Quinolizinones as PI3k inhibitors

Abstract

Novel PI3K inhibitors of the general Formula (1) are described along with methods of their preparation and their use in the treatment of diseases associated with the elevation or activation of the PI3K pathway, wherein R1 to R8 are defined as described.

Description

QUINOLIZINONES AS PI3K INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional No. 63 / 571,644, filed March 29, 2024, and U.S. Provisional No. 63 / 749,421, filed January 24, 2025, the disclosures of which are incorporated by reference 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 ( PI3 Ks) 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-C20, PI3K-C2y) and Class III PI3Ks (vps34) are monomeric enzymes primarily associated with endocytosis and autophagy (Posor et al., Biochim Biophys Acta 2015, 1851, 794; Backer, Biochem J. 2016, 473, 2251). The Class I PI3Ks are heterodimeric, consisting of a catalytic kinase subunit (pllOa, p, y, 5) 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, , y, and 6) based on the identity of their catalytic (pllOa, pliop, pllOy, or pliOS) and regulatory (p85a or its various splice variants, p85p, p55y, or plOl) subunits, giving rise to distinct roles in cellular physiology (Vanhaesebroeck et al., J Mol Med (Berl). 2016, 94, 5). PI3Ky 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., Nature2004, 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 a!., J Exp Med. 2013, 210, 1937), while PI3KP is known to serve a specific function in platelet aggregation (Liu et. a!., 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 et al., 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, idelalisib, pictilisib, taselisib, and others) have caused dose-dependent adverse events such as hyperglycemia, rash, fatigue, diarrhea, etc. (Jiang et al., Mol Biol Rep. 2020, 47, 4587) which are known on-target toxicities. Hyperglycemia is a result of the body not producing enough insulin or aberrant utilization. The pancreas regulates insulin release in response to changes in blood glucose levels, resulting in either glucose uptake by muscle and fat cells when insulin levels are high or gluconeogenesis by the liver when insulin levels are low. Tissue cellular response to insulin requires PI3K signaling through the ubiquitously expressed 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. Theseverity 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 pll05 sub-unit is highly expressed in immune cells, causes severe diarrhea and colitis. Inhibition with a dual inhibitor (taselisib), a potent PI3K6 inhibitor possessing modest PI3Ka inhibition led to gastrointestinal (Gl) side effects, but a highly selective and potent PI3K6 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 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.SUMMARY OF THE INVENTION

[0008] An aspect of the invention is a compound of Formula (1)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein: R1is aryl, heteroaryl or heterocyclyl, where each of the aryl, heteroaryl and heterocyclyl is unsubstituted or substituted, with the proviso that when R1is aryl or heteroaryl, a carboxylic acid or ester thereof is not a substituent at a position ortho to the point of attachment of the aryl or heteroaryl ring to the nitrogen atom of N-R3;R2is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF3, CFH2or CF2H, where the C1-C4 alkyl and C3-C7 cycloalkyl is unsubstituted or substituted, and where R2is not H, the carbon atom attached to R2is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer;R3is H or C1-C4 alkyl, where the C1-C4 alkyl is unsubstituted or substituted;R4is H, F, Cl, C1-C4 alkyl, C3-C7cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4 alkyl and C3-C7cycloalkyl is unsubstituted or substituted;R6is H, F, Cl, C1-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, CF3, CFH2or CF2H, where each of the C1-C4 alkyl, C3-C7 cycloalkyl and heteroaryl is unsubstituted or substituted;R7is H, F, Cl, C1-C4 alkyl, C3-C7 cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4 alkyl and C3-C7 cycloalkyl is unsubstituted or substituted; each Rs is independently H, F, Cl, C1-C4 alkyl, C3-C7 cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4 alkyl and C3-C7 cycloalkyl is unsubstituted or substituted;Rs is halogen;-O-Li-L2-L3-L4-L5-L6-L7-Rg;-S-Li-L2-L3-L4-L5-L6-L7-R9;-S(O)-L1-L2-L3-L5-L5-L7-R9;-SfOh-k-Lj-Ls-Ls-Ls-Ly-Rg;-( N R1o)-Li-L2-L3-L4-L5-L6-L7-Rg; or-L8-Lg-Lio-Lii-Li2-R14, wherein: each of Li, L2, L3, Ls and L7is independently (CHRn), (CH RH-O), (CHRn-S), (C3-C7 cycloalkyl), (CH2)I-4or a bond;L4is C=O, C=S or a bond; l_5is NR10, S, O or a bond;R9is H, C(=O)R12, C(=O)NR12R13, NR12R13, C(=O)OR12, C1-C3alkyl, C1-C6uoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of theC1-C6alkyl, C1-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively when NR10 is present, R9 and R1o together with the attached nitrogen atom may form a substituted or unsubstituted ring. In an exemplary embodiment, the ring is 4- to 7- membered substituted or unsubstituted non-aromatic heterocyclic ring containing (in addition to the nitrogen atom) 0, 1 or 2 heteroatoms which may be N, 0, S or Si, with the proviso that if the ring size is 4 or 5, the number of additional heteroatoms will be 0 or 1 and if the ring size is from 6 to 7, the number of additional heteroatoms will be 0, 1 or 2, where if the ring is substituted, the substituents include, but are not limited to, one or more of CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl,CH2CF3, an oxetane ring, or CORawhere Rais C1-C4 alkyl, O-C1-C4 alkyl, or NRbRcwhere Rb and Rcare independently H or C1-C4 alkyl; each of R1o and Ru is independently H or C1-C4 alkyl (such as CH3, CH2CH3 or CH(CH3)2), where the C1-C4 alkyl is unsubstituted or substituted; each of R12 and R13is independently H, Cs alkyl, cycloalCk1y-l, heterocyclyl, aryl or heteroaryl, where each of the Cs alCk1y-l, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively, R12 and R13together with the attached nitrogen atom may form a substituted or unsubstituted ring. In an exemplary embodiment, the ring is 4- to 7- membered substituted or unsubstituted non-aromatic heterocyclic ring containing (in addition to the nitrogen atom) 0, 1 or 2 heteroatoms which may be N, O, S or Si, with the proviso that if the ring size is 4 or 5, the number of additional heteroatoms will be 0 or 1 and if the ring size is from 6 to 7, the number of additional heteroatoms will be 0, 1 or 2, where if the ring is substituted, the substituents include, but are not limited to, one or more of CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, an oxetane ring, or CORawhere Rais C4alkyl, O-C1-C4alkyl, orC N1R- bRc where Rb and Rcare independently H or C1-C4 alkyl;Lsis (CHR15), (CHR15-O), (CHR15-S), (CHR15-NR1S), C=O, C=S or a bond;Lg is C3-C7 cycloalkyl that is optionally part of a bridged, fused or spiro ring system, C(R15)=C(R15), CEC or a bond;Lio is independently (CHR15), O, S, (NCR15), N(C=O) or a bond;Ln is (CHR15), C=O, C=S or a bond;L12 is H, (C3-C7cycloalkyl), heterocyclyl, aryl, heteroaryl or a bond, where each of the C3-C7cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and the C3-C7cycloalkyl and / or heterocyclyl is optionally part of a bridged, fused or spiro ring system;RMis H, CR1sR1eRn, OR17, SR17, NR1SR17, C6alkyl, C3flCu1o-roalkyl, cycloaClk1y-l, heterocyclyl, aryl or heteroaryl, where each of the C3alkyl, CC1-6fluoroalkyl, cCyc1-loalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, each of R15and R1eis independently H or C1-C3 alkyl; and each R17is independently H, C6alkyl, C1-C3fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Cg alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl is unsubstituted or substituted; or alternatively, R16and R17together with the attached nitrogen atom may form a substituted or unsubstituted ring. In an exemplary embodiment, the ring is 4- to 7- membered substituted or unsubstituted non-aromatic heterocyclic ring containing (in addition to the nitrogen atom) 0, 1 or 2 heteroatoms which may be N, O or S, with the proviso that if the ring size is 4 or 5, the number of additional heteroatoms will be 0 or 1 and if the ring size is from 6 to 7, the number of additional heteroatoms will be 0, 1 or 2, where if the ring is substituted, the substituents include, but are not limited to, one or more of Me, F, Cl, CF3, CFjH, CHjF, OCHa, cyclopropyl, CH2CF3, an oxetane ring, or CORawhere Rais C1-C4 alkyl, O-Ci-C4alkyl, or NRbRc where Rb and Rcare independently H or C1-C4 alkyl; with the proviso that when R5is -L8-L9-L10-L11-L12-R14, at least one of L8, L9, Lio, Lu, L12and RMis a carbon-containing moiety and R5is directly attached to the core structure by a carbon atom; or R5is a non-aromatic N-linked heterocyclic ringwhere the heterocyclic ring is substituted or unsubstituted, optionally contains one or more additional ring atoms selected from N, 0, Si and S, and is optionally part of a bridged, fused or spiro ring system. In particular embodiments, the N-linked heterocyclyl ring is a substituted or unsubstituted azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7- azaspiro[4.4]nonane or 2-azaadamantane.

[0009] In an exemplary embodiment, R1is selected from the following:R1s is a substituted or unsubstituted 5- or 6-membered nitrogen-containing heteroaryl ring or R18is selected from the following:where each A is independently C1-C4 alkyl, fluoroalkyl, C3-C7 cycloalkyl, N(Ra)2, (CH2)0-5-NRa-C(0)- C3-C7 cycloalkyl, (CH2)I-S-O-CI-C3 cycloalkyl, (CH2)I-S-O-(CH2)I-5-CI-C3 fluoroalkyl, (CH2)0-5-aryl, (CH2)0-5-heteroaryl, (CH2)0-5-heterocyclyl, (CH2)0-5-NRa-(CH2)0-5-heteroaryl or (CH2)0-5-NRa-(CH2)i-5- N-heterocyclyl, where the alkyl, fluoroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, A and A together with the attached -P(=O)- moiety may form a substituted or unsubstituted heterocyclyl ring;each B is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, (CH2)i.5-NRa-C(O)-C3-C7 cycloalkyl, (CH2)0-5- aryl, (CH2)0.5-heteroaryl, (CH2)0-5-heterocyclyl, (CH2)i-5-NRa-(CH2)0-5-heteroaryl or (CH2)>5-NRa- (CH2)2-5-N-heterocyclyl, O-Ci-5-alkyl, O-C0-5-cycloalkyl, O-C0-5-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, B and B together with the attached -[O or NH]-P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring, or alternatively, A and B together with the attached -P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring; each Rais independently H, C1-C4 alkyl, C(O)Ci-C3alkyl or C(O)-(CH2)I.5-O-CI-C3alkyl, where the alkyl is substituted or unsubstituted, or alternatively, Raand A together with the attached - S(=O)2- moiety may form a substituted or unsubstituted heterocyclic ring, or R1s and RM together form a substituted or unsubstituted heterocyclic ring (such as a 5- or 6- membered heterocyclic ring) containing one or more sulfur atoms (which includes the sulfoxide (SO) and sulfone (SO2) forms), nitrogen atoms (which includes the oxidized forms) and oxygen atoms; R1s is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted, or R19and R1g together form a heterocyclic ring as described herein; each R2O is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted;R21 is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted; and each X1, X2, X a3nd X4is independently CH, N or substituted C.

[0010] In an exemplary embodiment, R1iswherein R1g, R19, X2, X3 and X4are defined as described herein.

[0011] In an exemplary embodiment, R1iswherein R18, X2, X3and X4are defined as described herein.

[0012] In an exemplary embodiment, R1iswherein R18X2, X3 and X4are defined as described herein.

[0013] In an exemplary embodiment, R1is selected from the following:wherein R20and R24are defined as described herein.

[0014] In an exemplary embodiment, R1is selected from the following:X2, X3 and X4are defined as described herein;Y is O, NR2I or C(R4)2; and each R4, R20 and R21 is independently defined as described herein.

[0015] In an exemplary embodiment, R5is -(NR10)-LI-L2-L3-L4-L5-LS-L7-R9, where Li to L7, Rs and R10are as defined.

[0016] In an exemplary embodiment, R5is -O-L1-L2-L3-L4-L5-L6-L7-R9, where Li to L7and Rs are as defined.

[0017] In an exemplary embodiment, R5is -S-L1-L2-L3-L4-L5-L6-L7-R9; -S(O)-LI-L2-L3-L5-L6-L7-R9; or - S(O)2-LI-L2-L3-L5-I-6-L7-R9, where Li to L7and Rg are as defined.

[0018] In an exemplary embodiment, Rg is a 6-membered aryl ring; or is a 5- to 6- membered heteroaryl ring containing from 1-3 nitrogen atoms; or is a non-aromatic 3- to 7- membered carbocycle; or is a non-aromatic 4- to 7- membered heterocycle containing from 1 to 3 heteroatoms selected from N, O, S and Si with the proviso that if the ring size is 4 or 5 then the number of heteroatoms will be 1 or 2 and if the ring size is 6 or 7 the number heteroatoms will be 1, 2 or 3; or is a C6alkyCl1- group, where the aryl ring, the heteroaryl ring, the carbocycle, the heterocycle and the C6alkyCl1g-roup are unsubstituted or substituted with one or more of CH3,F, Cl, CF3, CF2H, CH2F, OCH3, -CH2CF3, cyclopropyl, -CN, N(CH3)2, an oxetane ring, a phenyl or phenoxy group optionally substituted with from 1 to 3 halogens (F, Cl or Br) or CH3groups, or CORawhere Rais C4alkyCl,1- O-Ci-C4alkyl or NRbRc, where Rb and Rcare independently H or C1-C4 alkyl.

[0019] In an exemplary embodiment of R5, each of L8, Lu and Ln is a bond and L9is not a bond.

[0020] In an exemplary embodiment of R5, each of La, Lio and Ln is a bond and L9is cycloalkyl that is optionally part of a bridged, fused or spiro ring system.

[0021] In an exemplary embodiment of R5, each of L8, Lio and Ln is a bond and L9is cycloalkyl that is part of a bridged ring system.

[0022] In an exemplary embodiment of R5, each of L8, Lio and Ln is a bond and L9is cycloalkyl that is part of a fused ring system.

[0023] In an exemplary embodiment of R5, each of L8, Lio and Ln is a bond and L9is cycloalkyl that is part of a spiro ring system.

[0024] In an exemplary embodiment of R5, each of L8, Lio and Ln is a bond and L9is C(R15)=C(R15).

[0025] In an exemplary embodiment of R5, each of L8, Lio and Ln is a bond and L9is C=C.

[0026] In an exemplary embodiment of R5, each of L8, L9, Lio and Ln is a bond and Li2is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted.

[0027] In an exemplary embodiment of R5, each of L8, L9, Lw and Ln is a bond and Li2is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and RMis H.

[0028] In an exemplary embodiment of R5, each of L8, L9, Lio and Ln is a bond and Li2is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and R14is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the C1-Ce alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted.

[0029] In an exemplary embodiment of R5, each of L8, L9, L10and Ln is a bond and Li2is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and Ru is -CRMR1SR1B.

[0030] In an exemplary embodiment of R5, each of Ls, L9, Lio and Lu is a bond and L12is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and RMis -OR1G or -OR17.

[0031] In an exemplary embodiment of R5, each of Ls, Ls, Lio and Lu is a bond and Li2is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and RMis -SR17.

[0032] In an exemplary embodiment of R5, each of L8, L9, Lio and Lu is a bond and Li2is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and R14is -NR1gRu.

[0033] In an exemplary embodiment, R5is

[0034] where Rd is H or CH3 and Reis CH3, Cs-Ce cycloalkyl, a six-membered aromaticor heteroaromatic ring containing from 0, 1 or 2 nitrogen atoms which may be optionally substituted with CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CN or N(CH3)2, or Rd and Retogether with the attached nitrogen atom may form a 4- to 7- membered non-aromatic heterocycle containing from 1 to 2 heteroatoms which may be either N or O, with the proviso that if the ring size is 4 or 5 the number of heteroatoms will be 1 and if the ring size is from 6 to 7, the number of heteroatoms will be 1 or 2, where the ring is unsubstituted or is substituted with one or more that includes, but is not limited to, CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, an oxetane ring, or CORawhere Rais C4alkyl, O-Ci-C4alkyl, or NC1R-bRc where Rb and Rcare independently H or C4alkyl. C1-

[0035] In an exemplary embodiment, R5is a N-linked non-aromatic heterocyclyl ringwhere the heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is optionally part of a bridged, fused or spiro ring system. In particular embodiments, the N-linked heterocyclyl ring is azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline,tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, l,3,8-triazaspiro[4.5]- decan-4-one, 1, 4-dioxa-7-azaspiro[4.4]nonane.

[0036] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is not part of a bridged, fused or spiro ring system.

[0037] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is part of a bridged, fused or spiro ring system.

[0038] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, does not contain additional atoms selected from N, O, Si and S, and is not part of a bridged, fused or spiro ring system.

[0039] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, does not contain additional atoms selected from N, O, Si and S, and is part of a bridged, fused or spiro ring system.

[0040] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is not part of a bridged, fused or spiro ring system.

[0041] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is part of a bridged, fused or spiro ring system.

[0042] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is not part of a bridged, fused or spiro ring system.

[0043] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is part of a bridged, fused or spiro ring system.

[0044] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is not part of a bridged, fused or spiro ring system.

[0045] In an exemplary embodiment, the N-linked non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is part of a bridged, fused or spiro ring system.

[0046] In an exemplary embodiment of Formula (1), the C4alkyl is preferably mC1e-thyl.

[0047] In an exemplary embodiment of Formula (1), halogen is preferably F.

[0048] In an exemplary embodiment of the compound of Formula (1), R1is selected fromwhere R18, R191 R20, R21, X1, X2, X3 and X4are defined as described herein.

[0049] In an exemplary embodiment of the compound of Formula (1), R1is selected fromwhere R18, R191 R20, R21, X1, X2, X3 and X4are as defined herein.

[0050] In an exemplary embodiment of the compound of Formula (1), R1is selected fromwhere RM and R24are defined as described herein.

[0051] In an exemplary embodiment of the compound of Formula (1), R2is CH3.

[0052] In an exemplary embodiment of the compound of Formula (1), R2is CH2F.

[0053] In an exemplary embodiment of the compound of Formula (1), R3is H.

[0054] In an exemplary embodiment of the compound of Formula (1), R4is H or F.

[0055] In an exemplary embodiment of the compound of Formula (1), R6is CH3or F.

[0056] In an exemplary embodiment of the compound of Formula (1), R7is CH3or F.

[0057] In an exemplary embodiment of R1, and X4arXe1i,n Xd2e,p Xe3ndently CH or CF.

[0058] In an exemplary embodiment of R1, X2is N, and Xi, X3and X4are independently CH or CF.

[0059] In an exemplary embodiment of R1, X2is N, and X2, X3and X4are independently CH or CF.

[0060] In an exemplary embodiment of R1, X4is N and Xi, X2and X3are independently CH or CF.

[0061] In an exemplary embodiment of R1, X3is N and Xi, X2and X4are independently CH or CF.

[0062] In an exemplary embodiment of R1, X2and X3are N, and X2and X4are independently CH or CF.

[0063] In an exemplary embodiment of R1, X2and X2are N, and X3and X4are independently CH or CF.

[0064] In an exemplary embodiment of R1, X2and X3are N, and Xi and X4are independently CH or CF.

[0065] In an exemplary embodiment of R1, X2and X4are N, and X2and X3are independently CH orCF.

[0066] In an exemplary embodiment of R1, Xi, X2and X3are N, and X4is CH or CF.

[0067] In an exemplary embodiment of R1, Xi, X2and X4are N, and X3is CH or CF.

[0068] In an exemplary embodiment of R1, X2, X3and X4are N, and Xi is CH or CF.

[0069] In an exemplary embodiment of R1, Xi, X3and X4are N, and X2is CH or CF.

[0070] In an exemplary embodiment of R1, X1, X2, X3and X4are N.

[0071] In an exemplary embodiment of the compound of Formula (1), R5is -O-Li-L2-L3-L4-L5-L6-L7-R9.

[0072] In an exemplary embodiment of the compound of Formula (1), R5is -S-Li-L2-L3-L4-L5-L6-L7-Rg.

[0073] In an exemplary embodiment of the compound of Formula (1), Rsis -S(O)-Li-L2-L3-L5-L6-L7-R9.

[0074] In an exemplary embodiment of the compound of Formula (1), R5is -S(O)2-Li-L2-L3-L5-LB-L7-R9.

