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, (1) wherein R1, R2, R4, R5, R6, R7, Q, Z, X1, X2, X3 and X4 are as defined and each site or atom marked with a * exists as a (R)- or (S)- stereocenter or as a mixture thereof.

Description

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

[0001] This application claims priority to U.S. Provisional Application No. 63 / 755,899, filed February 7, 2025, and U.S. Provisional Application No. 63 / 939,646, filed December 12, 2025, the disclosures of which are incorporated in their entireties for all purposes.BACKGROUND OF THE INVENTION

[0002] Phosphatidylinositol lipids (Pls) 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 Pls. PI3Ks are subdivided into 3 classes according to their structure and substrates. Class II PI3Ks (PI3K-C2a, PI3K-C2P, PI3K-C2y) and Class III PI3Ks (vps34) are monomeric enzymes primarily associated with endocytosis and autophagy (Posor etal., Biochim Biophys Acta 2015, 1851, 794; Backer, Biochem J. 2016, 473, 2251). The Class I PI3Ks are heterodimeric, consisting of a catalytic kinase subunit (pllOa, P, y, 6) 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 (a, P, y, and 6) based on the identity of their catalytic (pllOa, pliop, pllOy, or pllOS) and regulatory (p85a or its various splice variants, p85|3, p55y, or plOl) subunits, giving rise to distinct roles in cellular physiology (Vanhaesebroeck et al., J Mol Med (Berl). 2016, 94, 5). PI3 Ky and PI3K6 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). PI3Ka and P are more ubiquitously expressed and share similar but not identical roles. For example, PI3Ka has a nonredundant role in angiogenesis (Soler et al., J ExpMed. 2013, 210, 1937), while PI3K|3 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 PI3Ka or mutations which lead to upregulation of PI3Ka have been found to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon,brain, prostate, and skin cancers (Goncalves etal., N Eng J Med. 2018, 379,2052). In particular, PIK3CA, the gene encoding the pllOa subunit of PI3Ka, is frequently mutated or amplified in a variety of tumor types. Missense mutations occur in all domains of pllOa, 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 pllOa by p85 or facilitate direct interaction of pllOa with insulin receptor substrate 1 (IRS1)37, whereas kinase domain mutations increase interaction of pllOa 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, idelal isib, 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 pllOa 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 PI3Ka inhibitors are associated with hyperglycemia and rash due to the pllOa sub-unit role in insulin response (Rugo et al., The Breast 2022, 61, 156). Similarly, use of a selective PI3K6 inhibitor (idelalisib),where the pllOS sub-unit is highly expressed in immune cells, causes severe diarrhea and colitis. Inhibition with a dual inhibitor (taselisib), a potent PI3K8 inhibitor possessing modest PI3Ka inhibition led to gastrointestinal (Gl) side effects, but a highly selective and potent PI3K8 inhibitor (umbralisib) reported no Gl 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 PI3Ka isoform over wild type may suppress cancer signaling while having minimal effect on PI3K signaling in healthy cells bearing just wild type PI3Ka, leading to a reduction in the toxicities associated with nonselective PI3K inhibition (Castel et al., Nat Cancer 2021 2, 587).

[0007] There is currently an interest in developing PI3K inhibitors for cancer therapy (WO 2024 / 230803, WO 2024 / 211346, WO 2024 / 097172, WO 2023 / 081209, WO 2023 / 078401, WO 2023 / 060262, WO 2023 / 056407, WO 2021 / 202964). 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. Specifically, PI3K inhibitors that can target multiple cancer-causing mutated PI3K proteins with reduced activity against wild-type protein has the potential to provide therapeutic benefits to a broader patient population compared to PI3K inhibitors that can target only the H1047R mutation. The compounds of the present invention were observed to exhibit this activity profile, thus addressing a largely heretofore unmet need in this therapeutic area.SUMMARY OF THE INVENTION

[0008] An aspect of the invention is a compound of Formula (1)(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));Ri is selected from a 5- or 6-membered substituted or unsubstituted nitrogen-containing heteroaryl, a 4- to 6-membered substituted or unsubstituted nitrogen-containing heterocyclyl, oreach A is independently C1-C4 alkyl, fluoroalkyl, C3-C7 cycloalkyl, N(Ra)2, (CH2)o-5-NRa-C(0)-C3-C7 cycloalkyl, (CH2)I-5-0-(CH2)O-5-CI-C4 alkyl, (CH2)I-5-O-CI-C3cycloalkyl, (CH2)I-5-0-(CH2)O-5-CF3, (CH2)I-5-O-(CH2)I-5-CI-C3fluoroalkyl, (CH2)o-s-aryl, (CH2)o-5-heteroaryl, (CH2)o-5-heterocyclyl, (CH2)o-s-NRa-(CH2)o-5-heteroaryl or (CH2)o-5-NRa-(CH2)i-5-N-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted;each B is independently H, C1-C4 alkyl, C3-C7cycloalkyl, (CH2)I-5-OH, (CH2)o-s-N(Ra)2, (CH2)i-5-NRa-C(O)-C3-C7cycloalkyl, (CH2)o-s-aryl, (CH2)o-5-heteroaryl, (CH2)o-5-heterocyclyl, (CH2)O-5-C(0)-(CH2)I-5-O-C1-C4 alkyl, (CH2)i-5-NRa-(CH2)o-5-heteroaryl or (CH2)i-5-NRa-(CH2)2-5-N-heterocyclyl, O-Ci-5-alkyl, O-Co-5-cycloalkyl, O-Co-s-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted;each Rais independently H, C1-C4 alkyl, C3-C7cycloalkyl, C(O)Ci-C3alkyl, (CH2)i-5-fluoroalkyl, (CH2)I-5-OH, (CH2)I-5-NH2, (CH2)I-5-NH(CI-C4 alkyl), (CH2)I-5-N(CI. C4alkyl)2or C(O)-(CH2)I-5-O-CI-C3alkyl, where the alkyl and cycloalkyl are substituted or unsubstituted, or alternatively, for -S(=O)(A)(=NRa) or for -S(=O)(A)(NRa), Raand A together with the attached atoms, may form a substituted or unsubstituted heterocyclyl ring;R2is C1-C4 alkyl, CF3, CFH2or CF2H, and the carbon atom attached to R2(shown with an asterisk) exists as a (R)- or (S)- stereocenter or as a mixture thereof;R3is H or C1-C4 alkyl;R4is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H;Re is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H;each R7is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H; each of Xi, X2, and X3is independently N, CH or substituted C;X4is independently CH or substituted C;Q is NR3or O;Rs isa 5- or 6- membered heteroaryl ring A of the formula:that is optionally further substituted, where R9is H, CN or substituted or unsubstituted C1-C3 alkyl, and R10is substituted or unsubstituted C1-C3 alkyl, C1-C3 fluoroalkyl or substituted or unsubstituted cyclopropyl, and the S(=O)(=NR9)(R10) substituent exists as a (R)- or (S)-stereocenter or as a mixture thereof; ora non-aromatic heterocyclyl ring B containing at least one ring nitrogen atom and having the formula:that is optionally further substituted, where R9is H, -CN or substituted or unsubstituted C1-C3 alkyl, and R10is substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted cyclopropyl, where the heterocyclic ring is linked to the core structure through either a ring carbon atom or a ring nitrogen atom, and optionally contains one or more additional ring atoms selected from N, O and S, and is optionally part of a bridged, fused or spiro ring system, and where the S(=O)(=NR9)(R10) substituent exists as a (R)- or (S)- stereocenter or as a mixture thereof. In particular embodiments, the heteroaryl ring A is a substituted or unsubstituted pyrrole, pyridine, pyridone, oxazole, isoxazole, pyrazole, imidazole, thiazole, isothiazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, oxadiazole, thiadiazole, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine or 1,3,5-triazine; and the non-aromatic heterocyclyl ring B is a substituted or unsubstituted azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, or 2,6- diazaspiro[3.3]heptane;each site or atom marked with a * exists as a (R)- or (S)- stereocenter or as a mixture thereof.

[0009] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O and S, and is not part of a bridged, fused or spiro ring system.

[0010] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is 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.

[0011] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, does not contain additional atoms selected from N, O and S, and is not part of a bridged, fused or spiro ring system.

[0012] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, does not contain additional atoms selected from N, O and S, and is part of a bridged, fused or spiro ring system.

[0013] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, contains at least one sulfur ring atom, and is not part of a bridged, fused or spiro ring system.

[0014] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, contains at least one sulfur ring atom, and is part of a bridged, fused or spiro ring system.

[0015] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, contains at least one oxygen ring atom, and is not part of a bridged, fused or spiro ring system.

[0016] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, contains at least one oxygen ring atom, and is part of a bridged, fused or spiro ring system.

[0017] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is not part of a bridged, fused or spiro ring system.

[0018] In an exemplary embodiment, the non-aromatic heterocyclyl ring B of R5is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is part of a bridged, fused or spiro ring system.

[0019] In an exemplary embodiment of the compound of Formula (1), Ri is selected fromowhere A, B and Raare as defined.

[0020] In an exemplary embodiment of the compound of Formula (1), Ri is selected fromwhere B is as defined.

[0021] In an exemplary embodiment of the compound of Formula (1), R2is CH3.

[0022] In an exemplary embodiment of the compound of Formula (1), R2is CH2F or CHF2.

[0023] In an exemplary embodiment of the compound of Formula (1), Q = O or NR3, and R3is H.

[0024] In an exemplary embodiment of the compound of Formula (1), R4is H or F.

[0025] In an exemplary embodiment of the compound of Formula (1), Xi is N, and X2and X3are independently CH, CF, CCI or CCH3.

[0026] In an exemplary embodiment of the compound of Formula (1), X2is N, and Xi and X3are independently CH or CCH3.

[0027] In an exemplary embodiment of the compound of Formula (1), X3is N, and Xi and X2are independently CH, CF, CCI or CCH3.

[0028] In an exemplary embodiment of the compound of Formula (1), Xi and X3are N, and X2is CH or CCH3.

[0029] In an exemplary embodiment of the compound of Formula (1), Xi and X2are N, and X3is CH or CCH3.

[0030] In an exemplary embodiment of the compound of Formula (1), X2and X3are N, and Xi is CH or CCH3.

[0031] In an exemplary embodiment of the compound of Formula (1), Xi, X2and X3are N.

[0032] In an exemplary embodiment of the compound of Formula (1), Xi, X2and X3are independently CH, CF, CCI or CCH3.

[0033] In an exemplary embodiment of the compound of Formula (1), X4is CH or CF.

[0034] In an exemplary embodiment of the compound of Formula (1), Xi is N, X2and X3are independently CH, CF, CCI or CCH3, and X4is CH or CF.

[0035] In an exemplary embodiment of the compound of Formula (1), X2is N, Xi and X3are independently CH or CCH3, and X4is CH or CF.

[0036] In an exemplary embodiment of the compound of Formula (1), X3is N, Xi and X2are independently CH, CF or CCH3, and X4is CH or CF.

[0037] In an exemplary embodiment of the compound of Formula (1), Xi and X3are N, X2is CH or CCH3, and X4is CH or CF.

[0038] In an exemplary embodiment of the compound of Formula (1), Xi and X2are N, X3is CH or CCH3, and X4is CH or CF.

[0039] In an exemplary embodiment of the compound of Formula (1), X2and X3are N, Xi is CH or CCH3, and X4is CH or CF.

[0040] In an exemplary embodiment of the compound of Formula (1), Xi, X2and X3are N, and X4is CH or CF.

[0041] In an exemplary embodiment of the compound of Formula (1), Xi, X2and X3are independently CH, CF, CCI or CCH3, and X4is CH or CF.

[0042] In an exemplary embodiment of the compound of Formula (1), R6is CH3, Cl or F.

[0043] In an exemplary embodiment of the compound of Formula (1), each R7is independently H or F.

[0044] In an exemplary embodiment of the compound of Formula (1), R9is H.

[0045] In an exemplary embodiment of the compound of Formula (1), R10is CH3.

[0046] In an exemplary embodiment of the compound of Formula (1), R9is selected from H or CH3.

[0047] In an exemplary embodiment of the compound of Formula (1), R10is selected from CH3, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, and cyclopropyl.

[0048] In an exemplary embodiment of the compound of Formula (1), R9is H and R10is selected from CH3, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3and cyclopropyl.

[0049] In an exemplary embodiment of Formula (1), Ri is CN, CF3, OCF3or OCF2H.

[0050] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, and Ri is selected fromwhere A, B and Raare as defined.

[0051] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, and Ri is selected fromwhere B is as defined. In a further embodiment, Ri is CN, CF3, OCF3or OCF2H.

[0052] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, Ri is selected fromwhere A, B and Raare as defined, and R5is where ring A, R9and Rio are as defined.

[0053] In an exemplary embodiment of the compound of Formula (1), R2 is CH3or CH2F, Q is O or NR3, R3is H, Ri is selected fromwhere B is as defined, and R5is where ring A, R9and Rio are as defined. In a further embodiment„Ri is CN, CF3, OCF3or OCF2H.

[0054] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, Ri is selected fromwhere A, B and Raare as defined, and R5is where ring B, R9and Rio are as defined.

[0055] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, Ri is selected from\ — S-NR3\_ y pwhere B is as defined, and R5is — ''10where ring B, R9and Rio are as defined. In a further embodiment, Ri is CN, CF3, OCF3or OCF2H.

[0056] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, and Ri is selected fromwhere A, B and Raare as defined.

[0057] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, and Ri is selected fromwhere B is as defined. In a further embodiment, Ri is CN, CF3, OCF3or OCF2H.

[0058] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, Ri is selected fromwhere A, B and Raare as defined, and R5is "10where ring A, R9and Rio are as defined.

[0059] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, Ri is selected from! A; — s=NRg\. / pwhere B is as defined, and R5is '' — "10where ring A, R9and Rio are as defined. In a further embodiment, Ri is CN, CF3, OCF3or OCF2H.

[0060] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, Ri is selected from[ B — S-NRs\ v y / RIwhere A, B and Raare as defined, and R5is ''10where ring B, R9and Rio are as defined.

[0061] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, Ri is selected from / „ A0’ B;~~- S-NRsRwhere B is as defined, and R5is "10where ring B, R9and Rio are as defined. In a further embodiment, Ri is CN, CF3, OCF3or OCF2H.

[0062] In an exemplary embodiment, the compound of Formula (1) is a compound of Formula (2A), (2B), (2C) or (2D):(2A)(2B)(2D) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof,wherein:Xi, X2, X3, Ri, Rg, Rio, and rings A, B and Z are defined as for the compound of Formula (1), and each site or atom marked with a * exists as a (R)- or (S)- stereocenter or as a mixture thereof.

[0063] In an exemplary embodiment of the compounds of Formulae (1), (2A), (2B), (2C) and (2D), Z is a substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, or tetrazole.

[0064] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), Ri is selected fromwhere A, B and Raare defined as for the compound of Formula (1).

[0065] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), Ri is selected fromwhere B is defined as for the compound of Formula (1). In a further embodiment, Ri is CN, CF3, OCF3or OCF2H.

[0066] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), Xi is N, and X2and X3are independently CH, CF or CCH3.

[0067] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), X2is N, and Xi and X3are independently CH or CCH3.

[0068] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), X3is N, and Xi and X3are independently CH, CF or CCH3.

[0069] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), Xi and X3are N, and X2is CH or CCH3.

[0070] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), Xi and X2are N, and X3is CH or CCH3.

[0071] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), X2and X3are N, and Xi is CH or CCH3.

[0072] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), Xi, X2and X3are N.

[0073] In an exemplary embodiment of the compound of Formulas (2A), (2B), (2C), or (2D), Xi, X2and X3are independently CH, CF, CCI or CCH3.

[0074] An aspect of the invention is a pharmaceutical composition comprising any compound of the invention as described herein (such as any one of Formula (1), (2A), (2B), (2C), or (2D)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0075] In an exemplary embodiment, the pharmaceutical composition comprising any compound of the invention as described herein (such as any one of Formula (1), (2A), (2B), (2C), or (2D)) 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.

