Benzopyridinones and benzopyrimidinones 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 and X1, X2, X3 and X4 are as defined.

Description

BENZOPYRIDINONES AND BENZOPYRIMIDINONES AS PI3K INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 532,175, filed August 11, 2023, and U.S. Provisional Application No. 63 / 600,371, filed November 17, 2023, the disclosures of which are incorporated in their entireties for all purposes.BACKGROUND OF THE INVENTION

[0002] Phosphatidylinositol lipids (Pls) and their various phosphorylated subspecies are second messengers involved in a wide array of cellular vesicle trafficking and signal transduction processes. Phosphoinositide 3' kinases (PI3Ks) are a family of enzymes responsible for phosphorylation of the 3' hydroxyl position of the inositol ring of Pls. PI3Ks are subdivided into 3 classes according to their structure and substrates. Class II PI3Ks (PI3K-C2a, PI3 K-C2P, 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, 6) and one of several regulatory subunits that determine binding partners and subcellular localization. Class I PI3Ks are activated upon interaction with receptor tyrosine kinases (RTKs), Ras-related GTPases, G-protein coupled receptors, and / or related adaptor proteins, and in their active form convert phosphatidylinositol 4,5-diphosphate (PIP2) to phosphatidyl 3,4,5- triphosphate (PIP3) (Fruman et al., Cell 2017, 170, 605).

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

[0004] Class I PI3Ks are further subdivided into 4 isoforms (a, P, y, and 6) based on the identity of their catalytic (pllOa, pliop, pllOy, or pllOS) and regulatory (p85a or its various splice variants, p85|3, p55y, or plOl) subunits, giving rise to distinct roles in cellular physiology (Vanhaesebroeck et al., J Mol Med (Berl). 2016, 94, 5). PI3 Ky and PI3K6 are mostly expressed in leukocytes and play an important role in pro-inflammatory pathways (Hawkins et. al., Biochimica et Biophysica Acta 2015, 1851, 882; Okkenhaug et al., Science 2002, 297, 1031; Ali et al., Nature 2004, 431, 1007). PI3Ka and P are more ubiquitously expressed and share similar but not identical roles. For example, PI3Ka has a nonredundant role in angiogenesis (Soler et al., J ExpMed. 2013, 210, 1937), while PI3K|3 is known to serve a specific function in platelet aggregation (Liu et. al., Nat Rev Drug Discov. 2009, 8, 627; Jackson et al., Nat Med. 2005, 11, 507).

[0005] Elevation or constitutive activation of the PI3K pathway is one of the most frequent events in human cancers. The PI3K pathway is overactivated through a variety of mechanisms, including activating mutation of PI3K isoforms, up-regulation of PI3K isoforms, loss or inactivation of the tumor suppressor PTEN, or hyperactivation of tyrosine kinase growth factor receptors or other upstream signaling partners (Yang et al., Mol Cancer 2019, 18, 1). Mutations in the gene coding for PI3Ka or mutations which lead to upregulation of PI3Ka have been found to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers (Goncalves 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. The severity of the adverse event is dependent on the select isoform, for example PI3Ka inhibitors are associated with hyperglycemia and rash due to the pllOa sub-unit role in insulin response (Rugo et al., The Breast 2022, 61, 156). Similarly, use of a selective PI3K6 inhibitor (idelalisib), where the pllOS sub-unit is highly expressed in immune cells, causes severe diarrhea and colitis. Inhibition with a dual inhibitor (taselisib), a potent PI3K6 inhibitor possessing modest PI3Kainhibition led to gastrointestinal (Gl) side effects, but a highly selective and potent PI3K8 inhibitor (umbralisib) reported no Gl related adverse events (Gadkar et al., CPT Pharmacometrics Syst Pharmacol. 2021, 11, 616). Such amelioration of adverse events with highly isoform selective and potent inhibitors demonstrates that a strategy to mitigate toxicity by developing mutant selective isoform inhibitors is promising for decreasing the severity of toxicity.Furthermore, selective inhibition of the mutant PI3Ka isoform over wild type may suppress cancer signaling while having minimal effect on PI3K signaling in healthy cells bearing just wild type PI3Ka, leading to a reduction in the toxicities associated with nonselective PI3K inhibition (Castel et al., Nat Cancer 20212, 587).

[0007] There is currently an interest in developing PI3K inhibitors for cancer therapy (WO 2023 / 081209, WO 2023 / 078401, WO 2023 / 060262, WO 2023 / 056407, WO 2021 / 202964). 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:Ri is selected fromeach A is independently C1-C4 alkyl, fluoroalkyl, C3-C7 cycloalkyl, N(Ra)2, (CH2)o-5-NRa-C(0)-C3-C7cycloalkyl, (CH2)I-5-0-(CH2)O-5-CI-C4 alkyl, (CH2)I-5-O-CI-C3cycloalkyl, (CH2)I-5-0-(CH2)O-5-CF3, (CH2)I- 5-O-(CH2)I-5-CI-C3fluoroalkyl, (CH2)o-s-aryl, (CH2)o-5-heteroaryl, (CH2)o-5-heterocyclyl, (CH2)o-s-NRa- (CH2)o-5-heteroaryl or (CH2)o-5-NRa-(CH2)i-5-N-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, 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-C7cycloalkyl, (CH2)I-5-OH, (CH2)o-s-N(Ra)2, (CH2)i-5-NRa- C(O)-C3-C7cycloalkyl, (CHzJo-s-aryl, (CH2)o-5-heteroaryl, (CH2)o-5-heterocyclyl, (CH2)O-5-C(0)-(CH2)I-5- O-C1-C4 alkyl, (CH2)i-5-NRa-(CH2)o-5-heteroaryl or (CH2)i-5-NRa-(CH2)2-5-N-heterocyclyl, O-Ci-5-alkyl, O-Co-5-cycloalkyl, O-Co-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, C3-C7 cycloalkyl, C(O)Ci-C3alkyl, (CH2)i-5-fluoroalkyl, (CH2)I-5-OH, (CH2)I-5-NH2, (CH2)I.5-NH(CI.C4alkyl), (CH2)I.5-N(CI.C4alkyl)2or C(O)-(CH2)I-5-O-CI-C3alkyl, where the alkyl and cycloalkyl are substituted or unsubstituted, or alternatively, for -S(=O)(A)(=NRa) or for -S(=O)(A)(NRa), Raand A together with the attached atoms, may form a substituted or unsubstituted heterocyclyl ring;R2is H, Ci-C4alkyl, C3-C7 cycloalkyl, CF3, CFH2or CF2H, 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 Ci-C4alkyl;R4is H, Ci-C4alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H;Re is H, Ci-C4alkyl, C3-C7 cycloalkyl, heteroaromatic, CF3, CFH2or CF2H;R7is H, Ci-C4alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H; each Rs is independently H, Ci-C4alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H; each of Xi, X2, X3and X4is independently N, CH or substituted C;Rs is halogen;wherein: each of Li, L2, L3, Lsand L7is independently (CHRH), (CHRn-O), (CHRH-S), (C3-C7 cycloalkyl), (CH2)I-4or a bond;U is C=O, C=S or a bond;L5is NR10, S, O or a bond;R9is H, C(=O)Ri2, C(=O)NRi2Ri3, NRI2RI3, C(=O)ORi2, Ci-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively when NRio is present, R9and Rio 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, 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 Ci-C4alkyl, O-Ci-C4alkyl, or NRbRcwhere Rb and Rcare independently H or Ci-C4alkyl; each of Rio and Rn is independently H or Ci-C4alkyl (such as CH3, CH2CH3or CH(CH3)2), where the Ci-C4alkyl is unsubstituted or substituted; each of Ri2and Ri3is independently H, Ci-C6alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively, Ri2and Ri3together 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 Ci-C4alkyl, O-C1-C4 alkyl, or NRbRcwhere Rb and Rcare independently H or Ci-C4alkyl;Ls is (CHRis), (CHRis-O), (CHRis-S), (CHRI5-NRI6), C=O, C=S or a bond;L9is C3-C7cycloalkyl that is optionally part of a bridged, fused or spiro ring system, C(Ri5)=C(Ri5), C=C or a bond;Lio is independently (CHRis), O, S, (NCRis), N(C=O) or a bond;Ln is (CHRis), C=O, C=S or a bond;Li2is 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, CRisRieRi?, OR17, SR17, NRi6Ri7, CI-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, each of Ri5and RiSis independently H or C1-C3 alkyl; and each R17 is independently H, Ci-C6alkyl, Ci-C6fluoroalkyl, Ci-C6aminoalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively, RiSand Ri7together 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 nonaromatic 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, 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; with the proviso that when R5is -L8-L9-Lio-Lii-Li2-Ri4, at least one of Lg, L9, Lio, Ln, Li2and Ri4is a carbon-containing moiety and R5is directly attached to the (benzopyridinone or benzopyrimidinone) 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, 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.

[0009] In an exemplary embodiment, R5is -(NRIO)-LI-L2-L3-I-4-L5-L6-L7-R9, where Li to L7, R9and Rio are as defined.

[0010] In an exemplary embodiment, R5is -O-LI-L2-L3-I-4-L5-L6-L7-R9, where Li to L7and R9are as defined.

[0011] In an exemplary embodiment, R5is -S-L1-L2-L3-L4-L5-L6-L7-R9; -SfOj-Li-Lz-Lj-Ls-Le-Ly-RgJ or -S(O)2-LI-L2-L3-L5-L6-L7-R9, where Li to L7and R9are as defined.

[0012] In an exemplary embodiment, R9is 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 Ci-C6alkyl group, where the aryl ring, the heteroaryl ring, the carbocycle, the heterocycle and the Ci-C6alkyl group 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 Ci-C4alkyl, O-C1-C4 alkyl or NRbRc, where Rb and Rcare independently H or C1-C4 alkyl.

[0013] In an exemplary embodiment of R5, each of Lg, Lio and Ln is a bond and L9is not a bond.

[0014] In an exemplary embodiment of R5, each of Lg, Lio and Ln is a bond and L9is cycloalkyl that is optionally part of a bridged, fused or spiro ring system.

[0015] In an exemplary embodiment of R5, each of Lg, Lio and Ln is a bond and L9is cycloalkyl that is part of a bridged ring system.

[0016] In an exemplary embodiment of R5, each of Lg, Lio and Ln is a bond and L9is cycloalkyl that is part of a fused ring system.

[0017] In an exemplary embodiment of R5, each of Lg, Lio and Ln is a bond and L9is cycloalkyl that is part of a spiro ring system.

[0018] In an exemplary embodiment of R5, each of Lg, Lio and Ln is a bond and L9is C(Ri5)=C(Ri5).

[0019] In an exemplary embodiment of R5, each of Lg, Lio and Ln is a bond and L9is C=C.

[0020] In an exemplary embodiment of R5, each of Lg, 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.

[0021] In an exemplary embodiment of R5, each of Lg, 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 Ri4is H.

[0022] In an exemplary embodiment of R5, each of Lg, 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 Ri4is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted.

[0023] In an exemplary embodiment of R5, each of Lg, 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 Ri4is -CRi4Ri5Ri6.

[0024] In an exemplary embodiment of R5, each of Lg, 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 Ri4is -ORn or -ORi7.

[0025] In an exemplary embodiment of R5, each of Lg, 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 Ri4is -SRi7.

[0026] In an exemplary embodiment of R5, each of Lg, 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 Ri4is -NRI6RI7.

[0027] In an exemplary embodiment, R5iscycloalkyl, a six-membered aromatic or 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 Ci-C4alkyl, O-C1-C4 alkyl, or NRbRcwhere Rb and Rcare independently H or Ci-C4alkyl.

[0028] In an exemplary embodiment, R5is a N-linked non-aromatic heterocyclyl ringwhere the heterocyclyl ring is substituted or unsubstituted, optionally contains one or moreadditional 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] In an exemplary embodiment of the compound of Formula (1), Ri is selected fromwhere A and B are as defined.

[0040] In an exemplary embodiment of the compound of Formula (1), Ri is selected fromwhere A, B and Raare as defined.

[0041] In an exemplary embodiment of the compound of Formula (1), Ri is selected fromwhere B is as defined.

[0042] In an exemplary embodiment of the compound of Formula (1), R2is CH3.

[0043] In an exemplary embodiment of the compound of Formula (1), R2is CH2F.

[0044] In an exemplary embodiment of the compound of Formula (1), R3is H.

[0045] In an exemplary embodiment of the compound of Formula (1), R4is H or F.

[0046] In an exemplary embodiment, Xi is N, and X2and X3are independently CH or CF.

[0047] In an exemplary embodiment, X2is N, and Xi and X3are independently CH or CF.

[0048] In an exemplary embodiment, X3is N, and Xi and X3are independently CH or CF.

[0049] In an exemplary embodiment, Xi and X3are N, and X2is CH or CF.

[0050] In an exemplary embodiment, Xi and X2are N, and X3is CH or CF.

[0051] In an exemplary embodiment, X2and X3are N, and Xi is CH or CF.

[0052] In an exemplary embodiment, Xi, X2and X3are N.

[0053] In an exemplary embodiment, Xi, X2and X3are independently CH or CF.

[0054] In an exemplary embodiment, X4 is N.

[0055] In an exemplary embodiment, X4 is CH or CF.

[0056] In an exemplary embodiment, Xi is N, X2and X3are independently CH or CF, and X4is N.

[0057] In an exemplary embodiment, X2is N, Xi and X3are independently CH or CF, and X4is N.

[0058] In an exemplary embodiment, X3is N, Xi and X3are independently CH or CF, and X4is N.

[0059] In an exemplary embodiment, Xi and X3are N, X2is CH or CF, and X4is N.

[0060] In an exemplary embodiment, Xi and X2are N, X3is CH or CF, and X4is N.

[0061] In an exemplary embodiment, X2and X3are N, Xi is CH or CF, and X4is N.

[0062] In an exemplary embodiment, Xi, X2and X3are N, and X4is N.

[0063] In an exemplary embodiment, Xi, X2and X3are independently CH or CF, and X4is N.

[0064] In an exemplary embodiment, Xi is N, X2and X3are independently CH or CF, and X4is CH orCF.

[0065] In an exemplary embodiment, X2is N, Xi and X3are independently CH or CF, and X4is CH or CF.

[0066] In an exemplary embodiment, X3is N, Xi and X3are independently CH or CF, and X4is CH or CF.

[0067] In an exemplary embodiment, Xi and X3are N, X2is CH or CF, and X4is CH or CF.

[0068] In an exemplary embodiment, Xi and X2are N, X3is CH or CF, and X4is CH or CF.

[0069] In an exemplary embodiment, X2and X3are N, Xi is CH or CF, and X4is CH or CF.

