compound of Formula (1); R1is selected from; R10and R11are defined as described herein; the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer; and the listing of substituents within brackets indicates individual compounds containing one of each of the substituents.

[0083] In an exemplary embodiment of the compound of Formula (4), R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine or piperidine.

[0084] In an exemplary embodiment of the compound of Formula (4), Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

[0085] In an exemplary embodiment of the compound of Formula (4), R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine or piperidine; and Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

[0086] An aspect of the invention is a pharmaceutical composition comprising any compound of the invention as described herein (such as a compound of Formula (1), (2), (3) or (4)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0087] In an exemplary embodiment, the pharmaceutical composition comprising any compound of the invention as described herein or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof further comprises one or more anti-cancer agents.

[0088] Another aspect of the invention is a method of treating a disease in which PI3K activity is implicated in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of any compound of the invention as described herein (such as a compound of Formula (1), (2), (3) or (4)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0089] In an exemplary embodiment, the disease to be treated is cancer. In a particular embodiment, the disease is a cancer bearing a PI3Kα H1047 mutation (such as H1047R, H1047L, or H1047Y), a PI3Kα E545 mutation (such as E545K), or a PI3Kα E542 mutation (such as E542K). DETAILED DESCRIPTION OF THE INVENTION

[0090] The term "at risk for" as used herein, refers to a medical condition or set of medical conditions exhibited by a patient which may predispose the patient to a particular disease or affliction. For example, these conditions may result from influences that include, but are not limited to, behavioral, emotional, chemical, biochemical, or environmental influences.

[0091] The term "effective amount" as used herein, refers to a particular amount of a pharmaceutical composition comprising a therapeutic agent that achieves a clinically beneficial result (i.e., for example, a reduction of symptoms). Toxicity and therapeutic efficacy of such compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and additional animal studies can be used in formulating a range of dosages for human use. The dosages of such compounds lie preferably within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.

[0092] The term "symptom" as used herein, refers to any subjective or objective evidence of disease or physical disturbance observed by the patient. For example, subjective evidence is usually based upon patient self-reporting and may include, but is not limited to, pain, headache, visual disturbances, nausea and / or vomiting. Alternatively, objective evidence is usually a resultof medical testing including, but not limited to, body temperature, complete blood count, lipid panels, thyroid panels, blood pressure, heart rate, electrocardiogram, tissue body imaging scans and other medical testing results.

[0093] The term "disease" as used herein, refers to any impairment of the normal state of the living animal or one of its parts that interrupts or modifies the performance of the vital functions. Typically manifested by distinguishing signs and symptoms, a disease is usually a response to i) environmental factors (such as malnutrition, industrial hazards, or climate); ii) specific infective agents (such as worms, bacteria, or viruses); iii) inherent defects of the organism (such as genetic anomalies); and / or iv) combinations of these factors.

[0094] The terms "reduce", "inhibit", "diminish", "suppress", "decrease", "prevent" and grammatical equivalents thereof (including "lower", "smaller", etc.) when used in reference to the expression of any symptom in an untreated subject relative to a treated subject, indicate that the quantity and / or magnitude of the symptoms in the treated subject is lower than in the untreated subject by any amount that is recognized as clinically relevant by any medically trained personnel. In one embodiment, the quantity and / or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and / or at least 90% lower than the quantity and / or magnitude of the symptoms in the untreated subject.

[0095] The term "inhibitory compound" as used herein, refers to any compound capable of interacting with (i.e., for example, attaching, binding, etc.) to a binding partner under conditions such that the binding partner becomes unresponsive to its natural ligands. Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins / peptides.

[0096] The term "attached" as used herein, refers to any interaction between a medium (or carrier) and a drug. Attachment may be reversible or irreversible. Such attachment includes, but is not limited to, covalent bonding, ionic bonding, Van der Waals forces or friction, and the like. A drug is attached to a medium (or carrier) if it is impregnated, incorporated, coated, in suspension with, in solution with, mixed with, etc.

[0097] The term "drug" or "compound" as used herein, refers to any pharmacologically active substance capable of being administered which achieves a desired effect. Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides or nucleotides, polysaccharides, or sugars.

[0098] The term "administered" or "administering" as used herein, refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient. An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular administration, such as subcutaneous, intramuscular, or intraperitoneal), intravenous, oral ingestion, transdermal patch, topical, inhalation, suppository, etc.