[0075] In an exemplary embodiment of the compound of Formula (1), Rsis -(NR10)-Li-L2-L3-L4-L5-L6-L7-R9.

[0076] In an exemplary embodiment of the compound of Formula (1), R5is -Lg-Lg-Lio-Ln-LirRw.

[0077] In an exemplary embodiment of the compound of Formula (1), R6is CH3.

[0078] In an exemplary embodiment of the compound of Formula (1), R7is CH3.

[0079] In an exemplary embodiment of the compound of Formula (1), each R8is independently H orF.

[0080] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, and R1is selected fromwhere R18, RM, R2O, R21, X1, X2, X3an adre X d4e Xfi1n, e Xd2, a Xs3described herein.

[0081] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, and R1is selected fromwhere R2o and R21 are defined as described herein.

[0082] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, R1is selected fromwherein R20, Y, X2, X3and X4are defined as described herein, and Rsis a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.

[0083] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, R1g is selected fromwhere A, B and Raare defined as described herein, and Rsis a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.

[0084] In an exemplary embodiment of the compound of Formula (1), R2 is CH3 or CH2F, R3 is H, R1g is selected fromwhere B is defined as described herein, and Rsis a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.

[0085] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, R18is selected fromwhere A and B are defined as described herein, and Rsis a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.

[0086] In an exemplary embodiment, the compound of Formula (1) is a compound of Formula (2)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: R1and R5are defined as described herein for the compound of Formula (1), and the carbon marked with * is a chiral center and exists as a ( R)- and (S)-racemic mixture or as either the ( R)- or (S)- enantiomer.

[0087] In an exemplary embodiment of the compound of Formula (2), R1is selected fromwhere R18, R19, R20, R21, X1, X a2n,d X X34are defined as described herein.

[0088] In an exemplary embodiment of the compound of Formula (2), R1is selected fromX3 and X4are defined as described herein.

[0089] In an exemplary embodiment of the compound of Formula (2), R18is selected fromwhere A, B and Raare defined as described herein.

[0090] In an exemplary embodiment of the compound of Formula (2), R1g is selected fromwhere B is as defined herein.

[0091] In an exemplary embodiment of the compound of Formula (2), R1g is selected fromwhere A and B are defined as described herein.

[0092] In an exemplary embodiment of the compound of Formula (2), R5is -O-L1-L2-L3-L4-L5-L6-L7-R9 where -O-L1-L2-L3-L4-L5-L6-L7-R9 is defined as in the compound of Formula (1).

[0093] In an exemplary embodiment of the compound of Formula (2), R5is -S-LI-L2-L3-L4-L5-LS-L7-R9 where -S-L1-L2-L3-L4-L5-L6-L7-R9 is defined as in the compound of Formula (1).

[0094] In an exemplary embodiment of the compound of Formula (2), Rsis -(NR1O)-LI-L2-L3-L4-L5-L6- L7-R9 where -(NR1O)-LI-L2-L3-L4-L5-L6-L7-R9 is defined as in the compound of Formula (1).

[0095] In an exemplary embodiment of the compound of Formula (2), R5is -L8-L9-L10-L11-L12-R14 where -Ls-Lg-Lio-Lu-Lu-Ru is defined as in the compound of Formula (1).

[0096] In an exemplary embodiment of the compound of Formula (2), R5is a N-linked non-aromatic heterocyclyl ringis defined as in the compound of Formula (1).

[0097] In an exemplary embodiment of R1of Formula (2), and X4are indeXp1e,n Xd2e, Xnt3ly CH or CF.

[0098] In an exemplary embodiment of R1of Formula (2), X2 is N, and Xi, X3 and X4are independently CH or CF.