[0070] In an exemplary embodiment, Xi, X2and X3are N, and X4is CH or CF.

[0071] In an exemplary embodiment, Xi, X2and X3are independently CH or CF, and X4is CH or CF.

[0072] In an exemplary embodiment of the compound of Formula (1), R5is

[0073] In an exemplary embodiment of the compound of Formula (1), R5is

[0074] In an exemplary embodiment of the compound of Formula (1), R5is

[0075] In an exemplary embodiment of the compound of Formula (1), R5is

[0076] In an exemplary embodiment of the compound of Formula (1), R5isL7-R9.

[0077] In an exemplary embodiment of the compound of Formula (1), R5is -L8-L9-LIO-LH-LI2-RI4.

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

[0079] In an exemplary embodiment of the compound of Formula (1), R7is CH3.

[0080] In an exemplary embodiment of the compound of Formula (1), each Rgis independently H orF.

[0081] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, and Ri is selected fromwhere A and B are as defined.

[0082] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, andRi is selected fromwhere A, B and Raare as defined.

[0083] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, andRi is selected fromwhere B is as defined.

[0084] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, Ri is selected fromwhere A and B are as defined, 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.

[0085] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, Ri is selected fromwhere A, B and Raare as defined, 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.

[0086] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, Ri iswhere B is as defined, 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.

[0087] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isN, and Ri is selected fromwhere A and B are as defined.

[0088] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isN, and Ri is selected fromwhere A, B and Raare as defined.

[0089] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isN, and Ri is selected fromwhere B is as defined.

[0090] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isN, Ri is selected fromwhere A and B are as defined, 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.

[0091] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isN, Ri is selected fromwhere A, B and Raare as defined, 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.

[0092] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isN, Ri is selected fromwhere B is as defined, 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.

[0093] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isCH or CF, and Ri is selected fromwhere A and B are as defined.

[0094] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isCH or CF, and Ri is selected fromwhere A, B and Raare as defined.

[0095] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isCH or CF, and Ri is selected fromwhere B is as defined.

[0096] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isCH or CF, Ri is selected fromwhere A and B are as defined, 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.

[0097] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isCH or CF, Ri is selected fromwhere A, B and Raare as defined, 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.

[0098] In an exemplary embodiment of the compound of Formula (1), R2is CH3or CH2F, R3is H, X4isCH or CF, Ri is selected fromwhere B is as defined, 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.

[0099] 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:Xi, X2, X3, Ri and R5are defined as in 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.

[0100] 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:Xi, X2, X3, Ri and R5are defined as in 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.

[0101] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Ri is selected fromwhere A and B are defined as in the compound of Formula (1).

[0102] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Ri is selected fromwhere A, B and Raare defined as in the compound of Formula (1).

[0103] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Ri is selected fromwhere B is defined as in the compound of Formula (1).

[0104] In an exemplary embodiment of the compound of Formula (2) or Formula (3), 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).

[0105] In an exemplary embodiment of the compound of Formula (2) or Formula (3), R5is -S-L1-L2- L3-L4-L5-L6-L7-R9 where -S-L1-L2-L3-L4-L5-L6-L7-R9 is defined as in the compound of Formula (1).

[0106] In an exemplary embodiment of the compound of Formula (2) or Formula (3), R5is -(NRIO)-LI-L2-L3-I-4-L5-L6-L7-R9 where -(NRioJ-Li-l^-Ls-U-Ls-Le-l^-Rg is defined as in the compound of Formula (1).

[0107] In an exemplary embodiment of the compound of Formula (2) or Formula (3), R5is -L8-L9-L10-L11-L12-R14 where -L8-L9-L10-L11-L12-R14 is defined as in the compound of Formula (1).

[0108] In an exemplary embodiment of the compound of Formula (2) or Formula (3), R5is -Ls-Lg-Lio- L11-L12-R14 where Lg, L9, Lio and Ln are a bond; Li2is (C3-C7 cycloalkyl), heterocyclyl or heteroaryl, where each of the (C3-C7 cycloalkyl), heterocyclyl or heteroaryl is substituted or unsubstituted; and R14 is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is unsubstituted or substituted.

[0109] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Ri is selected fromwhere B is defined as in the compound of Formula (1); R5is -L8-L9-Li0-Ln-Li2-Ri4 where L8, L9, Lio and Ln are a bond; Li2is (C3-C7cycloalkyl), heterocyclyl or heteroaryl, where each of the (C3-C7cycloalkyl), heterocyclyl or heteroaryl is substituted or unsubstituted; and Ri4is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is unsubstituted or substituted.

[0110] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Ri is selected fromwhere B is defined as in the compound of Formula (1); R5is -L8-L9-Lio-Ln-Li2-Ri4 where Lg, L9, Lio and Ln are a bond; Li2is (C3-C7cycloalkyl), heterocyclyl or heteroaryl, where each of the (C3-C7cycloalkyl), heterocyclyl or heteroaryl is substituted or unsubstituted; Ri4is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is unsubstituted or substituted; and one of Xi or X2is N.

[0111] In an exemplary embodiment of the compound of Formula (2) or Formula (3), R5is -L8- L9-L10-L11-L12-R14 where L8, L9, Lio and Ln are a bond; Li2is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is substituted or unsubstituted; and Ri4is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is unsubstituted or substituted.

[0112] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Ri is selected fromwhere B is defined as in the compound of Formula (1); R5is -L8-L9-Lio-Ln-Li2-Ri4 where L8, L9, Lio and Ln are a bond; Li2is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is substituted or unsubstituted; and Ri4is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is unsubstituted or substituted.

[0113] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Ri is selected fromwhere B is defined as in the compound of Formula (1); R5is -L8-L9-Lio-Lii-Li2-Ri4 where L8, L9, Lio and Ln are a bond; Li2is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is substituted or unsubstituted; Ri4is heterocyclyl or heteroaryl, where each of the heterocyclyl or heteroaryl is unsubstituted or substituted; and one of Xi or X2is N.

[0114] In an exemplary embodiment of the compound of Formula (2) or Formula (3), R5is a N- linked non-aromatic heterocyclyl ringis defined as in the compound of Formula (1).

[0115] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Xi is N, and X2and X3are independently CH or CF.

[0116] In an exemplary embodiment of the compound of Formula (2) or Formula (3), X2is N, and Xi and X3are independently CH or CF.

[0117] In an exemplary embodiment of the compound of Formula (2) or Formula (3), X3is N, and Xi and X3are independently CH or CF.

[0118] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Xi and X3are N, and X2is CH or CF.

[0119] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Xi and X2are N, and X3is CH or CF.

[0120] In an exemplary embodiment of the compound of Formula (2) or Formula (3), X2and X3are N, and Xi is CH or CF.

[0121] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Xi, X2and X3are N.

[0122] In an exemplary embodiment of the compound of Formula (2) or Formula (3), Xi, X2and X3are independently CH or CF.

[0123] An aspect of the invention is a pharmaceutical composition comprising any compound of the invention as described herein (such as any one of Formula (1), (2) or (3)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0124] In an exemplary embodiment, the pharmaceutical composition comprising any compound of the invention as described herein (such as any one of Formula (1), (2) or (3)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof further comprises one or more anti-cancer agents.

[0125] Another aspect of the invention is a method of treating a disease in which PI3K activity is implicated in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of any compound of the invention as described herein (such as any one of Formula (1), (2), or (3)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0126] In an exemplary embodiment, the disease to be treated is cancer. In a particular embodiment, the disease is a cancer bearing a PI3Ka H1047 mutation (such as H1047R).DETAILED DESCRIPTION OF THE INVENTION

[0127] 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.

[0128] The term "effective amount" as used herein, refers to a particular amount of a pharmaceutical composition comprising a therapeutic agent that achieves a clinically beneficial result (i.e., for example, a reduction of symptoms). Toxicity and therapeutic efficacy of such compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio 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.

[0129] 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.

[0130] 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.

[0131] 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, atleast 75% lower than, and / or at least 90% lower than the quantity and / or magnitude of the symptoms in the untreated subject.

[0132] The term "inhibitory compound" as used herein, refers to any compound capable of interacting with ( / .e., for example, attaching, binding, etc.) to a binding partner under conditions such that the binding partner becomes unresponsive to its natural ligands. Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins / peptides.

[0133] 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.

[0134] 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.

[0135] The term "administered" or "administering" as used herein, refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient. An exemplary method of administering is by a direct mechanism such as, local tissue administration ( / .e., for example, extravascular administration, such as subcutaneous, intramuscular, or intraperitoneal), intravenous, oral ingestion, transdermal patch, topical, inhalation, suppository, etc.

[0136] The term "patient" as used herein, is a human or animal and needs not be hospitalized. For example, out-patients and persons in nursing homes are "patients." A patient may be a human or non-human animal of any age and therefore includes both adults and juveniles ( / .e., children). It is not intended that the term "patient" connote a need for medical treatment. Therefore, a patient may voluntarily be subject to experimentation, whether clinical or in support of basic science studies.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] The term "test compound" as used herein, refers to any compound or molecule considered a candidate as an inhibitory compound.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] The term "in vivo" as used herein refers to an event that takes place in a subject's body.

[0145] The term "in vitro" as used herein refers to an event that takes places outside of a subject's body.

[0146] The term "protein" as used herein, refers to any of numerous naturally occurring extremely complex substances (such as an enzyme or antibody) that contain amino acid residues joined by peptide bonds, and which include carbon, hydrogen, nitrogen, oxygen, and typically sulfur. In general, a protein comprises amino acids having an order of magnitude within the hundreds.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] The term "conjugate" as used herein, refers to any compound that has been formed by the joining of two or more moieties.

[0157] A "moiety" or "group" as used herein, is any type of molecular arrangement designated by formula, chemical name, or structure. Within the context of certain embodiments, a conjugate comprises one or more moieties or chemical groups. This means that the formula of the moiety is substituted at some position in order to be joined and be a part of the molecular arrangement of the conjugate. Although moieties may be directly covalently joined, it is not intended that the joining of two or more moieties must be directly to each other. A linking group, a crosslinking group, or a joining group refers to any molecular arrangement that will connect moieties by covalent bonds such as, but not limited to, one or more amide group(s). Additionally, although the conjugate may be unsubstituted, the conjugate may have a variety of additional substituents connected to the linking groups and / or connected to the moieties.

[0158] 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.

[0159] 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 atomor 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)-CH3 as 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 (N02), 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, OCF2CF2CF3 or OCH2CI), O-aryl (e.g., O-phenyl), O-heteroaryl, O-heterocyclyl, (CH2)I- 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., -C^CRf), alkenyl (e.g., -CRf=CRfRg), aryl (e.g., phenyl), arylalkyl (e.g., CH2Ph), heteroaryl (e.g., pyridyl or any 5- or 6- membered heteroaryl ring), heteroarylalkyl (e.g., CH2-pyridine), heterocyclyl, heterocycloalkyl and as well as, -NRfRg, -NRfC(=O)Rg, .NRfC(=O)NRfNRg, -NRf-C(=O)ORfSO2Rg, -C(=O)Rf, -C(=O)ORf, -C(=O)(CH2)i.3Rf, -C(=O)O(CH2)i.3Rf, -C(=O)(CH(CH3))(CH2)0.3Rf, -C(=0)0(CH(CH3))(CH2)o-3Rf, -C(=0)(C(CH3)2)(CH2)o-3Rf, -C(=0)0(C(CH3)2)(CH2)o-3Rf, -0Rf, -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.

[0160] 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.

[0161] 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.

[0162] The term "alkyl" as used herein, refers to any straight chain or branched, non-cyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term "lower alkyl" has the same meaning as alkyl but contains from 1 to 3 carbon atoms. The term "higher alkyl" has the same meaning as alkyl but contains from 4 to 10 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and the like, while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. As used herein, a methyl substituent may be depicted as "CH3" or "Me" or as a terminal bond with no indication of specific atoms.

[0163] 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".

[0164] The term "bicyclic compounds" as used herein, encompasses "bridged" compounds, "fused" compounds and "spiro" compounds as described.

[0165] The term "spiro" or "spirocyclic" as used herein, refers to chemical structures having at least two rings sharing one common atom. The rings may be cycloalkyl, heterocyclyl or a combination thereof, and may include one or more aryl or heteroaryl rings. Exemplary embodiments include l,4-dioxaspiro[4.5]decane, oxa-azaspiro[3.4]octane, diazaspiro[3.4]octane, diazaspiro[2.5]octane, spirocyclic azetidines and spirocyclic pyrrolidines and spirocyclic piperidines, where the other ring is cycloalkyl (e.g., cyclobutane, cyclopentane or cyclohexane) or heterocyclyl (e.g., piperidine, tetrahydropyran, tetrahydrofuran, azetidine or pyrrolidine).

[0166] The term "bridged" as used herein, refers to a compound containing two nonadjacent atoms common to two rings. Exemplary embodiments include, but are not limited to, norbornane, bicyclo[l.l.l]pentane, bicyclo[2.2.1]heptane, azabicyclo[3.1.0]hexane, 3,9- diazabicyclo[3.3.1]nonane, diazabicyclo[3.1.1]heptane, diazabicyclo[3.2.1]octane, 1,4-azabicyclo[2.2.1]heptane, 1,4 azabicyclo[2.2.2]octane, l,4-diazabicyclo[2.2.1]heptane, 1,4- diazabicyclo[2.2.2]octane, and other bridged piperazines and bridged piperidines.

[0167] The term "fused" as used herein, refers to polycyclic ring systems in which any two adjacent rings have two, and only two, adjacent atoms in common (ortho-fused) and polycyclic ring systems in which a ring contains two, and only two, adjacent atoms in common with each of two or more rings of a contiguous series of ortho-fused rings (ortho- and peri-fused). An exemplary embodiment is pentalene and dibenzoxepine (ortho-fused) and pyrene (ortho- and peri-fused). Ortho-fused systems have "n" common sides and "2n" common atoms while peri-fused systems have "n" common sides and less than "2n" atoms in common. Other exemplary fused systems include fused cyclopropyl rings, fused aziridines and fused azetidines, such as when these rings are fused to a pyrrolidine ring. Other examples include fused pyrrolidine rings (e.g, octahydropyrrolo[3,4-c]pyrrole and octahydrocyclopenta[c]pyrrole), fused pyridine rings, such as a pyridine ring fused with a cycloalkyl (e.g., cyclopentane) or with a heterocyclyl (e.g., tetra hydrofuran or tetrahydropyran), or other fused heteroaromatic rings (e.g., dihydro-5H- pyrazolo[5,l-b][l,3]oxazine and 6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazine).

[0168] 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).

[0169] 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.

[0170] The term "halogen" as used herein, refers to any fluoro, chloro, bromo, or iodo moiety.

[0171] 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.