[0099] The term "patient" as used herein, is a human or animal and needs not be hospitalized. For example, out-patients and persons in nursing homes are "patients." A patient may be a human or non-human animal of any age and therefore includes both adults and juveniles (i.e., children). It is not intended that the term "patient" connote a need for medical treatment. Therefore, a patient may voluntarily be subject to experimentation, whether clinical or in support of basic science studies. [000100] The term “subject” as used herein, refers to, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., monkeys); non-human mammals, such as cows, pigs, horses, sheep, mice, goats, cats, dogs; and / or birds, such as chickens, ducks and / or geese. [000101] The term "affinity" as used herein, refers to any attractive force between substances or particles that causes them to enter into and remain in chemical combination. For example, an inhibitor compound that has a high affinity for a receptor will provide greater efficacy in preventing the receptor from interacting with its natural ligands, than an inhibitor with a low affinity. [000102] The term "derived from" as used herein, refers to the source of a compound or sequence. In one respect, a compound or sequence may be derived from an organism or particular species. In another respect, a compound or sequence may be derived from a larger complex or sequence. [000103] The term "test compound" as used herein, refers to any compound or molecule considered a candidate as an inhibitory compound. [000104] The term "combination therapy" as used herein refers to refers to a dosing regimen of two or more different therapeutically active agents during a period of time, wherein thetherapeutically active agents are administered together or separately. In one embodiment the combination therapy is a non-fixed combination. [000105] The term "non-fixed combination" as used herein refers to two or more different therapeutic agents that are formulated as separate compositions or dosages such that they may be administered separately to a subject in need thereof either simultaneously or sequentially with variable intervening time limits. [000106] The term "synergy" or "synergistic" as used herein refers to the phenomenon where the combination of two therapeutic agents of a combination therapy is greater in terms of measured results than the sum of the effect of each agent when administered alone. [000107] The term "in vivo" as used herein refers to an event that takes place in a subject's body. [000108] The term "in vitro" as used herein refers to an event that takes places outside of a subject's body. [000109] The term "protein" as used herein, refers to any of numerous naturally occurring extremely complex substances (such as an enzyme or antibody) that contain amino acid residues joined by peptide bonds, and which include carbon, hydrogen, nitrogen, oxygen, and typically sulfur. In general, a protein comprises amino acids having an order of magnitude within the hundreds. [000110] The term "peptide" as used herein, refers to any of various amides that are derived from two or more amino acids by combination of the amino group of one acid with the carboxyl group of another and are usually obtained by partial hydrolysis of proteins. In general, a peptide comprises amino acids having an order of magnitude with the tens. [000111] The term "pharmaceutically acceptable" or "pharmacologically acceptable" as used herein, refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human. [000112] The term, "pharmaceutically acceptable carrier" as used herein, includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, a polyol (such as, for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.[000113] The term "pharmaceutically acceptable salt" as used herein, refers to a salt that does not adversely impact the biological activity and properties of the compound and is suitable for use in contact with the tissues of subjects without undue toxicity, irritation and / or allergic response and the like. Pharmaceutically acceptable salts include those derived from suitable inorganic acids, organic acids and bases, and include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, naphthalene sulfonic acid, lactic acid, succinic acid, oxalic acid, stearic acid, and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt (e.g., a sodium or a potassium salt), an alkaline earth metal salt (e.g., a calcium or a magnesium salt), a salt formed from an organic base, and an amino acid salt. Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, and ammonium and quaternary ammonium compounds. Specific metals include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts may be prepared include, for example, primary, secondary, and tertiary amines. [000114] The term "prodrug" as used herein, refers to a compound that is transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound. In various instances, a prodrug has improved physicochemical properties (such as bioavailability) and / or delivery properties over the parent compound. Prodrugs are typically designed to enhance pharmaceutically and / or pharmacokinetically based properties associated with the parent compound. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in subject. Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively. Prodrugs are well known to be prepared from carboxylic acids in the form of, for example, carboxylate esters or thioesters. [000115] The term, "purified" or "isolated" as used herein, may refer to a composition (such as, for example, a peptide composition) that has been subjected to treatment (e.g.,fractionation) to remove various other components, and which composition substantially retains its expressed biological activity. [000116] The term "sample" as used herein, includes, for example, environmental and biological samples. Environmental samples include material from the environment such as soil and water. Biological samples include animal (e.g., human), fluids (e.g., blood, plasma, and serum), solids (e.g., stool), tissue, liquid foods (e.g., milk), and solid foods (e.g., vegetables). For example, a pulmonary sample may be collected by bronchoalveolar lavage (BAL) which comprises fluid and cells derived from lung tissues. A biological sample may comprise a cell, tissue extract, body fluid, chromosomes or extrachromosomal elements isolated from a cell, genomic DNA (in solution or bound to a solid support such as for Southern blot analysis), RNA (in solution or bound to a solid support such as for Northern blot analysis), cDNA (in solution or bound to a solid support) and the like. [000117] The term "biologically active" as used herein, refers to any molecule having structural, regulatory or biochemical functions. For example, biological activity may be determined, for example, by restoration of wild-type growth in cells lacking protein activity. Cells lacking protein activity may be produced by many methods (i.e., for example, point mutation and frame-shift mutation). Complementation is achieved by transfecting cells which lack protein activity with an expression vector which expresses the protein, a derivative thereof, or a portion thereof. [000118] The term "label" or "detectable label" as used herein, refers to any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. Such labels include biotin for staining with labeled streptavidin conjugate, magnetic beads (e.g., Dynabeads®), fluorescent dyes (e.g., fluorescein, Texas Red®, rhodamine, green fluorescent protein, and the like), radiolabels (e.g.,3H,125I,35S,14C, or32P), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and calorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads. Patents teaching the use of such labels include, but are not limited to, U.S. Patent Nos.3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241 (all herein incorporated by reference in their entireties). The labels contemplated in the present invention may be detected by conventional methods. For example, radiolabels may be detected using photographic film or scintillation counters, fluorescent markers may be detected using a photodetector to detect emitted light. Enzymatic labels are typically detectedby providing the enzyme with a substrate and detecting, the reaction product produced by the action of the enzyme on the substrate, and calorimetric labels are detected by simply visualizing the colored label. [000119] The term "conjugate" as used herein, refers to any compound that has been formed by the joining of two or more moieties. [000120] A "moiety" or "group" as used herein, is any type of molecular arrangement designated by formula, chemical name, or structure. Within the context of certain embodiments, a conjugate comprises one or more moieties or chemical groups. This means that the formula of the moiety is substituted at some position in order to be joined and be a part of the molecular arrangement of the conjugate. Although moieties may be directly covalently joined, it is not intended that the joining of two or more moieties must be directly to each other. A linking group, a crosslinking group, or a joining group refers to any molecular arrangement that will connect moieties by covalent bonds such as, but not limited to, one or more amide group(s). Additionally, although the conjugate may be unsubstituted, the conjugate may have a variety of additional substituents connected to the linking groups and / or connected to the moieties. [000121] A "polymer" or "polymer group" as used herein, refers to a chemical species or group composed of repeatedly linked moieties. Within certain embodiments, it is preferred that the number of repeating moieties is 3 or more or greater than 10. The linked moieties may be identical in structure or may vary in their moiety structures. A "monomeric polymer" or "homopolymer" is a polymer that contains the same repeating, asymmetric subunit. A "copolymer" is a polymer derived from two or more types of monomeric species (i.e., two or more different chemical asymmetric subunits). "Block copolymers" are polymers comprised of two or more species of polymer subunits linked by covalent bonds. [000122] The term "substituted" as used herein, refers to at least one hydrogen atom of a molecular arrangement that is replaced with a substituent. The number of substituents present depends on the number of hydrogen atoms available for replacement and includes replacement of more than one hydrogen atom bound to a single atom (such as in the case of a carbon atom or a silicon atom which may be available for mono-, di- or tri-substitution or in the case of a nitrogen atom which may be available for mono-, di- or tri-substitution or in the case of an oxygen atom or a sulfur atom which may be available for mono-substitution). In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced (which provides, for example, -(CH2)-C(=O)-CH3as a substituent when the two hydrogen atoms of the middle carbon atom of -CH2-CH2-CH3are replaced). When substituted, one or more of the groups below are "substituents." Substituents include, but are not limited to, halogen (e.g., F, Cl, Br, I), hydroxy (OH), hydroxyalkyl (e.g., CH2-OH, CH(CH3)OH, C(CH3)2OH), oxo, cyano (CN), cyanoalkyl (e.g., CH2-CN, CH(CH3)CN, C(CH3)2CN), nitro (NO2), amino, alkylamino, dialkylamino, branched or unbranched alkyl (e.g., methyl, ethyl, propyl, isopropyl, sec-butyl, etc.), cycloalkyl (e.g., cyclopropyl), fluoroalkyl (e.g., CF3, CF2H, CH2F, CH2CF3, CH2CF2H, CHFCHF2, CF2CH2F, CF2CF3, CF2CH3, CF(CH3)2, CH2CH2CF3, CF2CH2CF3, CF2CF2CF3, etc.) or more generally, haloalkyl (e.g., CH2Cl, CH(CH3)Br, etc.), O-alkyl (alkoxy) (e.g., OCH3, OCH2CH3, OCH(CH3)2, etc.), O-cycloalkyl (e.g., O-cyclopropyl), O-haloalkyl (e.g., OCF2H, OCFH2, OCF3, OCH2CF3, OCH2CF2H, OCHFCHF2, OCF2CH2F, OCF2CF3, OCF2CH3, OCF(CH3)2, OCH2CH2CF3, OCF2CH2CF3, OCF2CF2CF3 or OCH2Cl), O-aryl (e.g., O-phenyl), O- heteroaryl, O-heterocyclyl, (CH2)1-3-cycloalkyl, (CH2)1-3-haloalkyl, (CH2)1-3-heterocyclyl, (CH2)1-3- aryl, (CH2)1-3-heteroaryl, thioalkyl (e.g., S-CH3), hydroxyalkyl (e.g., CH2OH), alkyl ether (e.g., CH2OCH3), alkynyl (e.g., -C≡CRf), alkenyl (e.g., -CRf=CRfRg), aryl (e.g., phenyl), arylalkyl (e.g., CH2Ph), heteroaryl (e.g., pyridyl or any 5- or 6-membered heteroaryl ring), heteroarylalkyl (e.g., CH2-pyridine), heterocyclyl, heterocycloalkyl and as well as -NRfRg, -NRfC(=O)Rg, -NRfC(=O)NRfNRg, -NRf-C(=O)ORfSO2Rg, -C(=O)Rf, -C(=O)ORf, -C(=O)(CH2)1-3Rf, -C(=O)O(CH2)1-3Rf, -C(=O)(CH(CH3))(CH2)0-3Rf, -C(=O)O(CH(CH3))(CH2)0-3Rf, -C(=O)(C(CH3)2)(CH2)0-3Rf, -C(=O)O(C(CH3)2)(CH2)0-3Rf, -ORf, -C(=O)NRfRg, -OC(=O)NRfRg, -SRf, -SORf, -S(=O)2Rf, -OS(=O)2Rf, -S(=O)ORf, and -P(O)RfRg, where each Rfand Rgmay be the same or different and are independently, hydrogen, alkyl (e.g., CH3), substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl, substituted heterocyclyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In addition, the above substituents may be further substituted with one or more of the above substituents, such that the substituent may constitute, for example, a substituted alkyl, a substituted aryl, a substituted heteroaryl, a substituted arylalkyl, a substituted heterocyclyl, or a substituted heterocycloalkyl. [000123] The term "unsubstituted" as used herein, refers to any compound that does not contain extra substituents attached to the compound. An unsubstituted compound refers to the chemical makeup of the compound without extra substituents (e.g., no non-hydrogen substituents). For example, unsubstituted proline is a proline amino acid even though the amino group of proline may be considered as disubstituted with alkyl groups.[000124] The term “bond” as used herein in describing a substituent with atoms on both sides, refers to the absence of that substituent. For example, in the 4-atom sequence A-B-C-D, when B and C are both listed as being bonds, the result is the 2-atom sequence A-D. If only B is listed as being a bond, the result is the 3-atom sequence A-C-D. [000125] The term "alkyl" as used herein, refers to any straight chain or branched, non-cyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term "lower alkyl" has the same meaning as alkyl but contains from 1 to 3 carbon atoms. The term "higher alkyl" has the same meaning as alkyl but contains from 4 to 10 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and the like, while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert- butyl, isopentyl, and the like. As used herein, a methyl substituent may be depicted as “CH3” or “Me” or as a terminal bond with no indication of specific atoms. [000126] The term "cycloalkyl" as used herein, refers to saturated and unsaturated cyclic alkyls. Representative saturated cyclic alkyls include, but are not limited to, C3-C14(such as C3-C7) cycloalkyls, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, and the like; while unsaturated cyclic alkyls include, but are not limited to, cyclobutenyl, cyclopentenyl and cyclohexenyl, cyclohexadiene, and the like. Cyclic alkyls are also referred to herein as "homocycles" or "homocyclic rings". [000127] The term "bicyclic compounds" as used herein, encompasses "bridged" compounds, "fused" compounds and "spiro" compounds as described. [000128] The term "spiro" or "spirocyclic" as used herein, refers to chemical structures having at least two rings sharing one common atom. The rings may be cycloalkyl, heterocyclyl or a combination thereof, and may include one or more aryl or heteroaryl rings. Examples include, but are not limited to, spirocyclic cyclopropanes, spirocyclic aziridines, spirocyclic cyclobutanes, spirocyclic azetidines, spirocyclic oxetanes, spirocyclic cyclopentanes, spirocyclic pyrrolidines, spirocyclic 1,3-dioxolanes, spirocyclic dioxanes, spirocyclic oxathiolanes, spirocyclic thiazolidines, spirocyclic cyclohexanes, spirocyclic piperidines and spirocyclic piperizines, where the other ring is cycloalkyl (e.g., cyclobutane, cyclopentane or cyclohexane) or heterocyclyl (e.g., piperidine, tetrahydropyran, tetrahydrofuran, azetidine or pyrrolidine).Exemplary embodiments include, but are not limited to, 1,4-dioxaspiro[4.5]decane, 1,4-dioxa-8-azaspiro[4.5]decane, 2- azaspiro[4.4]nonane, 2-azaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, oxa-azaspiro[3.4]octane, 6- azaspiro[3.4]octane, diazaspiro[3.4]octane, diazaspiro[2.5]octane, 6-azaspiro[2.5]octane, 1,3- dihydrospiro[indene-2,3'-pyrrolidine] and 3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]. [000129] The term "bridged" as used herein, refers to a compound containing two nonadjacent atoms common to two rings. Exemplary embodiments include, but are not limited to, norbornane, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, azabicyclo[3.1.0]hexane, 3,9- diazabicyclo[3.3.1]nonane, diazabicyclo[3.1.1]heptane, diazabicyclo[3.2.1]octane, 1,4- azabicyclo[2.2.1]heptane, 1,4 azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.1]heptane, 1,4- diazabicyclo[2.2.2]octane, and other bridged piperazines and bridged piperidines. [000130] The term “fused” as used herein, refers to polycyclic ring systems in which any two adjacent rings have two, and only two, adjacent atoms in common (ortho-fused) and polycyclic ring systems in which a ring contains two, and only two, adjacent atoms in common with each of two or more rings of a contiguous series of ortho-fused rings (ortho- and peri-fused). An exemplary embodiment is pentalene and dibenzoxepine (ortho-fused) and pyrene (ortho- and peri-fused). Ortho-fused systems have “n” common sides and “2n” common atoms while peri- fused systems have “n” common sides and less than “2n” atoms in common. Other exemplary fused systems include, but are not limited to, fused cyclopropyl rings, fused aziridine rings, fused cyclobutane rings, fused azetidine rings, fused cyclopentane rings, fused pyrrolidine rings, fused cyclohexane rings, fused piperidine rings, fused tetrahydropyran rings and fused piperazine rings, where each of these rings may be fused to an identical or different ring, such as a pyrrolidine ring. Other examples include fused pyrrolidine rings (e.g, octahydropyrrolo[3,4- c]pyrrole and octahydrocyclopenta[c]pyrrole), fused pyridine rings, such as a pyridine ring fused with a cycloalkyl (e.g., cyclopentane) or with a heterocyclyl (e.g., tetrahydrofuran or tetrahydropyran), or other fused heteroaromatic rings (e.g., dihydro-5H-pyrazolo[5,1- b][1,3]oxazine and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine). [000131] The term "aromatic" or "aryl" as used herein, refers to any aromatic carbocyclic (i.e., all of the ring atoms are carbon) substituent such as, but not limited to, phenyl (from benzene), tolyl (from toluene), xylyl (from xylene) or multi-ring systems (e.g., naphthyl (from naphthalene) and anthracenyl (from anthracene). [000132] The term "arylalkyl" or “aralkyl” as used herein, refers to any alkyl having at least one alkyl hydrogen atom replaced with an aryl moiety such as, but not limited to, benzyl, - (CH2)2phenyl, -(CH2)3phenyl, -CH(phenyl)2, and the like.[000133] The term "halogen" as used herein, refers to any fluoro, chloro, bromo, or iodo moiety. [000134] The term "haloalkyl" as used herein, refers to any alkyl where at least one hydrogen atom (and including all hydrogen atoms) has been replaced with a halogen atom, such as, for example, trifluoromethyl, dichloromethyl, difluoromethyl, monofluoromethyl, monobromomethyl, 1,1,1-trifluoroethyl and the like. [000135] The term "aminoalkyl" as used herein, refers to any alkyl where at least one hydrogen atom has been replaced with a nitrogen atom, such as, for example, -(CH2)1-5-NH2, -(CH2)1-5-NHCH3, -(CH2)1-5-N(CH3)2, -(CH2)1-5-NH-(CH2)1-5-N(CH3)2, and the like. [000136] The term "heteroaromatic" or "heteroaryl" as used herein, refers to any aromatic heterocyclic ring of 5 to 10 or more members and having at least one heteroatom selected from nitrogen, oxygen or sulfur, and containing at least 1 carbon atom, including, but not limited to, both mono- and bicyclic- ring systems, and where the nitrogen atom may be in an oxidized state. The heteroaryl ring may be attached as a substituent via a ring heteroatom or a carbon atom. Representative heteroaromatics include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, indole, isoindole, indazole, 7-azaindole, 4-azaindole, 5-azaindole, 6- azaindole, 7-azaindazole, pyridine, pyridone (e.g., 2-pyridone, 3-pyridone or 4-pyridone), pyrimidinone, oxopyrazine, pyridine oxide, quinoline, isoquinoline, oxazole, isoxazole, benzoxazole, pyrazole, imidazole, imidazopyrimidine, benzimidazole, thiazole, benzothiazole, isothiazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4- oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4- thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole), pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, triazolopyrazine, cinnoline, phthalazine, quinazoline, 1,8-naphthylpyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-b]pyrazine, pyrido[2,3-b]pyrazine, pteridine, triazolopyridines (e.g., [1,2,4]triazolo[4,3-a]pyridine) and the like. [000137] The term "heteroarylalkyl" as used herein, means any alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH2pyridinyl, -CH2pyrimidinyl, and the like. [000138] The term "heteroaromatic" or "heteroaryl" as used herein, refers to any aromatic heterocyclic ring of 5 to 10 or more members and having at least one heteroatom selected from nitrogen, oxygen or sulfur, and containing at least 1 carbon atom, including, but not limited to,both mono- and bicyclic- ring systems, and where the nitrogen atom may be in an oxidized state. The heteroaryl ring may be attached as a substituent via a ring heteroatom or a carbon atom. Representative heteroaromatics include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, indole, isoindole, indazole, 7-azaindole, 4-azaindole, 5-azaindole, 6- azaindole, 7-azaindazole, pyridine, pyridone (e.g., 2-pyridone, 3-pyridone or 4-pyridone), pyrimidinone, oxopyrazine, pyridine oxide, quinoline, isoquinoline, oxazole, isoxazole, benzoxazole, pyrazole, imidazole, imidazopyrimidine, benzimidazole, thiazole, benzothiazole, isothiazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4- oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4- thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole), pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, triazolopyrazine, cinnoline, phthalazine, quinazoline, 1,8-naphthylpyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-b]pyrazine, pyrido[2,3-b]pyrazine, pteridine, triazolopyridines (e.g., [1,2,4]triazolo[4,3-a]pyridine) and the like. [000139] The term "heterocycloalkyl" as used herein, refers to any alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH2morpholinyl, and the like. [000140] The term "alkylamino" as used herein, means at least one alkyl moiety attached through a nitrogen bridge (i.e., -N-(alkyl)n), where n = 1 or 2, such as alkylamino or dialkylamino) including, but not limited to, methylamino, ethylamino, dimethylamino, diethylamino, and the like. [000141] The term "alkyloxy" or “alkoxy”, as used herein, means any alkyl moiety attached through an oxygen bridge (i.e., -O-alkyl) such as, but not limited to, methoxy, ethoxy, and the like. [000142] The term "thioalkyl" as used herein, means any alkyl moiety attached through a sulfur bridge (i.e., -S-alkyl) such as, but not limited to, methylthio, ethylthio, and the like. [000143] The term "alkenyl" as used herein, refers to an unbranched or branched hydrocarbon chain having one or more carbon-carbon double bonds therein and may also be referred to as an "unsaturated alkyl". The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2- propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.[000144] The term "alkynyl" as used herein, refers to unbranched or branched hydrocarbon chain having one or more carbon-carbon triple bonds therein and may also be referred to as an "unsaturated alkyl". The triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl-, and 4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substituted with one or two suitable substituents. [000145] As used herein, “reactive groups” refer to nucleophiles, electrophiles, or radically active groups, i.e., groups that react in the presence of radicals. A nucleophile is a moiety that forms a chemical bond to its reaction partner (the electrophile) by donating both bonding electrons. Electrophiles accept these electrons. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge on an element and displaces the group it is bonded to. Alternatively, nucleophiles may take part in substitution of carbonyl group. Carboxylic acids are often made electrophilic by creating succinyl esters and reacting these esters with aminoalkyls to form amides. Other common nucleophilic groups are thiolalkyls, hydroxylalkyls, primary and secondary amines, and carbon nucleophiles such as enols and alkyl metal complexes. Other preferred methods of ligating proteins, oligosaccharides and cells using reactive groups are disclosed (Lemieux et al., Trends in Biotechnology 1998, 16, 506, incorporated herein by reference in its entirety). In yet another preferred method, one provides reactive groups for the Staudinger ligation, i.e., "click chemistry" with an azide comprising moiety and alkynyl reactive groups to form triazoles. Michael additions of a carbon nucleophile enolate with an electrophilic carbonyl, or the Schiff base formation of a nucleophilic primary or secondary amine with an aldehyde or ketone may also be utilized. Other methods of bioconjugation are provided (Hang et al. Accounts of Chemical Research 2001, 34, 727, and Kiick et al. Proc Natl Acad Sci US.A.2002, 99, 19, both of which are incorporated by reference in its entirety). [000146] The term "biocompatible" as used herein, refers to any material that does not illicit a substantial detrimental response in the host. There is always concern when a foreign object is introduced into a living body that the object will induce an immune reaction, such as an inflammatory response that will have negative effects on the host. In the context of this invention, biocompatibility is evaluated according to the application for which it was designed: for example, a bandage is regarded as biocompatible with the skin, whereas an implantedmedical device is regarded as biocompatible with the internal tissues of the body. Preferably, biocompatible materials include, but are not limited to, biodegradable and biostable materials. A substantial detrimental response has not occurred if an implant comprising the material is in close association to its implant site within the host animal and the response is better than a tissue response recognized and established as suitable from materials provided in an ASTM. ASTM subcommittee F04.16 on Biocompatibility Test Methods has developed biocompatibility standards for medical and surgical materials and devices which includes E1262-88, F612-20, F719-20e1, F720-17, F748-16, F749-20, F750-20, F756-17; F763-04, F813-20, F895-11, F981-04, F1027-86, F1408-20a, F1439-03, F1877-16, F1903-18, F1904-14, F1983-14, F1984-99, F2147-01, F2148-18, F2382-18, F2808-17, F1288-19 and F2909-19, each of which is incorporated herein by reference. For example, materials that are to be used in contact with the blood stream must be composed of materials that meet hemocompatibility standards. One of these tests is for damage to red blood cells, which can result in hemolysis that is, rupturing of the cells, as described in F756-17 Standard Practice for Assessment of Hemolytic Properties of Materials. [000147] As used herein, a "bioactive substance" refers to any of a variety of chemical moieties and that binds with a biomolecule such as, but not limited to, peptides, proteins, enzymes, receptors, substrates, lipids, antibodies, antigens, and nucleic acids. In certain preferred embodiments, the bioactive substance is a biomolecule but it is not intended that the bioactive substance be limited to biomolecules. In other preferred embodiments, the bioactive substances provide hydrophobic, hydrophilic, or electrostatic interactions, such as polycarboxylic acids that are anionic at physiological pH. In other preferred embodiment, the alkaline growth factors (with isoelectric point above 7) are retained via favorable electrostatic interactions by the polycarboxylates, and subsequently released in a controlled and sustained manner. [000148] “Cancer” is a term used for a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More particular examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal cancer, renal cell carcinoma, renal cancer (e.g., advanced renal cell carcinoma), ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastomamultiforme, cervical cancer, brain cancer, stomach cancer, urothelial carcinoma (including local advanced or metastatic urothelial carcinoma), bladder cancer, hepatoma, breast cancer and head and neck cancer. [000149] The term “stereoisomer” refers to compounds that have the same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, diastereomers and atropisomers. In the context of the present invention, the term “enantiomerically pure” is understood to mean that the compound in question with respect to the absolute configuration of the chiral center is present in an enantiomeric excess of more than 95%, preferably more than 97%. [000150] The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, atropisomers, tautomers and racemic and other mixtures thereof, such as enantiomers or diastereomeric enriched mixtures, all of which are within the scope of the present disclosure. Insofar as compounds of the invention as defined herein may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form. The synthesis of optically active compounds may be carried out by standard techniques of organic chemistry well known in the art such as, for example, by synthesis from optically active starting materials or by resolution of a racemic compound. Similarly, the enantiomeric or diastereomeric purity of a compound may be evaluated using standard laboratory techniques. [000151] In experimental procedures described herein where mixtures of stereoisomers (including but not limited to diastereomers, enantiomers, and geometric isomers) were generated during synthesis, their separation into stereochemically-enriched components was achieved by conventional techniques, such as chiral SFC, prep-HPLC, or other appropriate methods. Where appropriate, the absolute stereochemistry of the separated components was assigned by comparing the observed biological activity of the target compounds or appropriate intermediates thereof to similar components of known absolute stereochemistry and biological activity described in the literature. An exemplary publication used for reference in this manner includes, but is not limited to, Ketcham et al., J Med Chem (2024), 67, 4936-4949. [000152] The pharmaceutical compositions of the invention can take any suitable form for the desired route of administration. Where the composition is to be administered orally, any suitable orally deliverable dosage form can be used, including without limitation water, glycols,oils, alcohols, and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents, and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms. Injectable compositions or intravenous infusions are also provided in the form of solutions, suspensions, and emulsions. For parenteral compositions, the carrier usually comprises sterile water and possibly other ingredients to aid solubility. Injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution, or a mixture of a saline and a glucose solution. Suitable oils include, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives as needed, where the additives may facilitate administration of the composition to the skin and / or may facilitate preparation of the compositions to be delivered. These compositions may be administered in various ways, e.g., as a transdermal patch or as an ointment. Acid or base addition salts of the compounds of the invention are typically more suitable in the preparation of aqueous compositions due to their increased water solubility over the corresponding neutral form of the compounds. [000153] The pharmaceutical compositions of the invention may comprise one or more of a filler, diluent, adjuvant, vehicle, or other excipient to facilitate storage and / or administration of the active ingredients contained therein. [000154] In an exemplary embodiment, a pharmaceutical composition according to the present invention may contain one or more additional therapeutic agents, for example, to increase efficacy or to decrease undesired side effects. In a particular embodiment, the pharmaceutical composition further contains one or more additional therapeutic agents useful to treat or inhibit a disease mediated directly or indirectly by PI3K. Examples of such agents include, without limitation, agents to treat or inhibit cancer, Huntington’s disease, cystic fibrosis, liver fibrosis, renal fibrosis, pulmonary fibrosis, skin fibrosis, rheumatoid arthritis, diabetes, or heart failure. [000155] In a specific embodiment, the additional therapeutic agent to be included is an anti- cancer agent. Examples of an anti-cancer agent include, but are not limited to, DNA-damaging cytotoxic drugs, alkylating agents such as cyclophosphamide, dacarbazine, and cisplatin; anti-metabolites such as methotrexate, mercaptopurine, thioguanine, fluorouracil, and cytarabine; plant alkaloids such as vinblastine and paclitaxel; antitumor antibiotics such as doxorubicin, bleomycin and mitomycin; hormones / antihormones such as prednisone, tamoxifen, and flutamide; other types of anticancer agents such as asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, and derivatives, colony stimulating factors, amifostine, camptothecin, topotecan, thalidomide analogs such as lenalidomide, and proteasome inhibitors such as Velcade. [000156] In another embodiment, the present invention provides a method of inhibiting or treating diseases arising from abnormal cell proliferation and / or differentiation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds according to the present invention. In one embodiment, the method of inhibiting or treating disease comprises administering to a subject in need thereof, a composition comprising an effective amount of one or more compounds of the invention and a pharmaceutically acceptable carrier. The composition to be administered may further contain a therapeutic agent such as an anti-cancer agent. [000157] The compounds of the invention are defined herein by their chemical structures and / or chemical names and are generally listed according to the IUPAC or CAS nomenclature system. Abbreviations that are well known to one of ordinary skill in the art may be used. When a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is intended to be determinative of the compound’s identity, except in cases where reproduction through publication of the chemical structure is compromised. [000158] The present invention includes compounds labeled with various radioactive or nonradioactive isotopes. Examples of atomic isotopes may include, but are not limited to, deuterium (2H), tritium (3H), iodine-125 (125I), carbon-14 (14C), nitrogen-15 (15N), sulfur-35 (35S) and chlorine-36 (36Cl). In an exemplary embodiment, one or more hydrogen atoms in a compound of the invention can be replaced by deuterium. In various embodiments, a compound of the invention includes at least one deuterium atom, or two or more deuterium atoms, or three or more deuterium atoms, etc. As described herein, compounds of the invention may also be radiolabeled with a radioactive isotope such as tritium (3H), iodine-125 (125I), and carbon-14 (14C). A radiolabeled compound is useful as a therapeutic or prophylactic agent, provides a reagent for research such as for an assay, and / or provides a diagnostic agentfor techniques such as in vivo imaging. Synthetic methods for incorporating isotopes into organic compounds are well known in the art. [000159] In an embodiment of the invention, a compound of the invention as defined herein (such as a compound of any one of Formula (1), (2), (3) or (4)) or a pharmaceutically-acceptable salt thereof, exists as a single enantiomer being in an enantiomeric excess (% ee) of ≥ 95%, such as ≥ 98%, such as ≥ 99%. [000160] In an embodiment of the invention, a pharmaceutical composition comprises a compound of the invention as defined herein (such as a compound of any one of Formula (1), (2), (3) or (4)) or a pharmaceutically-acceptable salt thereof, where the compound exists as a single enantiomer being in an enantiomeric excess (% ee) of ≥ 95%, such as ≥ 98%, such as ≥ 99%. [000161] In an exemplary embodiment of the invention, the disease or disorder to be treated by the compounds of the invention is selected from congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal and spinal syndrome (CLOVES), mosaic tissue overgrowth syndromes, venous malformations and brain malformations associated with severe epilepsy or PIK3CA-related overgrowth syndrome (PROS) (Keppler-Noreuil et al., Am J Med Genet A.2015, 167A, 287; Kurek et al. Am. J. Hum. Genet.2012, 90, 1108). [000162] In an exemplary embodiment of the invention, the cancer to be treated is a cancer bearing a PI3K H1047 mutation (such as H1047R) (Thorpe et al., Nat Rev Cancer 2015, 15, 7). [000163] The compounds of the invention (such as defined by Formula (1), (2), (3) or (4)) are typically PI3Kα mutant-selective inhibitors that exhibit greater selectivity for any of the H1047R, H1047L, H1047Y, E542K, or E545K mutations over the wild-type. As such, the compounds may decrease the amount of phosphorylated AKT (pAKT) and decrease proliferation selectively in PI3Kα mutant cell lines, across several tumor types. [000164] A PI3Kα mutant selective inhibitor of the invention (such as defined by Formula (1), (2), (3) or (4)) dosed in combination with an aromatase inhibitor (AI) such as, but not limited to letrozole or anastrozole, a selective estrogen receptor modulator (SERM) such as, but not limited to tamoxifen, or a selective estrogen receptor degrader (SERD) such as, but not limited to, fulvestrant, elacestrant, or camizestrant may exhibit a combination benefit leading to tumor regression in ER+ / PI3Kα mutant tumors such as, but not limited to, the breast cancer xenograft model T47D, the breast cancer xenograft model MCF7, or the breast cancer xenograft modelBT483, at doses where little or no regression would be observed with either single agent. Similarly, triple combinations of a PI3Kα mutant selective inhibitor of the invention (such as defined by Formula (1), (2), (3) or (4)) dosed in combination with an aromatase inhibitor (AI), selective estrogen receptor modulator (SERM), or selective estrogen receptor degrader (SERD) in addition to a CDK4 or CDK4 / 6 inhibitor such as, but not limited to atirmociclib, ribociclib, abemaciclib, or palbociclib, may exhibit a combination benefit leading to tumor regression in ER+ / PI3Kα mutant tumors such as, but not limited to, the breast cancer xenograft model T47D, the breast cancer xenograft model MCF7, or the breast cancer xenograft model BT483, at doses where little or no regression would be observed with either single agent and greater regressions that would be observed with doublet combinations. [000165] A PI3K H1047R mutant selective inhibitor of the invention (such as defined by Formula (1), (2), (3) or (4)) dosed in combination with a HER2 inhibitor such as, but not limited to, tucatinib or trastuzumab may exhibit a combination benefit leading to tumor regression in ER- / HER2+ / PI3K H1047R mutant tumors such as, but not limited to, the breast cancer xenograft model HCC1954, at doses where little or no regression would be observed with either single agent. [000166] Compounds of Formula (1) of the present invention were generally prepared according to the synthetic route identified in Schemes 1-5: [000167] In Scheme 1, the synthesis of chloroisoquinoline intermediates used to access the compounds of the present invention may begin with an appropriately substituted 2,3-dihydro- 1H-inden-1-one. In the case of 1 where R6is methyl, this is commercially available. In other cases, the starting material may be prepared via established methods known to those skilled in the art. Nitrosation to convert indenones 1 to oxime derivatives 2 may be accomplished using established methods (for examples, see Touster, O.; Org. Reactions, VII, 1953, 327). A Beckmann-type rearrangement mediated by phosphorus pentachloride can convert oximes 2 into chloroisoquinolones 3 (Cushman, M., Dekow, F.W., Tetrahedron 1978, 34(10), 1435-9). An SNAr reaction or selective palladium-catalyzed Buchwald or Suzuki coupling of isoquinolone intermediates 3 can give substituted isoquinolones 4. Chlorination of intermediates 4 with reagents such as POCl3can provide isoquinolones 5.[000168] In order to convert the bromide of isoquinolones 5 to methyl ketones 6 (Scheme 2), a Stille coupling reaction may be employed using an appropriate tin reagent, such as (^- ethoxyvinyl)-tributyl tin, followed by acid hydrolysis (Sugiyama, et al., Bull. Chem. Soc. Jpn.1987, 60(2), 767-768). Alternatively, conversion of 5 to 6 may be accomplished by other established methods (for example, using a Heck coupling reaction with an appropriate enol-ether followed by acid hydrolysis (Mingcui, L., et al., Org. Biomol. Chem.2010, 8, 2012–2015). Ketones 6 may be reduced to alcohols 7, which can be converted to intermediates 8 by other established methods (for example, using Ms2O or PBr3). Subsequent SN2 substitution reactions of intermediates 8 with anilines 9 can give intermediates 10. Nucleophilic aromatic substitution reactions of 10 with ammonia or hydrazine provide adducts 11. Cyclization of intermediates 11 with alpha-halo ketones or aldehydes 12 provide tricyclic compounds 13 (Li, E. et al., Chemistry- A European Journal, 2016, 22, 11022; Beatty, J. et al., J. Med. Chem., 2020, 63, 3935; Garcia, M., et al., Tet. Lett., 2017, 58, 1952; Cupido, T., et al., Angew. Chemie. Int. Ed., 2009, 48, 2321). Single enantiomers of the compounds of the present invention 14 and 15 can be obtained after a chiral separation of a racemic mixture. Cyano-substituted compounds of the present invention may arise from intermediates 12 where W is a carbon substituted with a carboxylic ester. For example, ester 16 can be converted to nitrile 17 using standard established synthetic methods (for example, using NH3for amide formation, and then trifluoroacetic anhydride as a dehydrating agent to yield cyano-containing molecules). Single enantiomers 18 and 19 can be obtained after a chiral separation.[000169] Alternatively, the bromide of isoquinolones 3 can be converted to methyl ketones 20 (Scheme 3) using similar chemistry to those described in Scheme 2. An SNAr reaction or selective palladium-catalyzed Buchwald or Suzuki coupling of isoquinolone intermediates 20 can give substituted isoquinolones 21. Chlorination of intermediates 21 with reagents such as POCl3can provide chloroisoquinolones 6.[000170] Alternatively, the order of reactions may be adjusted to furnish compounds of the present invention, Scheme 4. Analogs 13 can be prepared from intermediates 5 or 20 using synthetic steps analogous to those described in Scheme 2.[000171] Alternatively, ketones 27 may be converted to chiral sulfinyl-imines 28 via known procedures, which may then in turn be reduced to sulfinyl-amines 29 in a stereo-controlled fashion using a suitable reducing agent (Datta and Ellman, J. Org. Chem.2010, 75, 6283–6285; Ellman et al., Acc. Chem. Res.2002, 35, 984-995; Ellman et al., J. Org. Chem.2007, 72, 626-629; Colyer et al., Journal of Organic Chemistry 2006, 71(18), 6859-6862). With use of the R isomer of the sulfinyl group, generally, resulting a predominantly the R, R – isomer of the product when (for example) the reducing agent used is a mixture of sodium borohydride and cerium chloride- heptahydrate. The use of this particular reducing system has been shown to be effective at reducing imines and may often give enhanced stereo-control in similar reductions (Hua et al, Synthesis 1991, (11), 970-4; Zhu et al, Journal of Chemical Research 2015, 39(7), 390-393). The major isomer may be separated from the other minor isomer via standard chromatographic means. As has been demonstrated in the preceding literature references a judicious choice ofthe antipode of the sulfinyl-imine and the reducing agent may give access to either antipode of the sulfinyl-amine. The sulfinyl-amines can be cleaved to the single enantiomer of the chiral amine 30 using standard conditions (such as hydrogen chloride in dioxane). Similarly, ketones 31 can be converted to the chiral amine 32 using the methods described to convert 27 to 30.Experimental [000172] All commercially available solvents and reagents were used as received. All1H NMR spectra were recorded using a Bruker Avance III HD 300 MHz or Bruker Avance III HD 400 MHz. MS samples were analyzed on a Shimadzu LCMS-2020 mass spectrometer with electrospray ionization operating in positive and negative ion mode. Samples were introduced into the mass spectrometer using chromatography. All final products had a purity of ≥ 90 %, unless specified otherwise in the experimental details. HPLC purity was measured on a Shimadzu Acquity HPLC system. [000173] The following represents acronyms used in the experimental section for well-known chemical solvents, reagents, parameters and techniques: 1H NMR: proton nuclear magnetic resonance spectroscopy ACN: acetonitrile AcOH: acetic acid c-Bu: cyclobutyl c-Pr: cyclopropyl CeCl3: cerium (III) chloride CH2Cl2: dichloromethaneCHCl3: chloroform Cs2CO3: cesium carbonate DBAD: di-tert-butyl azodicarboxylate DCM: dichloromethane DIBAL: diisobutylaluminum hydride DIEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DTAD: di-tert-butyl azodicarboxylate EA: ethyl acetate ee: enantiomeric excess Et2O: diethyl ether Et3N: triethylamine EtOAc: ethyl acetate EtOH: ethanol FA: formic acid H2O: water h: hours HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl: hydrochloric acid Hex: hexanes HPLC: high-performance liquid chromatography IPA: isopropanol K2CO3: potassium carbonate KOAc: potassium acetateLiOH: lithium hydroxide mCPBA: meta-chloroperoxybenzoic acid Me: methyl MeCN: acetonitrile MeOH: methanol mg: milligram min: minutes mL: milliliter Ms2O: methanesulfonic anhydride MsCl: methanesulfonyl chloride NaBH4: sodium borohydride N2: nitrogen Na2CO3: sodium carbonate Na2SO4: sodium sulfate NaCl: sodium chloride NaH: sodium hydrideNaOH: sodium hydroxide NaHCO3: sodium bicarbonate NaH2PO4: monosodium phosphate NH3: ammonia NH4HCO3: ammonium bicarbonate NMP: N-methylpyrrolidone Oxetane: 4-membered ring containing 3 carbon ring atoms and 1 oxygen ring atom. PBr3: phosphorous tribromide PCl5: phosphorous pentachloride Pd-PEPPSI-IHeptCl 3-chloropyridine: dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2- ylidene](3-chloropyridyl)palladium(II)Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0) Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) dichloridePE: petroleum ether POCl3: phosphorus oxychloride PPh3: triphenylphosphine Prep: preparative RuPhos: 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl TEA: triethylamine TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride THF: tetrahydrofuran Ti(OEt)4: Titanium (IV) ethoxide Ti(Oi-Pr)4: Titanium(IV) isopropoxide TLC: thin-layer chromatography Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene EXAMPLES Intermediates [000174] Preparation of Intermediate 1: 2-Methyl-5-(piperazin-1-yl)pyrimidineStep 1: Preparation of benzyl 4-(2-methylpyrimidin-5-yl)piperazine-1-carboxylate [000175] To a stirred solution / mixture of 5-bromo-2-methylpyrimidine (2.0 g, 11.5 mmol) and benzyl piperazine-1-carboxylate (2.0 g, 8.9 mmol) in toluene (30 mL) were added Cs2CO3(5.8 g, 17.8 mmol), Pd2(dba)3 (1.6 g, 1.8 mmol), and RuPhos (0.8 g, 1.8 mmol) at room temperature. Theresulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched with water (40 mL) at room temperature and the resulting mixture was then extracted with EtOAc (2 × 40 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. Afterfiltration, thefiltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EtOAc = 5:1 to afford benzyl 4- (2-methylpyrimidin-5-yl)piperazine-1-carboxylate (2.0 g, 72% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.40 (br, 2H), 7.38 (d, J = 4.3 Hz, 4H), 7.37 – 7.28 (m, 1H), 5.11 (s, 2H), 3.55 (t, J = 4.9 Hz, 4H), 3.20 (t, J = 5.2 Hz, 4H), 2.49 (s, 3H). Step 2: Preparation of 2-methyl-5-(piperazin-1-yl)pyrimidine [000176] To a stirred mixture of benzyl 4-(2-methylpyrimidin-5-yl)piperazine-1-carboxylate (2.0 g, 6.4 mmol) in MeOH (30 mL) was added Pd / C (10%, 500 mg, 4.7 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to yield 2-methyl-5-(piperazin-1- yl)pyrimidine (900 mg, 79% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 2H), 3.11 – 3.04 (m, 4H), 2.87 – 2.78 (m, 4H), 2.48 (s, 3H). [000177] Intermediate 2: Synthesis of 2',4'-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,5'-bipyrimidineStep 1: Preparation of 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine [000178] To a stirred mixture of 5-bromo-2,4-dimethylpyrimidine (500 mg, 2.67 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.36 g, 5.35 mmol) in dioxane (10 mL) were added Pd(dppf)Cl2(196 mg, 0.27 mmol) and KOAc (787 mg, 8.0 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture wasstirred at 100 °C for 1 h and then was cooled to room temperature and filtered. The filter cake was washed with EtOAc (3 x 20 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure to afford 500 mg crude product 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) pyrimidine. The crude product was used in the next step directly without further purification. MS (ES+) m / z = 235.1 [M+H]+. Step 2: Preparation of 5-bromo-2',4'-dimethyl-2,5'-bipyrimidine [000179] To a stirred mixture of 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (500 mg, 2.1 mmol) and 5-bromo-2-iodopyrimidine (608 mg, 2.1 mmol) in dioxane (10 mL) were added Pd(PPh3)4(247 mg, 0.21 mmol) and Na2CO3(679 mg, 6.4 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h and then was cooled to room temperature and filtered. The filter cake was washed with EtOAc (3 x 20 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2:MeOH = 10:1) to afford 5-bromo-2',4'-dimethyl- 2,5'-bipyrimidine (230 mg, 41% yield) as a yellow solid. MS: (ES+) m / z = 265.0 [M+H]+. Step 3: Preparation of 2',4'-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5'- bipyrimidine [000180] To a stirred mixture of 5-bromo-2',4'-dimethyl-2,5'-bipyrimidine (230 mg, 0.87 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (441 mg, 1.74 mmol) in dioxane (10 mL) were added Pd(dppf)Cl2(64 mg, 0.09 mmol) and KOAc (255 mg, 2.6 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 1 h and then was cooled to room temperature and filtered. The filter cake was washed with EtOAc (3 x 20 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure to afford 300 mg crude product 2',4'-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine. The crude product was used in the next step directly without further purification. MS: (ES+) m / z = 313.2 [M+H]+. [000181] Intermediate 3: Synthesis of 1-methyl-6-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrimidin-2-yl)pyridin-2(1H)-oneStep 1: Preparation of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one [000182] To a stirred mixture of isopropylmagnesium bromide (470 mg, 3.19 mmol, 2.8 M in 2-MeTHF) in THF (100 mL) was treated with 6-bromo-1-methylpyridin-2-one (10 g, 53.2 mmol) at -40 °C for 30 min under a nitrogen atmosphere followed by the addition of 2-methoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (33.61 g, 212.7 mmol) dropwise at -40 °C. The resulting mixture was stirred at -40 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous) at -40 °C. The mixture was acidified to pH 6 via the addition of HCl (1 N). The resulting mixture was extracted with CH2Cl2(3 x 150 mL). The combined organic layers were washed with brine (2 x 200 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 10 g of (1-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one) as a crude product which was used in the next step directly without further purification. MS: (ES+) m / z = 236.1 [M+H]+. Step 2: Preparation of 6-(5-bromopyrimidin-2-yl)-1-methylpyridin-2(1H)-one [000183] A mixture of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)- one (10 g, 42.5 mmol), Pd(dppf)Cl2(3.11 g, 4.25 mmol), CuCl (4.21 g, 42.5 mmol), and Cs2CO3(27.7 g, 85.1 mmol) in DMF (100 mL) was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with EtOAc (3 x 100 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (1:2), to afford 6-(5-bromopyrimidin-2-yl)-1-methylpyridin-2(1H)-one (2 g, 18% yield) as a yellow solid. MS: (ES+) m / z = 266.0 [M+H]+. Step 3: Preparation of 1-methyl-6-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)pyridin-2(1H)-one[000184] A solution of 6-(5-bromopyrimidin-2-yl)-1-methylpyridin-2(1H)-one (618 mg, 2.32 mmol), KOAc (684 mg, 6.97 mmol), Pd(dppf)Cl2(170 mg, 0.23 mmol) and bis(pinacolato)diboron (197 mg, 0.77 mmol) in dioxane (6 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with CH2Cl2(3 x 20 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure to afford 600 mg crude product 1-methyl-6-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrimidin-2-yl)pyridin-2(1H)-one. The crude product was used in the next step directly without further purification. MS: (ES+) m / z = 314.2 [M+H]+. [000185] Intermediate 4: Synthesis of 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrimidin-2-yl)pyridine 1-oxideStep 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [000186] A solution of 3-bromo-5-fluoro-2-methylpyridine (200 mg, 1.05 mmol) in dioxane (6 mL) was treated with bis(pinacolato)diboron (400 mg, 1.58 mmol) at room temperature, followed by the addition of KOAc (155 mg, 1.58 mmol), and Pd(dppf)Cl2(86 mg, 0.11 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 0.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered. The filtrate was dried (Na2SO4) and concentrated under reduced pressure to afford 200 mg 5-fluoro- 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a crude product. The crude product was used in the next step directly without further purification. MS: (ES+) m / z = 238.0 [M+H]+.Step 2: Preparation of 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine [000187] A solution of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (200 mg, 0.84 mmol) in dioxane (6 mL) and H2O (1.2 mL) was treated with 5-bromo-2- iodopyrimidine (240 mg, 0.84 mmol) at room temperature followed by the addition of Na2CO3(179 mg, 1.68 mmol) and Pd(PPh3)4(97 mg, 0.08 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The resulting mixture was then cooled to room temperature, filtered, and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Prep-TLC (100% EA) to afford 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine (150 mg, 69% yield) as an off-white solid. MS: (ES+) m / z = 269.9 [M+H]+. Step 3: Preparation of 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide [000188] A solution of 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine (110 mg, 0.41 mmol) in DCM (2 mL) was treated with m-CPBA (106 mg, 0.61 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was then concentrated under reduced pressure. The residue was purified by Prep-TLC (100% EA) to afford 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (70 mg, 60% yield) as an off-white solid. MS: (ES+) m / z = 284.0 [M+H]+. Step 4: Preparation of 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)pyridine 1-oxide [000189] To a solution of 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (200 mg, 0.7 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (268 mg, 1.06 mmol) in dioxane (10 mL) under a nitrogen atmosphere was added KOAc (196 mg, 2.0 mmol) and Pd(dppf)Cl2(52 mg, 0.07 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with dioxane (2 x 10 mL). The filtrate was dried (Na2SO4) and concentrated under reduced pressure to afford 200 mg of 5-fluoro-2-methyl- 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyridine 1-oxide as a crude product. The crude product was used in the next step directly without further purification. MS: (ES+) m / z = 332.2 [M+H]+. [000190] Intermediate 5: Synthesis of 2'-methyl-5-(tributylstannyl)-[2,5'-bipyrimidine] 1-oxideStep 1: Preparation of 2-methylpyrimidine-5-carbonitrile [000191] A mixture of 5-bromo-2-methylpyrimidine (60 g, 347 mmol), Zn(CN)2(61.1 g, 520 mmol) and Pd(PPh3)4(40.1 g, 34.7 mmol) in DMF (600 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 100 °C overnight. The mixture was then diluted with H2O (500 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 10:1 to 5:1, to afford 2-methylpyrimidine-5-carbonitrile (26.5 g, 64% yield) as a white solid.1H NMR (400 MHz, CDCl3): δ 8.90 (s, 2H), 2.83 (s, 3H). Step 2: Preparation of N'-hydroxy-2-methylpyrimidine-5-carboximidamide [000192] A mixture of 2-methylpyrimidine-5-carbonitrile (18.6 g, 156 mmol), hydroxylamine hydrochloride (32.6 g, 468 mmol) and TEA (79 g, 781 mmol) in EtOH (200 mL) was stirred at 80 °C for 1.5 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by trituration with H2O (200 mL) to afford N'- hydroxy-2-methylpyrimidine-5-carboximidamide (16.6 g, 70% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 8.91 (s, 2H), 6.08 (s, 2H), 2.63 (s, 3H). Step 3: Preparation of 5-bromo-2'-methyl-[2,5'-bipyrimidine] 1-oxide [000193] To a solution of N'-hydroxy-2-methylpyrimidine-5-carboximidamide (16 g, 105 mmol) and 2-bromopropanedial (23.8 g, 158 mmol) in i-PrOH (160 mL) was added TFA (1.35 g, 11.8 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2.5 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:0 to 1:1, toafford 5-bromo-2'-methyl-[2,5'-bipyrimidine] 1-oxide (7.0 g, 25% yield, 82% purity) as a yellow solid. MS: (ES+) m / z = 267.0 [M+H]+. Step 4: Preparation of 2'-methyl-5-(tributylstannyl)-[2,5'-bipyrimidine] 1-oxide [000194] To a stirred solution of 5-bromo-2'-methyl-[2,5'-bipyrimidine] 1-oxide (6 g, 22.5 mmol) in toluene (120 mL) was added Pd(PPh3)4(5.2 g, 4.5 mmol), LiCl (2.8 g, 67.4 mmol), and hexabutylditin (52.1 g, 90 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 16 h. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with CH2Cl2(3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:1, to afford 2'-methyl-5-(tributylstannyl)-[2,5'- bipyrimidine] 1-oxide (3 g, 30% yield) as a light yellow solid. MS: (ES+) m / z =479.1 [M+H]+. [000195] Intermediate 6: Synthesis of 2-methyl-3-(5-(tributylstannyl)pyrimidin-2-yl)pyridine 1-oxideStep 1: Preparation of 5-bromo-2-(2-methylpyridin-3-yl)pyrimidine [000196] A solution of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3 g, 13.7 mmol), 5-bromo-2-iodopyrimidine (3.9 g, 13.7 mmol), Pd(dppf)Cl2(1.12 g, 1.4 mmol), and K2CO3(5.68 g, 41.1 mmol) in dioxane (45 mL) and H2O (9 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was diluted with water (30 mL) at room temperature and then extracted with CH2Cl2(3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (65%), to afford 5-bromo-2-(2-methylpyridin-3-yl)pyrimidine (2.8 g, 82% yield) as a yellow liquid. MS: (ES+) m / z = 250.1 and 252.1 [M+H]+.Step 2: Preparation of 3-(5-bromopyrimidin-2-yl)-2-methylpyridine 1-oxide [000197] A solution of 5-bromo-2-(2-methylpyridin-3-yl)pyrimidine (2 g, 8.0 mmol) in CH2Cl2(20 mL) was treated with m-CPBA (2.76 g, 16 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction was quenched with water (30 mL) at room temperature. The aqueous layer was extracted with CH2Cl2(3 x 50 mL). The combined organic layers were washed with NaHCO3(2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH = 10:1, to afford 3-(5- bromopyrimidin-2-yl)-2-methylpyridine 1-oxide (1.71 g, 71% yield) as an off-white solid. MS: (ES+) m / z = 265.9 [M+H]+. Step 3: Preparation of 2-methyl-3-(5-(tributylstannyl)pyrimidin-2-yl)pyridine 1-oxide [000198] To a stirred solution of 3-(5-bromopyrimidin-2-yl)-2-methylpyridine 1-oxide (1.6 g, 6.0 mmol) in toluene (20 mL) was added Pd(PPh3)4(695 mg, 0.6 mmol), LiCl (510 mg, 12 mmol), and hexabutylditin (6.98 g, 12 mmol). The resulting mixture was stirred at 110 °C for 12 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with CH2Cl2(3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH = 10:1, to afford 2-methyl-3-(5-(tributylstannyl)pyrimidin-2-yl)pyridine 1-oxide (1.2 g, 42% yield) as a yellow solid. MS: (ES+) m / z = 478.2 [M+H]+. [000199] Intermediate 7: Synthesis of 2-(2-methylpyrimidin-5-yl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridazin-3-oneStep 1: Preparation of 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one [000200] To a stirred solution of 5-iodopyridazin-3(2H)-one (5 g, 22.5 mmol) and 2- methylpyrimidin-5-ylboronic acid (9.32 g, 68 mmol) in DCM (80 mL) were added pyridine N-oxide (8.57 g, 90 mmol), Cu(OAc)2(20.5 g, 113 mmol), and pyridine (8.91 g, 113 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The resultingmixture was then filtered, and the filter cake was washed with DCM (2 x 60 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:1, to afford 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin- 3(2H)-one (2.3 g, 33% yield) as a light yellow solid. MS: (ES+) m / z = 315.0 [M+H]+. Step 2: Preparation of 2-(2-methylpyrimidin-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazin-3(2H)-one [000201] To a stirred solution of 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one (150 mg, 0.56 mmol) in dioxane (5 mL) were added bis(pinacolato)diboron (171 mg, 0.67 mmol), Pd(dppf)Cl2(41 mg, 0.05 mmol), and KOAc (165 mg, 1.68 mmol) at room temperature. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction mixture was allowed to cool down to room temperature and filtered. The filter cake was washed with EtOAc (2 x 20 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. MS: (ES+) m / z = 315.1 [M+H]+. [000202] Intermediate 8: Synthesis of 1-methyl-6-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrimidin-2-yl)pyrazin-2(1H)-oneStep 1: Preparation of 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine [000203] To a stirred solution of 2-chloro-6-methoxy-pyrazine (10 g, 69.2 mmol) and bis(pinacolato)diboron (26.0 g, 102 mmol) in dioxane (50 mL) were added KOAc (20.4 g, 208 mmol) and Pd(dppf)Cl2(5.06 g, 6.9 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was cooled down to room temperature and filtered. The filter cake was washed with CH2Cl2(4 x 10 mL). The filtrate was concentrated under reduced pressure to afford 2-methoxy-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (16 g) as a black oil (crude product). The crudeproduct was used in the next step directly without further purification. MS: (ES+) m / z = 237.1 [M+H]+. Step 2: Preparation of 5-bromo-2-(6-methoxypyrazin-2-yl)pyrimidine [000204] To a stirred solution of 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazine (16 g, 67.8 mmol) and 5-bromo-2-iodopyrimidine (38.6 g, 136 mmol) in dioxane (200 mL) and H2O (20 mL) were added Pd(dppf)Cl2(4.96 g, 6.78 mmol) and K2CO3(28.1 g, 203 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with CH2Cl2(10 x 10 mL). The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:1, to afford 5-bromo-2-(6-methoxypyrazin-2-yl)pyrimidine (5.9 g, 33% yield) as a yellow solid. MS: (ES+) m / z = 267.0 [M+H]+. Step 3: Preparation of 6-(5-bromopyrimidin-2-yl)pyrazin-2-ol [000205] A solution of 5-bromo-2-(6-methoxypyrazin-2-yl)pyrimidine (3.5 g, 13.1 mmol) and iodotrimethylsilane (18.7 mL, 131 mmol) in ACN (10 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated, and the residue was purified by trituration with ethyl ether (10 mL). The precipitated solids were collected by filtration and washed with ethyl ether (4 x 10 mL) to give 6-(5-bromopyrimidin-2- yl)pyrazin-2-ol (2.5 g) as a yellow solid (crude product). The crude product mixture was used in the next step directly without further purification. MS: (ES+) m / z = 253.0 [M+H]+. Step 4: Preparation of 6-(5-bromopyrimidin-2-yl)-1-methylpyrazin-2(1H)-one [000206] To a stirred solution of 6-(5-bromopyrimidin-2-yl)pyrazin-2-ol (2 g, 7.9 mmol) and cesium carbonate (5.15 g, 15.8 mmol) in DMF (20 mL) was added methyl iodide (0.98 mL, 15.8 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc, to afford 6-(5-bromopyrimidin- 2-yl)-1-methylpyrazin-2(1H)-one (492 mg, 23% yield) as a yellow solid. MS: (ES+) m / z = 267.0 [M+H]+. Step 5: Preparation of 1-methyl-6-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)pyrazin-2(1H)-one[000207] To a stirred solution of 6-(5-bromopyrimidin-2-yl)-1-methylpyrazin-2(1H)-one (100 mg, 0.37 mmol) in dioxane (1.5 mL) was added bis(pinacolato)diboron (114 mg, 0.44 mmol), KOAc (74 mg, 0.74 mmol), and Pd(dppf)Cl2 (27 mg, 0.04 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The mixture was then cooled to room temperature and filtered. The filter cake was washed with CH2Cl2(4 x 10 mL). The filtrate was concentrated under reduced pressure to afford 170 mg of 1-methyl-6- (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyrazin-2(1H)-one as a crude product. The crude product was used in the next step directly without further purification. MS: (ES+) m / z = 315.2 [M+H]+. [000208] Example 1: Synthesis of (S)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline [000209] Example 2: Synthesis of (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)anilineStep 1: Preparation of 4-bromo-2-(hydroxyimino)-6-methyl-3H-inden-1-one. [000210] To a stirred solution of 4-bromo-6-methyl-2,3-dihydroinden-1-one (2 g, 8.9 mmol) in 12 M aqueous HCl (10 mL) and Et2O (10 mL) was added 3-methylbutyl nitrite (1.25 g, 10.7mmol) slowly dropwise at 0 °C. The resulting solution was stirred for 4 h at room temperature. The mixture was cooled to 0 °C, and the precipitated solids were collected by filtration and washed with H2O (3 x 50 mL) and Et2O (2 x 20 mL). The collected solids were concentrated and dried under vacuum to afford 4-bromo-2-(hydroxyimino)-6-methyl-3H-inden-1-one (1.5 g, 66%) as an off-white solid and the crude product was used in the next step directly without further purification. MS: (ES+) m / z = 253.9 [M+H]+.Step 2: Preparation of 5-bromo-3-chloro-7-methyl-2H-isoquinolin-1-one. [000211] To a stirred solution of 4-bromo-2-(hydroxyimino)-6-methyl-3H-inden-1-one (1.5 g, 5.90 mmol) in CHCl3 (30 mL) was slowly added PCl5 (2.46 g, 11.8 mmol) in portions at 0 °C. The resulting mixture was stirred for 3 h at room temperature and then concentrated under reduced pressure. To the crude product was added 4 M HCl in 1,4-dioxane (30 mL). The resulting solution was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by trituration with PE:EtOAc = 5:1 to afford 5- bromo-3-chloro-7-methyl-2H-isoquinolin-1-one (1 g, 61%) as a yellow solid. MS: (ES-) m / z = 269.9 [M-1]-. Step 3: Preparation of 5-bromo-3-(4,4-difluoropiperidin-1-yl)-7-methyl-2H-isoquinolin-1-one. [000212] To a stirred solution / mixture of 5-bromo-3-chloro-7-methyl-2H-isoquinolin-1-one (4 g, 14.7 mmol) and 4,4-difluoropiperidine (7.11 g, 58.7 mmol) in NMP (40 mL) was added DIEA (9.48 g, 73.4 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 130 °C. The reaction was quenched by the addition of ice water (150 mL) at 0 °C. The resulting mixture was then extracted with EtOAc (3 x 150 mL), and the combined organics were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:1, to afford 5-bromo-3-(4,4-difluoropiperidin-1-yl)-7- methyl-2H-isoquinolin-1-one (3.8 g, 72% yield) as a white solid. LCMS (ESI+) m / z = 356.9 (M+H). Step 4: Preparation of 5-bromo-1-chloro-3-(4,4-difluoropiperidin-1-yl)-7-methylisoquinoline. [000213] Into a 25 mL sealed tube was added 5-bromo-3-(4,4-difluoropiperidin-1-yl)-7- methyl-2H-isoquinolin-1-one (3.5 g, 9.8 mmol) and POCl3(45.1 g, 294 mmol) at room temperature. The resulting mixture was stirred for overnight at 130 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and was adjusted to pH 8 via the addition of a saturated NaHCO3solution. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (2 x 150 mL), and the combined organics were dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with PE:EA = 10:1, to afford 5-bromo-1-chloro-3-(4,4- difluoropiperidin-1-yl)-7-methylisoquinoline (3.4 g, 96% yield) as a yellow solid. Step 5: Preparation of 5-bromo-3-(4,4-difluoropiperidin-1-yl)-1-hydrazinyl-7-methylisoquinoline.[000214] To a stirred mixture of 5-bromo-1-chloro-3-(4,4-difluoropiperidin-1-yl)-7- methylisoquinoline (3.5 g, 9.3 mmol) in EtOH (35 mL) was added hydrazine hydrate (4.66 g, 93.2 mmol) dropwise at room temperature under an argon atmosphere. The resulting mixture was stirred for 6 h at 80 °C and then concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with EtOH (3 x 20 mL). This resulted in 5-bromo-3-(4,4- difluoropiperidin-1-yl)-1-hydrazinyl-7-methylisoquinoline (2.8 g, 81% yield) as a light brown solid. LCMS (ESI+) m / z = 371.1 (M+H). Step 6: Preparation of 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[3,4- a]isoquinoline. [000215] Into a 50 mL round-bottom flask was added 5-bromo-3-(4,4-difluoropiperidin-1-yl)- 1-hydrazinyl-7-methylisoquinoline (2 g, 5.4 mmol) and (diethoxymethoxy)ethane (25 mL) at room temperature. The mixture was acidified to pH 6 with 2,2,2-trifluoroacetic acid (10 mol%). The resulting mixture was stirred for 1.5 h at 100 °C under an argon atmosphere. The reaction was quenched by the addition of ice water (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH = 5:1, to afford 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[3,4-a]isoquinoline (1.4 g, 68% yield) as a light brown solid. LCMS (ESI+) m / z = 382.9 (M+H). Step 7: Preparation of 1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethan-1-one. [000216] To a stirred mixture of 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[3,4-a]isoquinoline (500 mg, 1.3 mmol) and Pd(PPh3)4(152 mg, 0.13 mmol) in 1,4- dioxane (8 mL) was added tributyl(1-ethoxyethenyl)stannane (568 mg, 1.6 mmol) dropwise at room temperature under an argon atmosphere. The resulting mixture was then stirred for overnight at 100 °C . The reaction mixture was cooled to 0 °C and concentrated aqueous HCl (0.5 mL) was then added. The resulting mixture was stirred for 0.5 h at room temperature. The reaction was quenched by the addition of ice water (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH = 5:1, to afford 1-[5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl]69thenone (320 mg, 71% yield) as a light yellow solid. LCMS (ESI+) m / z = 345.0 (M+H). Step 8: Preparation of 1-[5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[3,4-a]isoquinolin-7- yl]ethanol. [000217] To a stirred solution of 1-[5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl]ethanone (350 mg, 1.0 mmol) in MeOH (5 mL) was added NaBH4(46 mg, 1.2 mmol) in portions at 0 °C under an argon atmosphere. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of saturated NH4Cl solution (10 mL) at 0 °C. The resulting mixture was extracted with CH2Cl2(3 x 10 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:2, to afford 1-[5-(4,4-difluoropiperidin- 1-yl)-9-methyl-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl]ethanol (245 mg, 70% yield) as a light yellow solid. LCMS (ESI+) m / z = 347.0 (M+H). Step 9: Preparation of N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[3,4-a]isoquinolin- 7-yl)ethyl)-2-(methylsulfonyl)aniline. [000218] A solution of 1-[5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl]ethanol (80 mg, 0.23 mmol) in DCM (5 mL) was treated with Et3N (140 mg, 1.4 mmol) at 0 °C under a nitrogen atmosphere followed by the addition of Ms2O (161 mg, 0.92 mmol) in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the mixture was then added 2-methanesulfonylaniline (59 mg, 0.35 mmol) dropwise at 0 °C. The resulting mixture was then stirred overnight at room temperature. The reaction was quenched by the addition of ice water (20 mL) at 0 °C and the resulting mixture was extracted with CH2Cl2(3 x 20 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give (S)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline (Example 1) (43 mg, 35% yield) as a white solid:1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.25 (s, 1H), 7.68-7.61 (m, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.36-7.21 (m, 1H), 7.02 (s, 1H), 6.75 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 5.7 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 5.46-5.42 (m, 1H), 3.37 – 3.32 (m, 7H), 2.45 (s, 3H), 2.31 (s, 4H), 1.60 (d, J = 6.5 Hz, 3H); LCMS (ESI+) m / z = 500.2 (M+H), and (R)-N-(1-(5-(4,4-difluoropiperidin-1- yl)-9-methyl-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline (Example 2)(38 mg, 33% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.25 (s, 1H), 7.68-7.61 (m, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.36-7.21 (m, 1H), 7.02 (s, 1H), 6.75 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 5.7 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 5.46-5.42 (m, 1H), 3.37 – 3.32 (m, 7H), 2.45 (s, 3H), 2.31 (s, 4H), 1.60 (d, J = 6.5 Hz, 3H); LCMS (ESI+) m / z = 500.1 (M+H). [000219] Example 3: Synthesis of (S)-5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carbonitrile [000220] Example 4: Synthesis of (R)-5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carbonitrileStep 1: Preparation of 1-[1-chloro-3-(4,4-difluoropiperidin-1-yl)-7-methylisoquinolin-5-yl]ethenone. [000221] To a stirred solution of 5-bromo-1-chloro-3-(4,4-difluoropiperidin-1-yl)-7- methylisoquinoline (2 g, 5.3 mmol) in dioxane (40 mL) were added tributyl(1- ethoxyethenyl)stannane (2.12 g, 5.9 mmol) and Pd(PPh3)4(0.62 g, 0.53 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was then stirred overnight at 100 °C. To the mixture was then added aqueous HCl (1 M, 15 mL) at room temperature and the resulting mixture was stirred for 0.5 h. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic phases were then washed sequentially with a saturated NaHCO3aqueous solution (2 x 15 mL), brine (2 x 50 mL), and then dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:PE = 1:2, to afford 1-[1-chloro-3-(4,4-difluoropiperidin-1-yl)- 7-methylisoquinolin-5-yl]ethanone (920 mg, 51 % yield) as a yellow solid. MS: (ES+) m / z = 339.2 [M+H]+. Step 2: Preparation of 1-[1-chloro-3-(4,4-difluoropiperidin-1-yl)-7-methylisoquinolin-5-yl]ethanol. [000222] To a stirred solution of 1-[1-chloro-3-(4,4-difluoropiperidin-1-yl)-7- methylisoquinolin-5-yl]ethanone (920 mg, 2.7 mmol) in MeOH (15 mL) were added NaBH4(411 mg, 10.8 mmol) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with H2O (10 mL). The resulting mixture was extracted with EA (3 x 15 mL). The combined organic phases were washed with brine (3 x 15 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:PE = 2:1, to afford 1-[1-chloro-3- (4,4-difluoropiperidin-1-yl)-7-methylisoquinolin-5-yl]ethanol (536 mg, 58% yield) as a yellow- green solid. MS: (ES+) m / z = 341.1 [M+H]+. Step 3: Preparation of N-(1-(1-chloro-3-(4,4-difluoropiperidin-1-yl)-7-methylisoquinolin-5-yl)ethyl)-2- (methylsulfonyl)aniline. [000223] To a stirred solution of 1-[1-chloro-3-(4,4-difluoropiperidin-1-yl)-7- methylisoquinolin-5-yl]ethanol (500 mg, 1.47 mmol) in DCM (10 mL) were added TEA (891 mg, 8.8 mmol) and Ms2O (1.28 g, 7.4 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then 2-methanesulfonylaniline (2.50 g, 14.7 mmol) was added in the mixture at room temperature. The resulting mixture was stirred overnight. The reaction was quenched with H2O (10 mL) and the resulting mixture was extracted with EA (3 x 20 mL). The combined organic phases were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:1, to afford N-(1-(1-chloro-3-(4,4-difluoropiperidin-1-yl)- 7-methylisoquinolin-5-yl)ethyl)-2-(methylsulfonyl)aniline (320 mg, 44% yield) as a white solid. MS: (ES+) m / z = 494.3 [M+H]+. Step 4: Preparation of 3-(4,4-difluoropiperidin-1-yl)-7-methyl-5-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-1-amine.[000224] To a stirred solution of N-(1-(1-chloro-3-(4,4-difluoropiperidin-1-yl)-7- methylisoquinolin-5-yl)ethyl)-2-(methylsulfonyl)aniline (300 mg, 0.61 mmol) in dioxane (10 mL) were added tert-butyl carbamate (142 mg, 1.22 mmol), Cs2CO3 (594 mg, 1.83 mmol), Xantphos (70 mg, 0.12 mmol), and Pd2(dba)3(56 mg, 0.06 mmol) at room temperature. The resulting mixture was stirred for overnight at 90 °C. The reaction was then quenched with H2O (10 mL) and the resulting mixture was extracted with EA (3 x 20 mL). The combined organic phases were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:3, to afford 3-(4,4-difluoropiperidin-1-yl)-7-methyl-5-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-1-amine (160 mg, 56% yield) as a white solid. MS: (ES+) m / z = 475.3 [M+H]+. Step 5: Preparation of ethyl 5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carboxylate. [000225] To a solution of 3-(4,4-difluoropiperidin-1-yl)-7-methyl-5-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-1-amine (150 mg, 0.32 mmol) in EtOH (10 mL) was added NaHCO3(53 mg, 0.63 mmol) and 1-bromo-2-butanone (57 mg, 0.38 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-TLC, eluted with PE:EA = 2:1, to afford ethyl 5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carboxylate (105 mg, 58% yield) as a yellow solid. MS: (ES+) m / z = 571.3 [M+H]+. Step 6: Preparation of 5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carboxamide. [000226] A mixture of ethyl 5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carboxylate (100 mg, 0.18 mmol) in NH3in MeOH (7 M, 10 mL) was prepared at room temperature. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was then concentrated under reduced pressure to afford crude 5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carboxamide (100 mg) which used in the next step directly without further purification. MS: (ES+) m / z = 542.2 [M+H]+.Step 7: Preparation of 5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carbonitrile (isomers 1 and 2). [000227] To a solution of 5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carboxamide (100 mg, 0.19 mmol) in THF (5 mL) was added Et3N (37 mg, 0.37 mmol) and TFAA (78 mg, 0.37 mmol) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched by the addition of saturated NaHCO3aqueous solution (10 mL) at 0 °C and the resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The crude product was purified by prep-TLC, eluted with DCM:MeOH = 20:1, and then purified further by prep-chiral-HPLC to afford (S)-5- (4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1- a]isoquinoline-2-carbonitrile (Example 3) (18 mg, 19% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.22 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.33 – 7.29 (m, 1H), 7.22 (s, 1H), 6.76 – 6.73 (m, 1H), 6.68 (d, J = 5.7 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 5.47 – 5.44 (m, 1H), 3.32 – 3.30 (m, 7H), 2.50 (s, 3H), 2.44 – 2.33 (m, 4H), 1.60 (d, J = 6.5 Hz, 3H); MS (ES+) m / z = 524.4 [M+H], and (R)-5-(4,4-difluoropiperidin-1-yl)-9-methyl-7-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)imidazo[2,1-a]isoquinoline-2-carbonitrile (Example 4) (21 mg, 22% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.21 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.32 – 7.29 (m, 1H), 7.22 (s, 1H), 6.76 – 6.73 (m, 1H), 6.68 (d, J = 5.7 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H), 5.47 – 5.44 (m, 1H), 3.32 – 3.27 (m,7H), 2.44 (s, 3H), 2.38 – 2.24 (m, 4H), 1.60 (d, J = 6.4 Hz, 3H); MS: (ES+) m / z = 524.4 [M+H]. [000228] Example 5: Synthesis of (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[2,1- a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline [000229] Example 6: Synthesis of (S)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[2,1- a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline[000230] To a stirred solution of 3-(4,4-difluoropiperidin-1-yl)-7-methyl-5-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-1-amine (100 mg, 0.21 mmol) in 2-propanol (5 mL) were added chloroacetaldehyde (33 mg, 0.42 mmol) (50% in water) and NaHCO3 (44 mg, 0.53 mmol) at room temperature. The resulting mixture was heated to reflux for 2 h. The reaction mixture was then cooled to room temperature and diluted with dichloromethane (10 mL) and saturated sodium bicarbonate solution (15 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane (2 x 10 mL). The organic phases were combined and washed with brine (2 x 10 mL) and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The crude product was purified by prep-TLC, eluted with DCM:MeOH = 15:1, and the purified further via prep-analytical-SFC to afford (R)-N- (1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[2,1-a]isoquinolin-7-yl)ethyl)-2- (methylsulfonyl)aniline (Example 5) (26 mg, 24% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.94 (d, J = 1.4 Hz, 1H), 7.65 – 7.63 (m, 1H), 7.60 (d, J = 1.3 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.31 – 7.29 (m, 1H), 7.01 (s, 1H), 6.75 – 6.71 (m, 1H), 6.67 (d, J = 5.8 Hz, 1H), 6.59 – 6.49 (m, 1H), 5.42 – 5.41 (m, 1H), 3.32 (s, 3H), 3.25 – 3.23 (m 4H), 2.42 (s, 3H), 2.37 – 2.19 (m, 4H), 1.61 (d, J = 6.5 Hz, 3H); MS: (ES+) m / z = 499.4 [M+H]+, and (S)-N-(1-(5-(4,4- difluoropiperidin-1-yl)-9-methylimidazo[2,1-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline (Example 6) (25 mg, 23% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.94 (d, J = 1.4 Hz, 1H), 7.65 – 7.63 (m, 1H), 7.60 (d, J = 1.3 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.01 (s, 1H), 6.75 – 6.71 (m, 1H), 6.67 (d, J = 5.8 Hz, 1H), 6.59 – 6.49 (m, 1H), 5.43 – 5.40 (m, 1H), 3.32 (s, 3H), 3.25 – 3.22 (m, 4H), 2.42 (s, 3H), 2.37 – 2.19 (m, 4H), 1.61 (d, J = 6.5 Hz, 3H); MS: (ES+) m / z = 499.4 [M+H]+. [000231] Example 7: Synthesis of (S)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-2,9- dimethylimidazo[2,1-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline [000232] Example 8: Synthesis of (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-2,9- dimethylimidazo[2,1-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline[000233] To a stirred solution of 3-(4,4-difluoropiperidin-1-yl)-7-methyl-5-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-1-amine (100 mg, 0.21 mmol) in toluene (5 mL) was added NaHCO3 (35 mg, 0.42 mmol), 1-chloropropan-2-one (29 mg, 0.32 mmol), and 4Å molecular sieves (200 mg) at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-TLC, eluted with DCM:MeOH = 20:1, and then purified further via prep-chiral HPLC to afford (S)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-2,9- dimethylimidazo[2,1-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline (Example 7) (10 mg, 9% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.67 – 7.63 (m, 2H), 7.40 (s, 1H), 7.33 – 7.29 (m, 1H), 6.94 (s, 1H), 6.76 – 6.72 (m, 1H), 6.66 (d, J = 5.8 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 5.44 – 5.36 (m, 1H), 3.27 – 3.24 (m, 7H), 2.49 – 2.41 (m, 6H), 2.33 – 2.24 (m, 4H), 1.61 (d, J = 6.4 Hz, 3H); MS: (ES+) m / z = 513.2 [M+H]+, and (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)- 2,9-dimethylimidazo[2,1-a]isoquinolin-7-yl)ethyl)-2-(methylsulfonyl)aniline (Example 8) (8 mg, 7% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.67 – 7.61 (m, 2H), 7.40 (s, 1H), 7.33 – 7.29 (m, 1H), 6.94 (s, 1H), 6.76 – 6.72 (m, 1H), 6.66 (d, J = 5.8 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 5.41 – 5.38 (m, 1H), 3.27 – 3.24 (m, 7H), 2.50 – 2.43 (m, 6H), 2.33 – 2.24 (m, 4H), 1.61 (d, J = 6.4 Hz, 3H). MS: (ES+) m / z = 513.2 [M+H]+. [000234] Example 9: Synthesis of (R)-2-(difluoromethyl)-4-fluoro-N-(1-(9-fluoro-5-(2'-methyl- [2,5'-bipyrimidin]-5-yl)-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)anilineStep 1: Preparation of 5-acetyl-3-chloro-7-fluoroisoquinolin-1(2H)-one. [000235] To a stirred mixture of 5-bromo-3-chloro-7-fluoro-2H-isoquinolin-1-one (15 g, 54.3 mmol, prepared in a manner similar to that described in Steps 1 and 2 of Examples 1 and 2 starting from 4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one), and tributyl(1- ethoxyethenyl)stannane (23.5 g, 65.1 mmol) in dioxane (150 mL) was added Pd(PPh3)4(6.33 g, 5.4 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred at 100 °C overnight. The mixture was cooled to 0 °C and aqueous 1 N HCl (75 mL, 0.14 mmol) was then added dropwise over 2 min. The resulting mixture was then stirred at room temperature for an 1 h. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 50 mL). The filtrate was suspended in water (250 mL) and the resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic phases were washed with brineand then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2Cl2:MeOH = 10:1) to afford 5-acetyl-3-chloro-7-fluoroisoquinolin-1(2H)-one (7.4 g, 57% yield) as a yellow solid. LCMS (ESI+) m / z = 240.2 (M+H). Step 2: Preparation of (R,E)-N-(1-(3-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinolin-5-yl)ethylidene)-2- methylpropane-2-sulfinamide. [000236] To a stirred mixture of 5-acetyl-3-chloro-7-fluoroisoquinolin-1(2H)-one (6 g, 25 mmol) and (R)-2-methylpropane-2-sulfinamide (15.2 g, 12 mmol) in THF (60 mL) was added Ti(OEt)4(28.6 g, 125 mmol) dropwise at room temperature under argon atmosphere. The resulting mixture was then stirred at 80 °C overnight. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in water (150 mL). The resulting mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 1:1) to afford (R,E)-N-(1-(3-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinolin-5-yl)ethylidene)-2- methylpropane-2-sulfinamide (3.9 g, 45% yield) as a yellow solid. LCMS (ESI+) m / z = 342.9 (M+H). Step 3: Preparation of (R)-N-((R)-1-(3-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinolin-5-yl)ethyl)-2- methylpropane-2-sulfinamide. [000237] To a stirred solution of (R,E)-N-(1-(3-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinolin-5- yl)ethylidene)-2-methylpropane-2-sulfinamide (3.4 g, 9.9 mmol) in MeOH (65 mL) was added cerium(III) chloride heptahydrate (14.8 g, 39.7 mmol) dropwise at -40 °C under an argon atmosphere. The resulting mixture was stirred at -40 °C for 30 min. To the mixture was added NaBH4 (1.13 g, 29.8 mmol) in portions over 1 min at -40 °C and the resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched with water (50 mL) at 0 °C. The mixture was adjusted to pH 3 with 1N HCl (aq.) and was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re- crystallized from THF / heptane (1:4) to afford (R)-N-((R)-1-(3-chloro-7-fluoro-1-oxo-1,2- dihydroisoquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (2.8 g, 36% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 7.76 (d, J = 9.4 Hz, 2H), 6.52 (s, 1H), 5.92 (d, J = 7.2 Hz, 1H), 4.97 – 4.90 (m, 1H), 1.44 (d, J = 6.7 Hz, 3H), 1.11 (s, 9H).Step 4: Preparation of (R)-5-(1-aminoethyl)-3-chloro-7-fluoroisoquinolin-1(2H)-one [000238] To a stirred solution of (R)-N-((R)-1-(3-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinolin- 5-yl)ethyl)-2-methylpropane-2-sulfinamide (2 g, 5.8 mmol) in dioxane (20 mL) was added HCl in 1,4-dioxane (4 M, 20 mL) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (30 mL). The residue was adjusted to pH 8 via the addition of basic anion exchange resin. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford (R)-5-(1-aminoethyl)-3-chloro-7-fluoroisoquinolin-1(2H)-one (1.1 g, 79% yield) as a yellow solid. LCMS (ESI+) m / z = 241.5 (M+H). Step 5: Preparation of (R)-3-chloro-5-(1-((2-(difluoromethyl)-4-fluorophenyl)amino)ethyl)-7- fluoroisoquinolin-1(2H)-one [000239] To a stirred mixture of (R)-5-(1-aminoethyl)-3-chloro-7-fluoroisoquinolin-1(2H)-one (540 mg, 2.2 mmol) and 1-bromo-2-(difluoromethyl)-4-fluorobenzene (1.1 g, 4.5 mmol) in 1,4- dioxane (15 mL) were added (DiMeIHeptCl)Pd(cinnamyl)Cl (CAS:2138491-47-9) (262 mg, 0.22 mmol) and Cs2CO3(1.46 g, 4.5 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred at 110 °C for overnight and then the reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2Cl2:MeOH = 10:1) to afford (R)-3-chloro-5-(1-((2-(difluoromethyl)-4- fluorophenyl)amino)ethyl)-7-fluoroisoquinolin-1(2H)-one (800 mg, 75% yield) as a yellow solid. LCMS (ESI-) m / z = 383.1 (M-H). Step 6: Preparation of (R)-5-(1-((2-(difluoromethyl)-4-fluorophenyl)amino)ethyl)-7-fluoro-3-(2'- methyl-[2,5'-bipyrimidin]-5-yl)isoquinolin-1(2H)-one [000240] To a stirred mixture of (R)-3-chloro-5-(1-((2-(difluoromethyl)-4- fluorophenyl)amino)ethyl)-7-fluoroisoquinolin-1(2H)-one (310 mg, 0.8 mmol) and 2'-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine (36 mg, 1.2 mmol) in dioxane (1 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2(177 mg, 0.24 mmol) and Na2CO3(171 mg, 1.6 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture wasstirred at 100 °C overnight. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure, and the residue was dissolved in water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2Cl2:MeOH = 10:1) to afford (R)-5-(1-((2- (difluoromethyl)-4-fluorophenyl)amino)ethyl)-7-fluoro-3-(2'-methyl-[2,5'-bipyrimidin]-5- yl)isoquinolin-1(2H)-one (210 mg, 50% yield) as a yellow solid. LCMS (ESI-) m / z = 519.2 (M-H). Step 7: Preparation of (R)-N-(1-(1-chloro-7-fluoro-3-(2'-methyl-[2,5'-bipyrimidin]-5-yl)isoquinolin-5- yl)ethyl)-2-(difluoromethyl)-4-fluoroaniline [000241] A solution of (R)-5-(1-((2-(difluoromethyl)-4-fluorophenyl)amino)ethyl)-7-fluoro-3- (2'-methyl-[2,5'-bipyrimidin]-5-yl)isoquinolin-1(2H)-one (120 mg, 0.23 mmol) in phosphoroyl tribromide (6 mL) was stirred at 60 °C for 1.5 h under an argon atmosphere. The reaction was quenched by the addition of water / ice (10 mL) at 0 °C . The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used in the next step directly without further purification. LCMS (ESI+) m / z = 583.1 (M+H). Step 8: Preparation of (R)-2-(difluoromethyl)-4-fluoro-N-(1-(7-fluoro-1-hydrazineyl-3-(2'-methyl- [2,5'-bipyrimidin]-5-yl)isoquinolin-5-yl)ethyl)aniline [000242] To a stirred mixture of (R)-N-(1-(1-chloro-7-fluoro-3-(2'-methyl-[2,5'-bipyrimidin]-5- yl)isoquinolin-5-yl)ethyl)-2-(difluoromethyl)-4-fluoroaniline (120 mg, 0.21 mmol) in EtOH (10 mL) was added hydrazine monohydrate (206 mg, 4.1 mmol) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure and the crude product was used in the next step directly without further purification. LCMS (ESI+) m / z = 535.4 (M+H). Step 9: Preparation of (R)-2-(difluoromethyl)-4-fluoro-N-(1-(9-fluoro-5-(2'-methyl-[2,5'-bipyrimidin]- 5-yl)-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)aniline [000243] To a stirred mixture of (R)-2-(difluoromethyl)-4-fluoro-N-(1-(7-fluoro-1-hydrazineyl- 3-(2'-methyl-[2,5'-bipyrimidin]-5-yl)isoquinolin-5-yl)ethyl)aniline (100 mg, 0.19 mmol) in (diethoxymethoxy)ethane (20 mL) was added trifluoroacetic acid (10% in water, 2mL) dropwise at 0 °C. The resulting mixture was then stirred at 100 °C for 40 min. The mixture was then diluted with water (20 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford (R)-2-(difluoromethyl)-4-fluoro-N-(1-(9- fluoro-5-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)aniline (10 mg, 10% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 2H), 9.53-9.47 (m, 3H), 8.23-8.20 (m, 1H), 8.00 (s, 1H), 7.67-7.64 (m, 1H), 7.55-7.27 (m, 1H), 7.20-7.17 (m 1H), 7.05 – 6.94 (m, 1H), 6.41-6.38 (m, 1H), 5.94 (d, J = 6.2 Hz, 1H), 5.52 – 5.43 (m, 1H), 2.77 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H). LCMS (ESI) m / z = 545.2 (M+H). [000244] Example 14: Synthesis of (R)-2-(difluoromethyl)-N-(1-(5-(2',4'-dimethyl-[2,5'- bipyrimidin]-5-yl)-9-fluoro-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-3,4-difluoroanilineStep 1: Preparation of (R)-1-(1-bromo-3-chloro-7-fluoroisoquinolin-5-yl)ethan-1-amine [000245] Into a 250 mL round-bottom flask were added (R)-5-(1-aminoethyl)-3-chloro-7- fluoroisoquinolin-1(2H)-one (5 g, 21.1 mmol), ACN (100 mL) and phosphoroyl tribromide (18.2 g, 63.4 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under an argon atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford (R)-1-(1-bromo-3-chloro-7-fluoroisoquinolin-5-yl)ethan-1- amine as a crude product (8.3 g). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z = 302.9 (M+H). Step 2: Preparation of (R)-1-(3-chloro-7-fluoro-1-hydrazineylisoquinolin-5-yl)ethan-1-amine [000246] To a stirred solution of (R)-1-(1-bromo-3-chloro-7-fluoroisoquinolin-5-yl)ethan-1-amine (8.3 g, crude) in EtOH (100 mL) at 0 °C was added hydrazine monohydrate (100 mL) dropwise. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure to afford crude product (10 g). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z = 255.1 (M+H). Step 3: Preparation of (R)-1-(5-chloro-9-fluoro-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-1-amine [000247] To a stirred solution of ((R)-1-(3-chloro-7-fluoro-1-hydrazineylisoquinolin-5-yl)ethan- 1-amine (10 g, crude) and triethylorthoformate (100 mL) at 0 °C was added TFA / H2O (5mL / 50mL) dropwise. The resulting mixture was stirred at room temperature for 4 h. The mixture was adjusted to pH 7-8 via the addition of a saturated aqueous NaHCO3solution. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography to afford (R)-1-(5-chloro-9-fluoro-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethan-1-amine (2.0 g, 39% yield) as a brown solid.1H NMR (300 MHz, DMSO- d6): δ 9.50 (s, 1H), 8.14-8.11 (m, 1H), 7.97–7.83 (m, 1H), 7.85 (s, 1H), 4.78-4.71 (m, 1H), 1.34 (d, J = 6.5 Hz, 3H). Step 4: Preparation of (R)-1-(5-(2',4'-dimethyl-[2,5'-bipyrimidin]-5-yl)-9-fluoro-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethan-1-amine [000248] Into a 40 mL vial were added (R)-1-(5-chloro-9-fluoro-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethan-1-amine (100 mg, 0.38 mmol), dioxane (8 mL), 2',4'-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine (236 mg, 0.76 mmol), Na2CO3(120 mg, 1.1 mmol), H2O (0.8 mL), and Pd(PPh3)4(44 mg, 0.04 mmol) at room temperature. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was extracted with CH2Cl2:MeOH = 10:1 (2 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH = 5:1, to afford (R)-1-(5-(2',4'-dimethyl-[2,5'-bipyrimidin]-5-yl)-9-fluoro-[1,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethan-1-amine (88 mg, 56% yield) as a brown solid. LCMS (ESI) m / z = 413.0 (M-H). Step 5: Preparation of (R)-2-(difluoromethyl)-N-(1-(5-(2',4'-dimethyl-[2,5'-bipyrimidin]-5-yl)-9-fluoro- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-3,4-difluoroaniline [000249] Into a 8 mL vial were added (R)-1-(5-(2',4'-dimethyl-[2,5'-bipyrimidin]-5-yl)-9-fluoro- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-1-amine (80 mg, 0.19 mmol), dioxane (2 mL), 1- bromo-2-(difluoromethyl)-3,4-difluorobenzene (70 mg, 0.29 mmol), Cs2CO3 (126 mg, 0.38mmol), and (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol- 2-ylidene]dichloro(2-methylpyridine)palladium (16 mg, 0.02 mmol, CAS: 1612891-29-8) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under an argon atmosphere. The reaction was quenched with water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA = 10:1, to afford 80 mg of a crude product. The crude product was purified by Prep-HPLC to afford (R)-2-(difluoromethyl)-N-(1-(5-(2',4'-dimethyl-[2,5'-bipyrimidin]-5-yl)-9-fluoro- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-3,4-difluoroaniline (33 mg, 29% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 9.51 – 9.47 (m, 3H), 9.24 (s, 1H), 8.24 – 8.21 (m, 1H), 7.97 (s, 1H), 7.70 – 7.36 (m, 2H), 7.25 – 7.18 (m, 1H), 6.23 (d, J = 6.2 Hz, 1H), 6.21 – 6.15 (m, 1H), 5.54 – 5.46 (m, 1H), 2.86 (s, 3H), 2.70 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H); LCMS (ESI) m / z = 577.2 (M+H). [000250] Example 15: Synthesis of (R)-6-(5-(9-fluoro-7-(1-((6-methyl-2- (trifluoromethyl)pyridin-3-yl)amino)ethyl)-[1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2- yl)-1-methylpyridin-2(1H)-oneStep 1: Preparation of (R)-N-((R)-1-(7-fluoro-3-(2-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)pyrimidin- 5-yl)-1-oxo-1,2-dihydroisoquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide [000251] To a stirred solution of (R)-N-((R)-1-(3-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinolin- 5-yl)ethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.4 mmol) and 1-methyl-6-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyridin-2(1H)-one (2.04 g, 6.5 mmol) in dioxane (20 mL) and H2O (5 mL) were added Pd(dppf)Cl2(318 mg, 0.44 mmol) and Na2CO3(1.38 g, 13 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The reaction was quenched by the addition of ice water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. Afterfiltration, thefiltrate was concentrated under reduced pressure. The residue was purified by reversed-phaseflash chromatography to give (R)-N-((R)-1- (7-fluoro-3-(2-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)pyrimidin-5-yl)-1-oxo-1,2- dihydroisoquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (1.4 g, 65% yield) as a yellow green solid. LCMS (ESI) m / z = 496.1 (M+H). Step 2: Preparation of (R)-6-(5-(5-(1-aminoethyl)-1-bromo-7-fluoroisoquinolin-3-yl)pyrimidin-2-yl)-1- methylpyridin-2(1H)-one [000252] A solution of (R)-N-((R)-1-(7-fluoro-3-(2-(1-methyl-6-oxo-1,6-dihydropyridin-2- yl)pyrimidin-5-yl)-1-oxo-1,2-dihydroisoquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (1.0 g, 2 mmol) in phosphoroyl tribromide (10 mL) was stirred at 60 °C for 5 h. The resulting mixture was concentrated under reduced pressure to afford (R)-6-(5-(5-(1-aminoethyl)-1-bromo-7- fluoroisoquinolin-3-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one as a crude product (1 g yield), which was used in the next step directly without further purification. LCMS (ESI) m / z = 454.1 (M+H). Step 3: Preparation of (R)-6-(5-(5-(1-aminoethyl)-7-fluoro-1-hydrazineylisoquinolin-3-yl)pyrimidin-2- yl)-1-methylpyridin-2(1H)-one [000253] To a stirred solution of (R)-6-(5-(5-(1-aminoethyl)-1-bromo-7-fluoroisoquinolin-3- yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one (1.0 g, 2.2 mmol) in EtOH (10 mL) at room temperature was added hydrazine hydrate (20 mL, 0.19 mmol). The resulting mixture was stirred at 80 °C for 4 h. The resulting mixture was concentrated under reduced pressure to afford (R)-6- (5-(5-(1-aminoethyl)-7-fluoro-1-hydrazineylisoquinolin-3-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one as a crude product (1.0 g yield). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z = 406.2 (M+H). Step 4: Preparation of (R)-6-(5-(7-(1-aminoethyl)-9-fluoro-[1,2,4]triazolo[3,4-a]isoquinolin-5- yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one [000254] To a stirred solution of (R)-6-(5-(5-(1-aminoethyl)-7-fluoro-1-hydrazineylisoquinolin- 3-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one (200 mg, 0.49 mmol) in (diethoxymethoxy)ethane (5 mL) was added trifluoroacetic acid (10 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was then stirred at 100 °C for 1 h. The reaction was quenched by the addition of ice water (10 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. Afterfiltration, thefiltrate was concentrated under reduced pressure. The residue was purified by reversed-phaseflash chromatography to give (R)-6-(5-(7-(1-aminoethyl)-9-fluoro-[1,2,4]triazolo[3,4-a]isoquinolin-5- yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one (60 mg, 29% yield) as a yellow green solid. LCMS (ESI) m / z = 416.1 (M+H). Step 5: Preparation of (R)-6-(5-(9-fluoro-7-(1-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)- [1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one [000255] To a stirred solution of (R)-6-(5-(7-(1-aminoethyl)-9-fluoro-[1,2,4]triazolo[3,4- a]isoquinolin-5-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one (45 mg, 0.11 mmol) and 3-bromo-6- methyl-2-(trifluoromethyl)pyridine (52 mg, 0.22 mmol) in dioxane (2 mL) were added Cs2CO3(106 mg, 0.32 mmol) and (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3- dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (9 mg, 0.01 mmol, CAS:1612891-29-8) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The reaction was quenched by the addition of ice water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. Afterfiltration, thefiltrate was concentrated under reduced pressure. The residue was purified by reversed-phaseflash chromatography to give (R)-6-(5-(9-fluoro-7-(1-((6-methyl-2- (trifluoromethyl)pyridin-3-yl)amino)ethyl)-[1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-1- methylpyridin-2(1H)-one (7.5 mg, 12% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 9.52 – 9.48 (m, 3H), 8.24 – 8.21 (m, 1H), 7.99 (s, 1H), 7.69 – 7.56 (m, 2H), 7.13 (d, J = 8.6 Hz,1H), 6.91 (d, J = 8.7 Hz, 1H), 6.72 – 6.70 (m, 1H), 6.65 – 6.63 (m, 1H), 5.81 (d, J = 6.6 Hz, 1H), 5.60 – 5.52 (m, 1H), 3.57 (s, 3H), 2.29 (s, 3H), 1.66 (d, J = 6.6 Hz, 3H); LCMS (ESI+) m / z = 575.2 (M+H). [000256] Example 16: Synthesis of (R)-5-chloro-2-((1-(9-fluoro-5-(4-(methylsulfonyl)piperazin- 1-yl)-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrileStep 1: Preparation of (R)-1-(9-fluoro-5-(4-(methylsulfonyl)piperazin-1-yl)-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethan-1-amine [000257] Into a 8 mL vial were added (R)-1-(5-chloro-9-fluoro-[1,2,4]triazolo[3,4-a]isoquinolin- 7-yl)ethan-1-amine (200 mg, 0.76 mmol), 1-methanesulfonylpiperazine (248 mg, 1.5 mmol) and (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol- 2-ylidene]dichloro(2-methylpyridine)palladium (63 mg, 0.08 mmol, CAS:1612891-29-8) in dioxane (4 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under an argon atmosphere. The reaction was then quenched by the addition of ice water (40 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. Afterfiltration, thefiltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:1, to afford (R)-1-(9-fluoro-5-(4- (methylsulfonyl)piperazin-1-yl)-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-1-amine (200 mg, 67% yield) as a white solid. LCMS (ESI) m / z = 393.1 (M+H). Step 2: Preparation of (R)-5-chloro-2-((1-(9-fluoro-5-(4-(methylsulfonyl)piperazin-1-yl)- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrile [000258] To a stirred solution of (R)-1-(9-fluoro-5-(4-(methylsulfonyl)piperazin-1-yl)- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-1-amine (100 mg, 0.26 mmol), 2-bromo-5- chlorobenzonitrile (165 mg, 0.77 mmol), and Cs2CO3 (249 mg, 0.77 mmol) in dioxane (4 mL) was added (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene]dichloro(2-methylpyridine)palladium (21 mg, 0.026 mmol, CAS:1612891-29-8) inportions at room temperature under an argon atmosphere. The resulting mixture was stirred at 100 °C for 1.5 h under an argon atmosphere. The reaction was quenched by the addition of ice water (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. Afterfiltration, thefiltrate was concentrated under reduced pressure. The residue was purified by reversed- phaseflash chromatography to afford (R)-5-chloro-2-((1-(9-fluoro-5-(4- (methylsulfonyl)piperazin-1-yl)-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrile (47 mg, 35% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 9.35 (s, 1H), 8.15 – 8.08 (m, 1H), 7.67 – 7.60 (m, 2H), 7.34 – 7.27 (m, 1H), 7.04 (s, 1H), 6.86 (d, J = 6.8 Hz, 1H), 6.41 (d, J = 9.2 Hz, 1H), 5.47 – 5.39 (m, 1H), 3.5-3.43 (m, 4H), 3.41 – 3.26 (m, 4H), 3.00 (s, 3H), 1.62 (d, J = 6.7 Hz, 3H); LCMS (ESI) m / z = 528.0 (M+H). [000259] Example 17: Synthesis of (R)-6-(5-(9-fluoro-7-(1-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-3-methyl-[1,2,4]triazolo[3,4-a]isoquinolin-5- yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-oneStep 1: Preparation of (R)-1-(5-chloro-9-fluoro-3-methyl-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan- 1-amine [000260] Into a 100 mL round-bottom flask were added (R)-1-(3-chloro-7-fluoro-1- hydrazineylisoquinolin-5-yl)ethan-1-amine (800 mg, 3.14 mmol) and 1,1,1-triethoxyethane (20mL) at room temperature. To the above mixture was added TFA (2 mL) and H2O (20 mL) dropwise at 0 °C . The resulting mixture was stirred at room temperature for 1 h and then was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH = 5:1, to afford (R)-1-(5-chloro-9-fluoro-3-methyl- [1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-1-amine (150 mg, 17% yield) as a black solid. LCMS (ESI) m / z = 279.1 (M-H). Step 2: Preparation of (R)-6-(5-(7-(1-aminoethyl)-9-fluoro-3-methyl-[1,2,4]triazolo[3,4-a]isoquinolin- 5-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one [000261] Into a 40 mL vial were added (R)-1-(5-chloro-9-fluoro-3-methyl-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethan-1-amine (140 mg, 0.5 mmol), dioxane (10 mL), 1-methyl-6-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyridin-2(1H)-one (315 mg, 1.0 mmol), Na2CO3(106 mg, 1.0 mmol), H2O (2 mL) and Pd(PPh3)4(58 mg, 0.05 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 1 h under an argon atmosphere. The resulting mixture was cooled to room temperature and diluted with water (2 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH = 5:1, to afford (R)-6-(5-(7-(1-aminoethyl)-9-fluoro-3- methyl-[1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one (50 mg, 23% yield) as a black solid. LCMS (ESI) m / z = 430.2 (M-H). Step 3: Preparation of (R)-6-(5-(9-fluoro-7-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3- methyl-[1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one [000262] Into a 40 mL vial were added (R)-6-(5-(7-(1-aminoethyl)-9-fluoro-3-methyl- [1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one (150 mg, 0.35 mmol), dioxane (1 mL), Cs2CO3(228 mg, 0.70 mmol), 1-bromo-4-fluoro-2- (trifluoromethyl)benzene (102 mg, 0.42 mmol), and (SP-4-1)-[1,3-BIs[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2- methylpyridine)palladium (29 mg, 0.04 mmol, CAS: 1612891-29-8) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under an argon atmosphere. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH = 5:1, to afford the desired product (47 mg). The desired product was purified further by Prep-HPLC toafford (R)-6-(5-(9-fluoro-7-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3-methyl- [1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-1-methylpyridin-2(1H)-one (19 mg, 9% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 9.40-9.36 (m, 2H), 8.22 – 8.19 (m, 1H), 7.81 (s, 1H), 7.63 – 7.57 (m, 2H), 7.36 – 7.33 (m, 1H), 7.18 – 7.13 (m, 1H), 6.73-6.71 (m, 1H), 6.65 – 6.62 (m, 1H), 6.54-6.50 (m, 1H), 5.58 (d, J = 6.3 Hz, 1H), 5.49 – 5.41 (m, 1H), 3.54 (s, 3H), 2.22 (s, 3H), 1.63 (d, J = 6.6 Hz, 3H); LCMS (ESI) m / z = 592.3 (M+H). [000263] Example 18: Synthesis of (R)-5-fluoro-3-(5-(9-fluoro-7-(1-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-[1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-2- methylpyridine 1-oxideStep 1: Preparation of (R)-N-(1-(5-chloro-9-fluoro-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-4- fluoro-2-(trifluoromethyl)aniline [000264] Into a 40 mL vial were added (R)-1-(5-chloro-9-fluoro-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethan-1-amine (200 mg, 0.76 mmol), dioxane (10 mL), Cs2CO3(739 mg, 2.3 mmol), 4-fluoro-1-iodo-2-(trifluoromethyl)benzene (263 mg, 0.9 mmol), Xantphos (175 mg, 0.3 mmol), and Pd2(dba)3(138 mg, 0.15 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under an argon atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4.After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 1:1, to afford (R)-N-(1-(5-chloro-9- fluoro-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-4-fluoro-2-(trifluoromethyl)aniline (100 mg, 31% yield) as a yellow oil. LCMS (ESI) m / z = 427.1 (M+H). Step 2: Preparation of (R)-5-fluoro-3-(5-(9-fluoro-7-(1-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-[1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-2- methylpyridine 1-oxide [000265] Into an 8 mL vial were added (R)-N-(1-(5-chloro-9-fluoro-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethyl)-4-fluoro-2-(trifluoromethyl)aniline (80 mg, 0.19 mmol), dioxane (1 mL), Na2CO3 (40 mg, 0.37 mmol), 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)pyridine 1-oxide (93 mg, 0.28 mmol), XPhos Pd G3 (16 mg, 0.02 mmol), and Xantphos (22 mg, 0.04 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 1 h under an argon atmosphere. The resulting mixture was cooled to room temperature and quenched with water (1 mL). The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE:EA =1:3, to afford the desired product. The desired product was purified further by Prep- HPLC to afford (R)-5-fluoro-3-(5-(9-fluoro-7-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)- [1,2,4]triazolo[3,4-a]isoquinolin-5-yl)pyrimidin-2-yl)-2-methylpyridine 1-oxide (2 mg, 2% yield) as a white solid.1H NMR (400 MHz, CD3CN): δ 9.32 – 9.30 (m, 2H), 9.02 (s, 1H), 8.41 – 8.28 (m, 1H), 8.31 – 8.28 (m, 1H), 7.72 – 7.69 (m, 1H), 7.66 (s, 1H), 7.59 – 7.56 (m, 1H), 7.32 – 7.29 (m, 1H), 7.00 – 6.95 (m, 1H), 6.45 – 6.42 (m, 1H), 5.35 – 5.31 (m, 1H), 4.99 (d, J = 5.0 Hz, 1H), 2.71 – 2.66 (m, 3H), 1.68 (d, J = 6.7 Hz, 3H); LCMS (ESI) m / z = 596.2 (M+H). [000266] Example 19: Synthesis of (R)-5-chloro-2-((1-(6,9-difluoro-5-(4- (methylsulfonyl)piperazin-1-yl)-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrile[000267] To a stirred solution of (R)-5-chloro-2-((1-(9-fluoro-5-(4-(methylsulfonyl)piperazin-1- yl)-[1,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrile (32 mg, 0.06 mmol) was added Selectfluor™ (21 mg, 0.06 mmol) in MeCN (2 mL) batchwise at 0 °C. The resulting mixture was stirred for 0.5 h at 0 °C under a nitrogen atmosphere. The reaction was then poured into H2O (20 mL) at room temperature. The reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford (R)-5-chloro-2-((1-(6,9-difluoro-5-(4-(methylsulfonyl)piperazin-1-yl)-[1,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethyl)amino)benzonitrile (8 mg, 23% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 10.5 Hz, 1H), 7.66 (d, J = 2.6 Hz, 1H), 7.29 – 7.27 (m, 1H), 6.90 (s, 1H), 6.44 (d, J = 9.2 Hz, 1H), 5.44 – 5.40 (m, 1H), 3.72 – 3.43 (m, 8H), 3.00 (s, 3H), 1.66 (d, J = 6.5 Hz, 3H); MS: (ES+) m / z = 546.1 [M+H]+. [000268] Examples 10-13 and 20-32 in Table 1 can be prepared either in a manner similar to that described for Examples 1-9 and 14-19, or via the general methods depicted in Schemes 1 to 5 as well as via the references described in the accompanying text. Table 1. Examples 10 to 13 and 20 to 32Table 2. LCMS and NMR Data for Examples 10 to 13 and 20 to 32Assays and Compound Testing [000269] In vitro cell proliferation: determination of EC50 values for inhibition of proliferation in T-47D cells expressing mutant PI3Ka (H1047R) mutation and SK-BR-3 cells expressing WT PI3Ka. [000270] T-47D or SK-BR-3 cells were trypsinized, resuspended in culture media and seeded onto assay ready plates. T-47D culture media consisted of RPMI, 10% FBS and Insulin (0.2 units / mL). SK-BR-3 culture media consisted of McCoys 5a and 10% FBS. Cells were seeded at a density of 1,500 cells / well and dispensed in 50 μL onto 384 well assay ready plates (Corning, 89089-790). Assay ready plates had previously been stamped with 10-point dilutions of compounds of interest, as well as controls. The Echo655 is used to stamp plates at 40 nL of compound or DMSO. Cells were grown for 72 hours at 37 ° Celsius and 5% CO2. After 72 hours, cells were equilibrated at room temperature for 15 minutes.30 uL of CellTiter-Glo reagent is added to the plate, which is then shaken for 30 minutes at temperature at 300-500 rpm. Cellsare then read on an Envision plate reader. The percentage of inhibition of proliferation was calculated using the following formula: %Inhibition = 100 x (LumD– LumSample) / (LumD–LumInh), where D is obtained from cells treated with 0.1% DMSO only; Inh is obtained from cells treated with 10 uM Alpelisib. The concentration achieving 50% inhibition of proliferation (IC50) is calculated by fitting the Curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom) / (1 + 10^((LogEC50 - X)*HillSlope)). Reagent table:[000271] In vitro cell pAKT: determination of IC50 values for inhibition of phosphorylation of AKT (pAKT) in the following cell lines: SK-BR-3 cells expressing WT PI3Ka, T-47D cells expressing mutant PI3Ka (H1047R), MCF-7 cells expressing mutant PI3Ka (E545K), BT-483 cells expressing mutant PI3Ka (E542K), EFM-19 cells expressing mutant PI3Ka (H1047L), and MFE-280 cells expressing mutant PI3Ka (H1047Y).[000272] Cells, grown in culture media (specified below), were harvested, resuspended in assay media (specified below), and seeded onto assay ready plates. Cells were seeded at a density as outlined below and dispensed in 12.5 μL onto 384-well assay ready plates (Perkin Elmer, 6008238). Assay ready plates had previously been stamped with 10-point dilutions of compounds of interest, as well as controls. The Echo655 was used to stamp plates at 12.5 nL of compound or DMSO. Cells, in assay ready plates, were grown for 6 hours at 37°C and 5% CO2. After 6 hours, 4 μL of lysis buffer reagent were added to the plate, which was then centrifuged for 1 minute at 1000 rpm. Then the plate was incubated at room temperature for 30 minutes. After 30 minutes, 4 μL of antibody mix containing Eu cryptate, d2 cryptate, and detection buffer were added to the plate. The plate was centrifuged for 1 minute at 1000 rpm and then incubated overnight at room temperature with lid, protected from light. The plate was read on an BMG-PHERAstar FSX plate reader using the HTRF protocol. The percentage of inhibition of AKT phosphorylation was calculated using the following formula: % Inhibition = 100 x (pAKTHC – pAKTSample) / (pAKTHC –pAKTLC), where pAKTHC is obtained from cells treated with 0.2% DMSO only, pAKTLC is obtained from cells treated with 10 µM alpelisib, and pAKTSample referring to the well for which % inhibition is being calculated. The IC50 (concentration achieving 50% inhibition of pAKT) is calculated by fitting the curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X)*HillSlope)). [000273] SK-BR-3 culture media consisted of McCoy’s 5a and 10% FBS, and assay media consisted of DMEM (no phenol red) + 10% FBS. T-47D culture media consisted of RPMI, 10% FBS and insulin (0.2 U / mL), and assay media consisted of RPMI 1640 (no phenol red) + 10% FBS + 0.2 U / ml insulin. MCF-7 culture media consisted of EMEM + 10% FBS, and assay media consisted of DMEM (no phenol red) + 10% FBS. BT-483 culture media consisted of RPMI 1640 + 20% FBS + 10 µg / ml insulin, and assay media consisted of DMEM (no phenol red) + 10% FBS. EFM-19 culture media consisted of RPMI 1640 + 10% FBS , and assay media consisted of DMEM (no phenol red) + 10% FBS. MFE-280 culture media consisted of MEM + 10% FBS, and assay media consisted of DMEM (no phenol red) + 10% FBS. [000274] Cell density for dispensing into assay ready plates as follows: SK-BR-3 at 5,000 cells / well, T-47D at 5,000 cells / well, MCF-7 at 5,000 cells / well, BT-483 at 5,000 cells / well, EFM- 19 at 5,000 cells / well, MFE-280 at 10,000 cells / well. Reagent table:[000275] For EC50 values shown in Table 3, “A” refers to 1 nM < EC50 < 100 nM; “B” refers to 100 nM < EC50 < 1 µM; “C” refers to 1 µM < EC50 < 10 µM; and “D” refers to an EC50 > 10 µM. Table 3. Cellular proliferation data[000276] For IC50 values shown in Table 4, “A” refers to 1 nM < EC50 < 100 nM; “B” refers to 100 nM < EC50 < 1 µM; “C” refers to 1 µM < EC50 < 10 µM; and “D” refers to an EC50 > 10 µM. Table 4. Cellular pAKT data[000277] For IC50 values shown in Table 5, “A” refers to 1 nM < EC50 < 100 nM; “B” refers to 100 nM < EC50 < 1 µM; “C” refers to 1 µM < EC50 < 10 µM; and “D” refers to an EC50 > 10 µM. Table 5. Cellular pAKT dataReferences [000278] Ali, K., Bilancio, A., Thomas, M., Pearce, W., Gilfillan, A. 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Claims