[0099] In an exemplary embodiment of R1of Formula (2), Xi is N, and X2, X3and X4are independently CH or CF.[000100] In an exemplary embodiment of R1of Formula (2), X4is N and Xi, X2and X3are independently CH or CF.[000101] In an exemplary embodiment of R1of Formula (2), X3 is N and Xi, X2 and X4are independently CH or CF.[000102] In an exemplary embodiment of R1of Formula (2), Xi and X3are N, and X2and X4are independently CH or CF.[000103] In an exemplary embodiment of R1of Formula (2), Xi and X2are N, and X3and X4are independently CH or CF.[000104] In an exemplary embodiment of R1of Formula (2), X2and X3are N, and Xi and X4are independently CH or CF.[000105] In an exemplary embodiment of R1of Formula (2), X2 and X4are N, and X2 and X3 are independently CH or CF.[000106] In an exemplary embodiment of R1of Formula (2), Xi, X2and X3are N, and X4is CH or[000107] In an exemplary embodiment of R1of Formula (2), Xi, X2and X4are N, and X3is CH or[000108] In an exemplary embodiment of R1of Formula (2), X2, X3and X4are N, and Xi is CH orCF.[000109] In an exemplary embodiment of R1of Formula (2), Xi, X3and X4are N, and X2is CH orCF.[000110] In an exemplary embodiment of R1of Formula (2), and X4are NX.1, X2, X3[000111] In an exemplary embodiment of the compound of Formula (2), R1is selected fromwhere R18, R19, R2o, R2I, andX X1,4X a2r,e X3defined as described herein, and R5is a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.[000112] In an exemplary embodiment of the compound of Formula (2), R1is selected fromwhere R20, Y, X2, X3and X4are defined as described herein and R5is a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.[000113] In an exemplary embodiment of the compound of Formula (2), R1g is selected fromwhere A, B and Raare defined as described herein, and R5is a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.[000114] In an exemplary embodiment of the compound of Formula (2), R1g is selected fromwhere B is as defined herein, and R5is a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.[000115] In an exemplary embodiment of the compound of Formula (2), R1g is selected fromwhere A and B are defined as described herein, and R5is a N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is unsubstituted or substituted.[000116] In an exemplary embodiment, the compound of Formula (1) is a compound of Formula (3)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: R18, X1, X2, X3, X4, heteroaryl and heterocyclyl are defined as described herein and the heteroaryl and heterocyclyl rings may be further substituted.[000117] In an exemplary embodiment of R1of Formula (3), and X4are X1, X2, X3independently CH, CCI or CF.[000118] In an exemplary embodiment of R1of Formula (3), X2is N, and Xi, X3and X4are independently CH, CCI or CF.[000119] In an exemplary embodiment of R1of Formula (3), Xi is N, and X2, X3and X4are independently CH, CCI or CF.[000120] In an exemplary embodiment of Rxof Formula (3), X4is N and Xi, X2and X3are independently CH, CCI or CF.[000121] In an exemplary embodiment of R1of Formula (3), X3is N and Xi, X2and X4are independently CH, CCI or CF.[000122] In an exemplary embodiment of Rxof Formula (3), Xi and X3are N, and X2and X4are independently CH, CCI or CF.[000123] In an exemplary embodiment of R1of Formula (3), Xi and X2are N, and X3and X4are independently CH, CCI or CF.[000124] In an exemplary embodiment of R1of Formula (3), X2and X3are N, and Xi and X4are independently CH, CCI or CF.[000125] In an exemplary embodiment of R1of Formula (3), X2and X4are N, and X2and X3are independently CH, CCI or CF.[000126] In an exemplary embodiment of R1of Formula (3), Xi, X2and X3are N, and X4is CH, CCI or CF.[000127] In an exemplary embodiment of R3of Formula (3), Xi, X2and X4are N, and X3is CH, CCI or CF.[000128] In an exemplary embodiment of R3of Formula (3), X2, X3and X4are N, and Xi is CH, CCI or CF.[000129] In an exemplary embodiment of R3of Formula (3), Xi, X3and X4are N, and X2is CH, CCI or CF.[000130] In an exemplary embodiment of R1of Formula (3), and X4are NX.1, X2, X3[000131] In an exemplary embodiment of Formula (3), each heteroaryl is independently a 5- to 6- membered ring containing from 1-3 nitrogen atoms. In a further embodiment, the 5- membered heteroaryl ring additionally contains a sulfur atom or an oxygen atom. In every case, the 5- to 6- membered heteroaryl ring may be further substituted.[000132] In an exemplary embodiment of Formula (3), each heterocyclyl is independently a non-aromatic 4- to 7- membered ring containing from 1 to 3 nitrogen atoms. In a further embodiment, the 4- to 7- membered heterocyclic ring additionally contains from 1 to 2 oxygen or sulfur atoms, with the proviso that if the ring size is 4 or 5, the total number of ring heteroatoms is 1, 2 or 3, and if the ring size is 6 or 7, the total number of ring heteroatoms is 1, 2, 3 or 4. In every case, the 4- to 7- membered heterocyclic ring may be further substituted.[000133] In an exemplary embodiment of Formula (3), the heteroaryl is a pyridine, pyridone, oxazole, isoxazole, thiazole, isothiazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine or 1,3,5- triazine, where the heteroaryl ring may be further substituted.[000134] In an exemplary embodiment of Formula (3), the heterocyclyl is an azetidine, morpholine, thiomorpholine, pyrrolidinone, pyrrolidinine, 2-pyrroline, 3-pyrroline, pyrazolidine, 2-pyrazoline, 2-imidazoline, imidazolidine, piperidine or piperazine, where the heterocyclyl ring may be further substituted.[000135] In an exemplary embodiment of Formula (3), R18is (CH3)2SO2-, CF3-, CF2H-, -CN, CF3O-, CF2HO-, a N-linked pyrazole, a C-linked pyrazole or a pyridine.[000136] An aspect of the invention is a pharmaceutical composition comprising any compound of the invention as described herein (such as Formula (1), Formula (2) or Formula (3)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.[000137] In an exemplary embodiment, the pharmaceutical composition comprising any compound of the invention as described herein (such as Formula (1), Formula (2) or Formula (3)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof further comprises one or more anticancer agents.[000138] 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 Formula (1), Formula (2) or Formula (3)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.[000139] In an exemplary embodiment, the disease to be treated is cancer. In particular embodiments, 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[000140] 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.[000141] 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 LD5o(the dose lethal to 50% of the population)and the ED5o (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 LD5o / 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.[000142] 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.[000143] 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.[000144] 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.[000145] The term "inhibitory compound" as used herein, refers to any compound capable of interacting with (i.e., for example, attaching, binding, etc.) to a binding partner under conditions such that the binding partner becomes unresponsive to its natural ligands. Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins / peptides.[000146] 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.[000147] 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.[000148] The term "administered" or "administering" as used herein, refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient. An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular administration, such as subcutaneous, intramuscular, or intraperitoneal), intravenous, oral ingestion, transdermal patch, topical, inhalation, suppository, etc.[000149] The term "patient" as used herein, is a human or animal and needs not be hospitalized. For example, out-patients and persons in nursing homes are "patients." A patient may be a human or non-human animal of any age and therefore includes both adults and juveniles (i.e., children). It is not intended that the term "patient" connote a need for medical treatment. Therefore, a patient may voluntarily be subject to experimentation, whether clinical or in support of basic science studies.[000150] 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.[000151] 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.[000152] 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.[000153] The term "test compound" as used herein, refers to any compound or molecule considered a candidate as an inhibitory compound.[000154] The term "combination therapy" as used herein refers to refers to a dosing regimen of two or more different therapeutically active agents during a period of time, wherein the therapeutically active agents are administered together or separately. In one embodiment the combination therapy is a non-fixed combination.[000155] 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.[000156] 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.[000157] The term "in vivo" as used herein refers to an event that takes place in a subject's body.[000158] The term "in vitro" as used herein refers to an event that takes places outside of a subject's body.[000159] 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 typicallysulfur. In general, a protein comprises amino acids having an order of magnitude within the hundreds.[000160] 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.[000161] 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.[000162] 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.[000163] The term "pharmaceutically acceptable salt" as used herein, refers to a salt that does not adversely impact the biological activity and properties of the compound and is suitable for use in contact with the tissues of subjects without undue toxicity, irritation and / or allergic response and the like. Pharmaceutically acceptable salts include those derived from suitable inorganic acids, organic acids and bases, and include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, naphthalene sulfonic acid, lactic acid, succinic acid, oxalic acid, stearic acid, and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt (e.g., a sodium or a potassium salt), an alkaline earth metal salt (e.g., a calcium or a magnesium salt), a salt formed from an organic base, and an amino acid salt. Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, and ammonium and quaternary ammonium compounds. Specific metals include, but are not limited to, sodium, lithium,potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts may be prepared include, for example, primary, secondary, and tertiary amines.[000164] 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.[000165] 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.[000166] 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.[000167] 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.[000168] 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,125l,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.[000169] The term "conjugate" as used herein, refers to any compound that has been formed by the joining of two or more moieties.[000170] 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 linkinggroup, a crosslinking group, or a joining group refers to any molecular arrangement that will connect moieties by covalent bonds such as, but not limited to, one or more amide group(s). Additionally, although the conjugate may be unsubstituted, the conjugate may have a variety of additional substituents connected to the linking groups and / or connected to the moieties.[000171] 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.[000172] 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-CH3 are 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)i.3-haloalkyl, (CH2)i.3-heterocyclyl, (CH2)I-3- aryl, (CH2)i.3-heteroaryl, thioalkyl (e.g., S-CH3), hydroxyalkyl (e.g., CH2OH), alkyl ether (e.g., CH2OCH3), alkynyl (e.g., -CsCRf), 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)i-3Rf, -C(=O)O(CH2)i-3Rf, -C(=0)(CH(CH3))(CH2)o-3Rf, -C(=0)0(CH(CH3))(CH2)o-3Rf, -C(=0)(C(CH3)2)(CH2)o-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.[000173] 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.[000174] 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.[000175] 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, whilesaturated 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.[000176] 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".[000177] The term "bicyclic compounds" as used herein, encompasses "bridged" compounds, "fused" compounds and "spiro" compounds as described.[000178] 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, 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).[000179] 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, l,4-diazabicyclo[2.2.2]octane, other bridged piperazines and bridged piperidines.[000180] 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 aswhen these rings are fused to a pyrrolidine ring. Other examples include two fused pyrrolidine rings (octahydropyrrolo[3,4-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).[000181] 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).[000182] 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.[000183] The term "halogen" as used herein, refers to any fluoro, chloro, bromo, or iodo moiety.[000184] 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.[000185] 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)i-5-NH2, - (CH2)1-5-NHCH3, -(CH2)1-5-N(CH3)2, -(CHzJi-s-NH-JCHjJi-s-NJCHa)^ and the like.[000186] 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.[000187] The term "heteroarylalkyl" as used herein, means any alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH2pyridinyl, -CFhpyrimidinyl, and the like.[000188] 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.[000189] 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.[000190] 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.[000191] 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.[000192] 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.[000193] 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.[000194] 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 toanother 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.[000195] As used herein, "reactive groups" refer to nucleophiles, electrophiles, or radically active groups, i.e., groups that react in the presence of radicals. A nucleophile is a moiety that forms a chemical bond to its reaction partner (the electrophile) by donating both bonding electrons. Electrophiles accept these electrons. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge on an element and displaces the group it is bonded to. Alternatively, nucleophiles may take part in substitution of carbonyl group. Carboxylic acids are often made electrophilic by creating succinyl esters and reacting these esters with aminoalkyls to form amides. Other common nucleophilic groups are thiolalkyls, hydroxylalkyls, primary and secondary amines, and carbon nucleophiles such as enols and alkyl metal complexes. Other preferred methods of ligating proteins, oligosaccharides and cells using reactive groups are disclosed (Lemieux et al., Trends in Biotechnology 1998, 16, 506, incorporated herein by reference in its entirety). In yet another preferred method, one provides reactive groups for the Staudinger ligation, i.e., "click chemistry" with an azide comprising moiety and alkynyl reactive groups to form triazoles. Michael additions of a carbon nucleophile enolate with an electrophilic carbonyl, or the Schiff base formation of a nucleophilic primary or secondary amine with an aldehyde or ketone may also be utilized. Other methods of bioconjugation are provided (Hang et al. Accounts of Chemical Research 2001, 34, 727, and Kiick et al. Proc Natl Acad Sci US.A. 2002, 99, 19, both of which are incorporated by reference in its entirety).[000196] 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. Asubstantial 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.[000197] 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.[000198] "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 localadvanced or metastatic urothelial carcinoma), bladder cancer, hepatoma, breast cancer and head and neck cancer.[000199] 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%.[000200] 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.[000201] 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.[000202] 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, anysuitable orally deliverable dosage form can be used, including without limitation water, glycols, oils, alcohols, and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents, and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms. Injectable compositions or intravenous infusions are also provided in the form of solutions, suspensions, and emulsions. For parenteral compositions, the carrier usually comprises sterile water and possibly other ingredients to aid solubility. Injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution, or a mixture of a saline and a glucose solution. Suitable oils include, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives as needed, where the additives may facilitate administration of the composition to the skin and / or may facilitate preparation of the compositions to be delivered. These compositions may be administered in various ways, e.g., as a transdermal patch or as an ointment. Acid or base addition salts of the compounds of the invention are typically more suitable in the preparation of aqueous compositions due to their increased water solubility over the corresponding neutral form of the compounds.[000203] 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.[000204] 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.[000205] 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.[000206] 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.[000207] 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 the legibility of the chemical structures in the original application is adversely affected by publication of the application.[000208] 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 (125l), carbon-14 (14C), nitrogen-15 (15N), sulfur-35 (35S) and chlorine-36 (36CI). 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 deuteriumatoms, 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 (125l), 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.[000209] In an embodiment of the invention, a compound of the invention as defined herein (such as a compound of Formula (1), Formula (2) or Formula (3)) 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%.[000210] 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), Formula (2) or Formula (3)) 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%.[000211] 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).[000212] In an exemplary embodiment of the invention, the cancer to be treated is a cancer bearing a PI3K H1047 mutation (such as H1047R) (Thorpe et al., Nat Rev Cancer 2015, 15, 7).[000213] The compounds of the invention (such as defined by Formula (1), Formula (2), or Formula (3)) are typically PI3Ka mutant-selective inhibitors that exhibit greater selectivity for any of the H1047R, H1047L, H1047Y, E542K, or E545K mutations over the wild-type. As such, the compounds may decrease the amount of phosphorylated AKT (pAKT) and decrease proliferation selectively in PI3Ka mutant cell lines, across several tumor types.[000214] 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) such as, but not limited to letrozole or anastrozole, a selective estrogen receptor modulator (SERM) such as,but not limited to tamoxifen, or a selective estrogen receptor degrader (SERD) such as, but not limited to, fulvestrant, elacestrant, or camizestrant may exhibit a combination benefit leading to tumor regression in ER+ / 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 inhibitor such as, but not limited to atirmociclib, ribocicl ib, abemaciclib, or palbociclib, 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.[000215] A PI3K H1047R mutant selective inhibitor of the invention (such as defined by Formula (1), Formula (2) or Formula (3)) dosed in combination with a HER2 inhibitor such as, but not limited to, tucatinib or trastuzumab may exhibit a combination benefit leading to tumor regression in ER- / HER2+ / PI3K H1047R mutant tumors such as, but not limited to, the breast cancer xenograft model HCC1954, at doses where little or no regression would be observed with either single agent.[000216] Compounds of Formula (1), Formula (2) and Formula (3) of the present invention may be generally prepared according to the synthetic routes identified in Schemes 1-20.[000217] Substituted (hetero)aryl inputs necessary for the synthesis of compounds of Formula (1) are either commercially available or readily prepared via the use of known synthetic chemistry methods. For example, commercially available aminophenylphosphine oxide 1 may be used as a nucleophilic reactant in the subsequently described synthetic Schemes, or it can be transformed into the corresponding iodide 2 for use in transition metal-mediated couplings via a Sandmeyer reaction under standard reaction conditions, Scheme 1.Scheme 11 2[000218] The preparation of (hetero)aryl phosphate esters (e.g., dimethyl (2- bromophenyl)phosphonate 5) may be accomplished by copper-oxide-mediate couplings of (hetero)aryl boronic acids (e.g., 3) with dimethylphophonate to provide suitable coupling partners in transition metal-mediated couplings, Scheme 2. Such phosphate esters may be transformed by reaction with Grignard reagents into alkyl phosphinates (e.g., 6) that are also suitable for use as coupling partners.Scheme 2[000219] Halogen-substituted (hetero)aryl sulfones and sulfonamides are either readily available from commercial sources (e.g., 7 where Ra= CH3or NH2, respectively) or can be prepared via known synthetic chemistry methods, Scheme 3. For example, benzene thiols such as 8 may be alkylated with alkyl halides (e.g., iodoethane) under basic conditions to provide thioethers such as 9. Subsequently, the thioether functionality may be oxidized by any of a number of reagents (for example, such as meta-chloroperoxybenzoic acid) to afford aryl sulfones like 10. Alternatively, aryl sulfones 10 can be prepared from the corresponding aryl sulfinic acids 8 via SN2 alkylations with alkyl bromides or alkyl iodides in the presence of an appropriate base (e.g., potassium carbonate). Heteroarylsulfones (for example, pyridyl sulfone 13) may be prepared by reacting sodium methylsulfinate with 2-fluoro- or 2-chloropyridines (such as 11). The preparation of alkyl aryl sulfones (such as 19 or 20) containing oxygen- or nitrogen-linked chains may be achieved from an appropriate halogen methyl-substituted sulfone (e.g., but not limited to, l-bromo-2-((chloromethyl)sulfonyl)benzene 16). The synthesis of 16 may beachieved by alkylating aryl sulfinate 14 with bromochloromethane. Oxygen- or nitrogen- linked species inputs, 19 or 20, respectively, can be synthesized from 16 via alkylations of alcohols 17 or amines 18 in the presence of an appropriate base (e.g., but not limited to, sodium hydride or potassium carbonate).[000220] Sulfoximine-containing inputs may be prepared from thioethers, Scheme 4.Thioether-containing nitrobenzenes (for example, but not limited to, 21) may be reacted with ammonium carbamate in the presence of phenyliodonium reagents to yield sulfoximinecontaining intermediates like 22. The sulfoximine may optionally be further functionalized via an alkylation step to yield species such as 23. Reduction of the nitro group of 23 (e.g., by iron in the presence of ammonium chloride) can yield anilino sulfoximines 24.Scheme 4[000221] Halogen-substituted (hetero)aryl methylsulfones may be readily prepared from the appropriate substituted benzyl halides, Scheme 5. Displacement of the benzyl halide group of aryls such as 25 by alkali alkylsulfonates (such as sodium methanesulfinate) can yield the requisite sulfones 26. Halogen-substituted (hetero)aryl methylnitriles analogous to sulfones 26 may be prepared via similar SN2 displacements of benzyl halides by using potassium cyanide instead of sodium methanesulfinate to yield 28. Corresponding (methylsulfonyl)cyclopropyl (hetero)aryl halide inputs such as 31 may be prepared from 26 via a condensation / addition- cyclization sequence.Scheme 5[000222] Various halogen-substituted (hetero)aryl difluoromethyls, methyldifluoromethyls, and trifluoromethyls (32, 33, and 34) are commercially available inputs, Scheme 6.Scheme 632 33 34[000223] Pyridone inputs are either readily available from commercially available sources or may be prepared via known synthetic chemistry methods, Scheme 7. Bromopyridones such as 35 can be alkylated at the nitrogen position using standard alkylation conditions to yield substituted pyridones like 36.Scheme 7[000224] Dihydrobenzothiophene dioxide inputs may be readily prepared from commercially available benzothiophenes, Scheme 8. Oxidation of benzothiophenes 37 can be accomplished via a number of oxidizing reagents (e.g., m-CPBA) to give rise to benzothiophene dioxides 38. Subsequent partial reduction of compounds 38 (e.g., with NaBH4) can yield the requisite dihydrobenzothiophene dioxides 39.Scheme 8[000225] Dihydrobenzoisothiazole dioxide inputs may be readily prepared from commercially available 2-fluorobenzoate esters, Scheme 9. Nucleophilic displacement of the appropriate fluoride of 40 with phenylmethanethiol (41) after treatment with base (e.g., NaH) can yield thioethers 42. Oxidation of thioether moiety of 42 (e.g., with NCS) can give rise to sulfonyl chlorides 43. After reacting sulfonyl chlorides 43 with amines 44 (e.g., but not limited to, PG = benzyl or dimethoxylbenzyl) to furnish sulfonamides 45, the ester functionality within compounds 45 can be reduced (e.g, with di-isobutylaluminum hydride) to give rise to primary alcohols 46. Such sulfonamide-alcohol-containing species may then be cyclized (e.g., via standard Mitsunobu reaction conditions) to afford the requisite dihydrobenzoisothiazole dioxide inputs 47.Scheme 945 46 47[000226] The bicyclic cores of the present invention may be synthesized by cyclization methodologies, Scheme 10. The synthesis of pyridopyrimidinone core intermediates may begin with appropriately substituted 2-fluoropyridines 48. In the case of 48, where R7is methyl, this is commercially available. In other cases, the starting material may be prepared via established methods known to those skilled in the art. The addition of malonate functionality to 48 can be accomplished via base-mediated SNAr reactions under standard conditions (e.g., Cs2CO3andheat). Subsequent decarboxylation of 50 to yield heteroarylacetic esters 51 can be accomplished under thermal conditions (e.g., LiCI at 100 °C). Esters 51 may then be condensed with aryl malonates 52 to give rise to carboxylate-substituted pyridopyrimidinone intermediates 53 (for a similar transformation, see Kappe, T., et al., 1983, 114, 349). Decarboxylations of 53 via acidic or basic conditions can yield hydroxyl-substituted pyridopyrimidinone intermediates 54.Scheme 10[000227] Pyridopyridinones 56 can be functionalized in a number of ways to give rise to intermediates that enable the preparation of the compounds of the present invention; one such sequence is depicted in Scheme 11. The hydroxyl group of intermediates 56 may be converted to triflates 56. Alternatively, the hydroxyl group of intermediates 56 can be converted to the corresponding halides (e.g., Cl) via treatment with the appropriate phosphoryl oxyhalide (e.g., phosphoryl oxychloride), resulting in intermediates that could be elaborated further as described for the analogous triflates 57. Then, standard transition-metal-mediated couplings can be employed to selectively introduce side chains at the triflate position (e.g., Buchwald couplings with piperazine inputs) to yield 58. To convert the bromide within compounds 58 to the ketones 59, a Stille coupling reaction may be employed using an appropriate tin reagent such as (a- ethoxyvinyl)-tributyl tin followed by acid hydrolysis (Sugiyama, et al., Bull. Chem. Soc. Jpn. 1987, 60(2), 767-768). Alternatively, conversion of 58 to 59 may be accomplished by other establishedmethods, 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). It should be understood that apart from the methodology described in Scheme 11, there are other reported methods that can be utilized to prepare pyridopyrimidinones (for example, see the following reports and references cited therein: Schwartz, A., et al., J. Heterocyclic Chem. 1987, 24, 645;Newkome, G., et al., Heterocycles, 1988, 2, 385; Kudak, S., et al., J. Med. Chem. 2011, 54, 4773; Zhao, D. et al., Angew. Chem. Int. Ed. 2015, 54, 4508; Zhou, X., et al., Org. Lett. 2019, 21, 9114).Scheme 1[000228] Ketone-substituted pyridopyridones like 59 may be transformed into the compounds of the present invention in any of a number of ways; one such way is depicted in Scheme 12. Reduction of the ketones 59 to alcohols 60 may then be accomplished by use of an appropriate hydride reducing agent (such as sodium borohydride). Subsequently, the alcohol group within compounds 60 can be activated for further functionalization via its conversion to a leaving group such as a mesylate (compounds 61). Then, via SN2 displacements with nucleophilic amines 62 under basic conditions can convert 61 to the corresponding benzyl amines 63. Alternatively, should the nucleophilic amines be suitably activated via appropriate substitution patterns, such amines could be coupled directly with benzylic alcohols 60 to give the desired benzyl amines 63 (e.g., under Mitsunobu conditions). The individual stereoisomers of such amines 63 can be isolated after their separation via chiral chromatography methods (e.g., chiral HPLC).