[0172] 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)I-5-NHCH3, -(CH2)I-5-N(CH3)2, -(CH2)I-5-NH-(CH2)I.5-N(CH3)2, and the like.

[0173] 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 fromnitrogen, 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.

[0174] The term "heteroarylalkyl" as used herein, means any alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH2pyridinyl, -CH2pyrimidinyl, and the like.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] The term "alkynyl" as used herein, refers to unbranched or branched hydrocarbon chain having one or more carbon-carbon triple bonds therein and may also be referred to as an"unsaturated alkyl". The triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2-pentynyl-, and 4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substituted with one or two suitable substituents.

[0182] As used herein, "reactive groups" refer to nucleophiles, electrophiles, or radically active groups, / .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, hydroxyl a Iky Is, 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).

[0183] The term "biocompatible" as used herein, refers to any material that does not illicit a substantial detrimental response in the host. There is always concern when a foreign object is introduced into a living body that the object will induce an immune reaction, such as an inflammatory response that will have negative effects on the host. In the context of this invention, biocompatibility is evaluated according to the application for which it was designed: for example, a bandage is regarded as biocompatible with the skin, whereas an implanted medical device is regarded as biocompatible with the internal tissues of the body. Preferably, biocompatible materials include, but are not limited to, biodegradable and biostable materials. A substantial detrimental response has not occurred if an implant comprising the material is in close association to its implant site within the host animal and the response is better than atissue 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.

[0184] 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.

[0185] "Cancer" is a term used for a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More particular examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal cancer, renal cell carcinoma, renal cancer (e.g., advanced renal cell carcinoma), ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, urothelial carcinoma (including local advanced or metastatic urothelial carcinoma), bladder cancer, hepatoma, breast cancer and head and neck cancer.

[0186] 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%.

[0187] 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.

[0188] The pharmaceutical compositions of the invention can take any suitable form for the desired route of administration. Where the composition is to be administered orally, any suitable orally deliverable dosage form can be used, including without limitation water, glycols, oils, alcohols, and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents, and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms. Injectable compositions or intravenous infusions are also provided in the form of solutions, suspensions, and emulsions. For parenteral compositions, the carrier usually comprises sterile water and possibly other ingredients to aid solubility. Injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution, or a mixture of a saline and a glucose solution. Suitable oils include, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives as needed, where the additives may facilitate administration of the composition to the skin and / or may facilitate preparation of the compositions to be delivered. These compositions may be administered in various ways, e.g., as a transdermal patch or as an ointment. Acid or base addition salts of the compounds of theinvention are typically more suitable in the preparation of aqueous compositions due to their increased water solubility over the corresponding neutral form of the compounds.

[0189] 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.

[0190] 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.

[0191] In a specific embodiment, the additional therapeutic agent to be included is an anti-cancer agent. Examples of an anti-cancer agent include, but are not limited to, DNA-damaging cytotoxic drugs, alkylating agents such as cyclophosphamide, dacarbazine, and cisplatin; anti-metabolites such as methotrexate, mercaptopurine, thioguanine, fluorouracil, and cytarabine; plant alkaloids such as vinblastine and paclitaxel; antitumor antibiotics such as doxorubicin, bleomycin and mitomycin; hormones / antihormones such as prednisone, tamoxifen, and flutamide; other types of anticancer agents such as asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, and derivatives, colony stimulating factors, amifostine, camptothecin, topotecan, thalidomide analogs such as lenalidomide, and proteasome inhibitors such as Velcade.

[0192] 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.

[0193] 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 chemicalstructure and chemical name conflict, the chemical structure is intended to be determinative of the compound's identity.

[0194] 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 deuterium atoms, or three or more deuterium atoms, etc. As described herein, compounds of the invention may also be radiolabeled with a radioactive isotope such as tritium (3H), iodine-125 (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.

[0195] In an embodiment of the invention, a compound of the invention as defined herein (such as a compound of any one of Formula (1), (2), (3) or (4)) or a pharmaceutically-acceptable salt thereof, exists as a single enantiomer being in an enantiomeric excess (% ee) of > 95%, such as > 98%, such as > 99%.

[0196] In an embodiment of the invention, a pharmaceutical composition comprises a compound of the invention as defined herein (such as a compound of Formula I) 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%.

[0197] 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 a!., Am J Med Genet A. 2015, 167A, 287; Kurek et al. Am. J. Hum. Genet. 2012, 90, 1108).

[0198] 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).

[0199] The compounds of the invention (such as defined by Formula (1) through Formula (3)) are typically PI3Ka H1047R mutant-selective inhibitors that exhibit greater selectivity for the H1047R mutation over the wild-type. As such, the compounds may decrease the amount ofphosphorylated AKT (pAKT) and decrease proliferation selectively in PI3Ka H1047R mutant cell lines, preferably across several tumor types.

[0200] A PI3K H1047R mutant selective inhibitor of the invention (such as defined by Formula (1) through Formula (3)) dosed in combination with a selective estrogen receptor degrader (SERD) such as, but not limited to, fulvestrant, elacestrant, camizestrant or vepdegestrant may exhibit a combination benefit leading to tumor regression in ER+ / PI3K H1047R mutant tumors such as, but not limited to, the breast cancer xenograft model T47D, at doses where little or no regression would be observed with either single agent.

[0201] A PI3K H1047R mutant selective inhibitor of the invention (such as defined by Formula (1) through 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.

[0202] Compounds of Formula (1) of the present invention may be generally prepared according to the synthetic routes identified in Schemes 1-16.

[0203] 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 1

[0204] 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 betransformed by reaction with Grignard reagents into alkyl phosphinates (e.g., 6) that are also suitable for use as coupling partners.Scheme 2Cu O DIPEA

[0205] 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 halide (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 be achieved 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).Scheme 3

[0206] 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 sulfoximine-containing 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

[0207] The bicyclic cores of the present invention may be synthesized by any of a number of ring expansion or cyclization methodologies. In Scheme 1, the synthesis of isoquinolone core intermediates may begin with an appropriately substituted 2,3-dihydro-lH-inden-l-one 25. In the case of 25, where R7is methyl and each Rgis hydrogen, this is commercially available. In other cases, the starting material may be prepared via established methods known to those skilled in the art. Nitrosation of 25 to convert to the oxime derivative 26 may be accomplished using established methods (for examples see Touster, O.; Org. Reactions, VII, 1953, 327). A Beckmann-type rearrangement mediated by phosphorus pentachloride can convert 26 into 27 (Cushman, M.; Dekow, F.W. Tetrahedron 1978, 34(10), 1435-9). Alkylation of 27 with anappropriate electrophile and base will give 28. In the case of where Rsis methyl this may be accomplished with methyl iodide and an appropriate base (such as sodium hydride). Other electrophiles and alkylating agents, which would be known to those skilled in the art, may also be employed. In order to convert the bromide 28 to the methyl ketone 29, a Stille coupling reaction may be employed using an appropriate tin reagent such as (0-ethoxyvinyl)-tributyl tin followed by acid hydrolysis (Sugiyama, et al., Bull. Chem. Soc. Jpn. 1987, 60(2), 767-768). Alternatively, conversion of 28 to 29 may be accomplished by other established methods, for example using a Heck coupling reaction with an appropriate enol-ether followed by acid hydrolysis (Mingcui, L. et al., Org. Biomol. Chem., 2010, 8, 2012-2015). Reduction of the ketone 29 to the alcohol 30 may then be accomplished by use of an appropriate hydride reducing agent (such as sodium borohydride). It should be understood that apart from the methodology described in Scheme 1, there are other reported methods that can be utilized to prepare isoquinolones such as 27 or 28 and their derivatives. For examples: Li, B. et al., Tetrahedron Letters 2010, 51(29), 3748-3751; Wang, R.; et al., Organic & Biomolecular Chemistry 2011, 9(16), 5802-5808).Scheme 5

[0208] In Scheme 6, the alcohol 30 can be converted to amino derivatives 33 via a number of different methodologies. The alcohol may first be converted to intermediates 31 possessing a leaving group such as a bromide or a mesylate utilizing commonly known methods. Nucleophilic displacement on 31 gives compounds 33. An alternative is to use a Mitsunobu type of reaction with (hetero)aryl amines 32 directly with the alcohol 30 to give compounds 33 directly. In some cases, the transient use of an activating group (such as a 2,4-dinitrobenzenesulfonyl group) on the (hetero)aryl amine functionality can facilitate the Mitsunobu reaction. The use of 2,3- dichloro-5,6-dicyanobenzoquinone (DDQ) and triphenylphosphine may also be employed in the direct reaction of the alcohol 30 with a (hetero)aryl amine (Shalit, T.; et al., Tetrahedron Letters2010, 51, 5988-5991; Iranpoor, N.; et al., Tetrahedron 2009, 65, 3893-3899; Panday, S. K., Mini¬Reviews in Organic Chemistry 2019, 16(2), 127-140; Fukuyama, Tohru; et al., Tetrahedron Letters 1997, 38(33), 5831-5834).Scheme 6

[0209] A synthesis leading to a single enantiomer intermediate 38 is depicted in Scheme 7. This reaction sequence utilizes the formation of a chiral sulfinyl imine to control the stereochemistry. Such methods have been extensively reported. Ketone 28 may be converted to chiral sulfinylimine 34 via known procedures, which may then in turn be reduced to the sulfinyl-amine 35 in a stereo-controlled fashion using a suitable reducing agent (Datta and Ellman, J. Org. Chem. 2010, 75, 6283-6285; Ellman et al., Acc. Chem. Res. 2002, 35, 984-995; Ellman et al., J. Org. Chem. 2007, 72, 626-629; Colyer et al., Journal of Organic Chemistry 2006, 71(18), 6859-6862). With use of the R isomer of the sulfinyl group, generally, resulting a predominantly the R, R - isomer of the product when (for example) the reducing agent used is a mixture of sodium borohydride and cerium chloride-heptahydrate. The use of this particular reducing system has been shown to be effective at reducing imines and may often give enhanced stereo-control in similar reductions (Hua et al, Synthesis 1991, (11), 970-4; Zhu et al, Journal of Chemical Research 2015, 39(7), 390- 393). In the instance within Scheme 7 that the R2moiety is methyl, the benzylic stereocenter of 35 is indeed formally labeled as the R isomer as is denoted within the Scheme. Alternate substitution patterns within R2may formally change the assignment of the stereocenter of such analogs to S, however, even though the relative configuration of such molecules 35 yet remains the same to the instance when R2is methyl. The major isomer may be separated from the other minor isomer via standard chromatographic means. As has been demonstrated in the preceding literature references a judicious choice of the antipode of the sulfinyl-imine and the reducing agent may give access to either antipode of the sulfinyl-amine. The sulfinyl-amine can be cleavedto the single enantiomer of the chiral amine 36 using standard conditions (such as hydrogen chloride in dioxane). A standard coupling reaction of amine 36 with the (hetero)aryl halide 37 (such as an Ullman coupling or Buchwald-Hartwig coupling for 37, Hal = I or Br) may then give the resulting (hetero)aryl amine derivative 38 (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 36 with (hetero)aryl halides 37 may also give rise to intermediates 38 should the inputs 37 be reactive enough (e.g., Hal = F or Cl and Ri be an electron-withdrawing functionality).Scheme 7

[0210] Certain final compounds 40 may be prepared as outlined in Scheme 8. Intermediate 33 may be reacted under suitable Buchwald-Hartwig coupling conditions with an amine 39, 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 compound 40 may then be separated into its individual enantiomers (41 and 42) utilizing chiral chromatography (HPLC or SFC).

[0211] The single enantiomer 32 may be prepared directly as shown in Scheme 9 from the enantiomerically pure intermediate 30 using chemistry analogous to that shown in Scheme 8.Scheme 9

[0212] In some cases, the order of reactions may be adjusted as shown in Scheme 10. In this case aBuchwald-Hartwig coupling with the intermediate 35 and an appropriately substituted amine 39 may give 43. Removal of the sulfinyl group to give 44 may then be followed by a Buchwald- Hartwig coupling with (hetero)arylhalides (e.g., X = I or Br) to give compounds such as 46. Alternatively, intermediate 44 may undergo an SNAr reaction with suitably reactive (hetero)arylhalides 45 (e.g., X = F or Cl with Ri being an electron-withdrawing group) to give compounds 46.Scheme 10

[0213] Compounds where there is an oxygen or sulfur linked substitution from the 3-position of the isoquinolone ring may be prepared as shown in Scheme 11. The intermediate 38 may undergo a Buchwald-Hartwig coupling with an appropriate sulfhydryl compound to give 48. Alternatively intermediate 38 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 50.Scheme 11

[0214] In the cases where the substitution from the 3-position of the isoquinolone ring is either an alkyl or an alkenyl group, these compounds may be prepared as shown in Scheme 12. The intermediate 33 may undergo a Suzuki coupling reaction (Stanforth, S.P. Tetrahedron 1998, 54(3 / 4), 263-303) with a suitable alkenyl-boronate (or boronic acid) 51 to give 52. The racemate 52 may then be subjected to chiral chromatographic separation to give the enantiomers 53 and 54. Alternatively the double bond of 52 may be reduced under standard hydrogenation conditions (e.g., hydrogen with a palladium catalyst). Following chiral chromatographic separation this may give the enantiomers 55 and 56. In the case where R and R' do not form a symmetrical arrangement, further isomers may result which may also be separated chromatographically.Scheme 12

[0215] In the case where the substitution from the 3-position of the isoquinolone group is an aryl or heteroaryl group, these types of compounds may be prepared in an analogous method to that shown in Scheme 12. As depicted in Scheme 13, a Suzuki coupling reaction between 33 and an appropriate aryl (or heteroaryl) borononate (or boronic acid) may give, following chiral separation, the enantiomers 57 and 58.Scheme 13

[0216] An alternative mode of synthesis of aryl- or heteroaryl-substituted isoquinolones is depicted in Scheme 14. A Suzuki coupling reaction between intermediate 35 and an appropriate aryl or heteroaryl boronate (or boronic acid) followed by removal of the sulfinyl group may give 59. An Ullman or Buchwald-Hartwig coupling between 59 and (hetero)arylhalides 45 may give compounds such as 60. Alternatively, 59 may undergo an SNAr reaction with suitably (hetero)arylhalides 45 (e.g., where X = F or Cl and Ri is an electron-withdrawing group) to also give compounds 60.Scheme 14