[0076] 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 any one of Formula (1), (2A), (2B), (2C), or (2D)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0077] In an exemplary embodiment, the disease to be treated is cancer. In a particular embodiment, the disease is a cancer bearing a PI3Ka H1047 mutation (such as H1047R, H1047L, or H1047Y), a PI3Ka E545 mutation (such as E545K), or a PI3Ka E542 mutation (such as E542K).DETAILED DESCRIPTION OF THE INVENTION

[0078] 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.

[0079] 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 ( / .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 ED50 with 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.

[0080] 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 result of 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.

[0081] 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.

[0082] 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.

[0083] The term "inhibitory compound" as used herein, refers to any compound capable of interacting with ( / .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.

[0084] 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.

[0085] 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.

[0086] 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 ( / .e., for example, extravascular administration, such as subcutaneous, intramuscular, or intraperitoneal), intravenous, oral ingestion, transdermal patch, topical, inhalation, suppository, etc.

[0087] 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 ( / .e., children).It is not intended that the term "patient" connotes a need for medical treatment. Therefore, a patient may voluntarily be subject to experimentation, whether clinical or in support of basic science studies.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] The term "test compound" as used herein, refers to any compound or molecule considered a candidate as an inhibitory compound.

[0092] The term "combination therapy" as used herein refers to a dosing regimen of two or more different therapeutically active agents during a period of time, wherein the therapeutically active agents are administered together or separately. In one embodiment the combination therapy is a non-fixed combination.

[0093] 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.

[0094] 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.

[0095] The term "in vivo" as used herein refers to an event that takes place in a subject's body.

[0096] The term "in vitro" as used herein refers to an event that takes places outside of a subject's body.

[0097] 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.

[0098] 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.