[000229] A synthesis leading to a single enantiomer intermediate such as 71 is depicted inScheme 13. This reaction sequence utilizes the formation of a chiral sulfinyl imine to control the stereochemistry. Such methods have been extensively reported. Ketones 66 may be converted to chiral sulfinyl-imines 67 via known procedures, which may then in turn be reduced to the sulfinyl-amines 68 in a stereo-controlled fashion using a suitable reducing agent (Datta and Ellman, J. Org. Chem. 2010, 75, 6283-6285; Ellman etal., Acc. Chem. Res. 2002, 35, 984-995; Ellman et al., J. Org. Chem. 2007, 72, 626-629; Colyer et al., Journal of Organic Chemistry 2006, 71(18), 6859-6862). With use of the R isomer of the sulfinyl group, generally, resulting a predominantly the R, R - isomer of the product when (for example) the reducing agent used is a mixture of sodium borohydride and cerium chloride-heptahydrate. The use of this particular reducing system has been shown to be effective at reducing imines and may often give enhanced stereo-control in similar reductions (Hua et al, Synthesis 1991, (11), 970-4; Zhu et al, Journal of Chemical Research 2015, 39(7), 390-393). The major isomer may be separated from the other minor isomer via standard chromatographic means. As has been demonstrated in the preceding literature references a judicious choice of the antipode of the sulfinyl-imine and the reducing agent may give access to either antipode of the sulfinyl-amine. The sulf inyl-am ine can be cleaved to the single enantiomer of the chiral amine 69 using standard conditions (such as hydrogen chloride in dioxane). A standard coupling reaction of amine 69 with the (hetero)aryl halide 70 (such as an Ullman coupling or Buchwald-Hartwig coupling for 70, Hal = I or Br) maythen give the resulting (hetero)aryl amine derivative 71 (Yang et al, Organic Process Research & Development 2022, 26(6), 1690-1750; Surry and Buchwald, Chemical Science 2011, 2(1), 27-50). Alternatively, SNAr reactions with amines 69 with (hetero)aryl halides 70 may also give rise to intermediates 71 should the inputs 70 be reactive enough (e.g., Hal = F or Cl and R1be an electron-withdrawing functionality).Scheme 1368(Major diastereoisomer)Buchwald-Hartwig coupling69 or SNAr[000230] Certain final compounds 74-76 may be prepared as outlined in Scheme 14.Intermediates 72 may be reacted under suitable Buchwald-Hartwig coupling conditions with an amine 73, wherein R' and R" may be either alkyl or aryl or one of R' and R" may be hydrogen. R' and R" may also be joined to form a ring. In some cases, the R' and / or R" groups may be further elaborated prior to subsequent steps. The racemic compounds 74 may then be separated into individual enantiomers (75 and 76) utilizing chiral chromatography (HPLC or SFC).[000231] Single enantiomers 78 may be prepared directly as shown in Scheme 15 from the enantiomerically pure intermediates 77 using chemistry analogous to that shown in Scheme 15.Scheme 1577 73 78[000232] In some cases, the order of reactions may be adjusted as shown in Scheme 16. In this case a Buchwald-Hartwig coupling with the intermediates 79 and appropriately substituted amines 73 can give 80. Removal of the sulfinyl group to give 81 may then be followed by a Buchwald-Hartwig coupling with (hetero)arylhalides 82 (e.g., X = I or Br) to give compounds such as 83. Alternatively, intermediate 81 may undergo an SNAr reaction with suitably reactive (hetero)arylhalides 82 (e.g., X = F or Cl with R1being an electron-withdrawing group) to give compounds 83.Scheme 16[000233] Compounds where there is an oxygen- or sulfur-linked substitution from the 2- position of the pyridopyrimidinone ring may be prepared as shown in Scheme 17. The intermediate 77 may undergo a Buchwald-Hartwig coupling with an appropriate sulfhydryl compound to give 85. Alternatively intermediate 77 may undergo an SNAr reaction with an appropriate alcohol (this reaction may be mediated by a base, for example, sodium hydride) to give compounds such as 87.Scheme 17[000234] In the cases where the substitution from the 2-position of the pyridopyrimidinone ring system is either an alkyl or an alkenyl group, these compounds may be prepared as shown in Scheme 18. The intermediate 72 may undergo a Suzuki coupling reaction (Stanforth, S.P. Tetrahedron 1998, 54(3 / 4), 263-303) with suitable alkenyl-boronates 88 (or, alternatively, corresponding boronic acids) to give 89. The racemate 89 may then be subjected to chiral chromatographic separation to give the enantiomers 90 and 91. Alternatively the double bond of 89 may be reduced under standard hydrogenation conditions (e.g., hydrogen with a palladium catalyst). Following chiral chromatographic separation this may give the enantiomers 92 and 93. In the case where R and R' do not form a symmetrical arrangement, further isomers may result which may also be separated chromatographically.[000235] In the case where the substitution from the 2-position of the pyridopyrimidinone group is an aryl or heteroaryl group, these types of compounds may be prepared in an analogous method to that shown in Scheme 18. As depicted in Scheme 19, a Suzuki coupling reaction between 72 and an appropriate aryl (or heteroaryl) borononate (or boronic acid) may give, following chiral separation, the enantiomers 94 and 95.Scheme 19[000236] An alternative mode of synthesis of aryl- or heteroaryl-substituted pyridopyrimidinones is depicted in Scheme 20. A Suzuki coupling reaction between intermediates 79 and appropriate aryl or heteroaryl boronates (or boronic acids) followed by removal of the sulfinyl group can yield intermediates 96. An Ullman or Buchwald-Hartwig coupling between amines 95 and (hetero)arylhalides 82 may give compounds such as 97. Alternatively, amines 96 may undergo an SNAr reactions with suitably substituted (hetero)arylhalides 82 (e.g., where X = F or Cl and R1is an electron-withdrawing group) to also give compounds 97.Scheme 201. Suzuki coupling2. Sulfinyl removalAryl or heteroaryl boronate (or boronic add)Ullman orBuchwald-Hartwig coupling or SwAr62[000237] The chemistries depicted in Schemes 1 to 20 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.Experimental[000238] All commercially available solvents and reagents were used as received. AllXH 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.[000239] The following represents acronyms used in the experimental section for well-known chemical solvents, reagents, parameters and techniques:XH NMR: proton nuclear magnetic resonance spectroscopyAC2O: acetic anhydrideACN: acetonitrileAcOH: acetic acidBl NAP: 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl c-Bu: cyclobutyl c-Pr: cyclopropylGDI: carbonyl diimidazoleCeCI3: cerium (III) chlorideCH2CI2: dichloromethaneCH3I: iodomethaneCHCI3: chloroformCH3CN: acetonitrileCO2: carbon dioxideCs2CO3: cesium carbonateCsF: cesium fluorideCui: copper iodideCu2O: copper oxideDBAD: di-tert-butyl azodicarboxylateDBU: l,8-Diazabicyclo[5.4.0]undec-7-eneDCM: dichloromethaneDIBAL: diisobutylaluminum hydrideDIEA: N.N-diisopropylethylamineDIPEA: N.N--diisopropylethylamineDMA: N.N--dimethylacetamideDMF: A / ,A / -dimethylformamideDMSO: dimethyl sulfoxideDTAD: di-tert-butyl azodicarboxylateEA: ethyl acetate ee: enantiomeric excessEtzO: diethyl etherEt3N: triethylamineEt3SiH : triethylsilaneEtOAc: ethyl acetateEtOH: ethanolFA: formic acid h: hoursH2O: waterHATU: l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHBr: hydrobromic acidHCI: hydrochloric acidHex: hexanesHPLC: high-performance liquid chromatographyIPA: isopropanolK2CO3: potassium carbonateK3PO4: potassium triphosphateKOAc: potassium acetateLCMS: liquid chromatography mass spectrometryLiCI: lithium chlorideLiOH: lithium hydroxide mCPBA: meta-chloroperoxybenzoic acidMe: methylMeCN: acetonitrileMeOH: methanol mg: milligramMgSO4: magnesium sulfate min: minutes ml_: milliliterMsCI: methanesulfonyl chlorideMS2O: methanesulfonic anhydrideNaBH4: sodium borohydrideN2: nitrogenNaCI: sodium chlorideNa2COa: sodium carbonateNaH: sodium hydrideNal: sodium iodideNaOH: sodium hydroxideNaHCO3: sodium bicarbonateNaH2PO4: monosodium phosphateNa2SO3: sodium sulfiteNa2SO4: sodium sulfateNH3: ammoniaNH4CI: ammonium chlorideNH4HCO3: ammonium bicarbonateNH4OH: ammonium hydroxide(NH4)2CO3: ammonium carbonateNMP: M-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(l I )Pd(dppf)CI2: (l,r-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 etherPOCI3: phosphorus oxychloridePPh3: triphenylphosphinePrep: preparativePyBOP: benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphateRuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenylRuPhos-Pd-G3: methanesulfonato(2-dicydohexylphosphino-2' / 6’-di-isopropoxy-l,r-biphenyl)(2’- amino-l;l‘-biphenyl-2-yl)palladium(ll)SEM-CI: 2-(trimethylsilyl)ethoxymethyl chlorideSiO2: silicaTBAF: tetrabutylammonium fluorideTBAI: tetrabutylammonium iodide (See scheme 5)TBSCI: tert-butyldimethylsilyl chlorideTEA: triethylamineTFA: trifluoroacetic acidTHF: tetrahydrofuranTi(OEt)4: titanium (IV) ethoxideTi(Oi-Pr)4: titanium(IV) isopropoxideTLC: thin-layer chromatographyXantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneXphos-Pd-G4: (SP-4-3)-[Dicyclohexyl[2',4',6'-tris(l-methylethyl)[l,r-biphenyl]-2- yl]phosphine](methanesulfonato-KO)[2'-(methylamino-KN)[l,r-biphenyl]-2-yl-KC]palladiumZn(CN)2: zinc cyanide[000240] Intermediate 1: 2-methyl-5-(piperazin-l-yl)pyrimidineStep 1: Preparation of benzyl 4-(2-methylpyrimidin-5-yl)piperazine-l-carboxylate[000241] To a stirred mixture of 5-bromo-2-methylpyrimidine (2.0 g, 11.5 mmol) and benzyl piperazine-l-carboxylate (2.0 g, 8.9 mmol) in toluene (30.0 ml) were added CS2CO3 (5.8 g, 17.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.5 g, 1.8 mmol) and RuPhos (0.8 g, 1.8 mmol) at room temperature. The resulting mixture was stirred for overnight at 100 °C under a nitrogen atmosphere. The reaction was diluted with water (40 mL) at room temperature and the resulting mixture was extracted with EtOAc (2 x 40 mL). The combined organic phases were washed withbrine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2:MeOH, to afford benzyl 4-(2-methylpyrimidin-5-yl)piperazine-l-carboxylate (2.0 g, 72 % yield) as a yellow solid.XH NMR (400 MHz, DMSO-d6): 6 8.40 (s, 2H), 7.38 (d, J = 4.3 Hz, 4H), 7.37- 7.28 (m, 1H), 5.11 (s, 2H), 3.59 - 3.51 (m, 4H), 3.24 - 3.16 (m, 4H), 2.49 (s, 3H).Step 2: Preparation of 2-methyl-5-(piperazin-l-yl)pyrimidine[000242] To a stirred mixture of benzyl 4-(2-methylpyrimidin-5-yl)piperazine-l-carboxylate (2.0 g, 6.4 mmol) in MeOH (30 mL) was added 10% Pd / C (500 mg, 4.7 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford 2-methyl-5-(piperazin-l- yl)pyrim idine (900 mg, 79% yield) as a yellow solid.XH NMR (400 MHz, DMSO-ds): 6 8.35 (s, 2H), 3.11 - 3.04 (m, 4H), 2.87 - 2.78 (m, 4H), 2.48 (s, 3H).[000243] Intermediate 2: 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-oneStep 1: Preparation of 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one[000244] In two batches run in parallel, mixtures of 4-iodo-lH-pyridazin-6-one (2.5 g, 11.3 mmol), (2-methylpyrimidin-5-yl) boronic acid (4.66 g, 33.8 mmol), Cu(OAc)2(20.5 g, 113 mmol), and pyridine (8.91 g, 113 mmol, 9.1 mL) in DCE (300 mL) were degassed and purged with nitrogen three times. The two mixtures were then stirred at 60 °C for 12 h under an oxygen (15 psi) atmosphere. The reaction mixtures were then filtered, combined, and concentrated under reduced pressure to give a residue. The residue was diluted with DCM (200 mL) and washed with 10% aqueous ammonium hydroxide (5 x 30 mL). The organic phase was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was triturated with PE:EA = 1:1 (30 mL) at 25 °C for 10 min to afford 5-iodo-2- (2-methylpyrimidin-5-yl)pyridazin-3(2H)-one (5.04 g, 59% yield) as an off-white solid. LCMS: (ESI+) m / z = 314.8 (M+H).[000245] Intermediate 3: 5-fluoro-3-(4-iodo-6-oxopyridazin-l(6H)-yl)-2-methylpyridine 1- oxideStep 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine[000246] To a solution of 3-bromo-5-fluoro-2-methyl-pyridine (4.5 g, 23.7 mmol) and bis(pinacolato)diboron (6.62 g, 26.1 mmol) in dioxane (50 mL) was added KOAc (6.97 g, 71.1 mmol) and Pd(dppf)CI2(3.47 g, 4.74 mmol). The mixture was stirred at 70 °C for 16 h under a nitrogen atmosphere. The resulting mixture was then partitioned between EA (500 mL) and water (500 mL). The organic phase was separated, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (PE: EA = 50:1 to 15:1) to afford 5-fluoro-2- methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (5.2 g, 92% yield) as a yellow oil. XH NMR (400 MHz, CDCI3): 6 8.48 - 8.26 (m, 1H), 7.85 - 7.61 (m, 1H), 2.72 (s, 3H), 1.36 (s, 12H).Step 2: Preparation of 2-(5-fluoro-2-methyl-3-pyridyl)-5-iodo-pyridazin-3-one[000247] A mixture of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (5.0 g, 21.1 mmol), 4-iodo-lH-pyridazin-6-one (4.26 g, 19.2 mmol), Cu(OAc)2(6.96 g, 38.4 mmol), isoquinolin-6-ol (0.56 g, 3.83 mmol), TEA (19.4 g, 192 mmol, 26.7 mL), Na2SO4(27.2 g, 192 mmol) and boric acid (5.93 g, 95.9 mmol) in DCE (50 mL) was degassed and purged with oxygen three times. The mixture was then stirred at 50 °C for 5 h, then filtered and the filtrate was partitioned between DCM (500 mL) and saturated aqueous NaHCOj (500 mL). The organic phase was separated, washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE:EA = 50:1 to 8:1) to afford 2-(5-fluoro-2-methyl-3-pyridyl)-5-iodo-pyridazin- 3-one (2.4 g, 37% yield) as a yellow solid. LCMS: (ESP) m / z = 332.0 (M+H).Step 3: Preparation of 5-fluoro-3-(4-iodo-6-oxopyridazin-l(6H)-yl)-2-methylpyridine 1-oxide[000248] In two batches run in parallel, m-CPBA (85% purity, 2.02 g, 9.95 mmol) was added to a 0 °C mixture of 2-(5-fluoro-2-methyl-3-pyridyl)-5-iodo-pyridazin-3-one (1.9 g, 5.74 mmol) in DCM (30 mL) in portions. The mixture was then stirred at 25 °C for 12 h. To the mixture was then added saturated aqueous NaHSO3(50 mL) and the resulting mixture was stirred for 10 min. The mixture was then partitioned between DCM (200 mL) and water (200 mL). The organic phasewas separated, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was suspended in DMF (10 mL) and the precipitate was filtered off. The filtrate was then purified by prep-HPLC (column: Phenomenex luna C18 (250 x 70 mm, 10 pm); mobile phase: [H2O (0.225% FA)-ACN]; gradient: l%-30% B over 26 min) to afford 5-fluoro-3-(4-iodo-6-oxopyridazin-l(6H)-yl)-2-methylpyridine 1- oxide (1.53 g, 38% yield) as a yellow solid. LCMS: (ESI+) m / z = 347.8 (M+H).[000249] Intermediate 4: 5-bromo-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2- yl)pyrimidine 1-oxideStep 1: Preparation of 5-fluoro-l-methyl-6-oxo-l,6-dihydropyridine-2-carbonitrile[000250] To a mixture of 5-fluoro-6-oxo-lH-pyridine-2-carbonitrile (10 g, 72.4 mmol) and K2CO3(20.0 g, 145 mmol) in ACN (100 mL) was added iodomethane (15.4 g, 109 mmol). The mixture was stirred at 25 °C for 12 h and then the mixture was poured into ice water (100 mL) and stirred for 3 min. The mixture was then extracted three times with ethyl acetate (50 mL each). The organics were combined and washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (PE:EA = 100:1 to 3:1) to afford 5-fluoro-l-methyl-6-oxo-l,6- dihydropyridine-2-carbonitrile (7.5 g, 68% yield) as a white solid. LCMS: (ESI+) m / z = 153.1 (M+H).Step 2: Preparation of 5-fluoro-N'-hydroxy-l-methyl-6-oxo-l,6-dihydropyridine-2-carboximidamide[000251] To a solution of 5-fluoro-l-methyl-6-oxo-pyridine-2-carbonitrile (7.5 g, 49.3 mmol) in ethanol (75 mL) was added TEA (24.9 g, 247 mmol) and hydroxylamine hydrochloride (10.3 g, 148 mmol). The mixture was stirred at 80 °C for 0.5 h and then concentrated under reduced pressure. The residue was suspended in water (20 mL) and the resulting precipitate was collected by filtration to afford 5-fluoro-N'-hydroxy-l-methyl-6-oxo-l,6-dihydropyridine-2- carboximidamide (7.2 g, 78% yield) as a white solid. LCMS: (ES ) m / z = 186.0 (M+H).Step 3: Preparation of 5-bromo-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyrimidine 1- oxide[000252] In fourteen batches run in parallel, trifluoroacetic acid (369 mg, 3.24 mmol, 0.24 mL) was added to a mixture of 5-fluoro-N'-hydroxy-l-methyl-6-oxo-l,6-dihydropyridine-2- carboximidamide (500 mg, 2.70 mmol) and 2-bromopropanedial (611 mg, 4.05 mmol) in IPA (15 mL). The resulting mixture was stirred at 90 °C for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA = 3:1 to 0:1) to afford 5- bromo-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyrimidine 1-oxide (6.2 g, 55% yield) as a white solid. LCMS: (ESP) m / z = 300.0 (M+H).[000253] Intermediate s: 5-bromo-2'-methyl-[2,5'-bipyrimidine] 1-oxideStep 1: Preparation of 2-methylpyrimidine-5-carbonitrile[000254] In two batches run in parallel, a mixture of 5-bromo-2-methyl-pyrimidine (25.0 g,145 mmol), Zn(CN)j (23.9 g, 204 mmol), and Pd(PPhs)4 (16.7 g, 14.5 mmol) in DMF (150 mL) was stirred under a nitrogen atmosphere at 110 °C for 12 h and then was partitioned betweensaturated aqueous NaHCO3(200 mL) and DCM (100 mL). The aqueous phase was then further extracted with DCM (100 mL x 2). The combined organics were washed with brine (50 L x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE:EA = 10:1 to 5:1) to afford 2- methylpyrimidine-5-carbonitrile (21.7 g, 62% yield) as a white solid. LCMS: ( ESP) m / z = 120.1 (M+H).Step 2: Preparation of N'-hydroxy-2-methylpyrimidine-5-carboximidamide[000255] To a mixture of 2-methylpyrimidine-5-carbonitrile (21.7 g, 182 mmol) and TEA (92.2 g, 911 mmol, 127 mL) in EtOH (200 mL) was added hydroxylamine hydrochloride (38.0 g, 547 mmol) at 25 °C. The resulting mixture was then stirred at 80 °C for 2 h and then concentrated under reduced pressure to give a residue. The residue was triturated with water (20 mL) at 100 °C for 10 min and the resulting precipitate was collected by filtration and dried to afford N1- hydroxy-2-methylpyrimidine-5-carboximidamide (18.2 g, 66% yield) as white solid. LCMS: (ESP) m / z = 153.0 (M+H).Step 3: Preparation of 5-bromo-2'-methyl-[2,5'-bipyrimidine] 1-oxide[000256] In twenty-four batches run in parallel, 2-bromopropanedial (595 mg, 3.94 mmol) was added to a mixture of N'-hydroxy-2-methylpyrimidine-5-carboximidamide (0.5 g, 3.29 mmol) and TFA (674 mg, 5.92 mmol, 0.44 mL) in IPA (15 mL) at 25 °C. The resulting mixtures were heated to 80 °C for 2 h, then cooled to room temperature and quenched with saturated aqueous NaHCO3(20 mL) and extracted with DCM (20 mL x 3). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residues were triturated with EtOAc (20 mL) at 25 °C for 10 min and theprecipitates were collected by filtration, combined, and dried to afford 5-bromo-2'-methyl-[2,5'- bipyrimidine] 1-oxide (9.3 g, 41% yield) as a yellow solid. LCMS: ( ESI+) m / z = 268.9 (M+H).[000257] Intermediate 6: 2'-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5'- bipyrimidineStep 1: Preparation of 5-bromo-2'-methyl-2,5'-bipyrimidine[000258] To a stirred mixture of 2-methylpyrimidin-5-ylboronic acid (1 g, 7.25 mmol) and 5- bromo-2-iodopyrimidine (2.07 g, 7.25 mmol) in dioxane (15 mL) and H2O (3 mL) were added Pd(dppf)CI2(0.53 g, 0.73 mmol) and K2CO3 (3.01 g, 21.8 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C and then was filtered and the filter cake was washed with ethyl acetate (3 x 10 mL). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (eluted with PE:EA = 1:1) to afford 5-bromo-2'-methyl-2,5'-bipyrimidine (1.2 g, 67% yield) as a brown solid. LCMS: (ESI+) m / z = 251.0 (M+H).Step 2: Preparation of 2'-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine[000259] To a stirred mixture of 5-bromo-2'-rnethyl-2,5'-bipyrimidine (400 mg, 1.59 mmol) and bis(pinacolato)diboron (607 mg, 2.39 mmol) in dioxane (10 mL) were added Pd(dppf )CI2(117 mg, 0.16 mmol) and KOAc (469 mg, 4.78 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C. The resulting mixture was then filtered and the filter cake was washed with CH2CI2(3 x 20 mL). The filtrate was concentrated under reduced pressure to afford 2'-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2,5'-bipyrimidine (400 mg, 84% crude yield) which was used directly in the next step without further purification. LCMS: (ESI+) m / z = 299.1 (M+H).[000260] Intermediate 7: l-methyl-6-(trimethylstannyl)pyrazin-2(lH)-oneStep 1: Preparation of l-methyl-6-(trimethylstannyl)pyrazin-2(lH)-one[000261] A solution of 6-chloro-l-methylpyrazin-2-one (500 mg, 3.46 mmol) in dioxane (5 mL) was treated with Pd(PPh3)4 (799 mg, 0.69 mmol) at room temperature under a nitrogen atmosphere, followed by the dropwise addition of hexamethylditin (3.40 g, 10.4 mmol). The resulting mixture was stirred at 100 °C overnight and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase of MeCN in water, 0% to 70% gradient over 30 min) to afford l-methyl-6-(trimethylstannyl)pyrazin-2-one (300 mg, 32% yield) as a light yellow oil. LCMS: (ESP) m / z = 275.0 (M+H).[000262] Intermediate 8: 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-oneStep 1: Preparation of 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one[000263] Copper(ll) acetate (4.50 g, 24.8 mmol) and pyridine (1.96 g, 24.8 mmol) was added to a room temperature mixture of 2-methylpyrimidin-5-ylboronic acid (1.03 g, 7.43 mmol) and 5- iodo-2H-pyridazin-3-one (550 mg, 2.48 mmol) in DCM (10 ml). The resulting mixture was stirred at 60 °C for 12 h under an oxygen atmosphere, and then was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase of MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 min) to afford 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one (250 mg, 32% yield) as a light yellow solid. LCMS: (ES ) m / z = 315.4 (M+H).[000264] Intermediate 9: 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrim idin-2-yl)pyridine 1 -oxideStep 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine[000265] A mixture of 3-bromo-5-fluoro-2-methylpyridine (200 mg, 1.05 mmol) in dioxane (6 mL) at room temperature under a nitrogen atmosphere was treated with bis(pinacolato)diboron (400 mg, 1.58 mmol), followed by the addition of KOAc (155 mg, 1.58 mmol) and Pd(dppf)CI2(86 mg, 0.11 mmol). The resulting mixture was stirred at 100 °C for 0.5 h and then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 5- fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (200 mg crude yield) which was used directly in the next step without further purification. LCMS: (ESP) m / z = 238.0 (M+H).Step 2: Preparation of 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine[000266] A mixture of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (200 mg, 0.84 mmol) in dioxane (6 mL) and H2O (1.2 mL) ) at room temperature under a nitrogen atmosphere was treated with 5-bromo-2-iodopyrimidine (240 mg, 0.84 mmol), Na2CO3(179 mg, 1.68 mmol), and Pd(PPh3)4(97 mg, 0.08 mmol). The resulting mixture was stirred at 100 °C for 3 h, then filtered and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by prep-TLC (100% EA) to afford 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine (150 mg, 69% yield) as an off-white solid. LCMS: (ESI+) m / z = 269.9 (M+H).Step 3: Preparation of 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide[000267] A mixture of 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine (110 mg, 0.41 mmol) in DCM (2 mL) was treated with m-CPBA (106 mg, 0.61 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by prep-TLC (100% EA) to afford 3-(5-bromopyrimidin-2-yl)-5- fluoro-2-methylpyridine 1-oxide (70 mg, 60% yield) as an off-white solid. LCMS: (ESI+) m / z = 284.0 (M+H).Step 4: Preparation of 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)pyridine 1-oxide[000268] A mixture of 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (200 mg, 0.70 mmol) in dioxane (6 mL) at room temperature under a nitrogen atmosphere was treated with bis(pinacolato)diboron (268 mg, 1.06 mmol), KOAc (138 mg, 1.41 mmol) and Pd(dppf )CI2(52 mg, 0.070 mmol). The resulting mixture was stirred at 100 °C for 1 h and then filtered and concentrated under reduced pressure to afford 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyridine 1-oxide (~200 mg crude yield) which was used directly in the next step without further purification. LCMS: (ES ) m / z = 332.2 (M+H).[000269] Intermediate 10: 5-bromo-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2- yl)pyridazin-3(2H)-oneB2pinz,Step 1: Preparation of (5-fluoro-6-methoxypyridin-2-yl)boronic acid[000270] This intermediate was prepared using methods similar to those described in Intermediate 3, Step 1 using 6-bromo-3-fluoro-2-methoxypyridine in place of 3-bromo-5-fluoro- 2-methyl-pyridine. LCMS: (EST) m / z = 172.1 (M+H).Step 2: Preparation of 5-bromo-2-(5-fluoro-6-methoxypyridin-2-yl)pyridazin-3(2H)-one[000271] This intermediate was prepared using methods similar to those described in Intermediate 3, Step 2 using (5-fluoro-6-methoxypyridin-2-yl)boronic acid and 4-bromo-lH- pyridazin-6-one in place of 5-fluoro-2-methyl-3-(4,4,5;5-tetramethyl-l,3,2-dioxaborolan-2- yljpyridine and 4-iodo-lH-pyridazin-6-one, respectively. LCMS: (ESP) m / z = 300.1 (M+H).Step 3: Preparation of 5-bromo-2-(5-fluoro-6-hydroxypyridin-2-yl)pyridazin-3(2H)-one[000272] A mixture of 5-bromo-2-(5-fluoro-6-rriethoxypyridin-2-yl)pyridazin-3(2H)-one (1.0 g, 3.33 mmol) in hydrobromic acid (33 wt % in acetic acid, 10 mL) was stirred at 80°C for 2 h. The resulting mixture was concentrated under reduced pressure to afford 5-bromo-2-(5-fluoro-6- hydroxypyridin-2-yl)pyridazin-3(2H)-one (930 mg crude yield) as a yellow solid which was used as is in the next step without further purification. LCMS: (ESI+) m / z = 286.1 (M+H).Step 4: Preparation of 5-bromo-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyridazin-3(2H)- one[000273] To a stirred mixture of 5-bromo-2-(5-fluoro-6-hydroxypyridin-2-yl)pyridazin-3(2H)- one (300 mg, 1.05 mmol) and K2CO3 (290 mg, 2.10 mmol) in DMF (5 mL) was added Mel (298 mg, 2.10 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and then diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous NajSC , filtered, and then concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA = 1:2) to afford 5-bromo-2-(5-fluoro-l-methyl-6-oxo-l,6- dihydropyridin-2-yl)pyridazin-3(2H)-one (92 mg, 29% yield) as an off-white solid. LCMS: (ESP) m / z = 299.9 (M+H).[000274] Example 1: 7-methyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-oneStep 1: Preparation of 1,3-diethyl 2-(3-bromo-5-methylpyridin-2-yl)propanedioate[000275] To a stirred solution of 3-bromo-2-fluoro-5-methylpyridine (15 g, 78.9 mmol) and diethyl malonate (25.3 g, 158 mmol) in DMSO (150 mL) was added CS2CO3 (51.4 g, 158 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred for 6 h at100 °C. The mixture was diluted with ice water (500 mL) at room temperature and then extracted with EtOAc (3 x 500 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 4:1, to afford 1,3-diethyl 2-(3-bromo-5-methylpyridin-2-yl) propanedioate (6.8 g, 26% yield) as a colorless oil.XH NMR (400 MHz, chloroform-d): 6 8.38 - 8.33 (m, 1H), 7.73 - 7.68 (m, 1H), 5.20 (s, 1H), 4.32 - 4.21 (m, 4H), 2.33 (s, 3H), 1.30 - 1.27 (m, 6H).Step 2: Preparation of ethyl 2-(3-bromo-5-methylpyridin-2-yl)acetateOEt Y-A Br[000276] To a stirred solution of 1,3-diethyl 2-(3-bromo-5-methylpyridin-2-yl)propanedioate (3.9 g, 11.8 mmol) and H2O (0.53 mL, 29.5 mmol) in DMSO (40 mL, 563 mmol) was added LiCI (1.25 g, 29.5 mmol) at room temperature. The resulting mixture was stirred at 100°C for 1 day under an argon atmosphere. The mixture was diluted with ice water (200 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (10% to 70% CH3CN in H2O gradient over 30 min) to afford ethyl 2-(3- bromo-5-methylpyridin-2-yl)acetate (2 g, 66% yield) as a colorless oil.XH NMR (300 MHz, DMSO- d6): 6 8.38 - 8.34 (m, 1H), 8.00 - 7.93 (m, 1H), 4.14 - 4.07 (m, 2H), 3.93 (s, 2H), 2.30 (s, 3H), 1.22 - 1.16 (m, 3H).Step 3: Preparation of ethyl 9-bromo-2-hydroxy-7-methyl-4-oxoquinolizine-l-carboxylate[000277] Into a vial were added ethyl 2-(3-bromo-5-methylpyridin-2-yl)acetate (2 g, 7.75 mmol) and bis(2,4,6-trichlorophenyl) propanedioate (7.17 g, 15.5 mmol) in diphenyl ether (100mL) at room temperature. The mixture was then irradiated with microwave radiation for 30 min at 200 °C. The mixture was diluted with ice water (100 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (10% to 70% CH3CN in H2O gradient over 30 min) to afford ethyl 9-bromo-2- hydroxy-7-methyl-4-oxoquinolizine-l-carboxylate (700 mg, 28% yield) as a yellow oil.1H NMR (300 MHz, DMSO-d6): 6 11.38 (s, 1H), 8.85 - 8.82 (m, 1H), 7.92 (d, J = 1.7 Hz, 1H), 5.93 (s, 1H), 4.40 - 4.22 (m, 2H), 1.T1 (d, J = 1.2 Hz, 3H), 1.30 - 1.24 (m, 3H).Step 4: Preparation of 9-bromo-2-hydroxy-7-methylquinolizin-4-one[000278] A solution of ethyl 9-bromo-2-hydroxy-7-methyl-4-oxoquinolizine-l-carboxylate (700 mg, 2.15 mmol) in HBr in aqueous AcOH (40%, 1 mL) was stirred for 30 min at 100 °C under an argon atmosphere. The mixture was diluted with ice water (50 mL) and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from EtOAc (10 mL) to afford 9-bromo-2-hydroxy- 7-methylquinolizin-4-one (70 mg, 13% yield) as an orange solid.XH NMR (400 MHz, DMSO-d6): 6 10.98 (s, 1H), 8.65 - 8.61 (m, 1H), 7.79 (d, J = 1.6 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.82 (d, J = 2.4 Hz, 1H), 2.26 (d, J = 1.3 Hz, 3H).Step 5: Preparation of 9-bromo-7-methyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate[000279] To a stirred solution of 9-bromo-2-hydroxy-7-methylquinolizin-4-one (60 mg, 0.24 mmol) in pyridine (1 mL) was added triflic anhydride (0.08 mL, 0.47 mmol) dropwise at 0 °C underan argon atmosphere. The resulting mixture was stirred at 0 °C for 30 min. The reaction was then quenched with saturated aqueous NaHCO3(20 mL) at 0 °C. The resulting mixture was extracted with CH2CI2 (3 x 50 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS: ( ES ) m / z = 385.8.Step 6: Preparation of 9-bromo-7-methyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-4H-quinolizin-4-one[000280] To a stirred solution of 9-bromo-7-methyl-4-oxoquinolizin-2-yl trifluoromethanesulfonate (60 mg, 0.16 mmol) and 2-methyl-5-(piperazin-l-yl)pyrimidine (Intermediate 1, 55 mg, 0.31 mmol) in DMA was added DIPEA (0.08 mL, 0.47 mmol) dropwise at room temperature under an argon atmosphere. The resulting mixture was stirred at 80 °C for 1 h. The mixture was diluted with ice water (10 mL) at room temperature. The resulting precipitated solids were collected by filtration and dried by lyophilization to afford 9-bromo-7- methyl-2-(4-(2-methylpyrimidin-5-yl) piperazin-l-yl)-4H-quinolizin-4-one (50 mg, 78% yield) as a yellow solid.TH NMR (400 MHz, DMSO-d6): 6 8.58 (s, 1H), 8.43 (s, 2H), 7.73 (d, J = 1.6 Hz, 1H), 6.53 (d, J = 2.6 Hz, 1H), 5.94 (d, J = 2.6 Hz, 1H), 3.60 - 3.57 (m, 4H), 3.36 (m, 4H), 2.23 (d, J = 1.2 Hz, 3H).Step 7: Preparation of 9-acetyl-7-methyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-4H-quinolizin- 4-one[000281] To a stirred mixture of 9-bromo-7-methyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l- yl)-4H-quinolizin-4-one (80 mg, 0.19 mmol) and tributyl(l-ethoxyvinyl)tin (84 mg, 0.23 mmol) in dioxane (1 mL) was added Pd(PPh3)4(22 mg, 0.019 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred at 100 °C for 2 h. To the resulting mixture was added aqueous HCI (1 M, 1.0 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 min. The mixture was diluted with ice water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS: (EST) m / z = 378.2 (M+H).Step 8: Preparation of 9-(l-hydroxyethyl)-7-methyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-4H- quinolizin-4-one[000282] To a stirred solution of 9-acetyl-7-methyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l- yl)-4H-quinolizin-4-one (50 mg, 0.13 mmol) in MeOH (1 mL) was added NaBH4(10 mg, 0.26 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was then quenched with water (20 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (5% to 70% CH3CN in H2O over a 30 mingradient) to afford 9-(l-hydroxyethyl)-7-methyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-4H- quinolizin-4-one (30 mg, 60% yield) as a light yellow solid. LCMS: ( ESI+) m / z = 380.1 (M+H).Step 9: Preparation of 7-methyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-one (Example 1)[000283] To a stirred mixture of 9-(l-hydroxyethyl)-7-methyl-2-(4-(2-methylpyrimidin-5- yl)piperazin-l-yl)-4H-quinolizin-4-one (30 mg, 0.079 mmol) and TEA (48 mg, 0.47 mmol) in DCM (3 mL) was added methanesulfonyl methanesulfonate (41 mg, 0.24 mmol) at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 30 min. To the resulting mixture was added 2-methanesulfonylaniline (27 mg, 0.16 mmol) at room temperature. The mixture was then stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3(10 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by prep-HPLC to afford 7-methyl-2-(4-(2- methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin- 4-one (3.6 mg, 8.4% yield) as a light yellow solid. LCMS: (ESP) m / z = 533.2 (M+H);2H NMR (400 MHz, DMSO-dg): 6 8.54 (s, 1H), 8.45 (d, J = 1.3 Hz, 2H), 7.70 - 7.63 (m, 1H), 7.41 - 7.37 (m, 1H), 7.24 (s, 1H), 6.80 - 6.76 (m, 1H), 6.59 (d, J = 5.5 Hz, 1H), 6.54 (s, 1H), 6.45 (d, J = 8.5 Hz, 1H), 5.93 (s, 1H), 5.15 (d, J = 6.5 Hz, 1H), 3.60 (m, 4H), 3.30 (m, 4H), 3.26 (d, J = 1.1 Hz, 3H), 2.17 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.24 (s, 3H).