[0217] The synthesis of benzopyrimidinone core-containing compounds can be envisioned through known synthetic chemistry techniques, Scheme 15. Beginning from aminobenzoic acids 61 that are generally known or available commercially (such as from BLD Pharmatech Ltd.), intermediate quinazoline-2, 4-diones 62 can be generated under cyclization conditions. In an exemplary embodiment when Rs= H, cyclization may occur by treatment with urea at elevated temperatures. In exemplary embodiments when Rs= alkyl, cyclization may occur via a 2-step process consisting first of amide coupling with the corresponding alkylamine and HATU, followed by treatment with triphosgene. Chlorination of 62 can furnish intermediates of general structure 63. In an exemplary embodiment, chlorination can be effected by refluxing 62 in POCI3followed by neutralization with aqueous base (NaOH when Rs= H, or alternatively NaHCO3when Rs= alkyl). Intermediates of general structure 64 may then be generated by SNAr substitution. In exemplary embodiments, treatment of 63 with an amine, an amine hydrochloride salt, an alcohol, or a thiol (depending on whether R5is desired to be an N-l inked, O-linked, or S-linked moiety, respectively), in some embodiments with the addition of an appropriate base (e.g., but not limited to, DIEA, K2CO3, or NaH), in an appropriate solvent (e.g., but not limited to, ACN, NMP, or DMF) at room temperature or, in some embodiments, at elevated temperature (up to 140 °C), can yield intermediates of general structure 64. Intermediates of general structure 65 may then be generated by carbonylation of 64. In some exemplary embodiments, the bromine substituent of 64 is replaced with an acetyl group by treatment with tributyl(l-ethoxyvinyl)tin and a catalytic palladium species (e.g., but not limited to, Pd(PPh3)4or PdCI2( PPh3)2) at elevated temperature, followed by hydrolysis with aqueous HCI, to yield ketones 65. Intermediates 65 when R3= H can also be generated by formylation of 64 through a variety of known methods (e.g., but not limited to, palladium-catalyzed carbonylation in the presence of H2(Klaus, et a!.,Angew. Chem. I nt. Ed. 2006, 45, 154), or cyanation followed by DIBAL reduction). Intermediates 65 can serve as a platform for further expansion into diverse R2substitutions (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, alkyls, etc.) through a variety of known techniques (including but not limited to Prakash, et al., J. Am. Chem. Soc. 1989, 111, 393; Zhao, et al., Org. Lett. 2011, 13, 5342; Reichel, et al., Angew. Chem. Int. Ed. 2020, 59, 12268; etc.).Alcohol intermediates of general structure 66 can be prepared by reduction of 65. In an exemplary embodiment, the reduction was performed by treatment of 65 with NaBH4in MeOH. Conversion of 66 to (hetero)arylamines of general structures 67 and 68 can be accomplished via reactions conditions analogous to those described in Schemes 6-14.Scheme 15

[0218] An alternate mode of synthesis leading to single enantiomer benzopyrimidinone intermediates 71 is depicted in Scheme 16. This reaction sequence utilizes the formation of a chiral sulfinyl imine to set the stereocenter of the subsequent synthetic products. Ketones 65 may be converted to a chiral sulfinyl-imines 69 via known procedures, which may then in turn be reduced to sulfinyl-amines 70 in a stereo-controlled fashion using suitable reducing agents (Datta and Ellman, J. Org. Chem. 2010, 75, 6283-6285; Ellman et al., Acc. Chem. Res. 2002, 35, 984-995; Ellman et al., J. Org. Chem. 2007, 72, 626-629; Colyer et al., J. Org. Chem. 2006, 71(18), 6859-6862). The use of the R isomer of the sulfinyl group 69, generally, results predominantly in the R,R-isomer of 70 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., J. Chem. Res. 2015, 39(7), 390-393). In the instance within Scheme 16 that the R2moiety is methyl, the benzylic stereocenter of 35 is indeed formally labeled as the R isomer as is denoted within the Scheme. Alternate substitution patterns within R2may formally change the assignment of the stereocenter of such analogs to S, however, even though the relative configuration of suchmolecules 35 yet remains the same to the instance when R2is methyl. 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. Sulfinyl-amines 70 can be cleaved to the single enantiomer of chiral amines 71 using standard conditions (such as hydrogen chloride in dioxane). Standard coupling reactions of amines 45 with aryl iodides or aryl bromides 45 (such as an Ullman coupling or Buchwald-Hartwig coupling) may then give the resulting final compounds 72 (Yang et a!., Org. Process Res. & Dev. 2022, 26(6), 1690-1750; Surry and Buchwald, Chem. Sci. 2011, 2(1), 27-50).Scheme 16

[0219] The chemistries depicted in Schemes 1 to 16 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.

[0220] The following compounds of Formula (1) represent various embodiments of the present invention:Experimental

[0221] All commercially available solvents and reagents were used as received. All1H NMR spectra were recorded using a Bruker Avance III HD 300 MHz or Bruker Avance III HD 400 MHz. MS samples were analyzed on a Shimadzu LCMS-2020 mass spectrometer with electrospray ionization operating in positive and negative ion mode. Samples were introduced into the mass spectrometer using chromatography. All final products had a purity of > 90 %, unless specified otherwise in the experimental details. HPLC purity was measured on a Shimadzu Acquity HPLC system.

[0222] The following represents acronyms used in the experimental section for well-known chemical solvents, reagents, parameters and techniques:XH NMR: proton nuclear magnetic resonance spectroscopyACN: acetonitrileAcOH: acetic acidB2pin2: 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolaneBl NAP: 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl(BOC2)O: di-tert-butyl dicarbonate c-Bu: cyclobutylc-Pr: cyclopropylCDI: carbonyl diimidazoleCeCI3: cerium (III) chlorideCH2CI2: dichloromethaneCH3I: iodomethaneCHCI3: chloroformCO2: carbon dioxideCs2CO3: cesium carbonateCsF: cesium fluorideCuCI: cuprous chlorideDAST: diethylaminosulfur trifluorideDBAD: di-tert-butyl azodicarboxylateDBU: l,8-Diazabicyclo[5.4.0]undec-7-eneDCM: dichloromethaneDIBAL: diisobutylaluminum hydrideDIEA: A / , / \ / -diisopropylethylamineDMF: / V, / V-dimethylformamideDMSO: dimethyl sulfoxideDTAD: di-tert-butyl azodicarboxylateEA: ethyl acetate ee: enantiomeric excessEt2O: diethyl etherEt3N: triethylamineEt3Si H : triethylsilaneEtOAc: ethyl acetateEtOH: ethanolFA: formic acidh: hoursH2O: waterHATU: l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHCI: hydrochloric acidHex: hexanesHPLC: high-performance liquid chromatographyIPA: isopropanolK2CO3: potassium carbonateK3PO4: potassium triphosphateKOAc: potassium acetateLiOH: 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 chlorideNa2CO3: 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: A / -methylpyrrolidoneOxetane: 4-membered ring containing 3 carbon ring atoms and 1 oxygen ring atom.PBr3: phosphorous tribromidePCI5: phosphorous pentachloridePd / C: palladium on carbonPd-PEPPSI-IHeptCI 3-chloropyridine: dichloro[l,3-bis(2,6-di-4-heptylphenyl)imidazol-2- ylidene](3-chloropyridyl)palladium(ll)Pd(amphos)CI2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll)Pd(dppf)CI2: (l,l'-bis(diphenylphosphino)ferrocene)palladium(ll) dichloridePd(PPh3)4: tetrakis(triphenylphosphine)palladium(0)Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)PdCI2(PPh3)2: bis(triphenylphosphine)palladium(ll) dichloridePE: petroleum etherPOCI3: phosphorus oxychloridePPh3: triphenylphosphinePrep: preparativePyBOP: benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphateRuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenylRuPhos-Pd-G3: methanesulfonato(2-dicyclohexylphosphino-2',6'-di-isopropoxy-l,l'-biphenyl)(2'- amino-l,l'-biphenyl-2-yl)palladium(ll)SEM-CI: 2-(trimethylsilyl)ethoxymethyl chlorideSiO2: silicaT4P: 2,4,6-tributyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxideTBAF: tetrabutylammonium fluorideTBSCI: tert-butyldimethylsilyl chlorideTEA: triethylamineTFA: trifluoroacetic acidTHF: tetra hydrofuranTi(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, -biphenyl]-2- yl]phosphine](methanesulfonato-KO)[2'-(methylamino-KN)[l, -biphenyl]-2-yl-KC]palladium

[0223] Intermediate 1: (R)-N-((R)-l-(3-Chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5- yl)ethyl)-2-methylpropane-2-sulfinamideStep 1: Preparation of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-lH-inden-l-one

[0224] To a stirred solution of 4-bromo-6-methyl-2,3-dihydroinden-l-one (2 g, 8.89 mmol) in HCI (10 mL, 12 M) and Et2O (10 mL) was added 3-methylbutyl nitrite (1.25 g, 10.66 mmol) slowly dropwise at 0 °C. The resulting solution was stirred for 4 h at room temperature. The mixture was cooled to 0 °C. and the precipitated solids were collected by filtration and washed with H2O (3 x 50 mL). The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. This resulted in 4-bromo-2-(hydroxyimino)- 6-methyl-2,3-dihydro-lH-inden-l-one (1.5 g, 66% yield) as an off-white solid. MS: (ES+) m / z = 254.1 [M+H]+.Step 2: Preparation of 5-bromo-3-chloro-7-methyl-2H-isoquinolin-l-one

[0225] To a stirred solution of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-lH-inden-l-one (1.5 g, 5.90 mmol) in CHCI3(30 mL) was slowly added PCI5(2.46 g, 11.8 mmol) in portions at 0 °C. The resulting mixture was stirred for 3 h at room temperature and then concentrated under reduced pressure. To the crude product was added 4 M HCI in 1,4-dioxane (30 mL). The resulting solution was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by trituration with 5:1 PE / EtOAc to afford 5-bromo-3-chloro-7-methyl-2H- isoquinolin-l-one (1 g, 61% yield) as a yellow solid. MS: (ES ) m / z = 269.9 [M-l]'.Step 3: 5-bromo-3-chloro-2,7-dimethylisoquinolin-l-one

[0226] To a stirred solution of 5-bromo-3-chloro-7-methyl-2H-isoquinolin-l-one (1.3 g, 4.77 mmol) in DMF (10 mL) was slowly added NaH (0.17 g, 7.16 mmol) in portions at 0 °C. The resulting solution was stirred for 20 min at 0 °C. lodomethane (0.81 g, 5.72 mmol) was slowly added dropwise at 0 °C and the resulting solution was stirred overnight at room temperature. Thereaction was quenched with water (40 mL) and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4:1) to afford 5-bromo-3-chloro-2,7- dimethylisoquinolin-l-one (900 mg, 65% yield) as a reddish brown solid. MS: (ES+) m / z = 286.0 [M+H]+.Step 4: Preparation of 5-acetyl-3-chloro-2,7-dimethylisoquinolin-l-one

[0227] A mixture of 5-bromo-3-chloro-2,7-dimethylisoquinolin-l-one (2.6 g, 9.07 mmol), tributyl ( 1- ethoxyethenyl)stannane (3.60 g, 9.98 mmol) and Pd(PPh3)4(1.05 g, 0.91 mmol) in anhydrous 1,4- dioxane (25 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, treated with aqueous 1 N HCI (10 mL), and stirred for 15 min. The resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (3 x 60 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5- acetyl-3-chloro-2,7-dimethylisoquinolin-l-one (1.9 g, 83% yield) as a yellow solid. MS: ES+(m / z) = 250.1 [M+H]+.Step 5: Preparation of (R,E)-N-(l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5- yl)ethylidene)-2-methylpropane-2-sulfinamide

[0228] To a stirred solution of 5-acetyl-3-chloro-2,7-dimethylisoquinolin-l-one (9.8 g, 39.2 mmol) and (R)-2-methylpropane-2-sulfinamide (23.78 g, 196.2 mmol) in THF (200 mL) was added Ti(Oi-Pr)4(55.78 g, 196.2 mmol). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was quenched with saturated aqueous sodium chloride (200 mL). The resulting mixture was filtered and the filter cake waswashed with ethyl acetate (3 x 300 mL). The filtrate was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with H2O (3 x 200 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3:2) to afford (R,E)-N-(l-(3-chloro-2,7- dimethyl-l-oxo-l,2-dihydroisoquinolin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (9 g, 64% yield) as a yellow solid. MS: (ES+) m / z = 353.1 [M+H]+.Step 6: Preparation of (R)-N-((R)-l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5- yl)ethyl)-2-methylpropane-2-sulfinamide

[0229] To a stirred solution of (R,E)-N-(l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5- yl)ethylidene)-2-methylpropane-2-sulfinamide (10.5 g, 29.76 mmol) and CeCI3*7H2O (16.6 g, 44.6 mmol) in MeOH (120 mL) was added NaBH4(2.81 g, 74.4 mmol) at -78 °C. The resulting solution was stirred for 2 h at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (150 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:2) and then purified further by HP-Flash (25%-55% ACN in H2O (0.1% FA) in 45 min) to afford (R)-N-((R)-l-(3-chloro-2,7-dimethyl-l-oxo-l,2- dihydroisoquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (6.5 g, 61% yield) as an off-white solid. MS: (ES+) m / z = 355.0 [M+H]+.

[0230] Intermediate 2: (R)-5-(l-Aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-oneStep 1: Preparation of (R)-N-((R)-l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)- l,2-dihydroisoquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide

[0231] To a stirred solution of (R)-N-((R)-l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5- yl)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 1) (3 g, 8.5 mmol) and l-(2,2,2- trifluoroethyl)piperazine (3.55 g, 21.1 mmol) in dioxane (60 mL) was added Pd2(dba)3(0.77 g, 0.85 mmol), Cs2CO3(5.51 g, 16.9 mmol) and RuPhos (0.79 g, 1.69 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 100 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (50 mL x 2). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 2:1) to afford (R)-N-((R)-l-(2,7-dimethyl-l-oxo- 3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2-dihydroisoquinolin-5-yl)ethyl)-2-methylpropane-2- sulfinamide (3.6 g, 87% yield) as a yellow oil. MS: (ES+) m / z = 487.3 [M+H]+.Step 2: Preparation of (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one

[0232] To a stirred solution of (R)-N-((R)-l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin- l-yl)-l,2-dihydroisoquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (3.6 g, 7.4 mmol) in MeOH (37 mL) was added 4 M HCI in EtOAc (3.7 mL, 14.8 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and was washed with saturated aqueous NaHCO3(3 x 15 mL). The organcs were then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin- l(2H)-one (2.8 g, 98% yield) as a yellow solid. MS: (ES+) m / z = 383.2 [M+H]+.