[0099] 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.[000100] 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.[000101] 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 formedfrom 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.[000102] 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.[000103] 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.[000104] 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.[000105] 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.[000106] 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 detected by 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.[000107] The term "conjugate" as used herein, refers to any compound that has been formed by the joining of two or more moieties.[000108] 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 willconnect 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.[000109] 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 ( / .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.[000110] 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., CH2CI, 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, OCF2CF2CF3or OCH2CI), 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, -NRfC-(=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 Rf and 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.[000111] 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.[000112] 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.[000113] 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, tertbutyl, 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.[000114] 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".[000115] The term "bicyclic compounds" as used herein, encompasses "bridged" compounds, "fused" compounds and "spiro" compounds as described.[000116] 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. Exemplary embodiments include l,4-dioxaspiro[4.5]decane, oxa-azaspiro[3.4]octane, diazaspiro[3.4]octane, diazaspiro[2.5]octane, spirocyclic azetidines and spirocyclic pyrrolidines and spirocyclic piperidines, where the other ring is cycloalkyl (e.g., cyclobutane, cyclopentane or cyclohexane) or heterocyclyl (e.g., piperidine, tetrahydropyran, tetrahydrofuran, azetidine or pyrrolidine).[000117] 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[l.l.l]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, l,4-diazabicyclo[2.2.1]heptane, 1,4- diazabicyclo[2.2.2]octane, and other bridged piperazines and bridged piperidines.[000118] 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 perifused systems have "n" common sides and less than "2n" atoms in common. Other exemplary fused systems include fused cyclopropyl rings, fused aziridines and fused azetidines, such as when these rings are fused to 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,l-b][l,3]oxazine and 6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazine).[000119] The term "aromatic" or "aryl" as used herein, refers to any aromatic carbocyclic ( / .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).[000120] 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.[000121] The term "halogen" as used herein, refers to any fluoro, chloro, bromo, or iodo moiety.[000122] 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.[000123] 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.[000124] 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., [l,2,4]triazolo[4,3-a]pyridine) and the like.[000125] 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.[000126] The term "heterocycle" or "heterocyclyl" or "heterocyclic ring" as used herein, refers to a nonaromatic ring which is either saturated or unsaturated and which contains 1 or more heteroatoms independently selected from nitrogen, oxygen, sulfur, phosphorus and silicon, wherein each of the nitrogen, phosphorus and sulfur heteroatoms may be in an oxidized state, and each of the nitrogen and silicon heteroatoms is substituted or unsubstituted and the nitrogen heteroatoms may be optionally quaternized, and includes bicyclic rings in which any of the above heterocycles are fused to an aryl or heteroaryl ring. The heterocyclic ring may be attached as a substituent via a ring heteroatom or a carbon atom. In various embodiments, heterocycles may contain 3 to 14 or more ring atoms (such as 3- to 7-membered monocyclic rings or 7- to 10-membered bicyclic rings) and include, but are not limited to, 2H-azirine, azetidine, 2,3-dihydroazete, 1,3-diazetidine, 2H-oxete, thietane, 2H-thiete, azetidin-2-one, morpholine, thiomorpholine, pyrrolidinone, pyrrolidinine, 2-pyrroline, 3-pyrroline, pyrazolidine, 2-pyrazoline, pyridazinone, pyrazinone, oxazolidin-2-one, 2-imidazoline, imidazolidine, piperidine, oxopiperidine, tetrahydropyrimidinone, piperazine, oxopiperazine, diazepane, ethylene oxide (oxirane), ethylene imine (aziridine), 1,1-dioxoisothiazolidine, ethylene sulfide (thiirane), oxetane, propylene oxide, 1,3-dioxolane, 1,2-oxathiolane, 1,3-oxathiolane, sulfolane, 2,4-thiazolidinedione, succinimide, 4-methyl-l,4-azaphosphinane 4-oxide, oxadiazoIone, dioxane (e.g., 1,4-dioxane and 1,3-dioxane), hydantoin, valerolactam, tetrahydrofuran, tetrahydropyran, 2H-pyran, 4H-pyran, thiane, 2H-thiopyran, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, pyrrolizidine, l,4,5,6-tetrahydrocyclopenta[b]pyrrole, tetrahydropyridine, tetrahydropyrimidine, dihydropyridazine, 6-oxo-l,6-dihydropyridazine, 6-oxo-l,4-dihydropyridazine, 6-oxo-l,6- dihydropyrazine, 6-oxo-l,4-dihydropyrazine, tetrahydrothiophene, tetrahydrothiopyran, tetrahydrotriazolopyrazine, tetrahydropyrazolopyridine, dihydrotriazolopyrazine, dihydropyrazolopyrazine, dihydroimidazopyrazine, indoline, isoindoline, decahydroisoquinoline, decahydroquinoline, 1,2,3,4-tetrahydroquinoline, 1,2-dihydroquinoline, 2H-benzo[e][l,3]oxazine, 2H-benzo[b][l,4]oxazine, quinolin-2(lH)-one, isoquinolin-l(2H)-one, quinuclidine, triethylenediamine, 1-azaadamantane, 2-azaadamantane, 2,3-dihydroazepine, 2,5- dihydroazepine, oxepane, azonane, spiro[cyclobutane-l,3'-indole], l-oxaspiro[4,5]decane, 1,6- dioxaspiro[3,4]octane, 2-oxa-7-azaspiro[3,5]nonane, l,4-dioxa-7-azaspiro[4,4]nonane, 1,3- diazaspiro[4,4]non-2-en-4-one, 2,9-diazaspiro[5,5]undecan-l-one, oxa- diazabicyclo[3.3.1]nonane, 8-azaspiro[4,5]decane-7, 9-dione, l,4-dithia-7-azaspiro[4,4]nonane, and the like.[000127] 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.[000128] The term "alkylamino" as used herein, means at least one alkyl moiety attached through a nitrogen bridge ( / .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.[000129] The term "alkyloxy" or "alkoxy", as used herein, means any alkyl moiety attached through an oxygen bridge ( / .e., -O-alkyl) such as, but not limited to, methoxy, ethoxy, and the like.[000130] The term "thioalkyl" as used herein, means any alkyl moiety attached through a sulfur bridge ( / .e., -S-alkyl) such as, but not limited to, methylthio, ethylthio, and the like.[000131] 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.[000132] 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-l-butynyl, 4-propyl-2-pentynyl-,and 4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substituted with one or two suitable substituents.[000133] 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 etal. Proc Natl Acad Sci US. A. 2002, 99, 19, both of which are incorporated by reference in its entirety).[000134] 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 implanted medical 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, F719-20el, 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.[000135] 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.[000136] " 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, glioblastoma multiforme, 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.[000137] 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%.[000138] 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.[000139] 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.[000140] 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 alsoprovided 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.[000141] 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.[000142] 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.[000143] In a specific embodiment, the additional therapeutic agent to be included is an anticancer 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; antimetabolites 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.[000144] 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.[000145] 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.[000146] 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 agent for techniques such as in vivo imaging. Synthetic methods for incorporating isotopes into organic compounds are well known in the art.[000147] In an embodiment of the invention, a compound of the invention as defined herein (such as a compound of any one of Formula (1), (2A), (2B), (2C), or (2D)) 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%.[000148] In an embodiment of the invention, a pharmaceutical composition comprises a compound of the invention as defined herein (such as a compound of Formula (1)) 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%.[000149] 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).[000150] In an exemplary embodiment of the invention, the cancer to be treated is a cancer bearing a PI3Ka H1047 mutation (such as H1047R) (Thorpe et al., Nat Rev Cancer 2015, 15, 7).[000151] The compounds of the invention (such as defined by Formulas (1), (2A), (2B), (2C), and (2D)) are typically PI3Ka H1047R mutant-selective inhibitors that exhibit greater selectivity for the H1047R mutation over the wild-type. As such, the compounds may decrease the amount of phosphorylated AKT (pAKT) and decrease proliferation selectively in PI3Ka H1047R mutant cell lines, preferably across several tumor types.[000152] A PI3Ka H1047R mutant selective inhibitor of the invention (such as defined by Formulas (1), (2A), (2B), (2C), and (2D)) dosed in combination with an aromatase inhibitor (Al) 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, camizestrant, giredestrant or vepdegestrant may exhibit a combination benefit leading to tumor regression in ER+ / PI3Ka 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. Similarly, triple combinations of a PI3Ka mutant selective inhibitor of the invention (such as defined by Formula (1), Formula (2) or Formula (3)) dosed in combination with an aromatase inhibitor (Al), selective estrogen receptor modulator (SERM), or selective estrogen receptor degrader (SERD) in addition to a CDK4 or CDK4 / 6 inhibitorsuch as, but not limited to atirmociclib, ribocicl ib, abemaciclib, or pal bocicl ib, may exhibit a combination benefit leading to tumor regression in ER+ / PI3Ka 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.[000153] A PI3Ka H1047R mutant selective inhibitor of the invention (such as defined by Formulas (1), (2A), (2B), (2C), and (2D)) 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+ / PI3Ka 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.[000154] Compounds of Formulas (1), (2A), (2B), (2C), and (2D) of the present invention may be generally prepared according to the synthetic routes identified in Schemes 1-12.[000155] 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- lH-inden-l-one. In the case of 1 where R6is methyl and R7is hydrogen, 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, in which Rxis an (un)substituted (hetero)aryl or (un)substituted non-aromatic heterocyclyl group. In some cases, Rx may be an R5group as defined above. Alternatively, in some cases, Rxmay be a precursor to an R5group requiring one or more additional chemical modifications, such as the removal of protecting groups, or the addition, transformation or removal of one or more chemical moieties, to generate the R5groups of the present invention. Chlorination of intermediates 4 with reagents such as POCI3can provide isoquinolones 5.Scheme 1[000156] In order to convert the bromide of isoquinolones 5 to ketones 6 (Scheme 2), a Stille coupling reaction may be employed using an appropriate tin reagent, such as (1-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. etal., J. Med. Chem., 2020, 63, 3935; Garcia, M., et al., Tetrahedron Lett., 2017, 58, 1952; Cupido, T., et al., Angew. Chem. Int. Ed., 2009, 48, 2321). The mixtures of stereoisomers represented by 13 may be separated into their stereoenriched components 14 and 15 via chiral HPLC or chiral SFC. Cyano-substituted compounds of the present invention may arise from intermediates 16 where W of intermediates 13 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).Stereoenriched 18 and 19 can be obtained from the mixture of enantiomers 17 after a chiral separation.Scheme 2OH to X transformationRx= Rs, or (unjsubstituted (hetero)aryl, or (un)substituled non-aromatic heterocyclyl / L substitution X R? g X = OMs or halogen Y = H or NH310 N'W RyR^Br orCI chiral "Rx separation O 12 or CH(OEt)3R.-irRj W = N or C-RzR> ~ H, halogen, alkyl, or aminoCN nM / CO?AEt chiral separation 2) dehydration18 1916[000157] Alternatively, the bromide of isoquinolones 3 can be converted to methyl ketones 20 (Scheme 3) using synthetic chemistry methods similar to what is 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 POCI3can provide chloroisoquinolones 6.Scheme 321 6 Rx= R5, or (un)substituted (hetero)ary!, or(un)substituted non-aromatic heterocyclyl [000158] Alternatively, the order of reactions may be adjusted to furnish compounds of general structure 13, as depicted in Scheme 4. Compounds 13 can be prepared from intermediates 5 or 20, using synthetic steps analogous to those described in Scheme 2.Scheme 4ClHrJY Rz'y^Bror CIO 12(R?)2^^r'X^'RxCH(OEt)3Y = H or NH222Rx= Rs, or(un)substituted (hetero )aryl, or(un)substituted non-aromatic heterocyclylN-WR ‘6 N'W(R6as in Scheme 2HN' 'R2Brr £-R423 X1yx3W = N or C-RzYx2R = H, halogen, alkyl, or amino 13RZ= H, Chi, or alkylmethods as in Scheme 2 couplingRtCl N-Wmethods asin Scheme 2 (RRe'. 'y^RxRychlorinationHN' 'R2RI[ - -R4 W = N or C-RzXIYA3S H halogen, alkyl, or amino26A2 Rz= H. CN, or alkyl13[000159] 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), as depicted in Scheme 5.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 etal, Synthesis 1991, (11), 970-4; Zhu etal, J. of Chem. Res. 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 of the 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.Scheme 5OHromovaf of reductionRx= Rs, or (Major diastereoisomer from -9:1 mixture) (un Substituted (heterolaiyl, or (un)substituted non-aromatic heterocyclylas above rr A (P^Y 'Rx j W = N or C-R2H2N' RZRv= H. hategen, alkyl, or amino RZ= H, ON, or alkyl32 [000160] Synthesis of compounds of general structure 37 where Q = O may be synthesized as depicted in Scheme 6. Tricyclic bromides of general structure 23 can be elaborated to alcohols 33 using similar methodology as used to convert 5 to 7 in Scheme 2. Alcohols 33 may be converted to intermediates 36 that possess a leaving group suitable for effecting subsequent SN2 reactions, such as a bromide or a mesylate, utilizing commonly known methods. Nucleophilic displacement on 36 with (hetero)aryl alcohols 35 under basic conditions (e.g., K2CO3or NaH) can give rise to (hetero)aryl ether intermediates 37. Alternatively, Mitsunobu reactions coupling alcohols 33 with suitably active (hetero)aryl alcohols 35 can directly yield (hetero)aryl ethers 37. Alternatively, alcohols 33 can also be converted into (hetero)aryl ethers 37 via either SNAr reactions mediated under basic conditions (e.g., potassium t-butoxide or NaH) or Ullmann couplings with appropriately activated (hetero)aryl halides 34. It should be understood by thoseskilled in the art that synthesis of intermediates of general structure 37 may be accomplished through a number of other reaction sequences, including but not limited to routes analogous to those presented in Schemes 1-5.Scheme SHalOilman coupling or SwAr W - N or C-RzRY= H. halogen, alky t, or amino R2= H, CN, or alkyl OHil —Fl as in OH to X transformation 35X'Xvz X?- Scheme 233 Rx= R.-. or (im)substitufed (heterojaryl or (un)substituted non-arc-matic heterocyclylMitsunobu conditions37 [000161] In some cases, the mixture of stereoisomers represented by structures 37 may be used as-is in subsequent transformations. Alternatively, 37 may be separated into stereochemically enriched components 38 and 39 as depicted in Scheme 7 before being elaborated to the compounds of the present invention.Scheme 738 39 Rx= R5, or W = N or C-Rz(un)substituted (hetero)aryl, orY= H, halogen, alkyl, or amino (un)substituted non-aromatic heterocyciyl Rz= H, CN, or alkyl[000162] Preparation of sulfonimidoylation reagents may proceed as depicted in Scheme 8.Beginning from commercially available sulfonyl chlorides 40, treatment with ammonia may yield sulfonamides 41. In some cases, such as when Rio = methyl, intermediates of general structure 41 may also be commercially available. A G group may then be affixed via nucleophilic substitution with a reagent of general structure 42, in which X is a suitable leaving group, such as Br, Cl, F, I, OMs, or OTs, to yield sulfonimidoylation reagents of general structure 43. For compounds of the invention in which R9is H, G in Scheme 10 is TBS. Otherwise, G in Scheme 10 is R9as defined for Formula 1.Scheme 8O Q n H g- - NH3'' S'. NH2base % S N. GR^b b40 41 43G = TBS or Rg[000163] In cases of compounds of general structure 14 or 38 in which Rxis an R5precursor that must be further elaborated to yield examples of the present invention, this can be accomplished in any of a number of ways, including but not limited to those depicted in Schemes 9 and 10. For some intermediates 14 and 38 in which Rxis a (hetero)aryl or non- aromatic heterocyciyl group bearing a nitrogen atom with a suitable protecting group (PG) (e.g., Boc, Cbz, Teoc), further elaboration into examples of the present invention may be performed asdepicted in Scheme 9. The core may be fluorinated on the carbon adjacent to the Rxattachment point by treatment with an electrophilic fluorinating reagent, including, but not limited to, Selectfluor™ or N-fluorobenzenesulfonimide to yield 44. The PG group may then be removed using conditions suitable to the identity of PG (e.g., treatment with protic or Lewis acid when PG = Boc, treatment with hydrogen gas and solid-supported palladium or platinum when PG = Cbz, treatment with TBAF or other fluoride source when PG = Teoc) to generate free amines 45. The amines 45 may then be sulfonimidoylated. Intermediates 43 (Scheme 8) are first treated with PPh3CI2to form the corresponding sulfonimidoyl chloride in situ, then 45 is added to the reaction mixture. When G of 43 is R9, sulfonimidoylation yields intermediates 46 directly. When G of 43 is TBS, sulfonimidoylation of 45 may be followed by a TBS removal step via treatment with TBAF or HCI in methanol, yielding intermediates 46 where R9= H. The mixture of diastereomers represented by 46 may then be separated into stereoenriched examples of the present invention 47 and 48. It should be understood by those practiced in the art that examples of general structure 47 and 48 may also be synthesized employing alternate reaction conditions, reaction orders, or identities of protecting groups. For example, in some cases, fluorination of the pyridopyridinone core may take place after sulfonimidoylation or chiral separation.Alternatively, in some cases, the fluorination step may be omitted entirely to yield examples of the current invention where X4= CH. Furthermore, in some cases, intermediates 14 or 38 may possess an Rxgroup that already has a sulfonimidoyl substituent in place.Scheme 9N-Wfluorination deprotection38, 0 = 044 Rx« R5, or W = N or C-Rz(on Substituted (hetero)aryi, or Rv= H, halogen, alkyl, or amino (unisubstituted nan-aromatic heterocyclyl ON, or alky!N-W chirai sulfonimidoytation separation[000164] For some intermediates 49 or 50 in which Rxis a (hetero)aryl or non-aromatic heterocyclyl group bearing a thioether, further elaboration into examples of the presentinvention may be performed as depicted in Scheme 10. Thioethers may be oxidized to the corresponding sulfoximines via treatment with a hypervalent iodine species (e.g., (diacetoxyiodo)benzene) and a suitable ammonium source (e.g., ammonium acetate or ammonium carbamate). In cases where R9= H, this oxidation step yields intermediates of general structure 51 directly. In cases where R9= CN or (un)substituted alkyl, R9may be affixed to the nitrogen of the sulfoximine by treatment with an R9-X electrophile in the presence of a suitable base (e.g., triethylamine or potassium carbonate) to yield intermediates 51. The core may be fluorinated on the carbon adjacent to the Rxattachment point by treatment with an electrophilic fluorinating reagent, including, but not limited to, Selectfluor™ or N- fluorobenzenesulfonimide to yield 52. The mixture of diastereomers represented by 52 may then be separated into stereoenriched examples of the present invention 53 and 54. It should be understood by those practiced in the art that examples of general structure 53 and 54 may also be synthesized employing alternate reaction conditions, reaction orders, or identities of protecting groups. For example, in some cases, fluorination of the pyridopyridinone core may take place before sulfoximine formation or after chiral separation. Alternatively, in some cases, the fluorination step may be omitted entirely to yield examples of the current invention where X4= CH. Furthermore, in some cases, intermediates 49 or 50 may possess an Rxgroup that already has a sulfoximine group in place.Scheme 101) sulfoxlmine formation 2) Rg-X. base if necessary fluorination50, Q " O Rx= Rg. or W = N or C-Rz(un)substituted (hetero)aryL or Ry~ H, halogen, alkyl, or amino (unjsubstikited non-aromatic heterocyolyi RZ= H, CN. or alkyl N-W[000165] Isoquinolone intermediates 3 may be treated with reagents such as triflic anhydride or / V-phenyl-bis(trifluoromethanesulfonimide) to give isoquinolines 55. Nucleophilic aromatic substitution reactions of 55 with ammonia, hydrazine, or protected hydrazine derivatives provide adducts 56. Cyclization of intermediates 56 with alpha-halo ketones or aldehydes 12 provide tricyclic compounds 57. The bromide of tricyclic compounds 57 can be converted to ketones 58 (Scheme 3). Ketone compounds 58 may be elaborated to the compounds of the present invention using synthetic methods analogous to those described in Schemes 1 to 10.Scheme 111 NH3or N-i-NH;. triflation or NH-NHBoc 2 H+(optional)o xIN•:' 'Bror CI Rs. A >~RYStille coupling or a*. (RT)Z i,i Cl CHfOEt), Br 57 W = N or C-RzRY= H. halogen, alkyl, or aminoRz = H, CN. or alkyl[000166] An alternate approach to synthesizing tricyclic compounds 14 is provided in Scheme 12. Amino intermediates 32 can be converted into tricyclic compounds 14 via either SNAr reactions mediated under basic conditions (e.g., potassium t-butoxide or NaH) or Buchwald couplings with appropriately activated (hetero)aryl halides 34.Scheme 12Hat Rx= Rs, or 34 (un)substituted (hetero)aryl, or (un)substituted non-aromatic heterocyclyl Hal = I, Br, Cl, or F w = N or C-RzBuchwald coupling Rv= H, halogen, alkyl, or amino or SNAr Rz= H, CN, or alkyl[000167] The chemistries depicted in Schemes 1 to 12 demonstrate various modes of synthesis of the compounds described. It should be understood that other variations on these modes may be employed and that the precise protecting groups, the order of the listed reactions or the particular transition metals used in the catalyzed coupling reaction may be replaced with suitable alternatives that would be known to those skilled in the art.