[000284] Example 2: (R)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-one, and[000285] Example 3: (S)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-oneStep 1: Preparation of ethyl 9-bromo-2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizine-l-carboxylate[000286] To a stirred mixture of ethyl 2-(3-bromo-5-methylpyridin-2-yl)acetate (1 g, 3.87 mmol) in diphenyl ether (10 mL) was added bis(2,4,6-trichlorophenyl) 2-methylpropanedioate (3.7 g, 7.75 mmol) in portions at room temperature under an argon atmosphere. The mixturewas irradiated with microwave radiation at 200 °C for 30 min. The mixture was diluted with ice water (60 m L) at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL), and the combined organic phases were washed with brine and dried over anhydrous NajSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (30% to 80% of CH3CN in H2O over a 25 min gradient) to afford ethyl 9-bromo-2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizine-l-carboxylate (900 mg, 62% yield) as an off-white oil.XH NMR (400 MHz, DMSO-ds): 6 10.33 (s, 1H), 8.87 - 8.81 (m, 1H), 7.85 (d, J = 1.7 Hz, 1H), 4.33 - 4.24 (m, 2H), 2.27 (d, J = 1.3 Hz, 3H), 2.10 (s, 3H), 1.32 - 1.27 (m, 3H).Step 2: Preparation of 9-bromo-2-hydroxy-3,7-dimethyl-4H-quinolizin-4-one[000287] A solution of ethyl 9-bromo-2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizine-l- carboxylate (600 mg, 1.76 mmol) in a solution of hydrobromic acid in acetic acid (6 mL) was stirred for 1 h at 100 °C under an argon atmosphere. The reaction was quenched by the addition of ice water (30 mL) at room temperature. The precipitated solids were collected by filtration and washed with water (3 x 30 mL). The resulting mixture was concentrated under reduced pressure to afford in 9-bromo-2-hydroxy-3,7-dimethyl-4H-quinolizin-4-one (200 mg, 40% yield) as an off-white solid.:H NMR (400 MHz, DMSO-d6): 6 10.81 (s, 1H), 8.73 - 8.60 (m, 1H), 7.69 (d, J = 1.6 Hz, 1H), 6.71 (s, 1H), 2.26 (d, J = 1.3 Hz, 3H), 2.02 (s, 3H).Step 3: Preparation of 9-bromo-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate[000288] Into a 50 mL round-bottom flask were added 9-bromo-2-hydroxy-3,7-dimethyl-4H- quinolizin-4-one (350 mg, 1.31 mmol) and pyridine (5 mL) at room temperature. To this mixture was added triflic anhydride (958 mg, 3.39 mmol) in DCM in portions at 0 °C. The resultingmixture was stirred for 1 h at 0 °C. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 9-bromo-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (260 mg, 50% yield) as a brown solid. The crude product was used in the next step directly without further purification. LCMS: (ESP) m / z = 399.8.Step 4: Preparation of 9-bromo-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-4H- quinolizin-4-one[000289] To a stirred mixture of 9-bromo-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (200 mg, 0.50 mmol) and 2-methyl-5-(piperazin-l-yl)pyrimidine (Intermediate 1, 107 mg, 0.60 mmol) in DMA (3.3 mL, 36 mmol) was added DIEA (194 mg, 1.5 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C. The reaction was quenched by the addition of ice water (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA = 5:1, to afford 9-bromo-3,7-dimethyl-2-(4-(2- methylpyrimidin-5-yl)piperazin-l-yl)-4H-quinolizin-4-one (70 mg, 33% yield) as a white solid. LCMS: (ESP) m / z = 428.1.Step 5: Preparation of 9-acetyl-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-4H- quinolizin-4-one[000290] Into a 50 mL 2-necked round-bottom flask were added 9-bromo-3,7-dimethyl-2-(4- (2-methylpyrimidin-5-yl)piperazin-l-yl)-4H-quinolizin-4-one (100 mg, 0.23 mmol) in dioxane (3 mL) at room temperature. To the above mixture was added Pd(PPh3)4(54 mg, 0.047 mmol) and tributyl(l-ethoxyethenyl)stannane (110 mg, 0.30 mmol) in portions at room temperature. The resulting mixture was stirred at 60 °C overnight. The reaction was quenched by the addition of ice water (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (30% to 80% CH3CN in H2O over a 30 min gradient) to afford 9-acetyl-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-4H-quinolizin-4-one (50 mg, 53% yield) as a yellow solid. LCMS: (ESI+) m / z = 392.2 (M+H).Step 6: Preparation of 9-(l-hydroxyethyl)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)- 4H-quinolizin-4-one[000291] To a stirred mixture of 9-acetyl-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin- l-yl)-4H-quinolizin-4-one (40 mg, 0.10 mmol) in MeOH (1.2 mL) was added NaBH4(7.7 mg, 0.20 mmol) at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction was then quenched by the addition of ice water (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford crude 9-(l-hydroxyethyl)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-4H-quinol izin-4-one which was used in the next step immediately without further purification. LCMS: (ES ) m / z = 394.3 (M+H).Step 7: Preparation (R)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-one (Example 2) and (S)-3,7-dimethyl-2-(4-(2- methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4- one (Example 3)[000292] A mixture of 9-(l-hydroxyethyl)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5- yl)piperazin-l-yl)-4H-quinolizin-4-one (60 mg, 0.15 mmol) and Et3N (93 mg, 0.91 mmol) in DCM (1 mL) was stirred at 0 °C for 30 min under an argon atmosphere. To this mixture was added methanesulfonyl methanesulfonate (705 mg, 0.76 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice water (30 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (20% to 50% CH3CN in water over a gradient of 20 min). The resulting product (32 mg) was purified further by prep-chiral-HPLC to afford (R)-3,7- dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-one and (S)-3,7-dimethyl-2-(4-(2- methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin- 4-one (7.4 mg, 9% yield) and (S)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l- ((2-(methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-one (9.6 mg, 11% yield) each as a white solid:[000293] (R)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-one:1H NMR (400 MHz, DMSO-ds): 6 8.77 -8.64 (m, 1H), 8.46 (s, 2H), 7.70 - 7.61 (m, 1H), 7.43 - 7.35 (m, 1H), 7.31 (d, J = 1.8 Hz, 1H), 6.84 - 6.75 (m, 1H ), 6.64 (s, 1H), 6.59 (d, J = 5.8 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.24 - 5.09 (m, 1H), 3.40 - 3.37 (m, 3H), 3.32 - 3.21 (m, 8H), 2.51 (s, 3H), 2.25 (d, J = 1.3 Hz, 3H), 2.18 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H); LCMS: ( ESP) m / z = 547.3 (M+H).[000294] (S)-3,7-dimethyl-2-(4-(2-methylpyrimidin-5-yl)piperazin-l-yl)-9-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-4H-quinolizin-4-one::H NMR (400 MHz, DMSO-de): 6 8.78 - 8.66 (m, 1H), 8.46 (s, 2H), 7.70 - 7.62 (m, 1H), 7.44 - 7.35 (m, 1H), 7.31 (d, J = 1.7 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.64 (s, 1H), 6.59 (d, J = 5.8 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.26 - 5.11 (m, 1H), 3.40 - 3.37 (m, 3H), 3.32 - 3.22 (m, 8H), 2.51 (s, 3H), 2.25 (d, J = 1.2 Hz, 3H), 2.17 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H); LCMS: (ESP) m / z = 547.3 (M+H).[000295] Example 21: (R)-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3,7- dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4H-quinolizin-4-oneStep 1: Preparation of 9-acetyl-2-hydroxy-3,7-dimethyl-4H-quinolizin-4-one[000296] To a stirred mixture of 9-bromo-2-hydroxy-3,7-dimethylquinolizin-4-one (Examples 2 and 3, Step 2) (10 g, 37.3 mmol) in dioxane (100 mL) at room temperature under an argon atmosphere were added tributyl(l-ethoxyethenyl)stannane (20.2 g, 56.0 mmol) and Pd(PPh3)4 (4.3 g, 3.73 mmol). The resulting mixture was stirred at 100 °C overnight and then allowed tocool to room temperature. Aqueous 1 M HCI (110 mL) was added over 1 min at room temperature and the resulting mixture was stirred for 1 h. The mixture was then diluted with ice water (100 mL) and then extracted with CH2CI2 (3 x 100 mL). The combined organics were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2CI2:MeOH = 10:1) to afford 9-acetyl-2-hydroxy-3,7-dimethylquinolizin-4-one (7.5 g, 87% yield) as a light red solid. LCMS: ( ES ) m / z = 232.0 (M+H).Step 2: Preparation of 9-acetyl-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate[000297] To a stirred mixture of 9-acetyl-2-hydroxy-3,7-dimethyl-4H-quinolizin-4-one (7.5 g, 32.4 mmol) in pyridine (100 mL) under an argon atmosphere was added trifluoromethanesulfonic anhydride (18.3 g, 64.9 mmol) dropwise at -10 °C. The resulting mixture was stirred at -10 °C for 30 min and then was poured into saturated aqueous NaHCO3and then extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 9-acetyl-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (8.0 g, 68% crude yield) as a yellow solid which was used directly in the next step without further purification. LCMS: (ESP) m / z = 364.1 (M+H).Step 3: Preparation of 9-acetyl-3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4H-quinolizin-4- one[000298] To a stirred mixture of 9-acetyl-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (8.0 g, 22.0 mmol) and 2'-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2,5'-bipyrimidine (Intermediate 6) (9.85 g, 33.0 mmol) in dioxane (100 mL) and H2O (10 mL) at room temperature under a nitrogen atmosphere were added Pd(dppf )Ch (1.80 g, 2.20 mmol) and Na2CO3(7.0 g, 66.1 mmol) in portions. The resulting mixture was stirred at 90 °C for 2 h, cooled to room temperature, and then diluted with H2O (100 mL). The mixture was then extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2CI2:MeOH = 8:1) to afford 9- acetyl-3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4H-quinolizin-4-one (4.0 g, 47% yield) as a light yellow oil. LCMS: (ESI+) m / z = 386.1 (M+H).Step 4: Preparation of (R,E)-N-(l-(3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4-oxo-4H- quinolizin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide[000299] To a stirred mixture of 9-acetyl-3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4H- quinolizin-4-one (4.0 g, 10.4 mmol) and (R)-2-methylpropane-2-sulfinamide (2.52 g, 20.8 mmol) in toluene (80 mL) at room temperature under an argon atmosphere was added titanium ethoxide (5.90 g, 20.8 mmol) dropwise. The resulting mixture was stirred at 80 °C overnight, then cooled to room temperature and then poured into water (100 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (2 x 50 mL). The filtrate phases were separated, and the aqueous phase was extracted further with EtOAc (3 x 200 mL). The combined organics were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2CI2:MeOH = 15:1) to afford (R,E)-N-(l-(3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4- oxo-4H-quinolizin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide (4.0 g, 79% yield) as a light yellow solid. LCMS: (ESP) m / z = 489.3 (M+H).Step 5: Preparation of (R)-N-((R)-l-(3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4-oxo-4H- quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide[000300] To a stirred mixture of (R, E)-N-( l-(3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)- 4-oxo-4H-quinolizin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide (3.0 g, 6.14 mmol) in MeOH (25 mL) was added cerium(lll) chloride heptahydrate (4.57 g, 12.3 mmol) at 0 °C under an argon atmosphere. The mixture was then cooled to -40 °C and NaBH4(465 mg, 12.3 mmol) was added in portions over 5 min. The resulting mixture was stirred at -40°C for 2 h and then diluted with ice water (100 mL). The mixture was then extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography (C18 silica gel; mobile phase of MeCN in water (10 mmol / L NI- HCO3), 5% to 100% gradient over 30 min) to afford (R)-N-((R)-l-(3,7-dimethyl-2-(2'-methyl- [2,5'-bipyrimidin]-5-yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (1.26 g, 42% yield) as a light yellow solid. LCMS: (ESP) m / z = 491.3 (M+H).Step 6: Preparation of (R)-9-(l-aminoethyl)-3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4H- quinolizin-4-one[000301] To a stirred mixture of (R)-N-((R)-l-(3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5- yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.22 mmol) in MeOH (12 mL) was added hydrogen chloride (4.0 M in ethyl acetate, 0.61 mL, 2.44mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h, diluted with MeOH (50 mL), and then adjusted to pH 8 via the addition of saturated aqueous NaHCO3. The mixture was then extracted with DCM (3 x 50 mL). The combined organics were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase of MeCN in water (10 mmol / L NH4HCO3), 5% to 50% gradient over 30 min) to afford (R)-9-(l-aminoethyl)-3,7-dimethyl-2-(2'-methyl-[2,5'- bipyrimidin]-5-yl)-4H-quinolizin-4-one (440 mg, 93% yield) as a light yellow solid. LCMS: (ESI+) m / z = 387.1 (M+H).Step 7: Preparation of (R)-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3,7-dimethyl-2-(2'- methyl-[2,5'-bipyrimidin]-5-yl)-4H-quinolizin-4-one (Example 21)[000302] To a stirred solution of (R)-9-(l-aminoethyl)-3,7-dimethyl-2-(2'-methyl-[2,5'- bipyrimidin]-5-yl)-4H-quinolizin-4-one (50 mg, 0.13 mmol) and l-bromo-4-fluoro-2- (trifluoromethyl)benzene (47 mg, 0.19 mmol) in dioxane (2 mL) were added Cs2CO3(126 mg, 0.39 mmol) and [l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro- (2-methylpyridin-l-ium-l-yl)palladium (11 mg, 0.013 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred at 80 °C overnight, and then was cooled to room temperature and diluted with water (10 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by prep-HPLC and then purified further by prep-chiral-HPLC (column: CHIRALPAK AD-3; mobile phase of hexanes(0.1% FA):EtOH = 95:5) to afford (R)-9-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-3,7-dimethyl-2-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-4H-quinolizin-4-one (17.3 mg, 24 % yield, >99% ee) as a light yellow solid.XH NMR (400 MHz, DMSO- d5): 6 9.60 (s, 2H), 9.19 (s, 2H), 8.83 (s, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.23 (d, J = 5.1 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.50 - 6.42 (m, 1H), 5.49 (d, J = 6.3 Hz, 1H), 5.27 - 5.19 (m, 1H), 2.75 (s, 3H), 2.30 (d, J = 1.3 Hz, 3H), 2.25 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H); LCMS: (ESI+) m / z = 549.2 (M+H).[000303] Example 22: (R)-3,7-dimethyl-9-(l-((6-methyl-2-(trifluoromethyl)pyridin-3- yl)amino)ethyl)-2-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-4H-quinolizin-4-oneStep 1: Preparation of 9-acetyl-3,7-dimethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H- quinolizin-4-one[000304] A mixture of 9-acetyl-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (Example 21, Step 2) (6 g, 16.5 mmol), bis(pinacolato)diboron (8.39 g, 33.0 mmol), potassium acetate (3.24 g, 33.0 mmol) and Pd(dppf)CI2(1.21 g, 1.65 mmol) in dioxane (100 mL) was stirred at 100 °C overnight under an argon atmosphere. The mixture was then filtered, and the filter cake was washed with dioxane. The filtrate was concentrated under reduced pressure to afford 9-acetyl-3,7-dimethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-4H-quinolizin-4-one (6 g, crude yield) which was used in the next step directly without further purification. LCMS: (ESP) m / z = 342.1 (M+H).Step 2: Preparation of 9-acetyl-2-(2-bromopyrimidin-5-yl)-3,7-dimethyl-4H-quinolizin-4-one[000305] A mixture of 9-acetyl-3,7-dimethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 4H-quinolizin-4-one (6 g, 17.6 mmol), 2-bromo-5-iodopyrimidine (6.01 g, 21.1 mmol), Na2CO3(3.73 g, 35.2 mmol) and Pd(dppf)CI2(1.29 g, 1.76 mmol) in dioxane (100 mL) and H2O (10 mL) was stirred at 100 °C overnight under an argon atmosphere. The mixture was then cooled to room temperature and diluted with H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA) to afford 9-acetyl-2-(2- bromopyrimidin-5-yl)-3,7-dimethyl-4H-quinolizin-4-one (2.24 g, 34 % yield) as a brown solid. LCMS: (ESP) m / z = 371.9 (M+H).Step 3: Preparation of (R,E)-N-(l-(2-(2-bromopyrimidin-5-yl)-3,7-dimethyl-4-oxo-4H-quinolizin-9- yl)ethylidene)-2-methylpropane-2-sulfinamide[000306] To a stirred mixture of 9-acetyl-2-(2-bromopyrimidin-5-yl)-3,7-dimethyl-4H- quinolizin-4-one (2.25 g, 6.03 mmol) and (R)-2-methylpropane-2-sulfinamide (3.6 g, 30.5 mmol) in toluene (45 mL) under an argon atmosphere at room temperature was added titanium ethoxide (4.12 g, 18.0 mmol). The resulting mixture was stirred at 80 °C overnight and then cooled to room temperature. The mixture was poured into water (100 mL) and then filtered. The filter cake was washed with EtOAc (2 x 50 mL). The filtrate mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CFhC MeOH = 10:1) to afford (R,E)-N- (l-(2-(2-bromopyrimidin-5-yl)-3,7-dimethyl-4-oxo-4H-quinolizin-9-yl)ethylidene)-2- methylpropane-2-sulfinamide (2.24 g, 78% yield) as a brown solid. LCMS: (ESI+) m / z = 475.1 (M+H).Step 4: Preparation of (R)-N-((R)-l-(2-(2-bromopyrimidin-5-yl)-3,7-dimethyl-4-oxo-4H-quinolizin-9- yl)ethyl)-2-methylpropane-2-sulfinamide[000307] To a stirred mixture of (R,E)-N-(l-(2-(2-bromopyrimidin-5-yl)-3,7-dimethyl-4-oxo-4H- quinolizin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.2 g, 2.52 mmol) and cerium(lll) chloride heptahydrate (940 mg, 2.52 mmol) in MeOH (20 mL) and DCM (4 mL) was added NaBH4(191 mg, 5.05 mmol) in portions at -40 °C under an argon atmosphere. The resulting mixture was stirred at -40 °C for 2 h and then quenched with H2O (100 mL). The resulting mixture wasextracted with EtOAc (3 x 100 mt). The combined organics were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by prep-HPLC ( C18 silica gel; mobile phase of MeCN in water (5 mmol / L FA), 5% to 70% gradient over 30 min) to afford (R)-N-((R)-l-(2-(2-bromopyrimidin-5-yl)- 3,7-dimethyl-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (765 mg, 63% yield) as a yellow solid.XH NMR (400 MHz, DMSO-d5): 6 8.89 (s, 2H), 8.84 (s, 1H), 7.60 - 7.55 (m, 1H), 7.04 (s, 1H), 5.88 (d, J = 6.8 Hz, 1H), 4.93 - 4.86 (m, 1H), 2.39 (d, J = 1.3 Hz, 3H), 2.16 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H), 1.10 (s, 9H).Step 5: Preparation of (R)-N-((R)-l-(3,7-dimethyl-2-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2- yl)pyrimidin-5-yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide[000308] A mixture of (R)-N-((R)-l-(2-(2-bromopyrimidin-5-yl)-3,7-dimethyl-4-oxo-4H- quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.49 mmol), l-methyl-6- (trimethylstannyl)pyrazin-2-one (Intermediate 7) (275 mg, 1.01 mmol), mesyl[(tri-t- butylphosphine)-2-(2-aminobiphenyl)]palladium(ll) (40 mg, 0.067 mmol), and t-Bu3P»HBF4(19.5 mg, 0.067 mmol) in DMF (10 mL) was stirred at 80 °C overnight under an argon atmosphere. The mixture was then poured into water (70 mL) and then extracted with EtOAc (2 x 70 mL). The combined organics were washed with brine (1 x 70 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase of MeCN in water (10 mmol / L NH4HCO3), 10% to 95% gradient over 20 min) to afford (R)-N-((R)-l-(3,7-dimethyl-2-(2-(l-methyl-6-oxo-l,6- dihydropyrazin-2-yl)pyrimidin-5-yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2- sulfinamide (200 mg, 74% yield) as a yellow solid.rH NMR (400 MHz, DMSO-ds) 6 9.20 (d, J = 0.9 Hz, 2H), 8.87 (s, 1H), 8.22 - 8.20 (m, 1H), 7.79 - 7.85 (m. 1H), 7.65 - 7.53 (m, 1H), 7.08 (s, 1H), 5.92 (d, J = 6.8 Hz, 1H), 4.97 - 4.80 (m, 1H), 3.61 (s, 3H), 2.40 (d, J = 1.3 Hz, 3H), 2.23 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H), 1.11 (s, 9H).Step 6: Preparation of (R)-9-(l-aminoethyl)-3,7-dimethyl-2-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-4H-quinolizin-4-one[000309] To a stirred solution of (R)-N-((R)-l-(3,7-dimethyl-2-(2-(l-methyl-6-oxo-l,6- dihydropyrazin-2-yl)pyrimidin-5-yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2- sulfinamide (200 mg, 0.40 mol) in MeOH (5 mL) was added HCI in 1,4-dioxane (4.0 M, 0.2 mL, 0.80 mol) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 1 h and then adjusted to pH 8 via the addition of saturated aqueous NaHCO3. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase of MeCN in water (10 mmol / L NH4HCO3), 5% to 50% gradient over 30 min) to afford (R)-9-(l-aminoethyl)-3,7- dimethyl-2-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-4H-quinolizin-4-one (155 mg, 98% yield) as a yellow solid. LCMS: (ESI+) m / z = 403.3 (M+H).Step 7: Preparation of (R)-3,7-dimethyl-9-(l-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)- 2-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-4H-quinolizin-4-one (Example 22)[000310] A mixture of (R)-9-(l-aminoethyl)-3,7-dimethyl-2-(2-(l-methyl-6-oxo-l,6- dihydropyrazin-2-yl)pyrimidin-5-yl)-4H-quinolizin-4-one (38 mg, 0.09 mmol), 3-bromo-6-methyl-2-(trifluoromethyl)pyridine (27 mg, 0.11 mmol), Cs2CO3(92 mg, 0.28 mmol), and [l,3-bis[2,6- bis(l-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-l-ium-l-yljpalladium (7.9 mg, 0.01 mmol) in dioxane (2 mL) was stirred at 100 °C for 2 h under an argon atmosphere. The mixture was then poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2CI2:MeOH = 10:1) and then purified further by prep-HPLC (XBridge Prep OBD C18 column 30 x 150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 30% B in 2 min, 30% to 48% B in 11 min) to afford (R)-3,7-dimethyl-9-(l-((6-methyl-2- (trifluoromethyl)pyridin-3-yl)amino)ethyl)-2-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2- yl)pyrimidin-5-yl)-4H-quinolizin-4-one (28.5 mg, 54% yield, >99% ee) as a yellow solid.1H NMR (400 MHz, DMSO-ds): 6 9.25 (s, 2H), 8.83 (s, 1H), 8.21 (s, 1H), 7.79 (s, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.71 (d, J = 6.6 Hz, 1H), 5.28 - 5.20 (m, 1H), 3.62 (s, 3H), 2.32 - 2.28 (m, 6H), 2.25 (s, 3H), 1.60 (d, J = 6.5 Hz, 3H); LCMS: (ESP) m / z = 562.3 (M+H).[000311] Example 23: (R)-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3,7- dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-4H-quinolizin-4-oneStep 1: Preparation of (R,E)-N-(l-(2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizin-9-yl)ethylidene)-2- methylpropane-2-sulfinamide[000312] A mixture of 9-acetyl-2-hydroxy-3,7-dimethyl-4H-quinolizin-4-one (Example 21, Step 1) (10 g, 43.2 mmol) in toluene (40 mL) under a nitrogen atmosphere was treated with (R)-2- methylpropane-2-sulfinamide (15.7 g, 130 mmol) followed by the dropwise addition of titanium ethoxide (29.5 g, 130 mmol). The resulting mixture was stirred at 80 °C overnight, and then was poured into H2O (100 mL) at room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (2 x 50 mL). The filtrate mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2CI2:MeOH = 10:1) to afford (R,E)-N-(l-(2-hydroxy-3,7- dimethyl-4-oxo-4H-quinolizin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide (12.2 g, 84% yield) as a brown solid. LCMS: (ES ) m / z = 335.1 (M+H).Step 2: Preparation of (R)-N-((R)-l-(2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizin-9-yl)ethyl)-2- methylpropane-2-sulfinamide[000313] A mixture of (R,E)-N-(l-(2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizin-9- yl)ethylidene)-2-methylpropane-2-sulfinamide (12.2 g, 36.5 mmol) in MeOH (30 mL) under a nitrogen atmosphere was treated with CeCl3»7H2O (18.0 g, 72.9 mmol) at room temperature followed by the addition of NaBH4(2.76 g, 73.0 mmol) in portions at -40 °C. The resulting mixture was then stirred at -40 °C for 2 h, and then was quenched by the addition of water (100 mL) at0 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organics were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2Cl2:MeOH = 10:1) to afford (R)-N-((R)-l-(2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizin-9- yl)ethyl)-2-methylpropane-2-sulfinamide (8.5 g, 69% yield) as a light yellow solid. LCMS: (ESP) m / z = 337.2 (M+H).Step 3: Preparation of 9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-3,7-dimethyl-4-oxo-4H- quinolizin-2-yl trifluoromethanesulfonate[000314] To a stirred mixture of (R)-N-((R)-l-(2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizin-9- yl)ethyl)-2-methylpropane-2-sulfinamide (2.0 g, 5.9 mmol) and DMAP (1.4 g, 11.8 mmol) in DCM (20 mL) was added l,l,l-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (2.5 g, 7.1 mmol) in portions at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 2 h and then was diluted with ice water (50 mL) at 0°C. The resulting mixture was extracted with CH2CI2(3 x 80 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 1:1) to afford 9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)- 3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (2.1 g, 75% yield) as a light yellow oil. LCMS: (ES ) m / z = 469.1 (M+H).Step 4: Preparation of (R)-N-((R)-l-(3,7-dimethyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide[000315] To a stirred mixture of 9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-3,7-dimethyl-4- oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (1.3 g, 2.7 mmol) and bis(pinacolato)diboron (1.1 g, 4.1 mmol) in dioxane (15.0 mL) were added potassium acetate (545 mg, 5.5 mmol) and Rd(RPh3)2Cl2 (195 mg, 0.3 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred at 80 °C for 2 h and then was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with CH2CI2 (3 x 20 mL). The filtrate was concentrated under reduced pressure to afford (R)-N-((R)-l-(3,7-dimethyl-4-oxo-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2- sulfinamide (1.0 g, crude yield) which was used directly in the next step without further purification. LCMS: (ESP) m / z = 447.1 (M+H).Step 5: Preparation of (R)-N-((R)-l-(3,7-dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6- dihydropyridazin-4-yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide[000316] To a stirred mixture of (R)-N-((R)-l-(3,7-dimethyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.1 mmol) and 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3-one (Intermediate 2) (528 mg, 1.7 mmol) in dioxane (5 mL) and H2O (0.5 mL) under an argon atmosphere were added Na2CO3(237 mg, 2.2 mmol) and Pd(PPh3)4(129 mg, 0.1 mmol) in portions at room temperature. The resulting mixture was stirred at 100 °C for 2 h, then cooled to 0 °C and diluted with ice water (40 mL). The resulting mixture was extracted with CH2CI2(3 x 80 mL). The combined organics were washedwith brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase of MeCN in water (10 mmol / L NH4HCO3), 5% to 70% gradient over 40 min) to afford (R)-N-((R)-l-(3,7-dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)- 4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 35% yield) as a light yellow solid. LCMS: (ESP) m / z = 507.2 (M+H).Step 6: Preparation of (R)-9-(l-aminoethyl)-3,7-dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6- dihydropyridazin-4-yl)-4H-quinolizin-4-one[000317] To a stirred solution of (R)-N-((R)-l-(3,7-dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6- oxo-1, 6-dihydropyridazin-4-yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulf inamide (200 mg, 0.4 mmol) in methanol (5 mL) was added HCI (4 M in EtOAc, 0.2 mL) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 1 h and then adjusted to pH 8 via the addition of saturated aqueous NaHCO3. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase of MeCN in water (10 mmol / L NH4HCO3), 5% to 50% gradient over 30 min) to afford (R)-9-(l-aminoethyl)-3,7-dimethyl-2-(l-(2-methylpyrimidin- 5-yl)-5-oxo-l,6-dihydropyridazin-4-yl)-4H-quinolizin-4-one (140 mg, 88% yield) as a yellow solid. LCMS: (ESP) m / z = 403.0 (M+H).Step 7: Preparation of (R)-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3,7-dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-4H-quinolizin-4-one (Example 23)[000318] To a stirred mixture of (R)-9-(l-aminoethyl)-3,7-dimethyl-2-(l-(2-methylpyrimidin-5- yl)-6-oxo-l,6-dihydropyridazin-4-yl)-4H-quinolizin-4-one (4.0 g, 9.94 mmol) and l-bromo-4- fluoro-2-(trifluoromethyl)benzene (3.13 g, 12.9 mmol) in dioxane (20 mL) under an argon atmosphere were added CS2CO3 (9.71 g, 29.8 mmol) and [l,3-bis[2,6-bis(l-ethylpropyl)phenyl]- 4,5-dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-l-ium-l-yl)palladium (0.84 g, 0.99 mmol) in portions at room temperature. The resulting mixture was stirred at 100 °C, and then was cooled to 0 °C and diluted with ice water (30 mL). The mixture was extracted with EtOAc (3 x 60 mL). dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by prep-HPLC (Column: Xbridge Phenyl OBD column, 30 x 150 mm, 5 pm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; flow rate: 60 mL / min; Gradient (B%): 42% B to 57% B over 10 min) to afford (R)-9-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-3,7-dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6- dihydropyridazin-4-yl)-4H-quinolizin-4-one (2.53 g, 45% yield, >99% ee) as a yellow solid.1H NMR (400 MHz, DMSO-dg): 6 9.08 (s, 2H), 8.82 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.21- 7.14 (m, 2H), 6.49 - 6.42 (m, 1H), 5.50 (d, J = 6.3 Hz, 1H), 5.26 - 5.19 (m, 1H), 2.72 (s, 3H), 2.32- 2.25 (m, 6H), 1.59 (d, J = 6.5 Hz, 3H); LCMS: (ESP) m / z = 565.2 (M+H).