[0233] Intermediate 3: 2-Amino-3-(l-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N- methylbenzamideStep 1: Preparation of 2-amino-3-bromo-5-fluoro-N-methylbenzamide

[0234] To a solution of 2-amino-3-bromo-5-fluorobenzoic acid (5 g, 21.4 mmol) in THF (50 mL) was added CDI (4.16 g, 25.6 mmol) at 25 °C. The mixture was then stirred at 70 °C for 1 hr, and then methylamine hydrochloride (5.77 g, 85.5 mmol) and TEA (2.16 g, 21.4 mmol, 3 mL) was added. The resulting mixture was stirred at 70 °C for 1 hr. The reaction was quenched with water (50 mL) and extracted with EA (50 mL x 3). The combined organics were washed with water (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA = 1:0 to 1:1) to afford 2-amino-3-bromo-5- fluoro-N-methylbenzamide (4.7 g, 89% yield) as an off-white solid. LCMS (ES ) m / z = 247.1 (M+H), tR= 0.491 min (Method C).Step 2: Preparation of 3-acetyl-2-amino-5-fluoro-N-methylbenzamide

[0235] To a solution of 2-amino-3-bromo-5-fluoro-N-methylbenzamide (3.7 g, 15.0 mmol) and tributyl(l-ethoxyvinyl)stannane (7.45 g, 20.6 mmol) in dioxane (40 mL) under a nitrogen atmosphere was added Pd(PPh3)4(1.73 g, 1.50 mmol). The mixture was then stirred at 100 °C for 15 hr. Then, the solution was cooled to 0 °C and aqueous 1 M HCI (5 mL) was added. The mixture was then stirred at 0 °C for 30 min. Then, a saturated aqueous KF solution (50 mL) was added. The reaction mixture was then diluted with H2O (50 mL) and EA (50 mL) and stirred at 20 °C for 1 h. The mixture was filtered and extracted with EA (40 mL x 3). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA =1:0 to 0:1) to afford 3-acetyl-2-amino-5-fluoro-N-methylbenzamide (2.5 g, 79% yield) as a yellow solid. LCMS (ESP) m / z = 211.2 (M+H), tR= 0.514 min (Method C).Step 3: Preparation of 2-amino-5-fluoro-3-(l-hydroxyethyl)-N-methylbenzamide

[0236] To a solution of 3-acetyl-2-amino-5-fluoro-N-methylbenzamide (2.5 g, 11.9 mmol) in MeOH (30 mL) was added NaBH4(1.45 g, 38.3 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hr and then quenched by addition of saturated aqueous NH4CI (10 mL) at 0 °C. The resulting mixture was diluted with water (30 mL) and extracted with EA (20 mL x 3). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 0:1 to 4:1) to afford 2-amino-5-fluoro-3-(l-hydroxyethyl)-N-methylbenzamide (3.6 g, 99% yield) as a yellow oil. LCMS (ES ) m / z = 195.0 (M+H - H2O), tR= 0.362 min (Method C).Step 4: Preparation of 2-amino-3-(l-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N- methylbenzamide

[0237] To a solution of 2-amino-5-fluoro-3-(l-hydroxyethyl)-N-methylbenzamide (3.6 g, 17.0 mmol) and imidazole (3.46 g, 50.9 mmol) in DCM (30 mL) was added a solution of TBSCI (5.11 g, 33.9 mmol) in DMF (6 mL) at 0 °C. The mixture was stirred at 25 °C for 12 hr. The reaction mixture was then concentrated under reduced pressure. The mixture was then diluted with water (40 mL) and extracted with EA (30 mL x 3). The combined organics were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA = 1:0 to 10:1) to afford 2-amino-3-(l-((tert- butyldimethylsilyl)oxy)ethyl)-5-fluoro-N-methylbenzamide (4 g, 72% yield) as a white solid. LCMS (ESP) m / z = 327.1 (M+H), tR= 0.623 min (Method C).

[0238] Intermediate 4: (R)-5-(l-Aminoethyl)-3-chloro-2,7-dimethylisoquinolin-l(2H)-one

[0239] To a solution of (R)-N-((R)-l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)- 2-methylpropane-2-sulfinamide (Intermediate 1) (12 g, 33.8 mmol) was added 4 M HCI in dioxane (169 mL, 676 mmol). The mixture was stirred at 25 °C for 1 hr and then concentrated. The residue was recrystallized from PE:EA = 1:1 (100 mL). The suspension was then filtered, and the filter cake was dried under reduced pressure to afford (R)-5-(l-aminoethyl)-3-chloro-2,7- dimethylisoquinolin-l(2H)-one (9.9 g, HCI salt) as white solid. LCMS (ES ) m / z = 251.2 (M+H), tR= 0.413 min (Method C).

[0240] Intermediate 5: (R)-5-(l-Aminoethyl)-3-chloro-7-fluoro-2-methylisoquinolin-l(2H)-one

[0241] This intermediate was prepared using methods similar to those described for Intermediate 1 and Intermediate 4, using 4-bromo-6-fluoro-2,3-dihydro-lH-inden-l-one in place of 4-bromo-6- methyl-2,3-dihydro-lH-inden-l-one.

[0242] Intermediate 6: (R)-8-(l-Aminoethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-oneStep 1: Preparation of 8-bromo-3,6-dimethyl-2-thioxo-2,3-dihydroquinazolin-4(lH)-one

[0243] Methyl isothiocyanate (19.0 g, 261 mmol) was added to a mixture of 2-amino-3-bromo-5- methylbenzoic acid (30.0 g, 130 mmol) and TEA (45 mL, 326 mmol) in EtOH (500 mL) at roomtemperature under an argon atmosphere. The resulting mixture was stirred for 4 h at 100 °C. The mixture was then concentrated under reduced pressure. The residue was dissolved in Et2O (500 mL), and the precipitated solids were collected by filtration and washed with Et2O (2 x 300 mL) to afford 8-bromo-3,6-dimethyl-2-thioxo-2,3-dihydroquinazolin-4(lH)-one (31.8 g, 85% yield) as a brown solid.XH NMR (400 MHz, DMSO-ds): 8 10.74 (s, 1H), 7.79-7.69 (m, 1H), 7.73- 7.70 (m, 1H), 3.66 (s, 3H), 2.33 (s, 3H).Step 2: Preparation of 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one

[0244] Dimethyl sulfate (5.9 g, 47.3 mmol) was added portionwise to a stirred mixture of 8-bromo- 3,6-dimethyl-2-thioxo-2,3-dihydroquinazolin-4(lH)-one (9.0 g, 31.5 mmol) and NaOH (2.52 g, 63.1) in DMF (90 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred for 2 h at room temperature. The mixture was then cooled to 0 °C and quenched with ice water (50 mL). The resulting solid was washed with water (5 x 10 mL) and then dried under reduced pressure to afford 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (8.0 g, 85% yield) as a white solid.XH NMR (300 MHz, Chloroform-d): 87.99-7.91 (m, 1H), 7.83-7.76 (m, 1H), 3.60 (s, 3H), 2.73 (s, 3H), 2.46-2.40 (m, 3H).Step 3: Preparation of 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one

[0245] To a stirred mixture of 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (7.1 g, 23.7 mmol) and tributyl(l-ethoxyethenyl)stannane (10.3 g, 28.5 mmol) in 1,4-dioxane (100 mL) was added tetrakis(triphenylphosphine)palladium(0) (2.7 g, 2.4 mmol) portionwise at room temperature under an argon atmosphere. The resulting mixture was stirred overnight at 100 °C. The mixture was then cooled to 0 °C. Aqueous 1 N HCI (14.4 mL) was added in portions over 5 min at 0 °C. The resulting mixture was then stirred for 1 h at room temperature and then diluted with ice water (50 mL). The mixture was then extracted with EtOAc (3 x 50 mL), and the organics were concentrated under reduced pressure. The residue was purified by silica gel columnchromatography, (PE:EA = 1:0 increased to 5:1 over 30 min) to afford 8-acetyl-3,6-dimethyl-2- (methylthio)quinazolin-4(3H)-one (4.0 g, 64% yield) as a white solid.1H NMR (300 MHz, Chloroform-d): 68.22-8.15 (m, 1H), 7.86-7.79 (m, 1H), 3.64 (s, 3H), 2.87 (s, 3H), 2.66 (s, 3H), 2.51-2.44 (m, 3H).Step 4: Preparation of (R,E)-N-(l-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide

[0246] 8-Acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (10 g, 38.1 mmol), (R)-2- methylpropane-2-sulfinamide (9.23 g, 76.2 mmol), and Ti(OEt)4(21.7 g, 95.3 mmol) were combined in THF (200 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred overnight at 80 °C. The reaction was quenched with ice and salt (400 mL) at 0 °C. The resulting mixture was filtered, the filter cake was washed with EtOAc (2 x 200 mL). The resulting filtrate was extracted with EtOAc (2 x 400 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ES ) m / z = 366.0 (M+H)+.Step 5: Preparation of (R)-N-((R)-l-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide

[0247] To a stirred mixture of (R,E)-N-(l-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (50 g, 137 mmol) and CeCI3*7H2O (76.5 g, 205 mmol) in MeOH (400 mL) was added NaBH4(12.9 g, 342 mmol) in portions at -78 °C under an argon atmosphere. The resulting mixture was stirred for 2 h from -78 °C to room temperature.The reaction was quenched with saturated aqueous NH4CI (800 mL) at 0 °C. The resulting mixture was then extracted with CH2CI2 (3 x 800 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to 95% gradient in 30 min; detector, UV 254 nm) to afford (R)-N-((R)-l-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (42.6 g, 85% yield) as a white solid.1H NMR (400 MHz, Chloroform-d) 6 7.91 - 7.85 (m, 1H), 7.42 (d, J = 2.1 Hz, 1H), 5.13-5.04 (m, 1H), 4.27 (d, J = 5.7 Hz, 1H), 3.53 (d, J = 1.7 Hz, 3H), 2.63 (d, J = 1.4 Hz, 3H), 2.38 (s, 3H), 1.59 - 1.54 (m, 3H), 1.15 (s, 9H).Step 6: Preparation of (R)-8-(l-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one

[0248] To a stirred mixture of (R)-N-((R)-l-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (4 g, 10.9 mmol) in EtOAc was added aqueous 8 N HCI (50 mL) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with ice and salt (60 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 60 mL). The aqueous layer was adjusted to pH 10 with the addition of concentrated NH4OH. The resulting mixture was extracted with DCM (2 x 50 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford (R)-8- (l-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (2.8 g, 97% yield) as a white solid.XH NMR (400 MHz, DMSO-ds): 8 7.76-7.70 (m, 2H), 4.83-4.73 (m, 1H), 3.50 (s, 3H), 2.63 (s, 3H), 2.41 (s, 3H), 1.33 (d, J = 6.6 Hz, 3H).

[0249] Intermediate 7: tert-Butyl (R)-(l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5- yl)ethyl)carbamate

[0250] A solution of (R)-5-(l-aminoethyl)-3-chloro-2,7-dimethylisoquinolin-l(2H)-one (Intermediate 4, 3 g, 12.0 mmol), DIEA (1.55 g, 12.0 mmol) and (Boc)2O (3.92 g, 18.0 mmol) in THF (30 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was triturated with PE (50 mL) at 25 °C for 30 min to give tert-butyl (R)-(l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate (3.4 g, 81% yield) as a light-yellow solid. LCMS (ES ) m / z = 351.2 (M+H).

[0251] Intermediate 8: 7-(5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-5,6,7,8- tetrahydro-[l,2,4]triazolo[4,3-a]pyrazineStep 1: Preparation of 7-(5-bromopyrimidin-2-yl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazine

[0252] To a solution of 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine (926 mg, 7.46 mmol) and 5- bromo-2-fluoro-pyrimidine (1.1 g, 6.22 mmol) in DMSO (10 mL) was added DIEA (3.25 mL, 18.7 mmol). The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was then diluted with H2O (100 mL) and then extracted with 1:3 IPA:DCM (50 mL x 3). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with 10:1 PE:EA (20 mL), the resulting solids were collected via filtration, and the filter cake was washed with PE (20 mL) to afford 7-(5-bromopyrimidin-2-yl)- 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine (1.5 g, 85% yield) as off-white solids. LCMS (ESP) m / z = 281.1 (M+H).Step 2: Preparation of 7-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-5,6,7,8- tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine

[0253] A mixture of 7-(5-bromopyrimidin-2-yl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine (600 mg, 2.13 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (813 mg, 3.20 mmol), KOAc (314 mg, 3.20 mmol) and Pd(dppf)Cl2*CH2Cl2 (174 mg, 0.21 mmol) in dioxane (10 mL) was deoxygenated and purged with N2three times. The mixture was then stirred at 90 °C for 2 h. The reaction mixture was filtered, and the filtrate was used directly. LCMS (ES ) m / z = 329.2 (M+H).

[0254] Intermediate 9: (2-(l,3-Dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5-yl)boronic acidStep 1: Preparation of 4-bromo-l,3-dimethylpyridin-2(lH)-one

[0255] To a solution of 4-bromo-3-methylpyridin-2(lH)-one (900 mg, 4.79 mmol) in DMF (15 mL) was added K2CO3(1.98 g, 14.4 mmol) and iodomethane (1.02 g, 7.18 mmol). The mixture was stirred at 25 °C for 8 h. The mixture was diluted with water (50 mL) and then extracted three times with DCM (25 mL each). The combined organics were washed with brine (4 x 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-bromo-l,3- dimethylpyridin-2(lH)-one (1 g, 93% yield) as a white solid. LCMS (ESP) m / z = 202.0 (M+H).Step 2: Preparation of l,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2(lH)-one

[0256] To a mixture of 4-bromo-l,3-dimethylpyridin-2(lH)-one (950 mg, 4.70 mmol) and 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.39 g, 9.40 mmol) in dioxane (20 mL) was added KOAc (1.38 g, 14.1 mmol) and Pd(dppf)CI2(344 mg, 0.47 mmol). The resulting mixture was degassed and purged with N2three times. The mixture was then heated to 100 °C and stirred for 1 h. The reaction was then concentrated under reduced pressure to give l,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (3 g crude yield) as a black-brown solid, which was used in the next step without further purification. LCMS (ES ) m / z = 250.2 (M+H).Step 3: Preparation of 4-(5-bromopyrimidin-2-yl)-l,3-dimethylpyridin-2(lH)-one

[0257] To a mixture of l,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)- one (1.17 g, 4.70 mmol) and 5-bromo-2-iodo-pyrimidine (1.61 g, 5.64 mmol) in dioxane (10 mL) and H2O (1 mL) was added K2CO3(1.95 g, 14.1 mmol) and Pd(dppf)CI2(344 mg, 0.47 mmol). The resulting mixture was degassed and purged with N2three times. The mixture was heated to 100 °C and stirred for 2 h, then was filtered and the filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (eluted with PE:EA from 1:1 to 1:2) to afford 4- (5-bromopyrimidin-2-yl)-l,3-dimethylpyridin-2(lH)-one (900 mg, 61% yield) as a brown solid. LCMS (ESP) m / z = 280.0 (M+H).Step 4: Preparation of (2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5-yl)boronic acid

[0258] To a mixture of 4-(5-bromopyrimidin-2-yl)-l,3-dimethylpyridin-2(lH)-one (300 mg, 1.07 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (544 mg, 2.14 mmol) in dioxane (10 mL) was added KOAc (315 mg, 3.21 mmol) and Pd(dppf)CI2(78 mg, 0.11 mmol). The resulting mixture was degassed and purged with N2three times. The mixture was then heated to 100 °C and stirred for 1 hr. The reaction was concentrated under reduced pressure to give (2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4- yl)pyrimidin-5-yl)boronic acid (520 mg, crude yield) as a black-brown solid, which was used directly without further purification. LCMS (ES ) m / z = 246.1 (M+H).