[000168] The following compounds of Formula (1) represent various embodiments of the present invention:Experimental[000169] 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.[000170] In some Examples, chiral chromatography was used to separate enantiomeric and diastereomeric mixtures to provide enantiomerically and diastereomerocally-enriched products. For example, in the case of Example 3 and Example 4, Prep-Chiral-HPLC was used to separate the diasteromeric mixture (Column 1: CHIRALPAK IK, 5 pm, 20 mm, 250 mm; Mobile Phase A:EtOH: DCM = 1:1, Mobile Phase B: Hex (with 0.5% NH3(2 M in MeOH)); Flow rate: 20 mL / min; Gradient (B%): isocratic 45% B; Wavelength: 220 / 254 nm) and (Column 2: CHIRALPAK IF, 5 pm, 20 mm, 250 mm; Mobile Phase A: EtOH: DCM = 1:1, Mobile Phase B: Hex (with 0.5% NH3(2 M in MeOH)); Flow rate: 20 mL / min; Gradient (B%): isocratic 50% B; Wavelength: 220 / 254 nm). It should be understood that other variations on these methods of purification may be employed and that the precise columns and mobile phases may be replaced with suitable alternatives that would be known to those skilled in the art.[000171] When a sulfur atom having an oxidation state of +6 (abbreviated as S(VI)) is bonded to four different groups and is not part of a plane of symmetry, the sulfur atom is chiral and forms (R) and (S) chiral centers.[000172] The following represents acronyms used in the experimental section for well-known chemical solvents, reagents, parameters and techniques:XH NMR: proton nuclear magnetic resonance spectroscopyACN: acetonitrileAcOH: acetic acidB2pin2: 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(BOC2)O: di-tert-butyl dicarbonatec-Bu: cyclobutylc-Pr: cyclopropylCDI: carbonyl diimidazoleCeCI3: cerium (III) chlorideCeCl3•7H2O cerium (III) chloride heptahydrate CH2Cl2: dichloromethaneCH3I: iodomethaneCHCI3: chloroformCO2: carbon dioxideCs2CO3: cesium carbonateCsF: cesium fluorideCuCI: cuprous chlorideCui: copper iodideDAST: diethylaminosulfur trifluoride DBAD: di-tert-butyl azodicarboxylateDBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethaneDIBAL: diisobutylaluminum hydrideDIEA: A / , / \ / -diisopropylethylamineDMAc: dimethylacetamideDMAP: 4-dimethylaminopyridinesDMF: / V, / V-dimethylformamideDMSO: dimethyl sulfoxideDTAD: di-tert-butyl azodicarboxylateEA: ethyl acetateee: enantiomeric excessEt2O: diethyl etherEt3N: triethylamineEt3SiH: triethylsilaneEtOAc: ethyl acetateEtOH: ethanolFA: formic acidh: hoursH2O: waterHATU: l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHBr: hydrogen bromideHCI: hydrochloric acidHex: hexanesHMPA: hexamethylphosphoramideHPLC: high-performance liquid chromatographyIPA: isopropanolK2CO3: potassium carbonateK3PO4: potassium triphosphateKOAc: potassium acetateLiOH: lithium hydroxidemCPBA: meta-chloroperoxybenzoic acidMe: methylMeCN: acetonitrileMeOH: methanolmg: milligramMgSO4: magnesium sulfate min: minutesmL: milliliterMnO2: manganese dioxide MsCI: methanesulfonyl chloride Ms2O: methanesulfonic anhydride MTBE: methyl tert-butyl ether NaBH4: sodium borohydride N2: nitrogenNaCI: sodium chlorideNa2CO3: sodium carbonate NaH: sodium hydrideNal: sodium iodideNaOH: sodium hydroxide NaHCO3: sodium bicarbonate NaH2PO4: monosodium phosphate Na2SO3: sodium sulfiteNa2SO4: sodium sulfateNFSI: N-fluorobenzenesulfonimide NH3: ammoniaNH4CI: ammonium chloride NH4HCO3: ammonium bicarbonate NH4OH: ammonium hydroxide (NH4)2CO3: ammonium carbonate NMP: A / -methylpyrrolidoneOxetane: 4-membered ring containing 3 carbon ring atoms and 1 oxygen ring atom.PBr3: phosphorous tribromidePCI5: phosphorous pentachloridePd / C: palladium on carbonPd-PEPPSI-IHeptCI 3-chloropyridine: dichloro[l,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll)Pd(amphos)CI2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll) Pd(dppf)CI2: (l,l'-bis(diphenylphosphino)ferrocene)palladium(ll) dichloridePd(PPh3)4: tetrakis(triphenylphosphine)palladium(0)Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)PdCI2(PPh3)2: bis(triphenylphosphine)palladium(ll) dichloridePE: petroleum etherPhN(Tf)2: / V-phenyl-bis(trifluoromethanesulfonimide)Ph3PCI2: triphenylphosphine dichloridePOCI3: phosphorus oxychloridePPh3: triphenylphosphinePrep: preparativePyBOP: benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphateRuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenylRuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-l, -biphenyl)]palladium(ll) methanesulfonateSelectfluor™: l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SEM-CI: 2-(trimethylsilyl)ethoxymethyl chlorideSFC: supercritical fluid chromatographySiO2: silicaSOCI2: thionyl chlorideT4P: 2,4,6-tributyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxideTBAF: tetrabutylammonium fluorideTBSCI: tert-butyldimethylsilyl chlorideTEA: triethylamineTF2O: triflic anhydrideTFA: trifluoroacetic acidTHF: tetra hydrofuranTi(OEt)4: Titanium (IV) ethoxideTi(Oi-Pr)4: Titanium(IV) isopropoxideTLC: thin-layer chromatographyTMSOTf: trimethylsilyl trifluoromethanesulfonateTsOH: p-toluenesulfonic acidXantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneXphos-Pd-G4: (SP-4-3)-[Dicyclohexyl[2',4',6'-tris(l-methylethyl)[l, -biphenyl]-2- yl]phosphine](methanesulfonato-KO)[2'-(methylamino-KN)[l, -biphenyl]-2-yl-KC]palladiumEXAMPLES[000173] Preparation of 6-methyl-2-(trifluoromethyl)pyridin-3-ol (Intermediate 1):Step 1: Preparation of 2-iodo-3-methoxy-6-methylpyridine[000174] To a solution of 2-iodo-6-methyl-pyridin-3-ol (50 g, 213 mmol) in acetone (500 mL) was added K2CO3(58.8 g, 426 mmol) and Mel (19.9 mL, 319 mmol). The resultant mixture was stirred at 45 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, hexanes: EA = 100:1 to 85:15) to afford 2-iodo-3-methoxy-6-methylpyridine (50 g, 94% yield) as a white solid.XH NMR (400 MHz, CDCI3): δ 7.03 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 2.49 (s, 3H).Step 2: Preparation of 3-methoxy-6-methyl-2-(trifluoromethyl)pyridineVykNr[000175] To a solution of 2-iodo-3-methoxy-6-methylpyridine (48 g, 193 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (85 g, 443 mmol) in NMP (500 mL) was added HMPA (3.4 mL, 19.3 mmol) and Cui (36.7 g, 193 mmol). The resultant mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with H2O (1000 mL) and EtOAc (500 mL) and filtered. The organic phase was then separated, washed with brine (100 mL x 5), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, hexanes: EA = 100:1 to 85:15) to afford 3-methoxy-6- methyl-2-(trifluoromethyl)pyridine (39 g, 97% yield) as a yellow liquid. MS: ( ES ) m / z = 192.0 (M+H).Step 3: Preparation of 6-methyl-2-(trifluoromethyl)pyridin-3-ol[000176] A solution of 3-methoxy-6-methyl-2-(trifluoromethyl)pyridine (17.5 g, 91.6 mmol) in 48 wt.% HBr in water (100 mL) was stirred at 100 °C for 168 h. The reaction mixture was adjusted to pH 6-7 by the addition of a saturated aqueous Na2CO3solution at 0 °C and was extracted with EtOAc (50 mL x 3). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with PE (30 mL) at 25 °C for 10 min and filtered to afford 6-methyl-2-(trifluoromethyl)pyridin-3-ol (12.5 g, 77% yield) as an off-white solid. MS: ( ES ) m / z = 177.9 (M+H).[000177] Preparation of 2-(difluoromethyl)-6-methylpyridin-3-ol (Intermediate 2):OH OH F OHStep 1: Preparation of 3-hydroxy-6-methylpicolinaldehydeO OHN[000178] To a solution of 2-(hydroxymethyl)-6-methylpyridin-3-ol (25 g, 180 mmol) in DCE (500 mL) was added MnO2(93.7 g, 1.08 mol). The resultant mixture was stirred at 60 °C for 1.5 h. The reaction mixture was filtered, and the filter cake was washed with DCM. The crude product was purified by chromatography (silica gel, hexanes: EA = 3:1 to 1:1) to afford 3-hydroxy-6-methylpicolinaldehyde (10.4 g, 42% yield) as a white solid.XH NMR (400 MHz, CDCI3): δ 10.60 (s, 1H), 9.97 (s, 1H), 7.26 - 7.20 (m, 2H), 2.51 (s, 3H).Step 2: Preparation of 2-(difluoromethyl)-6-methylpyridin-3-ol[000179] Two batches of this reaction were each performed on a 2 g scale. To a solution of 3- hydroxy-6-methylpicolinaldehyde (2 g, 14.6 mmol) in DCM (60 mL) was added DAST (5.88 g, 36.5 mmol) at 0 °C. The resultant mixture was stirred at 0 °C for 10 min. Both batches were then combined and diluted with water (50 mL) at 0 °C and extracted with ethyl acetate (30 mL x 3). The combined organics were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, hexanes: EA = 1:0 to 75:25) to afford 2-(difluoromethyl)-6-methylpyridin-3-ol (2 g, 43% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 10.74 - 10.07 (m, 1H), 7.27 - 7.20 (m, 2H), 6.95 (t, J = 54.2 Hz, 1H), 2.38 (s, 3H).[000180] Preparation of 6-methyl-2-(trifluoromethoxy)pyridin-3-ol (Intermediate 3):B2Pin2OH Pd(dppf)CI2NaBOj CH3NO2, O2Step 1: Preparation of 3-bromo-6-methyl-2-(trifluoromethoxy)pyridineBr[000181] A solution of 3-bromo-6-methylpyridin-2-ol (4.0 g, 21.3 mmol) and 3,3-dimethyl-l- (trifluoromethyl)-l,2-benziodoxole (10.1 g, 31.9 mmol) in nitromethane (30 mL) was stirred at 100 °C for 16 h under an oxygen atmosphere. The resultant mixture was concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, DCM: PE = 1:3) to afford 3-bromo-6-methyl-2-(trifluoromethoxy)pyridine (1.4 g, 25% yield) as colorless oil. MS: (ES+) m / z = 256.0 [M+H],Step 2: Preparation of 6-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (trifluoromethoxy)pyridine[000182] To a stirred mixture of 3-bromo-6-methyl-2-(trifluoromethoxy)pyridine (100 mg, 0.39 mmol) in dioxane (3 mL) was added bis(pinacolato)diboron (298 mg, 1.17 mmol), Pd(dppf)CI2(43 mg, 0.06 mmol) and KOAc (96 mg, 0.98 mmol). The resultant mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The resulting mixture was then cooled to room temperature. The mixture was filtered and then concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, EA: PE = 1:4) to afford 6-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (trifluoromethoxy)pyridine (75 mg, 54% yield) as a white solid. MS: (ES+) m / z = 303.9 [M+H], Step 3: Preparation of 6-methyl-2-(trifluoromethoxy)pyridin-3-olOH[000183] To a stirred mixture of 6-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (trifluoromethoxy)pyridine (75 mg, 0.25 mmol) in THF (1 mL) and water (1 mL) was added sodium perborate (101 mg, 1.26 mmol) at 0 °C. The resultant mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (3 x5 mL). The combined organics were washed with brine (2 x 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-TLC (DCM: MeOH = 15:1) to afford 6-methyl-2- (trifluoromethoxy)pyridin-3-ol (35 mg, 73% yield) as a white solid. MS: (ES+) m / z = 194.0 [M+H];XH NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 2.33 (s, 3H).[000184] Synthesis of 5-chloro-2-(((R)-l-(6-fluoro-9-methyl-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile and 5-chloro-2-(((R)-l-(6-fluoro-9-methyl-5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile (Example 3 and Example 4)Chiral separationStep 1: Preparation of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-lH-inden-l-oneoBr[000185] To a stirred solution of 4-bromo-6-methyl-2,3-dihydroinden-l-one (20 g, 89.3 mmol) in DCM (200 mL) and THF (40 mL) was added 12 M HCI (3.7 mL, 44.7 mmol) and 3- methylbutyl nitrite (20.8 g, 179 mmol) dropwise at 0 °C. The resulting mixture was stirred for 4 h at room temperature under a nitrogen atmosphere. The mixture was then allowed to cool to 0 °C. The precipitated solids were collected by filtration and washed with Et2O (3 x 50 mL). The solids were dried under reduced pressure to afford 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-lH-inden-l-one (20 g, 77% yield) as an off-white solid. MS: (ES+) m / z = 253.9 [M+H],Step 2: Preparation of 5-bromo-3-chloro-7-methylisoquinolin-l(2H)-oneOBr[000186] To a stirred solution of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-lH-inden-l- one (20 g, 79.1 mmol) in DCM (400 mL) was added SOCI2(46.8 g, 395 mmol) dropwise at 0 °C. The resultant mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by trituration with PE: EA = 1:1. The precipitated solids were collected by filtration and washed with PE: EA = 1:1 (3 x 20 mL) to afford 5-bromo-3-chloro-7- methylisoquinolin-l(2H)-one (16 g, 74% yield) as a red solid. MS: (ES+) m / z = 271.9 [M+H],Step 3: Preparation of 5-bromo-3-chloro-7-methylisoquinolin-l-yl trifluoromethanesulfonateOTfBr[000187] To a stirred mixture of 5-bromo-3-chloro-7-methylisoquinolin-l(2H)-one (10 g, 36.9 mmol) and DMAP (9.0 g, 73.8 mmol) in DCM (200 mL) was added A / -phenyl- bis(trifluoromethanesulfonimide) (19.7 g, 55.4 mmol) dropwise at 0 °C. The resultant mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organics were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, PE: EA = 50:1) to afford 5-bromo-3-chloro-7- methylisoquinolin-l-yl trifluoromethanesulfonate (10 g, 67% yield) as an off-white solid. MS: (ES+) m / z = 403.6 [M+H],Step 4: Preparation of tert-butyl 2-(5-bromo-3-chloro-7-methylisoquinolin-l-yl)hydrazine-l-carboxylateBoc[000188] To a stirred mixture of 5-bromo-3-chloro-7-methylisoquinolin-l-yl trifluoromethanesulfonate (10 g, 24.8 mmol) and (tert-butoxy)carbohydrazide (16.3 g, 124.1 mmol) in N, N-dimethylacetamide (300 mL) was added DIEA (43 mL, 248 mmol) dropwise at room temperature. The resultant mixture was stirred at 100 °C for 1 h. The reaction mixture was then allowed to cool to room temperature and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organics were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by trituration with hexanes (80 mL). The precipitated solids were collected by filtration and washed with hexanes (3 x 20 mL) to afford tert-butyl 2-(5-bromo-3-chloro-7- methylisoquinolin-l-yl)hydrazine-l-carboxylate (7.6 g, 79% yield) as an off-white solid. MS: (ES+) m / z = 386.0 [M+H],Step 5: Preparation of 5-bromo-3-chloro-l-hydrazinyl-7-methylisoquinoline[000189] To a stirred solution of tert-butyl 2-(5-bromo-3-chloro-7-methylisoquinolin-l- yl)hydrazine-l-carboxylate (7.6 g, 19.7 mmol) in DCM (90 mL) was added 4 M HCI in dioxane (30 mL, 120 mmol) dropwise at room temperature. The resultant mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to afford methyl 5-bromo-3-chloro-l-hydrazinyl-7- methylisoquinoline (8 g, crude yield) which was used in the next step without further purification. MS: (ES+) m / z = 285.9 [M+H],Step 6: Preparation of 7-bromo-5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinoline N-NBr[000190] To a mixture of 5-bromo-3-chloro-l-hydrazinyl-7-methylisoquinoline (8 g, 28.1 mmol) in DCM (200 mL) was added trimethoxymethane (14.8 g, 140 mmol) and TsOH (4.80 g, 28.1 mmol). The resultant mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with CH2CI2 (3 x 80 mL). The combined organics were washed with water (2 x 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by trituration with ethyl acetate (80 mL) to afford 7-bromo-5- chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinoline (6.7 g, 84 % yield) as a yellow solid. MS: (ES+) m / z =296.8 [M+H],Step 7: Preparation of l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-l-one[000191] Into a 250 mL round-bottom flask was added 7-bromo-5-chloro-9-methyl- [l,2,4]triazolo[3,4-a]isoquinoline (5 g, 17.0 mmol) and tributyl(l-ethoxyethenyl)stannane (6.1 g, 17.0 mmol), Pd(PPh3)4 (1.95 g, 1.69 mmol), and dioxane (50 mL) at room temperature under a nitrogen atmosphere. The resultant mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. Then, aqueous 1 M HCI (20 mL) was added dropwise at room temperature. The resultant mixture was stirred at room temperature for 30 min at room temperature and was then extracted with CH2CI2 (3 x 100 mL). The combined organics were washed with brine (1 x 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, DCM: MeOH = 20:1) to afford l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4- a]isoquinolin-7-yl)ethan-l-one (3 g, 67% yield) as an off-white solid. MS: (ES+) m / z = 260.0 [M+H],Step 8: Preparation of l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-l-olHO'[000192] To a stirred solution of l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethan-l-one (800 mg, 3.1 mmol) in DCM (10 mL) and MeOH (10 mL) was added NaBH4(349 mg, 9.24 mmol) portionwise at 0 °C under a nitrogen atmosphere. The resultant mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction mixture was diluted with ice water (20 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, DCM: MeOH = 20:1) to afford l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-l-ol (390 mg, 48% yield) as a white solid. MS (ES+) m / z = 262.0 [M+H],Step 9: Preparation of 5-chloro-2-((l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrileN-N[000193] To a stirred mixture of l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethan-l-ol (630 mg, 2.41 mmol) and DIEA (3.11 g, 24.1 mmol) in DCM (35 mL) was added methanesulfonyl methanesulfonate (2.10 g, 12.0 mmol) portionwise at 0 °C under a nitrogen atmosphere. The resultant mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. Then, 2-amino-5-chlorobenzonitrile (1.84 g, 12.0 mmol) was added portionwise at 0 °C. The resultant mixture was stirred at 50 °C for an additional 3 h. The reaction mixture was diluted with water (15 mL) and was extracted with DCM (3 x 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by chromatography (silica gel, PE: EA = 2:3) to afford 5- chloro-2-((l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile (420 mg, 44% yield) as a yellow solid. MS (ES+) m / z = 396.0 [M+H],Step 10: Preparation of tert-butyl 4-(7-(l-((4-chloro-2-cyanophenyl)amino)ethyl)-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylateCl[000194] A mixture of 5-chloro-2-((l-(5-chloro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile (550 mg, 1.39 mmol), tert-butyl piperazine-l-carboxylate (775 mg, 4.16 mmol), Pd2(dba)3(127 mg, 0.14 mmol), Xantphos (161 mg, 0.28 mmol) and Cs2CO3(1.36 g, 4.16 mmol) in dioxane (15 mL) was stirred at 90 °C for 3 h under a nitrogen atmosphere. The resultant mixture was filtered, and the filter cake was washed with CH2CI2(3 x 30 mL). The filtrate was diluted with ice water (30 mL) and extracted with CH2CI2(3 x 30 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, DCM: EA = 2:3) to afford tert-butyl 4-(7-(l-((4-chloro- 2-cyanophenyl)amino)ethyl)-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l- carboxylate (300 mg, 39% yield) as a yellow solid. MS (ES+) m / z = 546.2 [M+H],Step 11: Preparation of tert-butyl 4-(7-(l-((4-chloro-2-cyanophenyl)amino)ethyl)-6-fluoro-9-methyl- [l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylateN-NCl[000195] To a stirred solution of tert-butyl 4-(7-(l-((4-chloro-2-cyanophenyl)amino)ethyl)-9- methyl-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (1.2 g, 2.2 mmol) in MeCN (40 mL) was added a solution of Selectfluor™ (1.56 g, 4.40 mmol) in ACN (40 mL) dropwise at 0 °C under a nitrogen atmosphere. The resultant mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, PE: EA = 1:5) to afford an impure product (~500 mg). This impure product was purified further by preparative achiral SFC to afford tert-butyl 4-(7-(l-((4-chloro-2- cyanophenyl)amino)ethyl)-6-fluoro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-5- yl)piperazine-l-carboxylate (120 mg, 11% yield) as a white solid. MS (ES+) m / z = 564.2 [M+H],Step 12: Preparation of 5-chloro-2-((l-(6-fluoro-9-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrileN-N[000196] To a stirred solution of tert-butyl 4-(7-(l-((4-chloro-2-cyanophenyl)amino)ethyl)-6- fluoro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (70 mg, 0.12 mmol) in DCM (3 mL) was added 4 M HCI in dioxane (1.0 mL, 4.0 mmol). The resultant mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reactionmixture was adjusted to pH 8 via the addition of a saturated aqueous NaHCO3solution and then concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to afford 5-chloro-2-((l-(6-fluoro-9-methyl-5-(piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrile (50 mg, 86% yield) as a white solid. MS (ES+) m / z = 464.1 [M+H],Step 13: Preparation of 2-((l-(5-(4-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)piperazin-l-yl)-6-fluoro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)-5-chlorobenzonitrileN-NIICl[000197] To a stirred solution of Ph3PCI2(215 mg, 0.65 mmol) in DCM (3 mL) was added Et3N (65 mg, 0.65 mmol) dropwise at room temperature under a nitrogen atmosphere. The resultant mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. Then, a solution of N-(tert-butyldimethylsilyl)methanesulfonamide (135 mg, 0.65 mmol) in DCM (1 mL) was added dropwise at 0 °C. The resultant mixture was stirred at 0 °C for an additional 30 min. To this mixture was then added a solution of Et3N (65 mg, 0.65 mmol) and 5-chloro-2-((l-(6-fluoro-9-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile (60 mg, 0.13 mmol) in DCM (1 mL) dropwise at 0 °C. The resultant mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (10 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organics were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE: EA = 1:5) to afford 2-((l-(5-(4-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)piperazin-l-yl)-6- fluoro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)-5-chlorobenzonitrile (28 mg, 33% yield) as a yellow solid. MS (ES+) m / z = 655.2 [M+H],Step 14: Preparation of 5-chloro-2-((l-(6-fluoro-9-methyl-5-(4-(S-methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrileN-NCl[000198] A mixture of 2-((l-(5-(4-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)piperazin- l-yl)-6-fluoro-9-methyl-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)-5- chlorobenzonitrile (28 mg, 0.04 mmol) and aqueous 1 M HCI (1 mL, 1.0 mmol) in MeOH (2 mL) was stirred at room temperature for 1 h under a nitrogen atmosphere. The mixture was adjusted to pH 8 via the addition of a saturated aqueous NaHCO3solution and extracted with CH2Cl2 (3 x 5 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep- TLC (DCM: MeOH = 10:1) to afford 5-chloro-2-((l-(6-fluoro-9-methyl-5-(4-(S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile (20 mg, 86% yield) as a white solid. MS (ES+) m / z = 541.1 [M+H],Step 15: Preparation of 5-chloro-2-(((R)-l-(6-fluoro-9-methyl-5-(4-((S)-S-methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrile and 5-chloro-2-(((R)-l-(6-fluoro-9-methyl-5-(4-((R)-S-methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)amino)benzonitrile (Example 3 and Example 4)[000199] The diastereomeric mixture of 5-chloro-2-((l-(6-fluoro-9-methyl-5-(4-(S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile (20 mg) was separated by Prep-Chiral-HPLC with the followingconditions (Column 1: CHIRALPAK IK, 5 pm, 20 mm, 250 mm; Mobile Phase A: EtOH: DCM = 1:1, Mobile Phase B: Hex (with 0.5% NH3(2 M in MeOH)); Flow rate: 20 mL / min; Gradient (B%): isocratic 45% B; Wavelength: 220 / 254 nm) and (Column 2: CHIRALPAK IF, 5 pm, 20 mm, 250 mm; Mobile Phase A: EtOH: DCM = 1:1, Mobile Phase B: Hex (with 0.5% NH3(2 M in MeOH)); Flow rate: 20 mL / min; Gradient (B%): isocratic 50% B; Wavelength: 220 / 254 nm) to afford Example 3 and Example 4.