[000319] Example 24: (R)-3-(5-(3,7-dimethyl-9-(l-((6-methyl-2-(trifluoromethyl)pyridin-3- yl)amino)ethyl)-4-oxo-4H-quinolizin-2-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (Example 24)Step 1: Preparation of 3-(5-(9-acetyl-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl)pyrimidin-2-yl)-5-fluoro- 2-methylpyridine 1-oxide[000320] To a stirred mixture of 9-acetyl-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (Example 21, Step 2) (500 mg, 1.38 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) at room temperature and under a nitrogen atmosphere was added 5-fluoro-2- methyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyridine 1-oxide (Intermediate 9) (501 mg, 1.52 mmol), Na2CO3(292 mg, 2.75 mmol), and Pd(PPh3)4 (159 mg, 0.14 mmol). The resulting mixture was stirred at 90 °C for 2 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (CH2Cl2:MeOH = 20:1) to afford 3-(5-(9-acetyl-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl)pyrimidin-2- yl)-5-fluoro-2-methylpyridine 1-oxide (125 mg, 21% yield) as a light yellow solid. LCMS: (ESI+) m / z = 419.2 (M+H).Step 2: Preparation of (R,E)-3-(5-(9-(l-((tert-butylsulfinyl)imino)ethyl)-3,7-dimethyl-4-oxo-4H- quinolizin-2-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide[000321] To a stirred mixture of 3-(5-(9-acetyl-3,7-dimethyl-4-oxo-4H-quinolizin-2- yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (100 mg, 0.24 mmol) in THF (5 mL) was added (R)-2-methylpropane-2-sulfinamide (145 mg, 1.19 mmol) and titanium ethoxide (273 mg, 1.19 mmo) at room temperature. The resulting mixture was then stirred at 80 °C for 5 h, then concentrated under reduced pressure. The residue was purified by prep-TLC (CH2CI2:MeOH = 10:1) to afford (R,E)-3-(5-(9-(l-((tert-butylsulfinyl)imino)ethyl)-3,7-dimethyl-4-oxo-4H-quinolizin- 2-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (75 mg, 60% yield) as a light yellow solid. LCMS: (ESP) m / z = 522.3 (M+H).Step 3: Preparation of 3-(5-(9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-3,7-dimethyl-4-oxo-4H- quinolizin-2-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide[000322] To a stirred mixture of (R, E)-3-(5-(9-(l-((tert-butylsulfinyl)im ino)ethyl)-3,7-dimethyl- 4-oxo-4H-quinolizin-2-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (120 mg, 0.23 mmol) in MeOH (1.5 mL) and DCM (1.5 mL) was added cerium(lll) chloride heptahydrate (214 mg, 0.58 mmol). The mixture was then cooled to -40 °C and NaBH4(23 mg, 0.60 mmol) was added in portions. The resulting mixture was stirred at -40 °C for 2 h and then diluted with water (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the combined organics were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by prep-TLC (CI-bC^MeOH = 10:1) to afford 3-(5-(9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-3,7-dimethyl-4-oxo-4H- quinolizin-2-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (100 mg, 83% yield) as a light yellow solid. LCMS: (ESP) m / z = 524.3 (M+H).Step 4: Preparation of (R)-3-(5-(9-(l-aminoethyl)-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl)pyrimidin-2- yl)-5-fluoro-2-methylpyridine 1-oxide[000323] A stirred mixture of 3-(5-(9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-3,7-dimethyl- 4-oxo-4H-quinolizin-2-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (100 mg, 0.19 mmol) in MeOH (2 mL) was treated with HCI (4 M in EtOAc, 0.1 mL) at room temperature. The resulting mixture was stirred for 2 h and then adjusted to pH 8 via the addition of aqueous Na2CO3. The resulting mixture was filtered and the filter cake was washed with MeOH (2 mL). The filtrate wasconcentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase of ACN in H2O (5 mmol / L NH4HCO3), 10% to 50% gradient over 10 min) to afford (R)-3-(5-(9-(l-aminoethyl)-3,7-dimethyl-4-oxo-4H-quinolizin-2- yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (70 mg, 87% yield) as a yellow solid. LCMS: (ESP) m / z = 420.2 (M+H).Step 5: Preparation of (R)-3-(5-(3,7-dimethyl-9-(l-((6-methyl-2-(trifluoromethyl)pyridin-3- yl)amino)ethyl)-4-oxo-4H-quinolizin-2-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide[000324] To a mixture of (R)-3-(5-(9-(l-aminoethyl)-3,7-dimethyl-4-oxo-4H-quinolizin-2- yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide (55 mg, 0.13 mmol) in dioxane (5 mL) were added 3-bromo-6-methyl-2-(trifluoromethyl)pyridine (63 mg, 0.2 mmol), Cs2CO3(85.4 mg, 0.26 mol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-l,l'- biphenyl)] palladium ( 11) methanesulfonate (12.4 mg, 0.01 mmol) under a nitrogen atmosphere. After stirring for 5 h at 100 °C, the mixture was filtered and the filter cake was washed with DCM (3 x 5 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by prep-HPLC (Column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 pm; Mobile Phase A: water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B in 8 min) and then purified further by prep-chiral-HPLC (Column: CHIRALPAKIH3;Mobile Phase A: Hex:(MeOH:DCM = 1:1) = 75:25) to afford (R)-3-(5-(3,7-dimethyl-9-(l-((6- methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)-4-oxo-4H-quinolizin-2-yl)pyrimidin-2-yl)-5- fluoro-2-methylpyridine 1-oxide (8.2 mg, 11% yield, >99% ee) as a light yellow solid.1H NMR (400 MHz, MeOD): 6 9.15 (s, 2H), 8.96 (s, 1H), 8.68 - 8.63 (m, 1H), 8.08 - 7.99 (m, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.26 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 5.25 - 5.14 (m, 1H), 2.80 (d, J = 1.1 Hz, 3H), 2.45 - 2.30 (m, 9H), 1.71 (d, J = 6.6 Hz, 3H); LCMS: (ESP) m / z = 579.3 (M+H).[000325] Example 25: (R)-3-(4-(9-(l-((4-chloro-2-(trifluoromethyl)phenyl)amino)ethyl)-7- fluoro-3-methyl-4-oxo-4H-quinolizin-2-yl)-6-oxopyridazin-l(6H)-yl)-5-fluoro-2-rnethylpyridine 1- oxideStep 1: Preparation of l-(tert-butyl) 3-ethyl 2-(3-bromo-5-fluoropyridin-2-yl)malonate[000326] To a stirred mixture of 3-bromo-2,5-difluoropyridine (5.0 g, 25.8 mmol) and 1-tert- butyl 3-ethyl propanedioate (9.70 g, 51.6 mmol) in DMSO (40 mL) under a nitrogen atmosphere at room temperature was added Cs2CO3(16.8 g, 51.6 mmol). The resulting mixture was stirred at 100 °C for 16 h and then cooled to room temperature. The resulting mixture was diluted with H2O (50 mL) and extracted with PE (3 x 60 mL). The combined organics were washed with brine (2 x 50 mL) and then were concentrated under reduced pressure to half volume. The resulting mixture was stirred for 0.5 h at 0 °C, then filtered and the filter cake was washed with cold PE (2 x 10 mL) to afford l-(tert-butyl) 3-ethyl 2-(3-bromo-5-fluoropyridin-2-yl)malonate (5.1 g, 54% yield) was obtained as an off-white solid. LCMS: (ESP) m / z = 362.0 (M+H).Step 2: Preparation of ethyl 2-(3-bromo-5-fluoropyridin-2-yl)acetate[000327] A mixture of l-(tert-butyl) 3-ethyl 2-(3-bromo-5-fluoropyridin-2-yl)malonate (50 g, 138 mmol) in DCM (200 mL) and trifluoroacetic acid (200 mL) was stirred at room temperature for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the resulting residue was suspended in DCM (300 mL). The mixture was then neutralized to pH 8 via the addition of aqueous Na2CO3and then extracted with DCM (3 x 200 mL). The combined organics were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 3:1) to afford ethyl 2-(3- bromo-5-fluoropyridin-2-yl)acetate (30 g, 83% yield) as a light yellow solid. LCMS: (ESP) m / z = 262.0 (M+H).Step 3: Preparation of ethyl 9-bromo-7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizine-l- carboxylate[000328] To a 0 °C mixture of methylmalonic acid (1.0 g, 8.47 mmol) and DMF (0.12 g, 1.70 mmol) in xylene (10 mL) under a nitrogen atmosphere was added oxalyl chloride (2.36 g, 18.6 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 h until a clear solution was obtained. Ethyl 2-(3-bromo-5-fluoropyridin-2-yl)acetate (1.48 g, 5.64 mmol) was then added in portions and the resulting mixture was stirred at 130 °C for 3 h. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM:MeOH = 10:1) to afford ethyl 9-bromo-7-fluoro-2-hydroxy-3- methyl-4-oxo-4H-quinolizine-l-carboxylate (0.8 g, 43% yield) as a yellow solid. LCMS: (ESP) m / z = 344.1 (M+H).Step 4: Preparation of 9-bromo-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one[000329] A mixture of ethyl 9-bromo-7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizine-l- carboxylate (4.0 g, 11.6 mmol) and hydrobromic acid (33 wt % in HOAc, 20 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted withCHzCp MeOH = 20:1) to afford 9-bromo-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one (2.78 g, 85% yield) as a yellow solid. LCMS: (ESP) m / z = 272.0 (M+H).Step 5: Preparation of 9-acetyl-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one[000330] A mixture of 9-bromo-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one (70 g, 257 mmol), tributyl(l-ethoxyethenyl)stannane (112 g, 309 mmol) and Pd(PPh3)4(29.7 g, 25.7 mmol) in dioxane (200 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. Aqueous 1 M HCI (300 mL) was then added dropwise at room temperature and the resulting mixture was stirred for 0.5 h. The mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2CI2:MeOH = 10:1) to afford 9-acetyl-7-fluoro-2-hydroxy-3-methyl-4H- quinolizin-4-one (53 g, 88% yield) as a red solid. LCMS: (ESP) m / z = 236.1 (M+H).Step 6: Preparation of (R,E)-N-(l-(7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9-yl)ethylidene)- 2-methylpropane-2-sulfinamide[000331] To a stirred mixture of 9-acetyl-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one (3.0 g, 12.8 mmol) and (R)-2-methylpropane-2-sulfinamide (7.73 g, 63.8 mmol) in toluene (30 mL) at room temperature was added titanium ethoxide (14.6 g, 63.8 mmol) in dropwise fashion. The resulting mixture was stirred at 80 °C for 16 h and then was cooled to room temperature and diluted with H2O (50 mL). The mixture was filtered, and the filter cake was washed with EtOAc (2 x 50 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organics were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluted with CH2CI2:MeOH = 10:1) to afford (R,E)-N-(l-(7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9-yl)ethylidene)-2- methylpropane-2-sulfinamide (3.6 g, 83% yield) as a brown solid. LCMS: (ESP) m / z = 339.1 (M+H).Step 7: Preparation of (R)-N-((R)-l-(7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9-yl)ethyl)-2- methylpropane-2-sulfinamide[000332] This intermediate was prepared using methods similar to those described in Example 23, Step 2 using (R,E)-N-(l-(7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9- yl)ethylidene)-2-methylpropane-2-sulfinamide in place of (R,E)-N-(l-(2-hydroxy-3,7-dimethyl-4- oxo-4H-quinolizin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide. LCMS: (ESP) m / z = 341.2 (M+H).Step 8: Preparation of 9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-7-fluoro-3-methyl-4-oxo-4H- quinolizin-2-yl trifluoromethanesulfonate[000333] This intermediate was prepared using methods similar to those described inExample 23, Step 3 using (R)-N-((R)-l-(7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9- yl)ethyl)-2-methylpropane-2-sulfinamide in place of (R)-N-((R)-l-(2-hydroxy-3,7-dimethyl-4-oxo- 4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide. LCMS: (ESP) m / z = 473.0 (M+H).Step 9: Preparation of (R)-N-((R)-l-(7-fluoro-3-methyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide[000334] This intermediate was prepared using methods similar to those described in Example 23, Step 4 using 9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-7-fluoro-3-methyl-4-oxo- 4H-quinolizin-2-yl trifluoromethanesulfonate in place of 9-((R)-l-(((R)-tert- butylsulfinyl)amino)ethyl)-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate. LCMS: (ESP) m / z = 451.2 (M+H).Step 10: Preparation of 3-(4-(9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-7-fluoro-3-methyl-4-oxo- 4H-quinolizin-2-yl)-6-oxopyridazin-l(6H)-yl)-5-fluoro-2-methylpyridine 1-oxide[000335] A mixture of (R)-N-((R)-l-(7-fluoro-3-methyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (260 mg, 0.58 mmol), 5-fluoro-3-(4-iodo-6-oxopyridazin-l(6H)-yl)-2-methylpyridine 1-oxide (Intermediate 3) (100 mg, 0.29 mmol), Pd(dppf)CI2(23.5 mg, 0.03 mmol), and Na2CO3(61 mg, 0.58 mmol) in dioxane (4 ml_) and H2O (0.4 mL) under a nitrogen atmosphere was stirred at 90 °C for 40 minutes. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (5 x 20 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Ci8silicagel; mobile phase of MeCN in water, 10% to 50% gradient over 10 min) to afford 3-(4-(9-(( R)-l- (((R)-tert-butylsulfinyl)amino)ethyl)-7-fluoro-3-methyl-4-oxo-4H-quinolizin-2-yl)-6-oxopyridazin- l(6H)-yl)-5-fluoro-2-methylpyridine 1-oxide (70 mg, 45% yield) as a yellow solid. LCMS: (ESP) m / z = 544.3 (M+H).Step 11: Preparation of (R)-3-(4-(9-(l-aminoethyl)-7-fluoro-3-methyl-4-oxo-4H-quinolizin-2-yl)-6- oxopyridazin-l(6H)-yl)-5-fluoro-2-methylpyridine 1-oxide[000336] This intermediate was prepared using methods similar to those described inExample 23, Step 6 using 3-(4-(9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-7-fluoro-3-methyl-4- oxo-4H-quinolizin-2-yl)-6-oxopyridazin-l(6H)-yl)-5-fluoro-2-methylpyridine 1-oxide in place of (R)-N-((R)-l-(3,7-dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-4-oxo- 4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide. LCMS: (ESP) m / z = 440.1 (M+H).Step 12: Preparation of (R)-3-(4-(9-(l-((4-chloro-2-(trifluoromethyl)phenyl)amino)ethyl)-7-fluoro-3- methyl-4-oxo-4H-quinolizin-2-yl)-6-oxopyridazin-l(6H)-yl)-5-fluoro-2-methylpyridine 1-oxide (Example 25)[000337] A mixture of (R)-3-(4-(9-(l-aminoethyl)-7-fluoro-3-methyl-4-oxo-4H-quinolizin-2-yl)- 6-oxopyridazin-l(6H)-yl)-5-fluoro-2-methylpyridine 1-oxide (45 mg, 0.10 mmol), RuPhos (9.6 mg, 0.02 mmol), Pd2(dba)3(9.4 mg, 0.01 mmol), Cs2CO3(66.7 mg, 0.2 mmol), and l-bromo-4-chloro-2-(trifluoromethyl)benzene (133 mg, 0.51 mmol) in dioxane (3 mL) under a nitrogen atmosphere was stirred at 90 °C for 16 h. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with CH2CI2 (5x10 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by prep-TLC (Cf^CkiMeOH = 8:1) and then purified further by prep-achiral SFC (Column: GreenSep Basic 3 x 15 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.3% 7 M NH3in MeOH); Flow rate: 70 mL / min; Gradient (B%): isocratic 16% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wavelength: 220 nm) to afford (R)-3-(4-(9-(l-((4-chloro-2-(trifluoromethyl)phenyl)amino)ethyl)-7-fluoro-3-methyl-4-oxo- 4H-quinolizin-2-yl)-6-oxopyridazin-l(6H)-yl)-5-fluoro-2-methylpyridine 1-oxide (12.0 mg, 19% yield, >99% ee) as a yellow solid.XH NMR (400 MHz, Methanol-d4): 6 9.14 - 8.87 (m, 1H), 8.73 - 8.58 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.89 - 7.68 (m, 1H), 7.62 - 7.52 (m, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 7.29 - 7.20 (m, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.30 - 5.14 (m, 1H), 2.40 (s, 3H), 2.38 (s, 3H), 1.73 (d, J = 6.8 Hz, 3H); LCMS: (ESP) m / z = 618.0 (M+H).[000338] Example 26: (R)-5-(7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3-methyl-4-oxo-4H-quinolizin-2-yl)-2'-methyl-[2,5'-bipyrimidine] 1-oxideStep 1: Preparation of (R)-9-(l-aminoethyl)-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one[000339] This intermediate was prepared using methods similar to those described in Example 23, Step 6 using (R)-N-((R)-l-(7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9- yl)ethyl)-2-methylpropane-2-sulfinamide (Example 25, Step 7) in place of (R)-N-((R)-l-(3,7- dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-4-oxo-4H-quinolizin-9- yl)ethyl)-2-methylpropane-2-sulfinamide. LCMS: (ESI+) m / z = 237.1 (M+H).Step 2: Preparation of (R)-7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2- hydroxy-3-methyl-4H-quinolizin-4-one[000340] A mixture of (R)-9-(l-aminoethyl)-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one (0.30 g, 1.27 mmol), l-bromo-4-fluoro-2-(trifluoromethyl)benzene (1.54 g, 6.35 mmol), palladium(2+) l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-l,2-didehydro-lX5-imidazole 3- chloropyridine dichloride (124 mg, 0.13 mmol), and Cs2CO3(1.24 g, 3.81 mmol) in 1,4-dioxane (3 ml) was stirred at 100 °C for 2 h. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with DCM (3 x 10 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by prep-TLC (PE:EA = 1:1) to afford (R)-7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2-hydroxy-3-methyl- 4H-quinolizin-4-one (160 mg, 32% yield) as a yellow solid. LCMS: (ESP) m / z = 399.4 (M+H).Step 3: Preparation of (R)-7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3-methyl- 4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate[000341] This intermediate was prepared using methods similar to those described inExample 23, Step 3 using (R)-7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2- hydroxy-3-methyl-4H-quinolizin-4-one in place of (R)-N-((R)-l-(2-hydroxy-3,7-dimethyl-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinam ide. LCMS: (ESI+) m / z = 531.4 (M+H).Step 4: Preparation of (R)-7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H-quinolizin-4-one[000342] This intermediate was prepared using methods similar to those described in Example 23, Step 4 using (R)-7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3- methyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate in place of 9-((R)-l-(((R)-tert- butylsulfinyl)amino)ethyl)-3,7-dimethyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate. LCMS: (ESF) m / z = 509.2 (M+H).Step 5: Preparation of (R)-5-(7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3- methyl-4-oxo-4H-quinolizin-2-yl)-2'-methyl-[2,5'-bipyrimidine] 1-oxide (Example 26)[000343] A mixture of (R)-7-fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3- methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H-quinolizin-4-one (100 mg, 0.20 mmol), 5-bromo-2'-methyl-[2,5'-bipyrimidine] 1-oxide (Intermediate 5) (63 mg, 0.24 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol) and Na2COg (42 mg, 0.39 mmol) in 1,4-dioxane (4 mL) and H2O (0.8 mL) was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture cooled toroom temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 pm; Mobile Phase A: water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min;Gradient (B%): 37% B to 67% B in 8 min) and then purified further by prep-chiral-HPLC (Column: CHIRALPAK IA3; Mobile Phase A: Hex (0.1% DEA):(EtOH:DCM = 1:1) = 70:30) to afford (R)-5-(7- fluoro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3-methyl-4-oxo-4H-quinolizin-2- yl)-2'-methyl-[2,5'-bipyrimidine] 1-oxide (25.2 mg, 23% yield, >99.0% ee) as a yellow solid.:H NMR (400 MHz, DMSO): 6 9.76 (s, 2H), 9.10 (d, J = 2.0 Hz, 1H), 8.94 - 8.92 (m, 1H), 8.72 (d, J = 1.9 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.41 - 7.35 (m, 2H), 7.23 - 7.19 (m, 1H), 6.50 - 6.46 (m, 1H), 5.64 (d, J = 6.4 Hz, 1H), 5.32 - 5.24 (m, 1H), 2.76 (s, 3H), 2.31 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H); LCMS: (ESP) m / z = 569.2 (M+H).[000344] Example 27: (R)-5-chloro-2-((l-(7-chloro-2-(l-(5-fluoro-l-methyl-6-oxo-l,6- dihydropyridin-2-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-3-methyl-4-oxo-4H-quinolizin-9- yl)ethyl)amino)benzonitrileStep 1: Preparation of 1-tert-butyl 3-ethyl 2-(3-bromo-5-chloropyridin-2-yl)propanedioate[000345] This intermediate was prepared using methods similar to those described in Example 25, Step 1 using 3-bromo-5-chloro-2-fluoropyridine in place of 3-bromo-2,5- difluoropyridine. LCMS: (ESI+) m / z = 378.0 (M+H).Step 2: Preparation of ethyl 2-(3-bromo-5-chloropyridin-2-yl)acetate[000346] This intermediate was prepared using methods similar to those described in Example 25, Step 2 using 1-tert-butyl 3-ethyl 2-(3-bromo-5-chloropyridin-2-yl)propanedioate in place of l-(tert-butyl) 3-ethyl 2-(3-bromo-5-fluoropyridin-2-yl)malonate. LCMS: (ESI+) m / z = 278.0 (M+H).Step 3: Preparation of ethyl 9-bromo-7-chloro-2-hydroxy-3-methyl-4-oxo-4H-quinolizine-l- carboxylate[000347] This intermediate was prepared using methods similar to those described in Example 25, Step 3 using ethyl 2-(3-bromo-5-chloropyridin-2-yl)acetate in place of ethyl 2-(3- bromo-5-fluoropyridin-2-yl)acetate. LCMS: (ESI+) m / z = 360.1 (M+H).Step 4: Preparation of 9-bromo-7-chloro-2-hydroxy-3-methyl-4H-quinolizin-4-one[000348] This intermediate was prepared using methods similar to those described in Example 25, Step 4 using ethyl 9-bromo-7-chloro-2-hydroxy-3-methyl-4-oxo-4H-quinolizine-l- carboxylate in place of ethyl 9-bromo-7-fluoro-2-hydroxy-3-methyl-4-oxo-4H-quinolizine-l- carboxylate. LCMS: (ESI+) m / z = 289.9 (M+H).Step 5: Preparation of 9-acetyl-7-chloro-2-hydroxy-3-methyl-4H-quinolizin-4-one[000349] This intermediate was prepared using methods similar to those described inExample 25, Step 5 using 9-bromo-7-chloro-2-hydroxy-3-methyl-4H-quinolizin-4-one in place of 9-bromo-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one. LCMS: (EST) m / z = 252.0 (M+H).Step 6: Preparation of (R,E)-N-(l-(7-chloro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9- yl)ethylidene)-2-methylpropane-2-sulfinamide[000350] This intermediate was prepared using methods similar to those described inExample 25, Step 6 using 9-acetyl-7-chloro-2-hydroxy-3-methyl-4H-quinolizin-4-one in place of 9-acetyl-7-fluoro-2-hydroxy-3-methyl-4H-quinolizin-4-one. LCMS: (ESI+) m / z = 355.1 (M+H).Step 7: Preparation of (R)-N-((R)-l-(7-chloro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9-yl)ethyl)-2- methylpropane-2-sulfinamide[000351] This intermediate was prepared using methods similar to those described in Example 25, Step 7 using (R,E)-N-(l-(7-chloro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9- yl)ethylidene)-2-methylpropane-2-sulfinamide in place of (R,E)-N-(l-(7-fluoro-2-hydroxy-3- methyl-4-oxo-4H-quinolizin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide. LCMS: (ESP) m / z =357.1 (M+H).Step 8: Preparation of 9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-7-chloro-3-methyl-4-oxo-4H- quinolizin-2-yl trifluoromethanesulfonate[000352] This intermediate was prepared using methods similar to those described inExample 25, Step 8 using (R)-N-((R)-l-(7-chloro-2-hydroxy-3-methyl-4-oxo-4H-quinolizin-9- yl)ethyl)-2-methylpropane-2-sulfinamide in place of (R)-N-((R)-l-(7-fluoro-2-hydroxy-3-methyl-4- oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide. LCMS: ( ESI+) m / z = 489.1 (M+H).Step 9: Preparation of (R)-N-((R)-l-(7-chloro-3-methyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide[000353] This intermediate was prepared using methods similar to those described in Example 25, Step 9 using 9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-7-chloro-3-methyl-4-oxo- 4H-quinolizin-2-yl trifluoromethanesulfonate in place of 9-((R)-l-((( R)-tert- butylsulfinyl)amino)ethyl)-7-fluoro-3-methyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate. LCMS: (EST) m / z = 467.2 (M+H).Step 10: Preparation of (R)-N-((R)-l-(7-chloro-2-(l-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2- yl)-6-oxo-l,6-dihydropyridazin-4-yl)-3-methyl-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2- sulfinamide[000354] This intermediate was prepared using methods similar to those described in Example 25, Step 10 using (R)-N-((R)-l-(7-chloro-3-methyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide and 5-bromo-2-(5- fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyridazin-3(2H)-one (Intermediate 10) in place of (R)-N-((R)-l-(7-fluoro-3-methyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H- quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide and 5-fluoro-3-(4-iodo-6-oxopyridazin- l(6H)-yl)-2-methylpyridine 1-oxide. LCMS: (ESI+) m / z = 560.0 (M+H).Step 11: Preparation of (R)-9-(l-aminoethyl)-7-chloro-2-(l-(5-fluoro-l-methyl-6-oxo-l,6- dihydropyridin-2-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-3-methyl-4H-quinolizin-4-one[000355] This intermediate was prepared using methods similar to those described in Example 23, Step 6 using (R)-N-((R)-l-(7-chloro-2-(l-(5-fluoro-l-methyl-6-oxo-l,6- dihydropyridin-2-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-3-methyl-4-oxo-4H-quinolizin-9-yl)ethyl)-2- methylpropane-2-sulfinamide in place of (R)-N-((R)-l-(3,7-dimethyl-2-(l-(2-methylpyrimidin-5- yl)-6-oxo-l,6-dihydropyridazin-4-yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2- sulfinamide. LCMS: (ESP) m / z = 456.0 (M+H).Step 12: Preparation of (R)-5-chloro-2-((l-(7-chloro-2-(l-(5-fluoro-l-methyl-6-oxo-l,6- dihydropyridin-2-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-3-methyl-4-oxo-4H-quinolizin-9- yl)ethyl)amino)benzonitrile (Example 27)[000356] To a mixture of (R)-9-(l-aminoethyl)-7-chloro-2-(l-(5-fluoro-l-methyl-6-oxo-l,6- dihydropyridin-2-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-3-methyl-4H-quinolizin-4-one (90 mg, 0.19 mmol) and 2-bromo-5-chlorobenzonitrile (83 mg, 0.38 mmol) in dioxane (5 mL) under a nitrogen atmosphere were added [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-l,l'- biphenyl)] palladium^ I) methanesulfonate (18 mg, 0.02 mmol) and CS2CO3 (186 mg, 0.57 mmol). The resulting mixture was stirred at 100 °C for 1 h and then was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA = 10:1) and then purified further by prep-HPLC (XBridgePrep OBD Cis Column, 30 x 150 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 37% B to 67 % B in 10 min) to afford (R)-5- chloro-2-((l-(7-chloro-2-(l-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)-6-oxo-l,6- dihydropyridazin-4-yl)-3-methyl-4-oxo-4H-quinolizin-9-yl)ethyl)amino)benzonitrile (49.6 mg, 42 % yield, >99.0% ee) as a yellow solid.1H NMR (Methanol-d4, 400 MHz): 6 9.13 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.65 - 7.42 (m, 3H), 7.41 - 7.20 (m, 3H), 6.76 - 6.58 (m, 1H), 6.44 (d, J = 7.2 Hz, 1H), 5.29 - 5.13 (m, 1H), 3.49 (s, 3H), 2.39 (s, 3H), 1.73 (d, J = 6.8 Hz, 3H); LCMS: (ESI+) m / z = 591.1 (M+H).[000357] Example 28: (R)-5-(7-chloro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3-methyl-4-oxo-4H-quinolizin-2-yl)-2-(5-fluoro-l-methyl-6 -oxo-1, 6-dihydropyridin-2- yl)pyrimidine 1-oxideStep 1: Preparation of 5-(9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-7-chloro-3-methyl-4-oxo-4H- quinolizin-2-yl)-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyrimidine 1-oxide[000358] This intermediate was prepared using methods similar to those described in Example 25, Step 10 using (R)-N-((R)-l-(7-chloro-3-methyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (Example 1 , Step 9) and 5-bromo-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyrimidine 1-oxide (Intermediate 4) in place of (R)-N-((R)-l-(7-fluoro-3-methyl-4-oxo-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide and 5-fluoro-3-(4- iodo-6-oxopyridazin-l(6H)-yl)-2-methylpyridine 1-oxide. LCMS: (ESP) m / z = 560.2 (M+H).Step 2: Preparation of (R)-5-(9-(l-aminoethyl)-7-chloro-3-methyl-4-oxo-4H-quinolizin-2-yl)-2-(5- fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyrimidine 1-oxide[000359] This intermediate was prepared using methods similar to those described in Example 23, Step 6 using 5-(9-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-7-chloro-3-methyl-4- oxo-4H-quinolizin-2-yl)-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyrimidine 1-oxide in place of (R)-N-((R)-l-(3,7-dimethyl-2-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4- yl)-4-oxo-4H-quinolizin-9-yl)ethyl)-2-methylpropane-2-sulfinamide. LCMS: (ES ) m / z = 456.1 (M+H).Step 3: Preparation of (R)-5-(7-chloro-9-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-3- methyl-4-oxo-4H-quinolizin-2-yl)-2-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyrimidine 1- oxide (Example 28)[000360] A mixture of (R)-5-(9-(l-aminoethyl)-7-chloro-3-methyl-4-oxo-4H-quinolizin-2-yl)-2- (5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)pyrirnidine 1-oxide (90 mg, 0.20 mmol), 1- bromo-4-fluoro-2-(trifluoromethyl)benzene (96 mg, 0.40 mmol), Pd2(dba)3(18 mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol), and Cs2CO3(193 mg, 0.60 mmol) in dioxane (5 mL) under a nitrogen atmosphere was stirred at 100 °C for 4 h. The resulting mixture cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (2 x 20 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by prep-TLC (CH2CI2:MeOH = 15:1). The crude product was purified by prep-HPLC (XBridge Prep Phenyl OBD C18 column, 30 x 150 mm, 5 pm; Mobile Phase A: water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 43% B to 58% B over 10 min) to afford (R)-5-(7-chloro-9-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-3-methyl-4-oxo-4H-quinolizin-2-yl)-2-(5-fluoro-l-methyl-6- oxo-1, 6-dihydropyridin-2-yl)pyrimidine 1-oxide (14 mg, 12% yield, >99.0% ee) as a yellow solid. XH NMR (CD3OD, 400 MHz): 6 9.13 (d, J = 1.6 Hz, 1H), 8.99 (d, J = 1.6 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 7.62 - 7.42 (m, 2H), 7.40 - 7.19 (m, 2H), 7.12 - 7.01 (m, 1H), 6.80 - 6.59 (m, 1H), 6.50 - 6.33 (m, 1H), 5.27 - 5.11 (m, 2H), 3.58 (s, 3H), 2.40 (s, 3H), 1.71 (d, J = 6.0 Hz, 3H); LCMS: (ESF) m / z = 618.0 (M+H).[000361] Examples 4-20 in Table 1 can be prepared either in a manner similar to that described for Examples 1 to 3 or via the general methods depicted in Schemes 1 to 20 as well as via the references described in the accompanying text.Table 1. Examples 4 to 20 and Examples 29 to 395Table 2. NMR and LCMS data for Examples 12, 13, 17 and 29-395Assays and Compound Testing[000362] In vitro cell proliferation: Determination of EC50 values for inhibition of proliferation in T-47D cells expressing mutant PI3Ka (H1047R) mutation and SK-BR-3 cells expressing WT PI3Ka.[000363] 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% COj. 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 following formula: % I n h ibition = 100 x (LumD- Lurnisampie) / (LumD-Lurnmh), where D is obtained from cells treated with 0.1% DMSO only; Inh is obtained from cells treated with 10 uM Alpelisib. The effective concentration achieving 50% inhibition of proliferation (EC50) is calculated by fitting the Curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom) / (1 + 10A((LogEC50 - X) * HillSlope)).Reagent table[000364] For EC50 values shown in Table 3, "A" refers to EC50 < 100 nM; "B" refers to 100 nM< EC50 < 300 nM; "C" refers to 300 nM < EC50 < 1 pM; "D" refers to 1 pM < EC50 < 3 pM; "E" refers to 3 pM < EC50 < 10 pM; "F" refers to EC50 > 10 pM.Table 3. Cellular proliferation data[000365] In vitro cell pAKT: determination of IC50 values for inhibition of phosphorylation of AKT (pAKT) in the following cell lines: SK-BR-3 cells expressing WT PI3Ka, T-47D cells expressing mutant PI3Ka (H1047R), MCF-7 cells expressing mutant PI3Ka (E545K), BT-483 cells expressing mutant PI3Ka (E542K), EFM-19 cells expressing mutant PI3Ka (H1047L), and MFE-280 cells expressing mutant PI3Ka (H1047Y).[000366] 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 centrifugedfor 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 + 10A((LoglC50 - X)*HillSlope)).[000367] 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. EFM-19 culture media consisted of RPMI 1640 + 10% FBS , and assay media consisted of DMEM (no phenol red) + 10% FBS. MFE-280 culture media consisted of MEM + 10% FBS, and assay media consisted of DMEM (no phenol red) + 10% FBS.[000368] Cell density for dispensing into assay ready plates as follows: SK-BR-3 at 5,000 cells / well, T-47D at 5,000 cells / well, MCF-7 at 5,000 cells / well, BT-483 at 5,000 cells / well, EFM- 19 at 5,000 cells / well, MFE-280 at 10,000 cells / well.Reagent table[000369] 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 ptM; "D" refers to 1 piM < IC50 < 3 ptM; "E" refers to 3 pM < IC50 < 10 ptM; "F" refers to IC50 > 10 pM.Table 4. Cellular pAKT dataReferences[000370] Ali, K., Bilancio, A., Thomas, M., Pearce, W., Gilfillan, A. M., Tkaczyk, C., Kuehn, N., Gray, A., Giddings, J., Peskett, E., Fox, R., Bruce, I., Walker, C., Sawyer, C., Okkenhaug, K., Finan, P., and Vanhaesebroeck, B. 2004. Essential role for the pllOdelta phosphoinositide 3-kinase in the allergic response. 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Claims