[0259] Intermediate 10: l-Methyl-6-(trimethylstannyl)pyrazin-2(lH)-oneStep 1: Preparation of 6-bromo-l-methylpyrazin-2-one

[0260] To a solution of 6-bromo-lH-pyrazin-2-one (6 g, 34.3 mmol) in DMF (60 mL) was added K2CO3(14.2 g, 103 mmol) at room temperature under a nitrogen atmosphere, lodomethane (9.73 g, 68.6 mmol) was added dropwise at 0 °C with stirring. The resulting mixture was then stirred at room temperature for 1 h. The reaction was then diluted with ice water (100 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organics were then 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 PE:EA = 1:1) to afford 6-bromo-l-methylpyrazin-2-one (3 g, 46% yield) as a white solid.1H NMR (400 MHz, DMSO-ds): 8 7.96 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 3.63 - 3.51 (m, 3H).Step 2: Preparation of l-methyl-6-(trimethylstannyl)pyrazin-2(lH)-one

[0261] To a solution of 6-bromo-l-methylpyrazin-2-one (2.0 g, 13.8 mmol) in dioxane (20 mL) was added Pd(PPh3)4 (3.19 g, 2.7 mmol) at room temperature under an argon atmosphere, followed by the dropwise addition of hexamethyldistannane (13.6 g, 41.5 mmol) with stirring. The resulting mixture was stirred at 100 °C overnight. The reaction was then quenched by the addition of ice water (50 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to afford l-methyl-6-(trimethylstannyl) pyrazin-2-one (700 mg, 18% yield) as a light-yellow oil. LCMS (ES ) m / z = 274.7 (M+H).

[0262] Intermediate 11: l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazin-2-one

[0263] To a stirred mixture of 6-bromo-l-methylpyrazin-2-one (Intermediate 10, Step 1, 200 mg, 1.06 mmol) and bis(pinacolato)diboron (403 mg, 1.59 mmol) in THF (5 mL) was added n-BuLi (0.63 mL, 1.59 mmol) in portions at -78 °C under an argon atmosphere. The resulting mixture was stirred at -78 °C for 5 h. The reaction was quenched by the addition of EtOH (20 mL) at 0 °C and the resulting mixture was concentrated under reduced pressure to afford l-methyl-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazin-2-one (200 mg, 80% crude yield) as a white solid. The crude product was used directly without further purification. LCMS (ESP) m / z = 237.0 (M+H).

[0264] Intermediate 12: (2-(l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)pyrimidin-5-yl)boronic acidStep 1: Preparation of 5-chloro-2-methylpyridazin-3(2H)-one

[0265] To a solution of 5-chloropyridazin-3(2H)-one (6 g, 46.0 mmol) and Cs2CO3(15 g, 46 mmol) in DMF (150 mL) was added iodomethane (13.1 g, 91.9 mmol). The reaction mixture was stirred at 30 °C for 8 h. The reaction mixture was then diluted with H2O (150 mL) and extracted with EtOAc (3 x 120 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (eluted with PE:EA = 1:1) to give 5-chloro-2-methylpyridazin-3(2H)-one (5.2 g, 74% yield) as a white solid.XH NMR (400 MHz, CDCI3): 6 7.71 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 3.76 (s, 3H).Step 2: Preparation of (l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)boronic acid

[0266] To a solution of 5-chloro-2-methylpyridazin-3(2H)-one (2.0 g, 13.8 mmol) and XPhos (1.32 g, 2.77 mmol) in dioxane (50 mL) was added KOAc (2.72 g, 27. 7 mmol) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (7.03 g, 27. 7 mmol) and Pd2(dba)3(1.27 g, 1.38 mmol). The reaction mixture was stirred at 90 °C for 4 h under a N2atmosphere. The reaction mixture was then concentrated to give a residue which was diluted with H2O (50 mL) and EtOAc (3 x 40 mL). The aqueous phase was then lyophilized to give (1- methyl-6-oxo-l,6-dihydropyridazin-4-yl)boronic acid (2.3 g, crude product) as a white solid,which was used as is in the next step without further purification. LCMS (ESP) m / z = 155.0 (M+H).Step 3: Preparation of 5-(5-bromopyrimidin-2-yl)-2-methylpyridazin-3(2H)-one

[0267] To a solution of (l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)boronic acid (1.5 g, 9.74 mmol) and 5-bromo-2-iodo-pyrimidine (2.78 g, 9.74 mmol) in dioxane (30 mL) and H2O (3 mL) was added K2CO3(2.69 g, 19.5 mmol) and Pd(dppf)CI2(713 mg, 0.97 mmol). The reaction mixture was stirred at 90 °C for 1 h under a N2atmosphere. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with PE:EA = 5:1 (50 mL) to give 5-(5-bromopyrimidin-2-yl)-2-methylpyridazin-3(2H)-one (1.2 g, 40% yield) as a yellow solid. LCMS (ESP) m / z = 266.9 (M+H).Step 4: Preparation of (2-(l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)pyrimidin-5-yl)boronic acid

[0268] To a solution of 5-(5-bromopyrimidin-2-yl)-2-methylpyridazin-3(2H)-one (0.50 g, 1.87 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (713 mg, 2.81 mmol) in dioxane (20 mL) was added KOAc (551 mg, 5.62 mmol) and Pd(dppf)CI2(137 mg, 0.19 mmol). The reaction mixture was stirred at 90 °C for 2 h under a N2atmosphere. The reaction mixture was then filtered, and the filter cake was rinsed with EtOAc (3 x 30 mL). The filtrate was then concentrated to give (2-(l-methyl-6-oxo-l,6-dihydropyridazin-4- yl)pyrimidin-5-yl)boronic acid (400 mg, crude product) as a gray solid which was used in the next step without further purification. LCMS (ESP) m / z = 232.9. (M+H).

[0269] Intermediate 13: l,3-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazin-2(lH)-oneStep 1: Preparation of 3-(benzyloxy)-5-chloro-2-methylpyrazine

[0270] A solution of 3,5-dichloro-2-methylpyrazine (5 g, 30.7 mmol) in THF (60 mL) was treated with NaH (1.1 g, 46.0 mmol) in portions at 0 °C under a nitrogen atmosphere. After 30 min, benzyl alcohol (4.98 g, 46.0) was added at 0 °C. The resulting mixture was then stirred at room temperature for 2 h. The reaction was quenched by the addition of water (100 mL) at 0°C. The resulting mixture was extracted with diethyl ether (3 x 200 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 3-(benzyloxy)-5-chloro-2-methylpyrazine (5.1 g, crude yield) as a yellow oil. LCMS (ES ) m / z = 235.1 (M+H).Step 2: Preparation of 6-chloro-3-methylpyrazin-2-ol

[0271] To a stirred solution of 3-(benzyloxy)-5-chloro-2-methylpyrazine (8 g, 49.0 mmol) in toluene (50 mL) was added BBr3(1.0 M in dichloromethane, 147 mL, 147 mmol) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h. The reaction wasquenched with MeOH at 0 °C and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2CI2:MeOH = 5:1) to afford 6-chloro-3-methylpyrazin-2-ol as a white solid (3.7 g, 75% yield). LCMS (ES ) m / z = 145.2 (M+H).Step 3: Preparation of 6-chloro-l,3-dimethylpyrazin-2(lH)-one

[0272] To a stirred solution of 6-chloro-3-methylpyrazin-2-ol (2 g, 13.8 mmol) and K2CO3(5.74 g, 41.5 mmol) in DMF (20 mL) was added iodomethane (3.93 g, 27.7 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was then stirred at room temperature for 1 h. The reaction was then quenched by the addition of water (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 1:1) to afford 6-chloro- l,3-dimethylpyrazin-2(lH)-one (1 g, crude yield) as an oil. LCMS (ESP) m / z = 159.2 (M+H).Step 4: Preparation of l,3-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazin- 2(lH)-one

[0273] To a stirred solution of 6-chloro-l,3-dimethylpyrazin-2-one (200 mg, 1.26 mmol) and 4, 4, 5, 5- tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.6 g, 6.31 mmol) in 1,4-dioxane (2 mL) were added Pd(dppf)CI2*CH2CI2(103 mg, 0.13 mmol) and KOAc (371 mg, 3.78 mmol) at room temperature. The resulting mixture was stirred at 90°C for 1 h under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with 1,4-dioxane (2mL). The filtrate was concentrated and used directly without further purification. LCMS: (ES ) m / z = 251.4 (M+H).EXAMPLES

[0274] Example 1: (R)-5-(l-((2-(Ethylsulfonyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-oneStep 1: Preparation of (2-bromophenyl)(ethyl)sulfane

[0275] To a solution of 2-bromobenzenethiol (2.7 g, 14.3 mmol) in acetone (10 mL) was added K2CO3(1.97 g, 28.6 mmol) followed by iodoethane (4.45 g, 28.6 mmol). The solution was then stirred at 50 °C for 12 h. The solution was partitioned between ethyl acetate (20 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to afford (2-bromophenyl)(ethyl)sulfane (3 g, 96% yield) as a yellow oil.1H NMR (400 MHz, CDCI3): 6 7.50 - 7.41 (m, 1H), 7.25 - 7.10 (m, 2H), 6.99 - 6.89 (m, 1H), 2.89 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).Step 2: Preparation of l-bromo-2-(ethylsulfonyl)benzene

[0276] To a solution of (2-bromophenyl)(ethyl)sulfane (2 g, 9.2 mmol) in DCM (20 mL) was added m-CPBA (4.8 g, 23.7 mmol, 85% purity) at 0 °C and the mixture was stirred at 25 °C for 1 hr. Tothe mixture was added a solution of Na2SO3(30 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA = 1:0 to 10:1) to afford l-bromo-2-(ethylsulfonyl)benzene (2.2 g, 89% yield) as a colorless oil. LCMS (ES ) m / z = 249.0 (M+H), tR= 0.500 min (Method C).Step 3: Preparation of (R)-5-(l-((2-(ethylsulfonyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one

[0277] To a solution of (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (Intermediate 2) (50 mg, 131 pmol) and l-bromo-2- (ethylsulfonyl)benzene (100 mg, 401 pmol) in toluene (3 mL) was added Cs2CO3(128 mg, 392 pmol) and RuPhos-Pd-G3 (22 mg, 26.2 pmol) and the mixture was stirred at 105 °C for 12 hr under a N2atmosphere. The reaction mixture was allowed to cool to room temperature and water (5 mL) was added. The mixture was then extracted with ethyl acetate (5 mL x 3) and the combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE: EA = 1:2) to afford a brown oil. Then the oil was purified further by prep-HPLC (column: Phenomenex luna C18 150*25mm*10 pm; mobile phase: [water(FA)-ACN]; gradient: 65%-75% B over 10 min) and the eluent was lyophilized to afford (R)-5-(l-((2-(ethylsulfonyl)phenyl)amino)ethyl)-2,7-dimethyl- 3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (12.5 mg, 8% yield) as a yellow solid. LCMS (ESP) m / z = 551.2 (M+H), tR= 0.592 min (Method C);XH NMR (400 MHz, DMSO-d6): 6 7.87 (s, 1H), 7.61 - 7.52 (m, 1H), 7.42 (s, 1H), 7.35 - 7.28 (m, 1H), 6.75 - 6.73 (m, 1H), 6.64 (br d, J = 6.0 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.36 (s, 1H), 5.21 - 5.18 (m, 1H), 3.48 (s, 3H), 3.29 - 3.23 (m, 4H), 3.02 - 2.71 (m, 8H), 2.31 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H).

[0278] Example 2: (R)-2,7-Dimethyl-5-(l-((2-(((2,2,2- trifluoroethoxy)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-oneStep 1: Preparation of (2-bromophenyl)(chloromethyl)sulfane

[0279] To a solution of l-bromo-2-methylsulfanyl-benzene (500 mg, 2.46 mmol) in DCM (6 mL) was added NCS (362 mg, 2.71 mmol) portionwise. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered through a short pad of silica, eluting with DCM (20 mL). The solvent was removed under reduced pressure to afford (2-bromophenyl)(chloromethyl)sulfane (550 mg, crude) as a colorless oil.XH NMR (400 MHz, CDCI3): 6 7.65 - 7.57 (m, 2H), 7.41 - 7.33 (m, 1H), 7.21 - 7.14 (m, 1H), 5.02 (s, 2H).Step 2: Preparation of (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)sulfane

[0280] To a solution of 2,2,2-trifluoroethanol (569 mg, 5.68 mmol) in DMF (2 mL) was added NaH (129 mg, 3.22 mmol, 60% purity). The mixture was stirred at 0 °C for 1.5 h under a nitrogen atmosphere, followed by Nal (284 mg, 1.89 mmol) and (2-bromophenyl)(chloromethyl)sulfane (450 mg, 1.89 mmol), then the mixture was allowed to warm to 25 °C and stirred for 12 h under a nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous NH4CI (20 mL) at 0 °C under a nitrogen atmosphere. The mixture was extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, eluent of 100% PE, 60 mL / min) to afford (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)sulfane (550 mg, crude) as a colorless oil.XH NMR (400 MHz, CDCI3): 8 7.61 - 7.46 (m, 2H), 7.34 - 7.29 (m, 1H), 7.15 - 7.10 (m, 1H), 5.16 (s, 2H), 4.08 - 4.00 (m, 2H).Step 3: Preparation of l-bromo-2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)benzene

[0281] To a solution of (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)sulfane (550 mg, 1.83 mmol) in DCM (8 mL) was added m-CPBA (1.11 g, 5.48 mmol, 85% purity) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was then quenched with saturated Na2SO3(60 mL) and the mixture was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-20% EA / PE, gradient @ 60 mL / min) to afford l-bromo-2-(((2,2,2- trifluoroethoxy)methyl)sulfonyl)benzene (480 mg, 79% yield) as a colorless oil. LCMS (ES ) m / z = 354.9 / 356.9 (M+Na), tR= 0.781 min (Method E).Step 4: Preparation of (R)-2,7-dimethyl-5-(l-((2-(((2,2,2- trifluoroethoxy)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one

[0282] A mixture of (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (Intermediate 2) (50 mg, 131 pmol), l-bromo-2-(((2,2,2- trifluoroethoxy)methyl)sulfonyl)benzene (152 mg, 458 pmol), Cs2CO3(170 mg, 523 pmol), RuPhos-Pd-G3 (109 mg, 131 pmol) in toluene (1 mL) was degassed and purged with N2three times, and then the mixture was stirred at 110 °C for 12 hrs under a nitrogen atmosphere. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, PE:EA = 2:1) to afford a crude product, which was then purified further by prep-HPLC (column: Phenomenex luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 60%-90% B over 10 min) and prep-HPLC (column: Waters xbridge 150*25mm*10pm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 60%-80% B over 8 min) toafford a yellow solid, which was further purified by SFC (column: DAICEL CHIRALCEL OJ- H(250mm*30mm, 5pm); mobile phase: [CO2-EtOH (0.1% NH3»H2O)]; B%: 20%, isocratic elution mode) to afford (R)-2,7-dimethyl-5-(l-((2-(((2,2,2- trifluoroethoxy)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (18.3 mg, 22% yield) as a white solid. LCMS (ES ) m / z = 635.3 (M+H), tR= 0.606 min (Method C);XH NMR (400 MHz, DMSO-ds): 8 7.89 (s, 1H), 7.60 - 7.58 (m, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.41 - 7.33 (m, 1H), 6.78 - 6.69 (m, 1H), 6.63 (d, J = 6.0 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 5.25 -5.16 (m, 1H), 5.14 - 5.03 (m, 2H), 4.47 - 4.35 (m, 2H), 3.49 (s, 3H), 3.29 - 3.24 (m, 2H), 3.12 - 2.68 (m, 8H), 2.32 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H).