[000200] Example 3: 5-chloro-2-(((R)-l-(6-fluoro-9-methyl-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile (3.0 mg, 15 % yield) as a white solid. LCMS: (ES+) m / z = 541.1 [M+H];1H NMR (400 MHz, CDCl3): δ8.91 (s, 1H), 8.58 (s, 1H), 7.71 - 7.64 (m, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.18 - 7.12 (m, 1H), 6.25 (d, J = 9.0 Hz, 1H), 5.52 - 5.41 (m, 1H), 5.10 - 5.00 (m, 1H), 4.15 - 3.95 (m, 2H), 3.69 - 3.50 (m, 2H), 3.49 - 3.28 (m, 2H), 3.20 - 3.00 (m, 2H), 2.97 (s, 3H), 2.53 (s, 3H), 1.70 (d, J = 6.5 Hz, 3H).[000201] Example 4: 5-chloro-2-(((R)-l-(6-fluoro-9-methyl-5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrile (2.9 mg, 15% yield) as a white solid. LCMS: (ES+) m / z = 541.1 [M+H];1H NMR (400 MHz, CDCl3): δ8.92 (s, 1H), 8.57 (s, 1H), 7.70 - 7.65 (m, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.19 - 7.11 (m, 1H), 6.25 (d, J = 9.0 Hz, 1H), 5.50 - 5.41 (m, 1H), 5.10 - 5.00 (m, 1H), 4.15 - 3.95 (m, 2H), 3.69 - 3.50 (m, 2H), 3.49 - 3.28 (m, 2H), 3.20 - 3.00 (m, 2H), 2.97 (s, 3H), 2.53 (s, 3H), 1.70 (d, J = 6.5 Hz, 3H).[000202] The absolute chiral configuration of the S(VI ) atom within each of Example 3 and Example 4 was not determined. Thus, Example 3 has the configuration of one of the two diastereomeric structures depicted above and Example 4 has the configuration of the other diastereomeric structure.[000203] Synthesis of 5-chloro-2-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)benzonitrile and 5-chloro-2-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)benzonitrile (Example 13 and Example 14)Step 1: Preparation of 4-bromo-6-chloro-2-(hydroxyimino)-3H-inden-l-oneoBr[000204] To a stirred mixture of 4-bromo-6-chloro-2,3-dihydroinden-l-one (1 g, 4.1 mmol) in THF (2.5 mL) and CH2CI2 (10 mL) was added 12 M HCI (0.12 mL, 1.4 mmol) and 3-methylbutyl nitrite (7.16 g, 61.1 mmol) dropwise at 0 °C. The resultant mixture was stirred for 4 h at room temperature. The reaction mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with Et2O (3 x 10 mL) and dried under vacuum to afford 4-bromo-6-chloro-2-(hydroxyimino)-3H-inden-l-one (1 g, 89% yield) as an off-white solid. MS (ES+) m / z = 274.3 [M+H],Step 2: Preparation of 5-bromo-3,7-dichloroisoquinolin-l(2H)-oneBr[000205] To a mixture of 4-bromo-6-chloro-2-(hydroxyimino)-3H-inden-l-one (1 g, 3.4 mmol) in CH2CI2 (10 mL) was added SOCI2(2.05 g, 17.2 mmol) dropwise at 0 °C. The resultant mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with PE: EA = 1:1 (3 x 10 mL) and dried under reduced pressure to afford 5-bromo-3,7-dichloroisoquinolin-l(2H)-one (0.65 g, 61% yield) as a red solid. MS (ES+) m / z = 291.8 [M+H],Step 3: Preparation of 5-bromo-3,7-dichloroisoquinolin-l-yl trifluoromethanesulfonateOTfBr[000206] To a mixture of 5-bromo-3,7-dichloroisoquinolin-l(2H)-one (20 g, 73.4mmol) and pyridine (10.8 g, 137 mmol) in DCM (100 mL) was added Tf2O (20 g, 71.0 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resultant mixture was stirredat room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with CH2CI2(3 x 100 mL). The combined organics were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by trituration with EtOH: H2O = 1:10 (110 mL). The precipitated solids were collected by filtration and washed with EtOH: H2O = 1:10 (3 x 20 mL) and dried under reduced pressure to afford 5- bromo-3,7-dichloroisoquinolin-l-yl trifluoromethanesulfonate (9 g, 62% yield) as a lightyellow solid. MS: (ES+) m / z = 423.9 [M+H],Step 4: Preparation of tert-butyl 2-(5-bromo-3,7-dichloroisoquinolin-l-yl)hydrazine-l-carboxylate B t oc.k " NJBr[000207] To a solution 5-bromo-3,7-dichloroisoquinolin-l-yl trifluoromethanesulfonate (9 g, 21 mmol) in DMAc (90 mL) was added DIEA (4.11 g, 31.8 mmol), followed by portionwise addition of Boc-hydrazine (4.2 g, 31.8 mmol) at 0 °C. The resultant mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The reaction mixture was diluted with H2O (90 mL) and stirred at room temperature for 0.5 h. The precipitated solids were collected by filtration and washed with H2O (2 x 20 mL) and dried under reduced pressure to afford tert-butyl 2-(5-bromo-3,7-dichloroisoquinolin-l-yl)hydrazine-l-carboxylate (6 g, 69% yield) as an off-white solid. MS: (ES+) m / z = 406.0 [M+H],Step 5: Preparation of 5-bromo-3,7-dichloro-l-hydrazinylisoquinolineBr[000208] To a solution of tert-butyl 2-(5-bromo-3,7-dichloroisoquinolin-l-yl)hydrazine-l- carboxylate (6 g, 14.7 mmol) in DCM (60 mL) was added 4 M HCI in dioxane (14.7 mL, 59.0 mmol) dropwise at room temperature. The resultant mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The precipitated solids were collected by filtration, washed with CH2CI2(2 x 30 mL) and dried under vacuum to afford 5-bromo-3,7-dichloro-l-hydrazinylisoquinoline (4 g, 88% yield) as a light-yellow solid. MS: (ES+) m / z = 305.9 [M+H],Step 6: Preparation of 7-bromo-5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolineN-N[000209] To a solution of 5-bromo-3,7-dichloro-l-hydrazinylisoquinoline (4 g, 13.0 mmol) in THF (60 mL) was added triethyl orthoformate (3.86 g, 26.1 mmol) followed by the dropwise addition of TFA (2.97 g, 26.1 mmol) at room temperature. The resultant mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with H2O (40 mL). The precipitated solids were collected by filtration, washed with H2O (2 x 20 mL), and dried under reduced pressure to afford 7-bromo-5,9-dichloro- [l,2,4]triazolo[3,4-a]isoquinoline (3 g, 72% yield) as an off-white solid. MS: (ES+) m / z = 315.9 [M+H],Step 7: Preparation of l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-l-oneN[000210] To a solution of 7-bromo-5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinoline (3 g, 9.5 mmol) in dioxane (90 mL) was added tributyl(l-ethoxyethenyl)stannane (3.76 g, 10.4 mmol), Pd(PPh3)4(1.09 g, 0.95 mmol), and Na2CO3(0.50 g, 4.73 mmol) at room temperature under a nitrogen atmosphere. The resultant mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction mixture was adjusted to pH 1 via the addition of aqueous 1 M HCI. The resultant mixture was extracted with CH2CI2(3 x 60 mL). The combined organics were washed with brine (2 x 60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by trituration with MTBE (20 mL) to afford l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-l- one (2 g, 75% yield) as an off-white solid. MS: (ES+) m / z = 280.0 [M+H],Step 8: Preparation of tert-butyl 4-(7-acetyl-9-chloro-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate[000211] To a stirred solution of l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-l- one (3 g, 10.7 mmol) in DMSO (30 mL) was added tert-butyl piperazine-l-carboxylate (10.0 g, 53.6 mmol), DIEA (27.7 g, 214 mmol), and 4 A molecular sieves (3 g) at room temperature under a nitrogen atmosphere. The resultant mixture was stirred at 110 °C for an additional 6 h. The reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organics were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, PE: EA = 2:3) to afford tert-butyl 4-(7-acetyl-9-chloro- [l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (3.5 g, 76% yield) as a yellow solid. MS: (ES+) m / z = 430.0 [M+H],Step 9: Preparation of tert-butyl (S)-4-(9-chloro-7-(l-hydroxyethyl)-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylateN-NNJ.. L NHO' 'BOC[000212] A stirred solution of tert-butyl 4-(7-acetyl-9-chloro-[l,2,4]triazolo[3,4-a]isoquinolin- 5-yl)piperazine-l-carboxylate (4.3 g, 10.0 mmol) in THF (120 mL) was treated with (3aR)-l- methyl-3,3-diphenyl-tetrahydropyrrolo[l,2-c][l,3,2]oxazaborole (1.39 g, 5.00 mmol) at room temperature under a nitrogen atmosphere. To the reaction mixture was added BH3*THF (20 mL, 20.0 mmol, 1 M in THF) dropwise at -40 °C. The resultant mixture was stirred at -40 °C for an additional 1 h. The reaction mixture was diluted with water (50 mL), extracted with CH2CI2 (3 x 100 mL), and filtered. The filtrate was concentrated under reduced pressure. Thecrude material was then diluted with MeOH (30 mL) at room temperature under a nitrogen atmosphere. The resultant mixture was stirred at 60 °C for 2 h and was concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, DCM: MeOH = 20:1) to afford tert-butyl (S)-4-(9-chloro-7-(l-hydroxyethyl)-[l,2,4]triazolo[3,4- a]isoquinolin-5-yl)piperazine-l-carboxylate (3 g, 70% yield) as a light yellow solid. MS: (ES+) m / z = 432.0 [M+H],Step 10: Preparation of tert-butyl (R)-4-(9-chloro-7-(l-(4-chloro-2-cyanophenoxy)ethyl)- [l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylateN-'NI N >[000213] To a stirred solution of tert-butyl (S)-4-(9-chloro-7-(l-hydroxyethyl)- [l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (2 g, 4.6 mmol), 5-chloro-2- hydroxybenzonitrile (2.13 g, 13.9 mmol) and PPh3(3.0 g, 11.6 mmol) in DCM (50 mL) was added a solution of DTAD (4.26 g, 18.5 mmol) in DCM (50 mL) dropwise at 0 °C. The resultant mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography to afford tert-butyl (R)-4-(9-chloro-7-(l-(4-chloro-2- cyanophenoxy)ethyl)-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (1.76 g, 68% yield) as a white solid. MS: (ES+) m / z = 567.2 [M+H],Step 11: Preparation of tert-butyl (R)-4-(9-chloro-7-(l-(4-chloro-2-cyanophenoxy)ethyl)-6-fluoro- [l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylateBoc[000214] To a stirred solution of tert-butyl (R)-4-(9-chloro-7-(l-(4-chloro-2- cyanophenoxy)ethyl)-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (830 mg, 1.46 mmol) in ACN (120 mL) was added a solution of Selectfluor™ (415 mg, 1.17 mmol) in ACN (120 mL) dropwise at 0 °C. The resultant mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography to afford tert-butyl (R)- 4-(9-chloro-7-(l-(4-chloro-2-cyanophenoxy)ethyl)-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin- 5-yl)piperazine-l-carboxylate (300 mg, 31% yield) as a white solid. MS: (ES+) m / z = 585.0 [M+H],Step 12:_Preparation of (R)-5-chloro-2-(l-(9-chloro-6-fluoro-5-(piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethoxy)benzonitrileN-NN T N F ICl[000215] To a stirred solution of tert-butyl (R)-4-(9-chloro-7-(l-(4-chloro-2- cyanophenoxy)ethyl)-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (360 mg, 0.62 mmol) and 2,6-dimethylpyridine (531 mg, 4.92 mmol) in DCM (5 mL) was added trimethylsilyl triflate (546 mg, 2.46 mmol) at 0 °C under a nitrogen atmosphere. Theresultant mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with CH2CI2 (3 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to afford (R)-5-chloro-2-(l-(9-chloro-6-fluoro-5-(piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethoxy)benzonitrile (220 mg, 73% yield) as a light yellow solid. MS: (ES+) m / z = 484.9 [M+H],Step 13: Preparation of 2-((lR)-l-(5-(4-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)piperazin-l-yl)-9-chloro-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethoxy)-5-chlorobenzonitrile[000216] To a solution of (R)-5-chloro-2-(l-(9-chloro-6-fluoro-5-(piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethoxy)benzonitrile (100 mg, 0.21 mmol) and Et3N (104 mg, 1.03 mmol) in ACN (10 mL) was added3-(((tert-butyldimethylsilyl)amino)-(methylene)sulfinyl)-l-methyl-lH-imidazol-3-ium trifluoromethanesulfonate (CAS# 2305948-69-8, 175 mg, 0.41 mmol) portionwise at 25 °C. The resultant mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE: EA = 1:1) to afford 2-((lR)-l-(5-(4-(N-(tert-butyldimethylsilyl)-S- methylsulfonimidoyl)piperazin-l-yl)-9-chloro-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)-5-chlorobenzonitrile (100 mg, 72% yield) as a white solid. MS: (ES+) m / z = 675.9 [M+H],Step 14: Preparation of 5-chloro-2-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S-methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethoxy)benzonitrile and 5-chloro-2-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S-methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethoxy)benzonitrile (Example 13 and Example 14)Example 13 and Example 14[000217] To a stirred solution of 2-((lR)-l-(5-(4-(N-(tert-butyldimethylsilyl)-S- methylsulfonimidoyl)piperazin-l-yl)-9-chloro-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)-5-chlorobenzonitrile (130 mg, 0.19 mmol) in MeOH (6 mL) was added aqueous 1 M HCI (3 mL, 3.0 mmol) dropwise at room temperature under a nitrogen atmosphere. The resultant mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. The reaction mixture was adjusted to pH 8 via the addition of a saturated aqueous NaHCO3solution and extracted with CH2CI2 (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, DCM: MeOH = 10:1) and was further purified twice by Prep-Chiral-HPLC (Columnl: CHIRAL ART Cellulose-SB, 5 pm, 20 mm, 250 mm; Mobile Phase A: MeOH: DCM=1: 1, Mobile Phase B: Hex (with 0.5% NH3(2 M in MeOH)); Flow rate: 20 mL / min; Gradient (B%)70% B;Wavelength: 220 / 254 nm; and Column 2: CHIRALPAK IF, 5 pm, 20 mm, 250 mm; Mobile Phase A: EtOH: DCM = 1:1, Mobile Phase B: Hex (with 0.5% NH3(2 M in MeOH)); Flow rate: 20 mL / min; Gradient (B%)50% B; Wavelength: 220 / 254 nm) to afford Example 13 and Example 14.[000218] Example 13: 5-chloro-2-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethoxy)benzonitrile (19.6 mg, 18% yield) as a white solid. MS: (ES+) m / z = 562.1 [M+H];1H NMR (400 MHz, DMSO-d6:) δ9.38 (s, 1H), 8.55 (s, 1H), 7.99 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.60 - 7.57 (m, 1H), 7.12 (d, J = 9.1 Hz, 1H), 6.33 - 6.30 (m, 1H), 3.72 (s, 1H), 3.71 - 3.31 (m, 8H), 2.84 (s, 3H), 1.75 (d, J = 6.4 Hz, 3H).[000219] Example 14: 5-chloro-2-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethoxy)benzonitrile (13.6 mg, 12% yield) as a white solid. MS: (ES+) m / z = 562.1 [M+H];1H NMR (400 MHz, DMSO-d6): δ9.39 (s, 1H), 8.56 (s, 1H), 7.99 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.60 - 7.57 (m, 1H), 7.12 (d, J = 9.1 Hz, 1H), 6.34 - 6.30 (m, 1H), 3.73 (s, 1H), 3.60 - 3.40 (m, 8H), 2.84 (s, 3H), 1.75 (d, J = 6.4 Hz, 3H).[000220] The absolute chiral configuration of the S(VI ) atom within each of Example 13 and Example 14 was not determined. Thus, Example 13 has the configuration of one of the two diastereomeric structures depicted above and Example 14 has the configuration of the other diastereomeric structure.[000221] Synthesis of N-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S-methylsulfonimidoyl)piperazin- l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3- amine and N-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S-methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine (Example 43 and Example 44)Step 1: Preparation of (R)-N-(l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethylidene)-2- methylpropane-2-sulfinamideN-N[000222] To a stirred mixture of l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethan-l- one (12 g, 43 mmol, prepared as described in Example 13 and Example 14, Step 7) in toluene (120 mL) was added (R)-2-methylpropane-2-sulfinamide (26.0 g, 214 mmol) and Ti(OEt)4(48.9 g, 214 mmol). The resultant mixture was stirred at 80 °C for 10 h. The reaction mixture was then diluted with water (100 mL) at room temperature. The precipitated solids were collected by filtration and washed with CH2CI2 (5 x 50 mL). The resulting mixture was extracted with CH2CI2 (3 x 100 mL). The combined organics were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, PE: EA = 1:2) to afford (R)-N-(l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethylidene)-2- methylpropane-2-sulfinamide (11 g, 67 % yield) as a yellow solid. MS: (ES+) m / z = 382.8 [M+H],Step 2: Preparation of (R)-N-((R)-l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2- methylpropane-2-sulfinamideN-NHN[000223] To a stirred solution of (R)-N-(l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethylidene)-2-methylpropane-2-sulfinamide (11 g, 29 mmol) and cerium(lll) chloride heptahydrate (21.4 g, 57.4 mmol) in DCM (60 mL) and MeOH (60 mL) was added NaBH4(2.2 g, 57 mmol) portion wise at -40 °C under a nitrogen atmosphere. The resultant mixture was stirred at -40 °C for 1 h under a nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and was extracted with CH2CI2 (2 x 100 mL). The combined organics were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-Achiral-SFC to afford (R)-N-((R)-l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2- methylpropane-2-sulfinamide (9 g, 82 % yield) as a white solid. MS: (ES+) m / z = 384.8 [M+H], Step 3: Preparation of tert-butyl 4-(7-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-9-chloro- [l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylateHN[000224] A solution of (R)-N-((R)-l-(5,9-dichloro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2- methylpropane-2-sulfinamide (9 g, 23 mmol) in dioxane (100 mL) was treated with tert-butylpiperazine-l-carboxylate (3.9 g, 21 mmol), Pd2(dba)3(3.2 g, 3.5 mmol), RuPhos (2.2 g, 4.7 mmol) and Cs2CO3(2.3 g, 70 mmol) at room temperature. The resultant mixture was stirred at 80 °C for 10 h under a nitrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, PE: EA = 1:3) to afford tert-butyl 4-(7-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-9-chloro-[l,2,4]triazolo[3,4- a]isoquinolin-5-yl)piperazine-l-carboxylate (5 g, 40 % yield) as a yellow solid. MS: (ES+) m / z = 535.3 [M+H],Step 4: Preparation of tert-butyl (R)-4-(7-(l-aminoethyl)-9-chloro-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylateN-N[000225] A solution of tert-butyl 4-(7-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-9-chloro- [l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (5 g, 9.3 mmol) and iodine (9.5 g, 37 mmol) in THF (45 mL) and H2O (5 mL) was stirred overnight at 50 °C. The reaction mixture was diluted with a saturated aqueous sodium thiosulfate solution (100 mL) at room temperature. The resulting mixture was adjusted to pH 8 with a saturated aqueous NaHCO3solution and was extracted with CH2CI2(3 x 100 mL). The combined organics were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, PE: EA = 1:1) to afford tert-butyl (R)-4-(7-(l-aminoethyl)-9-chloro-[l,2,4]triazolo[3,4- a]isoquinolin-5-yl)piperazine-l-carboxylate (2.8 g, 70% yield). MS: (ES+) m / z = 431.1 [M+H],Step 5: Preparation of tert-butyl (R)-4-(9-chloro-7-(l-((2-(difluoromethoxy)-6-methylpyridin-3-yl)amino)ethyl)-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate[000226] To a stirred solution of tert-butyl (R)-4-(7-(l-aminoethyl)-9-chloro- [l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (1.0 g, 2.3 mmol) and 3- bromo-2-(difluoromethoxy)-6-methylpyridine (1.7 g, 7.0 mmol) in 1,4-dioxane (10 mL) was added RuPhos (0.22 g, 0.46 mmol), Pd2(dba)3(0.21 g, 0.23 mmol) and Cs2CO3(2.3 g, 7.0 mmol) at room temperature. The resultant mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was filtered, and the filter cake was washed with DCM (2 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, PE: EA = 1:2) to afford tert-butyl (R)-4-(9-chloro-7- (l-((2-(difluoromethoxy)-6-methylpyridin-3-yl)amino)ethyl)-[l,2,4]triazolo[3,4-a]isoquinolin- 5-yl)piperazine-l-carboxylate (340 mg, 25% yield) as a yellow solid. MS: (ES+) m / z = 588.2 [M+H],Step 6: Preparation of tert-butyl (R)-4-(9-chloro-7-(l-((2-(difluoromethoxy)-6-methylpyridin-3-yl)amino)ethyl)-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylateN-N[000227] To a stirred solution of tert-butyl (R)-4-(9-chloro-7-(l-((2-(difluoromethoxy)-6- methylpyridin-3-yl)amino)ethyl)-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l- carboxylate (390 mg, 0.66 mmol) in MeCN (4 mL) was added N-fluorodibenzenesulfonimide (NFSI) (209 mg, 0.66 mmol) at room temperature. The resultant mixture was stirred overnight at 50 °C. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford tert-butyl (R)-4-(9-chloro-7-(l-((2-(difluoromethoxy)-6-methylpyridin-3- yl)amino)ethyl)-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l-carboxylate (120 mg, 30% yield) as an off-white solid. MS: (ES+) m / z = 606.2 [M+H],Step 7: Preparation of (R)-N-(l-(9-chloro-6-fluoro-5-(piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine[000228] To a stirred solution of tert-butyl (R)-4-(9-chloro-7-(l-((2-(difluoromethoxy)-6- methylpyridin-3-yl)amino)ethyl)-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-5-yl)piperazine-l- carboxylate (120 mg, 0.24 mmol) and 2,6-lutidine (127 mg, 1.19 mmol) in DCM (1 mL) was added TMSOTf (220 mg, 0.99 mmol) at room temperature. The resultant mixture was stirred 0.5 h at room temperature. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford (R)-N-(l-(9- chloro-6-fluoro-5-(piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2- (difluoromethoxy)-6-methylpyridin-3-amine (90 mg, 90% yield) as a white solid. MS: (ES+) m / z = 506.1 [M+H],Step 8: Preparation of N-((lR)-l-(5-(4-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)piperazin-l-yl)-9-chloro-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine[000229] To a stirred solution of (R)-N-(l-(9-chloro-6-fluoro-5-(piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine (95 mg, 0.19 mmol) and Et3N (95 mg, 0.94 mmol) in MeCN (2 mL) was added 3-(N-(tert- butyldimethylsilyl)-S-methylsulfonimidoyl)-l-methyl-lH-imidazol-3-ium trifluoromethanesulfonate (159 mg, 0.38 mmol) at room temperature. The resultant mixture was stirred 1 h at room temperature. The reaction mixture was diluted with water (15 mL)and was extracted with CH2CI2 (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, PE: EA = 2:1) to afford N-((lR)-l-(5-(4-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)piperazin-l-yl)-9- chloro-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6- methylpyridin-3-amine (96 mg, 74 % yield) as a white solid. MS: (ES+) m / z = 697.2 [M+H], Step 9: Preparation of N-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S-methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine and N-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S-methylsulfonimidoyl)piperazin-l-yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine (Example 43 and Example 44)Example 43 and Example 44[000230] To a stirred solution of N-((lR)-l-(5-(4-(N-(tert-butyldimethylsilyl)-S- methylsulfonimidoyl)piperazin-l-yl)-9-chloro-6-fluoro-[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine (96 mg, 0.14 mmol) in MeOH (1 mL) was added 2 M HCI in MeOH (0.14 mL, 0.28 mmol). The resultant mixture was stirred 0.5 h at room temperature. The reaction mixture was adjusted to pH 7 by the addition of a saturated aqueous NaHCO3solution. The crude product was purified by reverse phase flash chromatography to afford a white solid (75 mg). The residue was further purified by Prep- Chiral-HPLC (Column: CHIRALPAK IF-3; Mobile Phase A: Hex (0.1% DEA): (MeOH: DCM=1: 1) = 30: 70; Flow rate: 1 mL / min; Gradient (B%)) to afford Example 43 and Example 44.[000231] Example 43: N-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S-methylsulfonimidoyl)piperazin-l- yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine (34.3 mg, 43% yield) as an off-white solid. MS: (ES+) m / z = 583.1 [M+H];1H NMR (400 MHz, DMSO-dg): 69.37 (s, 1H), 8.49 - 8.37 (m, 1H), 7.98 - 7.45 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.04 (d, J = 7.1 Hz, 1H), 5.37 - 5.22 (m, 1H), 3.72 (d, J = 1.8 Hz, 1H), 3.61 - 3.36 (m, 8H), 2.85 (d, J = 1.6 Hz, 3H), 2.22 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H).