IN THE CLAIMS 1. A compound of Formula (1):or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein: Z is heteroaryl, wherein the heteroaryl is substituted or unsubstituted; R1is aryl, heteroaryl or heterocyclyl, where each of the aryl, heteroaryl and heterocyclyl is unsubstituted or substituted, with the proviso that when R1is aryl or heteroaryl, a carboxylic acid or ester thereof is not a substituent at a position ortho to the point of attachment of the aryl or heteroaryl ring to the nitrogen atom of N-R3; R2is H, C1-C4alkyl, C3-C7cycloalkyl, CF3, CFH2or CF2H, where the C1-C4alkyl and C3-C7cycloalkyl is unsubstituted or substituted, and where R2is not H, the carbon atom attached to R2is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer; R3is H or C1-C4alkyl, where the C1-C4alkyl is unsubstituted or substituted; R4is H, F, Cl, C1-C4alkyl, C3-C7cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4alkyl and C3-C7cycloalkyl is unsubstituted or substituted; R6is H, F, Cl, C1-C4alkyl, C3-C7cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4alkyl and C3-C7cycloalkyl is unsubstituted or substituted;each R7is independently H, F, Cl, C1-C4alkyl, C3-C7cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4alkyl and C3-C7cycloalkyl is unsubstituted or substituted; and R5is heteroaryl or a non-aromatic N-linked heterocyclic ring , where the heteroaryl and the heterocyclic ring are substituted or unsubstituted, and where the heterocyclic ring optionally contains one or more additional ring atoms selected from N, O, Si and S, and is optionally part of a bridged, fused or spiro ring system.

2. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the following:wherein: R8is selected from the following:; each A is independently C1-C4alkyl, fluoroalkyl, C3-C7cycloalkyl, N(Ra)2, (CH2)0-5-NRa-C(O)-C3-C7cycloalkyl, (CH2)1-5-O-C1-C3cycloalkyl, (CH2)1-5-O-(CH2)1-5-C1-C3fluoroalkyl, (CH2)0-5-aryl, (CH2)0-5- heteroaryl, (CH2)0-5-heterocyclyl, (CH2)0-5-NRa-(CH2)0-5-heteroaryl or (CH2)0-5-NRa-(CH2)1-5-N- heterocyclyl, where the alkyl, fluoroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, A and A together with the attached -P(=O)- moiety may form a substituted or unsubstituted heterocyclyl ring;each B is independently H, C1-C4alkyl, C3-C7cycloalkyl, (CH2)1-5-NRa-C(O)-C3-C7cycloalkyl, (CH2)0-5- aryl, (CH2)0-5-heteroaryl, (CH2)0-5-heterocyclyl, (CH2)1-5-NRa-(CH2)0-5-heteroaryl or (CH2)1-5-NRa- (CH2)2-5-N-heterocyclyl, O-C1-5-alkyl, O-C0-5-cycloalkyl, O-C0-5-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, B and B together with the attached -[O or NH]-P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring, or alternatively, A and B together with the attached -P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring; each Rais independently H, C1-C4alkyl, C(O)C1-C3alkyl or C(O)-(CH2)1-5-O-C1-C3alkyl, where the alkyl is substituted or unsubstituted, or alternatively, Raand A together with the attached - S(=O)2- moiety may form a substituted or unsubstituted heterocyclic ring, or R8and R9together form a substituted or unsubstituted heterocyclic ring (such as a 5- or 6- membered heterocyclic ring) containing one or more sulfur atoms (which includes the sulfoxide (SO) and sulfone (SO2) forms), nitrogen atoms (which includes the oxidized forms) and oxygen atoms; R9is H, C1-C4alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted, or R9and R8together form a heterocyclic ring as described herein; each R10is independently H, C1-C4alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted; R11is H, C1-C4alkyl, C3-C7cycloalkyl, CF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted; and each X1, X2, X3and X4is independently CH, N or substituted C.

3. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1iswherein R8, R9, X2, X3and X4are as defined.

4. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1iswherein R8, X2, X3and X4are as defined.

5. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1iswherein R8, X2, X3and X4are as defined.

6. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the following:wherein R10and R11are as defined.

7. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the following:wherein: Y is O, NR11or C(R4)2; and X2, X3, X4, R4, R10and R11are as defined.

8. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected fromand R8is selected fromwhere X2, X3, X4, R9, A and B are as defined.

9. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected fromwhere X2, X3, X4, R9, A, B and Ra are as defined.

10. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected fromwhere X2, X3, X4, R9and B are as defined.

11. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3, CH2F or CHF2.

12. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R3is H.

13. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R4is H, F or Cl.

14. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3, CH2F or CHF2; and R3is H.

15. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2 is CH3, CH2F or CHF2; R3 is H; and R4 is H, F or Cl.

16. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3, CH2F or CHF2; R3is H; and R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1,4-dioxa-7- azaspiro[4.4]nonane or 2-azaadamantane.

17. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected fromwhere X2, X3, X4, R9, A, B and Raare as defined; R3is H; and R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7- azaspiro[4.4]nonane or 2-azaadamantane.

18. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (2)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: each X1, X2, X3and X4is independently CH, N or substituted C; R8is selected from; the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer, and R5, Z, A, B and Raare as defined.

19. The compound according to claim 18 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2- azaadamantane.

20. The compound according to claim 18 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

21. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (3)(3) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: each X2, X3and X4is independently CH, N or substituted C; R8is selected from; R9is H, C1-C4alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted, or R8and R9together form a substituted or unsubstituted heterocyclic ring (such as a 5- or 6- membered heterocyclic ring) containing one or more sulfur atoms (which includes the sulfoxide(SO) and sulfone (SO2) forms), nitrogen atoms (which includes the oxidized forms) and oxygen atoms; the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer, and R5, Z, A, B and Raare as defined.

22. The compound according to claim 21 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2- azaadamantane.

23. The compound according to claim 21 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

24. The compound according to claim 21 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R8and R9together form a heterocyclic ring with the result that themoiety is selected fromwherein: Y is O, NR11or C(R4)2; and X2, X3, X4, R4, R10and R11are as defined.

25. The compound according to claim 2 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (4)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from; R10, R11, R5and Z are as defined; and the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer.

26. The compound according to claim 25 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R5is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2- azaadamantane.

27. The compound according to claim 25 or a solvate, enantiomer, diastereomer, tautomer,polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

28. A pharmaceutical composition comprising the compound of any one of claims 1 to 27 or asolvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition according to claim 28, further comprising one or more anti-cancer agents.

30. The pharmaceutical composition according to claim 29, wherein the one or more anti-canceragents are selected from the group consisting of cyclophosphamide, dacarbazine, cisplatin,methotrexate, mercaptopurine, thioguanine, fluorouracil, cytarabine, vinblastine, paclitaxel, doxorubicin, bleomycin, mitomycin, prednisone, tamoxifen, flutamide, asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, amifostine, camptothecin, topotecan, thalidomide, lenalidomide, a CDK inhibitor and a proteasome inhibitor.

31. A method of treating a disease in which PI3K activity is implicated in a subject in need ofsuch treatment, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 27 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the disease is cancer.

33. The method of claim 31, wherein the disease is congenital lipomatous overgrowth, vascularmalformations, epidermal naevi, scoliosis / skeletal and spinal syndrome (CLOVES), mosaic tissue overgrowth syndromes, venous malformations and brain malformations associated with severe epilepsy or PIK3CA-related overgrowth syndrome (PROS).

34. The method of claim 31, wherein the disease is cancer bearing a PI3K H1047 mutation.

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