[0283] Example 3: 6-Fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (Enantiomer 1)

[0284] Example 4: 6-Fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (Enantiomer 2)Step 1: Preparation of N-(2-(l-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-6-(methylcarbamoyl)phenyl)-3-(4-fluorophenyl)bicyclo[l.l.l]pentane-l-carboxamide

[0285] To a solution of 2-amino-3-(l-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N- methylbenzamide (Intermediate 3) (500 mg, 1.53 mmol) and 3-(4- fluorophenyl)bicyclo[l.l.l]pentane-l-carboxylic acid (347 mg, 1.68 mmol) in EtOAc (10 mL) was added T4P (3.31 g, 4.59 mmol, 50% purity) and pyridine (606 mg, 7.66 mmol). The mixture was then stirred at 25 °C for 3 hr. The reaction mixture was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-(2-(l-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-6- (methylcarbamoyl)phenyl)-3-(4-fluorophenyl)bicyclo[l.l.l]pentane-l-carboxamide (800 mg, crude) as an off-white solid. LCMS (ES ) m / z = 515.3 (M+H), tR= 0.735 min (Method C).Step 2: Preparation of 8-(l-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2-(3-(4- fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methylquinazolin-4(3H)-one

[0286] To a solution of N-(2-(l-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-6- (methylcarbamoyl)phenyl)-3-(4-fluorophenyl)bicyclo[l.l.l]pentane-l-carboxamide (750 mg, 1.46 mmol) in DMF (10 mL) was added K2CO3(604 mg, 4.37 mmol). The mixture was stirred at 90 °C for 12 hr. The reaction mixture was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:0 to 93:7) to afford 8-(l-((tert-butyldimethylsilyl)oxy)ethyl)- 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methylquinazolin-4(3H)-one (670 mg, 92% yield) as a white solid. LCMS (ESP) m / z = 497.3 (M+H), tR= 0.920 min (Method D).Step 3: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-8-(l- hydroxyethyl)-3-methylquinazolin-4(3H)-one

[0287] To a solution of 8-(l-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2-(3-(4- fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methylquinazolin-4(3H)-one (620 mg, 1.25 mmol) in THF (5 mL) was added TBAF (1 M, 2.5 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was then partitioned between H2O (20 mL) and EtOAc (20 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:0 to 4:1) to afford 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-8-(l-hydroxyethyl)-3- methylquinazolin-4(3H)-one (410 mg, 85% yield) as a white solid. LCMS (ES ) m / z = 383.3 (M+H), tR=1.044 min (Method E).Step 4: Preparation of 8-(l-bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l- yl)-3-methylquinazolin-4(3H)-one

[0288] To a solution of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-8-(l-hydroxyethyl)- 3-methylquinazolin-4(3H)-one (320 mg, 837 pmol) in DCM (5 mL) was added PBr3(453 mg, 1.67 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The reaction was then quenched with H2O (10 mL) at 0 °C and the mixture was adjusted to pH 7 with a saturated aqueous NaHCO3solution. The resulting mixture was extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to afford 8-(l-bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan- l-yl)-3-methylquinazolin-4(3H)-one (300 mg, crude) as a white solid. LCMS (ESP) m / z = 445.1 (M+H), tR= 0.709 min (Method C).Step 5: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l- ((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one

[0289] To a solution of 2-methylsulfonylaniline (230 mg, 1.34 mmol) in DMF (5 mL) was added NaH (90 mg, 2.25 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 30 min. 8-(l- Bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methylquinazolin-4(3H)- one (350 mg, 786 pmol) was added to the mixture and stirred at 25 °C for another 0.5 hr. The reaction mixture was quenched by addition of saturated NH4CI solution (50 mL) at 0 °C, and then extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 58%-88% B over 10 min) to afford 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (110 mg, 26% yield) as a white solid. LCMS (ESP) m / z = 536.3 (M+H), tR= 0.736 min (Method C).Step 6: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l- ((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (Enantiomer 1) and (S)-6-fluoro-2- (3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (Enantiomer 2)

[0290] The enantiomers of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l- ((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (110 mg, 205 pmol) were separated by SFC (Neutral condition: column: DAICEL CHIRALPAK IC (250mm*30mm,10 pm); mobile phase: [CO2-i-PrOH / ACN]; B%: 40%, isocratic elution mode) and isolated as white solids.

[0291] 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (Enantiomer 1) (48.8 mg). LCMS (ES ) m / z = 536.3 (M+H), tR= 0.666 min (Method C);XH NMR (400 MHz, CDCI3): 6 7.80 - 7.77 (m, 2H), 7.45 - 7.42 (m, 1H), 7.26 - 7.21 (m, 2H), 7.06 - 7.02 (m, 2H), 6.85 - 6.62 (m, 2H), 6.51 (d, J = 8.4 Hz, 1H), 5.63 - 5.43 (m, 1H), 3.78 (s, 3H), 3.14 (s, 3H), 2.63 (s, 6H), 1.68 (d, J = 6.8 Hz, 3H).

[0292] 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3-methyl-8-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (Enantiomer 2) (52.6 mg). LCMS (ESP) m / z = 536.3 (M+H), tR= 0.671 min (Method C);XH NMR (400 MHz, CDCI3): 6 7.82 - 7.78 (m, 2H),7.43 - 7.42 (m, 1H), 7.27 - 7.21 (m, 2H), 7.08 - 7.03 (m, 2H), 6.85 - 6.69 (m, 2H), 6.52 (d, J = 8.4 Hz, 1H), 5.58 - 5.52 (m, 1H), 3.81 (s, 3H), 3.15 (s, 3H), 2.65 (s, 6H), 1.70 (d, J = 6.8 Hz, 3H).

[0293] Example 5: (R)-7-Fluoro-2-methyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one

[0294] Example 6: (R)-4,7-Difluoro-2-methyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-oneStep 1: Preparation of (R)-3-chloro-7-fluoro-2-methyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one

[0295] To a solution of (R)-5-(l-aminoethyl)-3-chloro-7-fluoro-2-methylisoquinolin-l(2H)-one(Intermediate 5) (300 mg, 1.18 mmol) and l-bromo-2-methylsulfonyl-benzene (554 mg, 2.36 mmol) in toluene (3 mL) was added Cs2CO3(1.15 g, 3.53 mmol), Pd2(dba)3(108 mg, 118 pmol) and RuPhos (55 mg, 118 pmol). The mixture was stirred at 110 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 5:1) to afford (R)-3-chloro-7-fluoro-2-methyl-5- (l-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (160 mg, 29% yield) as a yellow solid. LCMS (ESP) m / z = 409.0 (M+H), tR=1.009 min (Method E).Step 2: Preparation of (R)-7-fluoro-2-methyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one

[0296] To a solution of (R)-3-chloro-7-fluoro-2-methyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (150 mg, 367 pmol) and l-(2,2,2- trifluoroethyl)piperazine (124 mg, 734 pmol) in dioxane (2 mL) was added Cs2CO3(359 mg, 1.10 mmol) and RuPhos-Pd-G3 (31 mg, 37 pmol). The mixture was stirred at 130 °C for 12 hr. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (Phenomenex luna C18 150*25mm*10pm; mobile phase: [water(FA)- ACN]; gradient: 48%-78% B over 10 min) to afford (R)-7-fluoro-2-methyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)- one (40 mg, 19% yield) as a white solid. LCMS (ES ) m / z = 541.2 (M+H), tR= 0.570 min (Method C);XH NMR (400 MHz, CDCI3): 6 8.06 - 7.94 (m, 1H), 7.92 - 7.77 (m, 1H), 7.45 - 7.35 (m, 1H), 7.27 - 7.20 (m, 1H), 6.89 - 6.70 (m, 2H), 6.37 - 6.18 (m, 2H), 5.05 - 4.86 (m, 1H), 3.64 (s, 3H), 3.16 (s, 3H), 3.16 - 2.69 (m, 10H), 1.65 (br d, J = 6.8 Hz, 3H).Step 3: Preparation of (R)-4,7-difluoro-2-methyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3- (4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one

[0297] To a solution of (R)-7-fluoro-2-methyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4- (2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (25 mg, 46 pmol) in ACN (2 mL) was added SelectFluor™ (49 mg, 139 pmol), Et3SiH (8.1 mg, 69 pmol) and Pd(PPh3)4(53 mg, 46 pmol). The mixture was stirred at 50 °C for 2 hr. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (Phenomenex luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 47%-77% B over 10 min) to afford (R)-4,7-difluoro-2-methyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (17 mg, 62% yield) as a yellow solid. LCMS(ES ) m / z = 559.2 (M+H), tR= 0.920 min (Method E);XH NMR (400 MHz, CDCI3): 8 8.06 - 7.98 (m, 1H), 7.81 - 7.79 (m, 1H), 7.54 - 7.52 (m, 1H), 7.26 - 7.22 (m, 1H), 6.84 - 6.72 (m, 2H), 6.34 (d, J = 8.4 Hz, 1H), 5.40 - 5.28 (m, 1H), 3.64 (s, 3H), 3.54 - 3.51 (m, 2H), 3.17 (s, 3H), 3.13 - 2.97 (m, 6H), 2.83 - 2.71 (m, 2H), 1.63 (br d, J = 6.4 Hz, 3H).

[0298] Example 7: (R)-2,7-Dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(l-(2,2,2- trifluoroethyl)piperidin-4-yl)isoquinolin-l(2H)-oneStep 1: Preparation of (R)-3-chloro-2,7-dimethyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one

[0299] A mixture of l-bromo-2-methylsulfonyl-benzene (619 mg, 2.63 mmol), (R)-5-(l-aminoethyl)- 3-chloro-2,7-dimethylisoquinolin-l(2H)-one (Intermediate 4) (330 mg, 1.32 mmol), Pd2(dba)3(121 mg, 131 |imol), RuPhos (123 mg, 263 pmol) and Cs2CO3(1.29 g, 3.95 mmol) in toluene (6 mL) was degassed and purged with N2three times, and then the mixture was stirred at 110 °C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 3:1) to afford (R)-3-chloro-2,7-dimethyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (180 mg, 29% yield) as a yellow solid. LCMS (ESP) m / z = 405.2 (M+H), tR= 0.597 min (Method C).Step 2: Preparation of (R)-2,7-dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(l-(2,2,2-trifluoroethyl)-l,2,3,6-tetrahydropyridin-4-yl)isoquinolin-l(2H)-one

[0300] A mixture of (R)-3-chloro-2,7-dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (170 mg, 420 pmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridine (183 mg, 630 pmol), Pd(dppf)Cl2*CH2CI2(69 mg, 84 pmol), and Na2CO3(134 mg, 1.26 mmol) in dioxane (4 mL) and H2O (0.5 mL) was degassed and purged with N2three times, and then the mixture was stirred at 90 °C for 12 hr under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 2:1) to afford (R)-2,7-dimethyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-3-(l-(2,2,2-trifluoroethyl)-l,2,3,6-tetrahydropyridin-4- yl)isoquinolin-l(2H)-one (150 mg, 60% yield) as a yellow solid. LCMS (ES ) m / z = 534.2 (M+H), tR= 0.902 min (Method E).Step 3: Preparation of (R)-2,7-dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(l- (2,2,2-trifluoroethyl)piperidin-4-yl)isoquinolin-l(2H)-one

[0301] To a mixture of 10% Pd / C (60 mg, 56 pmol) in MeOH (5 mL) was added (R)-2,7-dimethyl-5- (l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(l-(2,2,2-trifluoroethyl)-l,2,3,6-tetrahydropyridin- 4-yl)isoquinolin-l(2H)-one (140 mg, 262 pmol) under a nitrogen atmosphere. The suspension was degassed and purged with H2three times. The mixture was stirred under H2(15 psi) at 25 °C for 12 hr. Then, 20% Pd(OH)2 / C (37 mg, 52.5 pmol) was added to the mixture and stirred at 50 °Cfor another 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 150*25mm*10pm; mobile phase: (water(FA)-ACN]; gradient: 48%-78% B over 10 min) to afford (R)-2,7-dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(l-(2,2,2- trifluoroethyl)piperidin-4-yl)isoquinolin-l(2H)-one (51 mg, 36% yield) as an off-white solid. LCMS (ESP) m / z = 536.3 (M+H), tR= 0.555 min (Method C);XH NMR (400 MHz, CDCI3): 6 8.16 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.26 - 4.22 (m, 1H), 6.80 - 6.69 (m, 2H), 6.59 (s, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.08 - 4.95 (m, 1H), 3.69 (s, 3H), 3.24 - 3.13 (m, 5H), 3.12 -3.04 (m, 2H), 2.76 - 2.70 (m, 1H), 2.58 (t, J = 11.6 Hz, 2H), 2.41 (s, 3H), 2.01 (d, J = 12.4 Hz, 2H), 1.92 - 1.78 (m, 2H), 1.65 (br d, J = 6.4 Hz, 3H).