[000232] Example 44: N-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S-methylsulfonimidoyl)piperazin-l- yl)-[l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-2-(difluoromethoxy)-6-methylpyridin-3-amine (32.7 mg, 41% yield) as an off-white solid. MS: (ES+) m / z = 583.1 [M+H];1H NMR (400 MHz, DMSO-dg): 69.37 (s, 1H), 8.50 - 8.38 (m, 1H), 7.97 - 7.47 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.04 (d, J = 7.1 Hz, 1H), 5.45 -5.11 (m, 1H), 3.72 (d, J = 1.8 Hz, 1H), 3.56 - 3.33 (m, 8H), 2.85 (d, J = 1.6 Hz, 3H), 2.22 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H).[000233] The absolute chiral configuration of the S(VI ) atom within each of Example 43 and Example 44 was not determined. Thus, Example 43 has the configuration of one of the two diastereomeric structures depicted above and Example 44 has the configuration of the other diastereomeric structure.[000234] Examples 1-24 in Table 1 can be prepared in a manner similar to that described in Schemes 1 to 12, the experimental methods described for Examples 3, 4, 13,14, 43, and 44 and / or the references described in the accompanying text. The absolute configuration of chiral S(VI) atoms of the compounds listed in Table 1 was not determined. Thus, the depicted configuration at a chiral S(VI) atom of a particular compound is arbitrarily assigned an R- or S- configuration.Table 1. Examples 1-24Structure Example IUPACNameN-N5-chloro-2-((R)-l-(6-fluoro-9-methyl-5- p ||N(4-((S)-S- 1 methylsulfonimidoyl)piperazin-l-yl)-OA F p[l,2,4]triazolo[3,4-a]isoquinolin-7- '"'NHyl)ethoxy)benzonitrileClN-N5-chloro-2-((R)-l-(6-fluoro-9-methyl-5- P ll ™ (4-((R)-S- 2 methylsulfonimidoyl)piperazin-l-yl)- nAFk^N", zp[l,2,4]triazolo[3,4-a]isoquinolin-7- / S'NHyl)ethoxy)benzonitrileClN-N'> 5-chloro-2-(((R)-l-(6-fluoro-9-methyl- ll j "5-(4-((S)-S- V5^ I ^NX^S1JU F L N NHMHN^*F^N / " s\ 3 methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7- '° yl)ethyl)amino)benzonitrile C!T1 T1 TI -nV \^— n-n~Z\= / N-N5-chloro-2-(((R)-l-(6-fluoro-9-methyl- IIN5-(4-((R)-S- d ( 0 ”n*n— — / s\Zz 4 methylsulfonimidoyl)piperazin-l-yl)- I F > ’ Y ¥ z Z—— / / ZZ \ \<<- I « NH[l,2,4]triazolo[3,4-a]isoquinolin-7-N<$< I °0 0 yl)ethyl)amino)benzonitrile > >.'Mx^o2Cl '° zX X6-fluoro-9-methyl-7-((R)-l-((6-methyl- 2-(trifluoromethyl)pyridin-3- 5 yl)oxy)ethyl)-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinoline6-fluoro-9-methyl-7-((R)-l-((6-methyl- 2-(trifluoromethyl)pyridin-3- 6 yl)oxy)ethyl)-5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolinehl-NN-((R)-l-(6-fluoro-9-methyl-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)- HAF7 [l,2,4]triazolo[3,4-a]isoquinolin-7- AF3C A ''' yl)ethyl)-6-methyl-2- N- J (trifluoromethyl)pyridin-3-amineN-NN-((R)-l-(6-fluoro-9-methyl-5-(4-((R)- IAIN'>S-methylsulfonimidoyl)piperazin-l-yl)- 8 [l,2,4]triazolo[3,4-a]isoquinolin-7- HA F <, N,pyl)ethyl)-6-methyl-2- wJx4'NH(trifluoromethyl)pyridin-3-amine N<3IN-N 7-((R)-l-(4-chloro-2- -x y^yAN '>(methylsulfonyl)phenoxy)ethyl)-6- 9 fluoro-9-methyl-5-(4-((S)-S- F k_NK,pO O0S^. methylsulfonimidoyl)piperazin-l-yl)- <'' I ' NHzS> A [l,2,4]triazolo[3,4-a]isoquinolineCl7-((R)-l-(4-chloro-2- (methylsulfonyl)phenoxy)ethyl)-6- fluoro-9-methyl-5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinoline4-chloro-N-((R)-l-(6-fluoro-9-methyl- 5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)-2-(methylsulfonyl)aniline4-chloro-N-((R)-l-(6-fluoro-9-methyl- 5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)-2-(methylsulfonyl)anilineN-N5-chloro-2-((R)-l-(9-chloro-6-fluoro-5- (4-((S)-S- 13 methylsulfonimidoyl)piperazin-l-yl)- F OO [l,2,4]triazolo[3,4-a]isoquinolin-7- ^X^k < NHyl)ethoxy)benzonitrile ClN-N5-chloro-2-((R)-l-(9-chloro-6-fluoro-5- Qx >\ J-L(4-((R)-s- Y'XtXX 14 methylsulfonimidoyl)piperazin-l-yl)- „Js. F L A X ( / ' o zN s. i.fi <4> ' S / j. [l,2,4]triazolo[3,4-a]isoquinolin-7- > z — / NHyl)ethoxy)benzonitrile s <Cl^^u,. z '\T / \l^~3 \ Z G \<=^——> / d. V vox5-chloro-2-(((R)-l-(9-chloro-6-fluoro-5- z • (4-((S)-S- 15 methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethyl)amino)benzonitrileN”N5-chloro-2-(((R)-l-(9-chloro-6-fluoro-5-CIYYN(4-((R)-s- 16 methylsulfonimidoyl)piperazin-l-yl)- 1 F I M P[l,2,4]triazolo[3,4-a]isoquinolin-7- / 'NHyl)ethyl)amino)benzonitrile Cl9-chloro-6-fluoro-7-((R)-l-((6-methyl- 2-(trifluoromethyl)pyridin-3- 17 yl)oxy)ethyl)-5-(4-((R)-S- X X.?. o OZ.zmethylsulfonimidoyl)piperazin-l-yl)-.ww 's4' ' [l,2,4]triazolo[3,4-a]isoquinoline d 'y*11-— Z= / =^^2 Y Y^ 0 o—-=Z -= / —9-chloro-6-fluoro-7-((R)-l-((6-methyl- / / Q oZ zA( ^ U. T~“ 2-(trifluoromethyl)pyridin-3- u. U. u. IX.18 yl)oxy)ethyl)-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolineo / _ _N-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)- m*^\v -g?\4z — 19 [l,2,4]triazolo[3,4-a]isoquinolin-7- / z: x^yl)ethyl)-6-methyl-2- p (trifluoromethyl)pyridin-3-amine " O' zTN-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)- 20 [l,2,4]triazolo[3,4-a]isoquinolin-7- X_ z yl)ethyl)-6-methyl-2- Oxt >.z<> "4f ' (trifluoromethyl)pyridin-3-amineQ / ,\ Jz~yu__x / \ z=N-N9-chloro-7-((R)-l-(4-chloro-2- v / y *7cQ / *-iYyV (methylsulfonyl)phenoxy)ethyl)-6- 21 fluoro-5-(4-((S)-S- F k. NKzp0 0 Ss methylsulfonimidoyl)piperazin-l-yl)- 1 < 'NH[l,2,4]triazolo[3,4-a]isoquinolineClN-N9-chloro-7-((R)-l-(4-chloro-2- (methylsulfonyl)phenoxy)ethyl)-6- 22 fluoro-5-(4-((R)-S- o o s; methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolineClN-N4-chloro-N-((R)-l-(9-chloro-6-fluoro-5- ji ^J N (4-((S)-S- 23 methylsulfonimidoyl)piperazin-l-yl)- O HAF[l,2,4]triazolo[3,4-a]isoquinolin-7- "c" 1 NHyl)ethyl)-2-(methylsulfonyl)anilineSX| 11ClN-N4-chloro-N-((R)-l-(9-chloro-6-fluoro-5- (4-((R)-S-c'YYi!'N>24 methylsulfonimidoyl)piperazin-l-yl)- O H uNuA P S,9 > [l,2,4]triazolo[3,4-a]isoquinolin-7-4'NHyl)ethyl)-2-(methylsulfonyl)anilineCl[000235] Examples 25-48 in Table 2 can be prepared in a manner similar to that described in Schemes 1 to 12, the experimental methods described for Examples 3, 4, 13, 14, 43, and 44 and / or the references described in the accompanying text. The absolute configuration of chiral S(VI) atoms of the compounds listed in Table 2 was not determined. Thus, thedepicted configuration at a chiral S(VI) atom of a particular compound is arbitrarily assigned an R- or S- configuration.Table 2. Examples 25-42Structure Example IUPACNameN-Nw?9-chloro-6-fluoro-7-((R)-l-((6-methyl-2- (trifluoromethoxy)pyridin-3-yl)oxy)ethyl)-5- 25F. 4. 1 ' 'NH (4-((R)-S-methylsulfonimidoyl)piperazin-l- F^T n | yl)-[l,2,4]triazolo[3,4-a]isoquinoline FC24H24ClF4N7O3SN-N9-chloro-6-fluoro-7-((R)-l-((6-methyl-2- JL F I N o(trifluoromethoxy)pyridin-3-yl)oxy)ethyl)-5- 26(4-((S)-S-methylsulfonimidoyl)piperazin-l-F'Y°Y / K 'NHyl)-[l,2,4]triazolo[3,4-a]isoquinolineFF N^JC24H24ClF4N7O3SN-NC'YY^N>2-((R)-l-(9-chloro-5-(l-((S)-S- 1. I N. Omethylsulfonimidoyl)piperidin-4-yl)- 27N^X] 'nh[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)-5-fluorobenzonitrileFC25H24ClFN6O2SN-NCIYV?2-((R)-l-(9-chloro-5-(l-((R)-S- 0 methylsulfonimidoyl)piperidin-4-yl)- 28*NH[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)-5-fluorobenzonitrile FC25H24ClFN6O2SIl ^*19-chloro-7-((R)-l-((2-(difluoromethyl)-6- _ _ F L N ®F ^N--^nhmethylpyridin-3-yl)oxy)ethyl)-6-fluoro-5-(4- 29((R)-S-methylsulfonimidoyl)piperazin-l-yl)- YS4[l,2,4]triazolo[3,4-a]isoquinolineC24H25ClF3N7O2SN-N9-chloro-7-((R)-l-((2-(difluoromethyl)-6- ^ L N ®^NK^NHmethylpyridin-3-yl)oxy)ethyl)-6-fluoro-5-(4- 30((S)-S-methylsulfonimidoyl)piperazin-l-yl)- II J [l,2,4]triazolo[3,4-a]isoquinolineC24H25ClF3N7O2SN~NavvV2-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S-OA F A-NKO methylsulfonimidoyl)piperazin-l-yl)- 31[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)-5-fluorobenzonitrile FC24H22ClF2N7O2SN-NC'IV?2-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S-OA * kA >? methylsulfonimidoyl)piperazin-l-yl)- 32[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)-5-fluorobenzonitrile ^NHFC24H22ClF2N7O2SN-NAx>fSlJ^N'A 3-(difluoromethyl)-4-((R)-l-(6-fluoro-9- A F I N 0F O ^A-NHmethyl-5-(4-((R)-S- 33 methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)benzonitrileNC26H26F3N7O2SN-N3-(difluoromethyl)-4-((R)-l-(6-fluoro-9- F pF^M=NH methyl-5-(4-((S)-S- 34 methylsulfonimidoyl)piperazin-l-yl)- [l,2,4]triazolo[3,4-a]isoquinolin-7- '' ll ‘yl)ethoxy)benzonitrileNC26H26F3N7O2SN-NY7-((R)-l-(2-(difluoromethyl)-4- « F I M 0F fluorophenoxy)ethyl)-6-fluoro-9-methyl-5- | 'S=NH 35As i (4-((R)-S-methylsulfonimidoyl)piperazin-l- yl)-[l,2,4]triazolo[3,4-a]isoquinoline FC25H26F4N6O2SN-NN7-((R)-l-(2-(difluoromethyl)-4- F oAFkJsj? fluorophenoxy)ethyl)-6-fluoro-9-methyl-5- 7 S=NH 36(4-((S)-S-methylsulfonimidoyl)piperazin-l- F" Yyl)-[l,2,4]triazolo[3,4-a]isoquinolineFC25H26F4N6O2SN-N7-((R)-l-((2-(difluoromethyl)-6- methylpyridin-3-yl)oxy)ethyl)-6-fluoro-9- k, N,£MH37 methyl-5-(4-((R)-S-FXS NT^S methylsulfonimidoyl)piperazin-l-yl)- xjJ1[l,2,4]triazolo[3,4-a]isoquinolineC25H28F3N7O2SN-Nx ^x Jt >Ti iN7-((R)-l-((2-(difluoromethyl)-6- JL F I N P methylpyridin-3-yl)oxy)ethyl)-6-fluoro-9- J N'=NH 38 methyl-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)- P'V I[l,2,4]triazolo[3,4-a]isoquinolineC25H28F3N7O2SN-N1 HNY Y '' N^5-fluoro-2-((R)-l-(6-fluoro-9-methyl-5-(4- 1 F I N P((S)-S-methylsulfonimidoyl)piperazin-l-yl)- Nx1 S=NH 39[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)benzonitrile1QFC25H25F2N7O2SN-NTni t I o 5-fluoro-2-((R)-l-(6-fluoro-9-methyl-5-(4-OAF» ((R)-S-methylsulfonimidoyl)piperazin-l-yl)- 40NK^X|NH[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)benzonitrileFC25H25F2N7O2SN-Ni ir ^N5-chloro-2-((R)-l-(9-methyl-5-(4-((S)-S-OA methylsulfonimidoyl)piperazin-l-yl)-?“NH41[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)benzonitrileClC25H26ClN7O2SN~N1 11N1 L M o 5-chloro-2-((R)-l-(9-methyl-5-(4-((R)-S- methylsulfonimidoyl)piperazin-l-yl)- i S=NH 42[l,2,4]triazolo[3,4-a]isoquinolin-7- rS4yl)ethoxy)benzonitrileClC25H26ClN7O2SN~NN-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S- methylsulfonimidoyl)piperazin-l-yl)- 43 [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)- FyO-JX *’NH2-(difluoromethoxy)-6-methylpyridin-3- F amineC24H26ClF3N8O2SN-NC'TY?N-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S-HHNNA»Fmethylsulfonimidoyl)piperazin-l-yl)- ’c 44 [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-FY°yV4'NH2-(difluoromethoxy)-6-methylpyridin-3- F amineC24H26ClF3N8O2SN-NC'IV "6-chloro-3-((R)-l-(9-chloro-6-fluoro-5-(4- JL F L M o((S)-S-methylsulfonimidoyl)piperazin-l-yl)- 45'S'NH[l,2,4]triazolo[3,4-a]isoquinolin-7- yl)ethoxy)picolinonitrileClC23H21Cl2FN8O2SN~NN6-chloro-3-((R)-l-(9-chloro-6-fluoro-5-(4-nUX,FkxN / „ 'C.? ((R)-S-methylsulfonimidoyl)piperazin-l-yl)-Nx / '' H 46'$k JL N [l,2,4]triazolo[3,4-a]isoquinolin-7- NL^J yl)ethoxy)picolinonitrileClC23H21Cl2FN8O2SN-Nc,YyVN-((R)-l-(9-chloro-6-fluoro-5-(4-((R)-S- JU F I N O methylsulfonimidoyl)piperazin-l-yl)- HN^*bV 47 [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)- V F¥ vk ' ''NH6-methyl-2-(trifluoromethoxy)pyridin-3- H |F N^xJJ amineC24H25ClF4N8O2SN-NYXJlJ^Y^N, XX] N-((R)-l-(9-chloro-6-fluoro-5-(4-((S)-S- JC F k p methylsulfonimidoyl)piperazin-l-yl)- 48 [l,2,4]triazolo[3,4-a]isoquinolin-7-yl)ethyl)-FF¥ F °YS< NH6-methyl-2-(trifluoromethoxy)pyridin-3- amineC24H25ClF4N8O2STable 3. NMR and LCMS data for Examples 1-2, 5-6, 17-18, and 25-42, and 45-48Example LCMS (m / z)1H NMR data (MHz, solvent, ppm)1H NMR (400 MHz, DMSO-d6): δ9.31 (s, 1H), 8.39 (s, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.59 - 7.49 (m, 1H), 1 ES+ 542.1 [M+H]7.05 (d, J = 9.1 Hz, 1H), 6.35 - 6.24 (m, 1H), 3.71 (d, J = 1.2 Hz, 1H), 3.42 - 3.36 (m, 11H), 2.84 (s, 3H), 1.78 (d, J = 5.6 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.31 (s, 1H), 8.40 (s, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.59 - 7.50 (m, 1H), 2 ES+ 542.1 [M+H]7.05 (d, J = 9.2 Hz, 1H), 6.35 - 6.26 (m, 1H), 3.71 (d, J = 1.7 Hz, 1H), 3.49 - 3.30 (m, 11H), 2.84 (s, 3H), 1.78 (d, J = 5.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.32 (s, 1H), 8.40 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.46 - 7.35 (m, 2H), 6.31 - 6.25 (m, 1H), 5 ES+ 566.2 [M+H]3.74 - 3.70 (m, 1H), 3.46 - 3.36 (m, 8H), 2.85 (d, J = 1.6 Hz, 3H), 2.47 (s, 3H), 2.41 (s, 3H), 1.71 (d, J = 6.1 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.32 (s, 1H), 8.39 (s, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.44 - 7.35 (m, 2H), 6.31 - 6.26 (m, 1H), 6 ES+ 566.2 [M+H]3.74 - 3.70 (m, 1H), 3.46 - 3.36 (m, 8H), 2.85 (d, J = 1.6 Hz, 3H), 2.47 (s, 3H), 2.41 (s, 3H), 1.72 (d, J = 6.1 Hz, 3H).1H NMR (400 MHz, CD3OD): δ9.34 (s, 1H), 8.62 - 8.57 (m, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.39 - 7.33 (m, 2H), 6.43 - 6.34 17 ES+586.2 [M+H](m, 1H), 3.95 - 3.85 (m, 2H), 3.65 - 3.20 (m, 6H), 2.98 (s, 3H), 2.49 (s, 3H), 1.80 (d, J = 6.3 Hz, 3H).1H NMR (400 MHz, CD3OD): δ9.34 (s, 1H), 8.61 - 8.54 (m, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.40 - 7.33 (m, 2H), 6.43 - 6.34 18 ES+586.15[M+H](m, 1H), 3.86 - 3.85 (m, 2H), 3.65 - 3.20 (m, 6H), 2.98 (s, 3H), 2.48 (s, 3H), 1.80 (d, J = 6.3 Hz, 3H).XH NMR (400 MHz, DMSO-ds): 69.38 (s, 1H), 8.54 - 8.53 (m,1H), 7.83 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.13 (d, J ES+ 602.2 [M+H]= 8.3 Hz, 1H), 6.27 - 6.23 (m, 1H), 3.74 (s, 1H), 3.45 - 3.40 (m, 8H), 2.85 (s, 3H), 2.35 (s, 3H), 1.73 (d, J = 6.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.38 (s, 1H), 8.54 - 8.53 (m, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.13 (d, J ES+ 602.1 [M+H]= 8.3 Hz, 1H), 6.26 - 6.22 (m, 1H), 3.73 (s, 1H), 3.46 - 3.41 (m, 8H), 2.85 (s, 3H), 2.35 (s, 3H), 1.73 (d, J = 6.2 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.92 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.34 - 7.27 (m, 1H), ES+ 527.0 [M+H] 7.17 - 7.09 (m, 1H), 6.84 - 6.77 (m, 1H), 5.80 - 5.70 (m, 1H),4.36 - 4.20 (m, 2H), 3.08 - 2.89 (m, 6H), 2.37 - 2.28 (m, 2H), 2.14 - 2.03 (m, 2H), 1.95 (d, J = 6.6 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.96 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.56 (s, 1H), 7.34 - 7.27 (m, 1H), ES+ 527.0 [M+H] 7.17 - 7.09 (m, 1H), 6.86 - 6.79 (m, 1H), 5.82 - 5.74 (m, 1H),4.36 - 4.20 (m, 2H), 3.16 - 2.94 (m, 6H), 2.37 - 2.28 (m, 2H), 2.14 - 2.03 (m, 2H), 1.95 (d, J = 6.6 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.90 (s, 1H), 8.85 - 8.65 (m, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.96 (d, J = 8.5 Hz, ES+568.1 [M+H] 2H), 6.19 - 5.81 (m, 1H), 4.03 - 3.90 (m, 2H), 3.51- 3.33 (m,4H), 3.16 - 2.94 (m, 2H), 2.96 (s, 3H), 2.53 (s, 3H), 1.79 (d, J = 6.4 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.90 (s, 1H), 8.85 - 8.65 (m, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.96 (d, J = 8.7 Hz, ES+568.1[M+H] 2H), 6.19 - 5.81 (m, 1H), 4.02 - 3.91 (m, 2H), 3.65 -3.28 (m,4H), 3.16 - 2.94 (m, 2H), 2.96 (s, 3H), 2.53 (s, 3H), 1.79 (d, J = 6.4 Hz, 3H).XH NMR (400 MHz, CDCI3): 68.88 (s, 1H), 8.74 - 8.73 (m, 1H),7.99 (d, J = 2.2 Hz, 1H), 7.34 - 7.32 (m, 1H), 7.12 - 7.09 (m, ES+ 546.1 [M+H] 1H), 6.71 - 6.68 (m, 1H), 6.17 - 6.12 (m, 1H), 4.02 (s, 2H),3.60 - 3.32 (m, 4H), 3.15 - 3.00 (m, 2H), 2.93 (s, 3H), 1.80 (d, J = 6.4 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.89 (s, 1H), 8.74 - 8.73 (m, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.35 - 7.33 (m, 1H), 7.12 - 7.10 (m, ES+ 546.1 [M+H] 1H), 6.71 - 6.67 (m, 1H), 6.17 - 6.10 (m, 1H), 4.00 (s, 2H),3.60 - 3.32 (m, 4H), 3.15 - 3.00 (m, 2H), 2.94 (s, 3H), 1.85 (d, J = 6.4 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.93 (s, 1H), 8.59 (s, 1H), 7.91 (s, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.26 - ES+ 558.2 [M+H] 6.95 (m, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.32 - 6.23 (m, 1H), 4.05(s, 2H), 3.70 - 3.33 (m, 4H), 3.20 - 3.04 (m, 2H), 2.99 (s, 3H), 2.52 (s, 3H), 1.84- 1.79 (d, J = 5.2 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.95 (s, 1H), 8.59 (s, 1H), 7.91 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.26 - ES+ 558.2 [M+H] 6.94 (m, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.33 - 6.20 (m, 1H), 4.05(s, 2H), 3.69 - 3.32 (m, 4H), 3.22 - 3.05 (m, 2H), 3.00 (s, 3H), 2.52 (s, 3H), 1.84- 1.79 (d, J = 5.4 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.90 (s, 1H), 8.55 (s, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.31 - 7.30 (m, 1H), 7.10 (d, J = 1.0 Hz, 1H), ES+ 551.2 [M+H] 6.97 - 6.87 (m, 1H), 6.59 - 6.56 (m, 1H), 6.12 - 6.08 (m, 1H),4.05 - 4.02 (m, 2H), 3.64 - 3.28 (m, 4H), 3.09 - 3.06 (m, 2H), 2.96 (s, 3H), 2.51 (s, 3H), 1.77 - 1.70 (d, J = 5.6 Hz, 3H).XH NMR (400 MHz, CDCI3): 68.90 (s, 1H), 8.55 (s, 1H), 7.74 (d,J = 1.7 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.12 (d, J = 1.0 Hz, 1H), ES+ 551.2 [M+H] 6.98 - 6.87 (m, 1H), 6.59 - 6.56 (m, 1H), 6.12 - 6.08 (m, 1H),4.04 - 4.01 (m, 2H), 3.65 - 3.28 (m, 4H), 3.10 - 3.08 (m, 2H), 2.96 (s, 3H), 2.51 (s, 3H), 1.77 - 1.70 (d, J = 5.6 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.32 (s, 1H), 8.38 (s, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.37 - 7.12 (m, 3H), 6.26 - 6.22 (m, 1H), ES+ 548.1 [M+H]3.71 (d, J = 1.8 Hz, 1H), 3.42 - 3.38 (m, 8H), 2.85 (d, J = 1.6 Hz, 3H), 2.47 (s, 3H), 2.39 (s, 3H), 1.72 (d, J = 6.0 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.32 (s, 1H), 8.38 (s, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.36 - 7.09 (m, 3H), 6.27 - 6.22 (m, 1H), ES+ 548.1 [M+H]3.72 (d, J = 1.7 Hz, 1H), 3.42 - 3.39 (m, 8H), 2.85 (d, J = 1.6 Hz, 3H), 2.48 (s, 3H), 2.39 (s, 3H), 1.72 (d, J = 6.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.32 (s, 1H), 8.40 (s, 1H), 7.86 - 7.73 (m, 2H), 7.44 - 7.34 (m, 1H), 7.10 - 7.02 (m, 1H), 6.28 ES+ 526.2 [M+H]- 6.25 (m, 1H), 3.72 (s, 1H), 3.50 - 3.34 (m, 11H), 2.84 (d, J = 1.6 Hz, 3H), 1.75 (d, J = 6.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.32 (s, 1H), 8.40 (s, 1H), 7.86 - 7.73 (m, 2H), 7.45 - 7.33 (m, 1H), 7.14 - 6.97 (m, 1H), 6.34 ES+ 526.2 [M+H]- 6.20 (m, 1H), 3.72 (s, 1H), 3.48 - 3.36 (m, 11H), 2.85 (d, J = 1.6 Hz, 3H), 1.74 (d, J = 6.2, 3H).1H NMR (400 MHz, DMSO-d6): δ9.28 (s, 1H), 8.34 - 8.29 (m, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.65 - ES+ 524.1 [M+H] 7.58 (m, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.02 (s, 1H), 6.38 - 6.28(m, 1H), 3.75 (d, J = 1.8 Hz, 1H), 3.50 - 3.36 (m, 5H), 3.31 (s, 6H), 2.84 (s, 3H), 1.76 (d, J = 6.3 Hz, 3H).XH NMR (400 MHz, DMSO-ds): 69.28 (s, 1H), 8.33 - 8.28 (m,1H), 7.92 (d, J = 2.6 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.66 - 42 ES+ 524.1 [M+H] 7.59 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.02 (s, 1H), 6.37 - 6.26(m, 1H), 3.76 (d, J = 1.8 Hz, 1H), 3.46 - 3.36 (m, 5H), 3.30 (s, 6H), 2.84 (s, 3H), 1.76 (d, J = 6.4 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.89 (s, 1H), 8.77 - 8.75 (m, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 9.0 45 ES+ 563.1 [M+H] Hz, 1H), 6.20 - 6.18 (m, 1H), 4.26 - 4.03 (m, 2H), 3.52 - 3.42(m, 4H), 3.10 - 3.08 (m, 2H), 2.96 (s, 3H), 1.85 (d, J = 5.6 Hz, 3H).1H NMR (400 MHz, CDCl3): δ8.91 (s, 1H), 8.77 - 8.76 (m, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 9.0 46 ES+ 563.1 [M+H] Hz, 1H), 6.21 - 6.17 (m, 1H), 4.25 - 4.05 (m, 2H), 3.53 - 3.44(m, 4H), 3.11 - 3.07 (m, 2H), 2.97 (s, 3H), 1.85 (d, J = 5.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.37 (s, 1H), 8.51 - 8.34 (m, 1H), 7.86 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.68 (d, J 47 ES+ 601.2 [M+H] = 8.1 Hz, 1H), 6.30 (d, J = 7.1 Hz, 1H), 5.48 - 5.14 (m, 1H),3.72 (d, J = 1.9 Hz, 1H), 3.65 - 3.35 (m, 6H), 3.30 (s, 2H), 2.85 (d, J = 1.6 Hz, 3H), 2.23 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H).1H NMR (400 MHz, DMSO-d6): δ9.37 (s, 1H), 8.57 - 8.38 (m, 1H), 7.86 (d, J = 2.2 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.68 (d, J 48 ES+ 601.2 [M+H] = 8.1 Hz, 1H), 6.30 (d, J = 7.1 Hz, 1H), 5.38 - 5.22 (m, 1H),3.72 (d, J = 1.8 Hz, 1H), 3.67 - 3.36 (m, 6H), 3.31 (s, 2H), 2.85 (d, J = 1.6 Hz, 3H), 2.23 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H).Assays and Compound Testing[000236] In vitro cell proliferation: determination of IC50 values for inhibition of proliferation in T-47D cells expressing mutant PI3Ka (H1047R) mutation and SK-BR-3 cells expressing WT PI3Ka.[000237] 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 pL 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. Cells are then read on an Envision plate reader. The percentage of inhibition of proliferation was calculated using the followingformula: %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 lOuM 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 + 10A((LogEC50 - X)*HillSlope)).Reagent tableReagent Vendor Cat No.Cell Titer Gio 2.0 Assay 500 mL Promega G9243Corning 384-well Low Flange Black Flat Bottom Corning 89089-790 Polystyrene TC-treated Microplates, 10 per Bag,with Lid, Sterile SKU: 3571PBS Solarbio P1020Trypan blue solution 0.4% Fisher T10282Fetal Bovine Serum Australia origin Sigma 82051-458Gibco RPMI 1640 Medium Fisher 11875093Gibco McCoy's 5A (modified) Medium, HEPES Fisher 12330031DMEM, high glucose, HEPES, no phenol red Fisher 21063045Insulin, human recombinant, zinc solution Fisher 12585-014[000238] For IC50 values shown in Table 4, " A" refers to IC50 < 100 nM; " B" refers to 100 nM < IC50 < 300 nM; " C" refers to 300 nM < IC50 < 1 pM; " D" refers to 1 pM < IC50 < 3 pM; " E" refers to 3 pM < IC50 < 10 pM; " F" refers to IC50 > 10 pM.Table 4. Cellular proliferation dataExample # Avg T-47D EC50 Avg SKBR3 EC501 A D2 A D3 A D4 A D5 A D6 A D13 A D14 A E17 A E18 A E25 B D26 B E27 D FC EA EA EA EA EA EA EA DA DA EA EA EA EA DB EB EB EB FB FA C48 B E[000239] 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).[000240] 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 pL 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 pL 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 pL 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 pM 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)).[000241] 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 pg / ml insulin, and assay media consisted of DMEM (no phenol red) + 10% FBS.[000242] 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. Reagent tableReagent Vendor Cat No.Gibco RPMI 1640 Medium, no phenol red Fisher 11835030Gibco RPMI 1640 Medium Fisher 11875093McCoy's 5A (Modified) Medium, HEPES Fisher 12330031DMEM, high glucose, HEPES, no phenol red Fisher 21063045Gibco Trypsin-EDTA (0.5%), no phenol red Fisher 15400054Eagle's Minimum Essential Medium ATCC 30-2003MEM Medium Gibco 42360032PBS Solarbio P1020Trypan blue solution 0.4% Fisher T10282Fetal Bovine Serum Australia origin Gibco 10099141CProxiPlate-384 Plus, White, TC treated, Case of Perkin Elmer 6008238160Insulin Aladin 1189675Trypsin-EDTA SolarBio T1300Phospho-AKTl / 2 / 3 (Ser473) cellular HTRF kit Revvity 64AKSPEYT-47D Cells ATCC HTB-133SK-BR-3 Cells ATCC HTB-30MCF-7 Cells ATCC HTB-22BT-483 Cells ATCC HTB-121[000243] For IC50 values shown in Table 5, " A" refers to IC50 < 100 nM; " B" refers to 100 nM < IC50 < 300 nM; " C" refers to 300 nM < IC50 < 1 pM; " D" refers to 1 pM < IC50 < 3 pM; " E" refers to 3 pM < IC50 < 10 pM; " F" refers to IC50 > 10 pM.Table 5. 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Claims