IN THE CLAIMS1. A compound of Formula (1)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein: R1is aryl, heteroaryl or heterocyclyl, where each of the aryl, heteroaryl and heterocyclyl is unsubstituted or substituted, with the proviso that when R1is aryl or heteroaryl, a carboxylic acid or ester thereof is not a substituent at a position ortho to the point of attachment of the aryl or heteroaryl ring to the nitrogen atom of N-R3;R2is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF3, CFH2or CF2H, where the C1-C4 alkyl and C3-C7 cycloalkyl is unsubstituted or substituted, and where R2is not H, the carbon atom attached to R2is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer;R3is H or C1-C4 alkyl, where the C1-C4 alkyl is unsubstituted or substituted;R4is H, F, Cl, C1-C4 alkyl, C3-C7 cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4 alkyl and C3-C7 cycloalkyl is unsubstituted or substituted;R6is H, F, Cl, C1-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, CF3, CFH2or CF2H, where each of the C1-C4 alkyl, C3-C7 cycloalkyl and heteroaryl is unsubstituted or substituted;R7is H, F, Cl, C1-C4 alkyl, C3-C7 cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4 alkyl and C3-C7 cycloalkyl is unsubstituted or substituted; each Rg is independently H, F, Cl, C1-C4 alkyl, C3-C7 cycloalkyl, CN, CF3, OCF3, CFH2or CF2H, where the C1-C4 alkyl and C3-C7 cycloalkyl is unsubstituted or substituted;Rs is halogen;-O-Li-L2-L3-L4-L5-L6-L7-Rg;-S-Li-L2-L3-L4-L5-L6-L7-R9;-S(O)-L1-L2-L3-L5-L5-L7-R9;-S(O)2-L1-L2-L3-L5-L6-L7-R9;-(NR1O)-LI-L2-L3-L4-L5-L6-I-7-R9; or-Ls-Lg-Lio-Lii-Li2-R14, wherein: each of Li, L2, L3, Lg and L7is independently (CHRu), (CHRu-O), (CHRu-S), (C3-C7 cycloalkyl), (CH2)I-4 or a bond;L4is C=O, C=S or a bond;Lsis NR10, S, O or a bond;Rgis H, C(=O)R12, C(=O)NR12R13, NR12R13, C(=O)OR12, CC16- alkyl, CC13- fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of theC1- C6alkyl, C1-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively when NR10 is present, Rgand R10together with the attached nitrogen atom may form a substituted or unsubstituted ring; each of R1o and RH is independently H or C1-C4 alkyl (such as CH3, CH2CH3or CH(CH3)2), where the C1- C4alkyl is unsubstituted or substituted; each of R12and R13is independently H,C1- Cg alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of theC1-C3alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively, R12and R13together with the attached nitrogen atom may form a substituted or unsubstituted ring;L8 is (CHR15), (CHRis-O), (CHR15-S), (CHR15-NR16), C=0, C=S or a bond;L9 is C3-C7 cycloalkyl that is optionally part of a bridged, fused or spiro ring system, C(R15)=C(R15), CEC or a bond;L10 is independently (CHR15), O, S, (NCR15), N(C=O) or a bond;Ln is (CHR15), C=O, C=S or a bond;L12 is H, (C3-C7cycloalkyl), heterocyclyl, aryl, heteroaryl or a bond, where each of the C3-C7cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and the C3-C7cycloalkyl and / or heterocyclyl is optionally part of a bridged, fused or spiro ring system;R14 is H, CR15R16R17, OR17, SR17, NR16R17, C1-C6alkyl, C1-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the C1-C6alkyl, C1-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, each of R15and R16is independently H or C1-C3 alkyl; and each R17is independently H, C1-C6alkyl, C1-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the C1-C6alkyl, C1-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively, R16and R17together with the attached nitrogen atom may form a substituted or unsubstituted ring; with the proviso that when R5is -L8-L9-L10-L11-L12-R14, at least one of L8, L9, L10, L11, L12 and R14is a carbon-containing moiety and R5is directly attached to the core structure by a carbon atom; or R5is a non-aromatic N-linked heterocyclic ring , where the heterocyclic ring is substituted or unsubstituted, optionally contains one or more additional ring atoms selected from N, O, Si and S, and is optionally part of a bridged, fused or spiro ring system. In particular embodiments, the N- linked heterocyclyl ring is a substituted or unsubstituted azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1, 4-dioxa-7-azaspiro[4.4]nonane or 2- azaadamantane.