IN THE CLAIMS1. A compound of Formula (1)(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));Ri is selected from a 5- or 6-membered substituted or unsubstituted nitrogen-containing heteroaryl, a 4- to 6-membered substituted or unsubstituted nitrogen-containing heterocyclyl, oreach A is independently C1-C4 alkyl, fluoroalkyl, C3-C7 cycloalkyl, N(Ra)2, (CH2)o-5-NRa-C(0)-C3-C7 cycloalkyl, (CH2)I-5-0-(CH2)O-5-CI-C4 alkyl, (CH2)I-5-O-CI-C3cycloalkyl, (CH2)I-5-0-(CH2)O-5-CF3, (CH2)I-5-O-(CH2)I-5-CI-C3fluoroalkyl, (CH2)o-5-aryl, (CH2)o-5-heteroaryl, (CH2)o-5-heterocyclyl, (CH2)o-5-NRa-(CH2)o-5-heteroaryl or (CH2)o-5-NRa-(CH2)i-5-N-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted;each B is independently H, C1-C4 alkyl, C3-C7cycloalkyl, (CHzh-s-OH, (CH2)o-5-N(Ra)2, (CH2)i-5-NRa-C(O)-C3-C7cycloalkyl, (CH2)o-5-aryl, (CH2)o-5-heteroaryl, (CH2)o-5-heterocyclyl, (CH2)o-5-C(O)-(CH2)1-5-O-C1-C4 alkyl, (CH2)i-5-NRa-(CH2)o-5-heteroaryl or (CH2)i-5-NRa-(CH2)2-s-N-heterocyclyl, O-Ci-5-alkyl, O-Co-5-cycloalkyl, O-Co-5-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted;each Rais independently H, C1-C4 alkyl, C3-C7cycloalkyl, C(O)Ci-C3alkyl, (CH2)1-5-fluoroalkyl, (CH2)1-5-OH, (CH2)I-5-NH2, (CH2)I-5-NH(CI-C4 alkyl), (CH2)I-5-N(CI. C4alkyl)2or C(O)-(CH2)I-5-O-CI-C3alkyl, where the alkyl and cycloalkyl are substituted or unsubstituted, or alternatively, for -S(=O)(A)(=NRa) or for -S(=O)(A)(NRa), Raand A together with the attached atoms, may form a substituted or unsubstituted heterocyclyl ring;R2is C1-C4 alkyl, CF3, CFH2or CF2H, and the carbon atom attached to R2(shown with an asterisk) exists as a (R)- or (S)- stereocenter or as a mixture thereof;R3is H or C1-C4 alkyl;R4is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H;R6is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H;each R7is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H; each of Xi, X2, and X3is independently N, CH or substituted C;X4is independently CH or substituted C;Q is NR3or O;Rs isa 5- or 6- membered heteroaryl ring A of the formula:V X( A J— S=NR9—that is optionally further substituted, where R9is H, -CN or substituted or unsubstituted C1-C3 alkyl, and Ri0is substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted cyclopropyl, and the S(=O)(=NR9)(RI0) substituent exists as a (R)- or (S)- stereocenter or as a mixture thereof; ora non-aromatic heterocyclyl ring B containing at least one ring nitrogen atom and having the formula:Y oB / -■- S-NRcR10that is optionally further substituted, where R9is H, -CN or substituted or unsubstituted C1-C3 alkyl, and R10is substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted cyclopropyl, where the heterocyclic ring is linked to the core structure through either a ring carbon atom or a ring nitrogen atom, and optionally contains one or more additional ring atoms selected from N, O and S, and is optionally part of a bridged, fused or spiro ring system, and where the S(=O)(=NR9)(RI0) substituent exists as a (R)- or (S)- stereocenter or as a mixture thereof;each site or atom marked with a * exists as a (R)- or (S)- stereocenter or as a mixture thereof.