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 R5is -(NR1O)-LI-L2-L3-L4-L5-L6-L7-R9, where Li to L7, R9 and R1o are 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 R5is -O-L1-L2-L3-L4-L5-L6-L7-R9, where Li to L7and R9are 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 -S-L!-L2-L3-L4-L5-L6-L7-R9; -S(O)-LI-L2-L3-LS-L6-L7-R9; or -S(O)2-LI-I_2-L3-L5-I_6-L7-R9, where Li to L7and Rg are as defined.

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 -L8-L9-L10-L11-L12-R14, where L8to L12 and R14are as defined.

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 R5is a non-aromatic N-linked heterocyclyl ringwhere the heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional ring atoms selected from N, O, Si and S, and is optionally part of a bridged, fused or spiro ring system.

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 R1is selected fromR1s is a substituted or unsubstituted 5- or 6-membered nitrogen-containing heteroaryl ring or R1g is selected from the following:where each A is independently C1-C4 alkyl, fluoroalkyl, C3-C7 cycloalkyl, N(Ra)2, (CH2)0-5-NRa-C(0)-C3-C7cycloalkyl, (CH2)1-5-O-C1-C3 cycloalkyl, (CH2)1-5-O-(CH2)1-5-CI-C3 fluoroalkyl, (CH2)0-5-aryl, (CH2)0-5- heteroaryl, (CH2)0-5-heterocyclyl, (CH2)0-5-NRa-(CH2)0-5-heteroaryl or (CH2)0-5-NRa-(CH2)i-5-N- heterocyclyl, where the alkyl, fluoroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, A and A together with the attached -P(=O)- moiety may form a substituted or unsubstituted heterocyclyl ring; each B is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, (CH2)1-5-NRa-C(O)-C3-C7cycloalkyl, (CH2)0-5-aryl, (CH2)0-5-heteroaryl, (CH2)0-5-heterocyclyl, (CH2)1-5-NRa-(CH2)0-5-heteroaryl or (CH2)1-5-NRa-(CH2)2-5-N- heterocyclyl, O-C1-5-alkyl, O-C0-5-cycloalkyl, O-C0-5-heterocyclyl, where the alkyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, B and B together with the attached [O or NH]-P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring, or alternatively, A and B together with the attached -P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring; each Rais independently H, C1-C4 alkyl, C(O)Ci-C3alkyl or C(O)-(CH2)I.5-O-CI-C3alkyl, where the alkyl is substituted or unsubstituted, or alternatively, Raand A together with the attached -S(=O)2- moiety may form a substituted or unsubstituted heterocyclic ring, or R1s and R19together form a substituted or unsubstituted heterocyclic ring (such as a 5- or 6- membered heterocyclic ring) containing one or more sulfur atoms (which includes the sulfoxide (SO) and sulfone (SO2) forms), nitrogen atoms (which includes the oxidized forms) and oxygen atoms; R1s is H, C1-C4 alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted, or R19and R18together form a heterocyclic ring; each R2O is independently H, C1-C4 alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted;R2I is H, C1-C4 alkyl, C3-C7cycloalkyl, CF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted; and each X1, X2, X a3nd X4is independently CH, N or substituted C.

8. The compound according to claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected fromY is O, NR2I or C(R4)2; andX2, X3, X4and each R4, R20 and Rsi are defined as in claim 7.

9. The compound according to claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected fromwhere R1s, R1g, R20, R21, X1, X2, X3and X4are as defined in claim 7.

10. The compound according to claim 1 or claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F.

11. The compound according to claim 1 or claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R3 is H.

12. The compound according to claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3 or CH2F, R3is H and R1is selected from13. The compound according to claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and R1is selected from14. The compound according to claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R18is selected from15. The compound according to claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R18is selected from16. The compound according to claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R18is selected from17. The compound according to claim 1 or claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and R5is -S-LI-L2-L3-L4-L5-L6-L7-R9.

18. The compound according to claim 1 or claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and R5is -(NR1O)-L1-L2-L3-L4-L5-LS-L7-R9.

19. The compound according to claim 1 or claim 7 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and R5is -L8-L9-Lio-Lu-L12-R14.

20. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (2)or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: R1and R5are defined as for the compound of Formula (1), and the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer.

21. The compound according to claim 20 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected fromR1s is selected from the following:where each A is independently C1-C4 alkyl, fluoroalkyl, C3-C7 cycloalkyl, N(Ra)2, (CH2)0-5-NRa-C(0)-C3-C7cycloalkyl, (CH2)I.5-O-CI-C3 cycloalkyl, (CH2)1-5-O-(CH2)I.5-C1-C3 fluoroalkyl, (CH2)0-5-aryl, (CH2)0-5- heteroaryl, (CH2)0-5-heterocyclyl, (CH2)0-5-NRa-(CH2)0-5-heteroaryl or (CH2)0-5-NRa-(CH2)i-5-N- heterocyclyl, where the alkyl, fluoroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, A and A together with the attached -P(=O)- moiety may form a substituted or unsubstituted heterocyclyl ring;each B is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, (CH2)i.5-NRa-C(O)-C3-C7cycloalkyl, (CH2)0-5-aryl, (CH2)0-5-heteroaryl, (CH2)0-5-heterocyclyl, (CH2)i-5-NRa-(CH2)0-5-heteroaryl or (CH2)i.5-NRa-(CH2)2.5-N- heterocyclyl, O-Ci-5-alkyl, O-C0-5-cycloalkyl, O-C0-5-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or alternatively, B and B together with the attached -[O or NH]-P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring, or alternatively, A and B together with the attached -P(=O)-O- moiety may form a substituted or unsubstituted heterocyclyl ring; each Rais independently H, C1-C4 alkyl, C(O)C1-C3alkyl or C(O)-(CH2)1-5-O-C1-C3alkyl, where the alkyl is substituted or unsubstituted, or alternatively, Raand A together with the attached -S(=O)2- moiety may form a substituted or unsubstituted heterocyclic ring, or R19and R18together form a substituted or unsubstituted heterocyclic ring (such as a 5- or 6- membered heterocyclic ring) containing one or more sulfur atoms (which includes the sulfoxide (SO) and sulfone (SO2) forms), nitrogen atoms (which includes the oxidized forms) and oxygen atoms; R19is H, C1-C4 alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted, or R19and R18together form a heterocyclic ring; each R20is independently H, C1-C4 alkyl, C3-C7cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted;R2I is H, C1-C4 alkyl, C3-C7cycloalkyl, CF3, CFH2or CF2H, where the alkyl and cycloalkyl is substituted or unsubstituted; and each X1, X2, X a3nd X4is independently CH, N or substituted C.

22. The compound according to claim 20 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R1is selected from23. A pharmaceutical composition comprising the compound of any one of claims 1 to 22 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

24. The pharmaceutical composition according to claim 23, further comprising one or more anticancer agents.

25. The pharmaceutical composition according to claim 24, 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.

26. 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 22 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

27. The method of claim 25, wherein the disease is cancer.

28. The method of claim 26, 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).

29. The method of claim 26, wherein the disease is a cancer bearing a PI3Ka H1047R mutation.

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