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 Ri is selected fromowhere A, B and Raare as defined.

3. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Ri is selected fromwhere B is as defined.

4. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R5is a 5- or 6- membered heteroaryl ring A of the formula:that is optionally further substituted, where R9 is H, -CN or substituted or unsubstituted C1-C3 alkyl, and R10is substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted cyclopropyl, and the S(=0)(=NR9)(RIO) substituent exists as a (R)- or (S)- stereocenter or as a mixture thereof.

5. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R5is a non-aromatic heterocyclyl ring B containing at least one ring nitrogen atom and having the formula:oS-NRgR10that is optionally further substituted, where R9is H, -CN or substituted or unsubstituted Ci-C3alkyl, and Rio is substituted or unsubstituted Ci-C3alkyl or substituted or unsubstituted cyclopropyl, where the heterocyclic ring is linked to the core structure through either a ring carbon atom or a ring nitrogen atom, and optionally contains one or more additional ring atoms selected from N, O and S, and is optionally part of a bridged, fused or spiro ring system, and where the S(=O)(=NR9)(RI0) substituent exists as a (R)- or (S)- stereocenter or as a mixture thereof.

6. 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 or CH2F, Q is O or NR3, R3 is H, and Ri is selected fromOwhere A, B and Raare as defined.

7. 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 CH3or CH2F, Q is O or NR3, R3is H, and Ri is selected fromwhere B is as defined.

8. 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 or CH2F, Q is O or NR3, R3 is H, Ri is selected fromwhere A, B and Raare as defined, and R5is are as defined.

9. 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 CH3or CH2F, Q is O or NR3, R3is H, Ri is selected fromS=NRgwhere B is as defined, and R5is R10where ring A, R9and Rio are as defined.

10. 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 CH3or CH2F, Q is O or NR3, R3 is H, Ri is selected fromOwhere A, B and Raare as defined, and R5is where ring B, R9and Rio 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 CH3or CH2F, Q is O or NR3, R3is H, Ri is selected fromwhere B is as defined, and R5is where ring B, R9and Rio are as defined.

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 R2is CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, and Ri is selected fromwhere A, B and Raare as defined.

13. 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 CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, and Ri is selected fromwhere B is as defined.

14. 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 CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, Ri is selected fromOwhere A, B and Raare as defined, and R5is where ring A, R9and Rio are as defined.

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 R2is CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, Ri is selected from\ A S=NRgwhere B is as defined, and R5is ' — '10where ring A, R9and Rio are as defined.

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 CH3or CH2F, Q is O or NR3, R3 is H, X4is CH or CF, Ri is selected fromOwhere A, B and Raare as defined, and R5is are as defined.

17. 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 CH3or CH2F, Q is O or NR3, R3is H, X4is CH or CF, Ri is selected fromB } — S^NRgwhere B is as defined, and R5is ' — '10where ring B, R9and Rio are as defined.

18. A pharmaceutical composition comprising the compound of any one of claims 1 to 17 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition according to claim 18, further comprising one or more anticancer agents.

20. The pharmaceutical composition according to claim 19, wherein the one or more anti-cancer agents 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.

21. 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 the compound of any one of claims 1 to 17 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein the disease is cancer.

23. The method of claim 21, wherein the disease is 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).

24. The method of claim 21, wherein the disease is a cancer bearing a PI3Kα H1047R mutation.

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