[0302] Example 8: 5-((lR)-l-((2-(N,S-Dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Diastereomer 1)

[0303] Example 9: 5-((lR)-l-((2-(N,S-Dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Diastereomer 2)Step 1: Preparation of (2-fluorophenyl)(imino)(methyl)- A6-sulfanone

[0304] To a solution of l-fluoro-2-methylsulfanyl-benzene (2 g, 14.1 mmol) in MeOH (50 mL) was added (NH4)2CO3(2.03 g, 21.1 mmol) and (bis(acetoxy)iodo)benzene (11.3 g, 35.2 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 1:1) to afford (2-fluorophenyl)(imino)(methyl)-A6-sulfanone (2.4 g, 98% yield) asan off-white solid.XH NMR (400 MHz, CDCI3): 8 7.98 - 7.95 (m, 1H), 7.68 - 7.56 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.27 - 7.20 (m, 1H), 3.29 (s, 3H).Step 2: Preparation of (2-fluorophenyl)(methyl)(methylimino)- A6-sulfanone

[0305] To a solution of (2-fluorophenyl)(imino)(methyl)-A6-sulfanone (1 g, 5.77 mmol) in DMF (10 mL) was added NaH (700 mg, 17.50 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Then CH3I (4.56 g, 32.1 mmol) was added to the mixture and the mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched by the addition of a saturated aqueous NH4CI solution (50 mL) at 0 °C. The resulting mixture was then extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 5:1) to afford (2- fluorophenyl)(methyl)(methylimino)- A6-sulfanone (950 mg, 87% yield) as a yellow solid. LCMS (ESF) m / z = 188.1 (M+H), tR= 0.387 min (Method L).Step 3: Preparation of 5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7- dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one

[0306] To a solution of (2-fluorophenyl)(methyl)(methylimino)- A6-sulfanone (147 mg, 784 pmol) and (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)- one (Intermediate 2) (100 mg, 261 pmol) in IPA (0.1 mL) was added DIEA (371 mg, 2.87 mmol, 0.5 mL) and 4A molecular sieves (100 mg) at 25 °C. The mixture was then stirred at 110 °C for 5 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 44%-74% B over 10 min) to afford 5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (50 mg, 34% yield) as a yellow solid. LCMS (ES ) m / z = 550.3 (M+H), tR= 0.549 min (Method E);XH NMR (400 MHz, CDCI3): 8 8.13 (br s, 1H), 7.84 - 7.74 (m, 1H), 7.49 - 7.36 (m, 2H), 7.26 - 7.21 (m, 1H), 6.81 - 6.71 (m, 1H), 6.38 - 6.30 (m, 1H), 6.24 (d, J = 13.6 Hz, 1H), 5.04 - 4.85 (m, 1H), 3.65 (s, 3H), 3.18 (d, J = 5.6 Hz, 3H), 3.15 - 2.85 (m, 10H), 2.78 (d, J = 4.0 Hz, 3H), 2.39 (d, J = 6.0 Hz, 3H), 1.62 - 1.60 (m, 3H).Step 4: Preparation of 5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7- dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Diastereomer 1) and 5- ((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Diastereomer 2)

[0307] 5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (50 mg, 91 pmol) was purified by SFC (neutral condition; column: DAICEL CHIRALCEL OD-H(250mm*30mm,5pm); mobile phase: [CO2-EtOH]; B%: 35%, isocratic elution mode) to afford 5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (Diastereomer 1) and 5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (Diastereomer 2) as yellow solids.

[0308] 5-((lR)-l-((2-(N,S-Dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Diastereomer 1) (19 mg). LCMS (ESP) m / z = 550.3 (M+H), tR= 0.519 min (Method C);XH NMR (400 MHz, CDCI3): 8 8.11 (s, 1H), 7.77 - 7.75 (m, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.38 (br d, J = 6.4 Hz, 1H), 7.26 - 7.18 (m, 1H), 6.80 - 6.68 (m, 1H), 6.33 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 5.03 - 4.87 (m, 1H), 3.63 (s, 3H), 3.15 (s, 3H), 3.13 - 2.79 (m, 10H), 2.77 (s, 3H), 2.37 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H).

[0309] 5-((lR)-l-((2-(N,S-Dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Diastereomer 2) (18 mg). LCMS (ESP) m / z = 550.3 (M+H), tR= 0.513 min (Method C);XH NMR (400 MHz, CDCI3): 8 8.12 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.36 (br d, J = 4.0 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 6.33(d, J = 8.4 Hz, 1H), 6.24 (s, 1H), 5.01 - 4.84 (m, 1H), 3.63 (s, 3H), 3.16 (s, 3H), 3.14 - 2.78 (m, 10H), 2.76 (s, 3H), 2.39 (s, 3H), 1.62 (br d, J = 6.8 Hz, 3H).

[0310] Example 10: 2,7 -Dimethyl-5-((lR)-l-((6-methyl-2-(S-methylsulfonimidoyl)pyridin-3- yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-oneStep 1: Preparation of 3-fluoro-6-methyl-2-(methylthio)pyridine

[0311] To a solution of 2,3-difluoro-6-methyl-pyridine (900 mg, 6.97 mmol) in DMF (10 mL) was added sodium methanethiolate (489 mg, 6.97 mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. The reaction was quenched with water (10 mL) and extracted with EA (20 mi x 3). The organic phases were combined and washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (PE:EA = 1:0, 10:1) to afford 3-fluoro-6-methyl-2-(methylthio)pyridine (700 mg, 60% yield) as white oil. LCMS (ES ) m / z = 158.1 (M+H), tR= 0.849 min (Method E).Step 2: Preparation of (3-fluoro-6-methylpyridin-2-yl)(imino)(methyl)- A6-sulfanone

[0312] To a mixture of 3-fluoro-6-methyl-2-(methylthio)pyridine (650 mg, 4.13 mmol) and (acetoxy(phenyl)-iodanyl)acetate (3.33 g, 10.3 mmol) in MeOH (5 mL) was added (NH4)2CO3(596 mg, 6.2 mmol). The mixture was stirred at 25°C for 12 hours and then concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE:EA = 1:0, 0:1) to afford (3-fluoro-6-methylpyridin-2-yl)(imino)(methyl)- A6-sulfanone (630 mg, 72% yield) as yellow oil. LCMS (ES ) m / z = 188.9 (M+H), tR= 0.248 min (Method E).Step 3: Preparation of 2,7-dimethyl-5-((lR)-l-((6-methyl-2-(S-methylsulfonimidoyl)pyridin-3- yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one

[0313] To a solution of (3-fluoro-6-methylpyridin-2-yl)(imino)(methyl)- A6-sulfanone (148 mg, 784 pmol), (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin- l(2H)-one (Intermediate 2) (100 mg, 261 pmol) in IPA (0.5 mL) was added DIEA (371 mg, 2.87 mmol, 0.5 mL) and 4A molecular sieves (80 mg). The mixture was stirred at 130 °C for 4 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 43%-73% B over 10 min) to afford 2,7-dimethyl-5-((lR)-l-((6-methyl- 2-(S-methylsulfonimidoyl)pyridin-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (54 mg, 36% yield) as a yellow solid. LCMS (ESP) m / z = 551.1 (M+H), tR= 0.922 min (Method E);XH NMR (400 MHz, CDCI3): 6 8.07 (s, 1H), 7.63 - 7.51 (m, 1H), 7.42 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.50 - 6.40 (m, 1H), 6.19 (d, J = 5.2 Hz, 1H), 4.81 - 4.78 (m, 1H), 3.59 (s, 3H), 3.33 (d, J = 6.0 Hz, 3H), 3.09 - 2.70 (m, 10H), 2.37 - 2.33 (m, 6H), 1.58 (d, J = 6.8 Hz, 3H).

[0314] Example 11: (R)-2,7-Dimethyl-5-(l-((2-(((l-methyl-lH-pyrazol-4- yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin- l(2H)-oneStep 1: Preparation of 4-(((2-fluorophenyl)thio)methyl)-l-methyl-lH-pyrazole

[0315] To a solution of 4-(chloromethyl)-l-methyl-pyrazole hydrochloride (300 mg, 1.80 mmol) in DMF (5 mL) was added K2CO3(496 mg, 3.59 mmol) and 2-fluorobenzenethiol (230 mg, 1.80 mmol). The mixture was stirred at 60 °C for 12 hr. The reaction mixture was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic phase was separated, washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 4:1) to afford 4-(((2- fluorophenyl)thio)methyl)-l-methyl-lH-pyrazole (340 mg, 85% yield) as an colorless oil. LCMS (ES ) m / z = 222.9 (M+H), tR= 0.500 min (Method C).Step 2: Preparation of 4-(((2-fluorophenyl)sulfonyl)methyl)-l-methyl-lH-pyrazole

[0316] To a solution of 4-(((2-fluorophenyl)thio)methyl)-l-methyl-lH-pyrazole (340 mg, 1.53 mmol) in DCM (5 mL) was added m-CPBA (620 mg, 3.05 mmol, 85% purity) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by adding aqueous Na2SO3at 25 °C. The mixture was then diluted with H2O (10 mL) and then extracted with DCM (20 mL x 2). The combined organic layers were washed with saturated NaHCO3solution (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 1:1) to afford 4-(((2-fluorophenyl)sulfonyl)methyl)-l-methyl-lH-pyrazole (360 mg, 92% yield) as a colorless oil. LCMS (ES ) m / z = 255.1 (M+H), tR= 0.516 min (Method C).Step 3: Preparation of (R)-2,7-dimethyl-5-(l-((2-(((l-methyl-lH-pyrazol-4- yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin- l(2H)-one

[0317] A mixture of 4-(((2-fluorophenyl)sulfonyl)methyl)-l-methyl-lH-pyrazole (133 mg, 523 pmol), (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Intermediate 2) (100 mg, 261 pmol), DIEA (371 mg, 2.87 mmol, 0.5 mL), and 4A molecular sieves (50 mg) in IPA (0.1 mL) was degassed and purged with N2three times. The mixture was stirred at 130 °C for 6 hr under a nitrogen atmosphere. The reaction mixture was dissolved in ACN (2 mL) and filtered to give a filtrate. The filtrate was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 45%-75% B over 10 min) to afford (R)-2,7-dimethyl-5-(l-((2-(((l-methyl-lH-pyrazol-4- yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin- l(2H)-one (83 mg, 51% yield) as a white solid. LCMS (ESP) m / z = 617.3 (M+H), tR= 0.593 min (Method C);XH NMR (400 MHz, CDCI3): 68.11 (s, 1H), 7.48 - 7.47 (m, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.25 - 7.16 (m, 1H), 7.13 (s, 1H), 6.72 (br d, J = 5.2 Hz, 1H), 6.64 - 6.63 (m, 1H), 6.28 (d, J = 8.4 Hz, 1H), 6.21 (s, 1H), 4.95 - 4.81 (m, 1H), 4.41 - 4.25 (m, 2H), 3.86 (s, 3H), 3.63 (s, 3H), 3.22 - 2.72 (m, 10H), 2.38 (s, 3H), 1.59 (br d, J = 6.4 Hz, 3H).

[0318] Example 12: (R)-3-(4-(5-Fluoro-2-methylpyridin-3-yl)piperazin-l-yl)-2,7-dimethyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-oneStep 1: Preparation of tert-butyl 4-(5-fluoro-2-methylpyridin-3-yl)piperazine-l-carboxylate

[0319] To the solution of 3-bromo-5-fluoro-2-methyl-pyridine (1.9 g, 10.0 mmol) and tert-butyl piperazine-l-carboxylate (2.79 g, 15.0 mmol) in toluene (30 mL) was added Cs2CO3(9.77 g, 30.0 mmol), BINAP (623 mg, 1.0 mmol) and Pd(OAc)2(224 mg, 1.0 mmol) and the mixture was stirred at 80 °C for 12 hr under a nitrogen atmosphere. The solution was filtered through a celite pad, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, PE:EA = 75:25 to 50:50) to afford tert-butyl 4-(5-fluoro-2-methylpyridin-3-yl)piperazine-l- carboxylate (2.5 g, 76% yield) as a yellow solid. LCMS (ES ) m / z = 296.3 (M+H), tR= 0.514 min (Method C).Step 2: Preparation of l-(5-fluoro-2-methylpyridin-3-yl)piperazine

[0320] To a solution of tert-butyl 4-(5-fluoro-2-methylpyridin-3-yl)piperazine-l-carboxylate (2.5 g, 8.46 mmol) in DCM (9 mL) was added TFA (4.61 g, 40.4 mmol) at 0 °C and the solution stirred at 25 °C for 1 hr. The solution was concentrated to produce a crude product. The crude product was dissolved in MeOH (10 mL) and adjusted to pH 8 by the addition of aqueous ammonia. Thesolution was purified by prep-HPLC purification (column: Kromasil Eternity XT 250*80mm*10pm; mobile phase: [water (NH4OH)-ACN]; gradient: 1%-31% B over 20 min) and the eluent was lyophilized to afford l-(5-fluoro-2-methylpyridin-3-yl)piperazine (0.8 g, 48% yield) as a yellow oil. XH NMR (400 MHz, CDCI3) 8: 8.05 (d, J = 2.4 Hz, 1H), 7.01-6.95 (m, 1H), 3.14 - 2.96 (m, 4H), 2.95 - 2.73 (m, 4H), 2.46 (d, J = 0.4 Hz, 3H).Step 3: Preparation of (R)-3-(4-(5-fluoro-2-methylpyridin-3-yl)piperazin-l-yl)-2,7-dimethyl-5-(l- ((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one

[0321] A solution of (R)-3-chloro-2,7-dimethyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (Example 7, Step 1) (0.2 g, 301 pmol), l-(5-fluoro-2-methylpyridin-3-yl)piperazine (0.2 g, 1.02 mmol), Cs2CO3(982 mg, 3.01 mmol) and BINAP-Pd-G3 (30 mg, 30 pmol) in dioxane (10 mL) was stirred at 100 °C for 12 hr under a nitrogen atmosphere. The solution was filtered through a celite pad, and the filtrate was concentrated. The residue was purified by prep-TLC (PE:EA = 1:4) to afford yellow oil. Then the yellow oil was purified further by prep-HPLC purification (column: Phenomenex Luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 48%-78% B over 10 min) and the eluent was lyophilized to afford (R)-3-(4-(5-fluoro-2-methylpyridin-3-yl)piperazin-l-yl)-2,7- dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (64 mg, 37% yield) as a yellow solid. LCMS (ESP) m / z = 564.2 (M+H), tR= 0.937 min (Method E);XH NMR (400 MHz, CDCI3): 8 8.19 - 8.09 (m, 2H), 7.79 - 7.76 (m, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.13 - 7.11 (m, 1H), 6.80 - 6.66 (m, 2H), 6.39 (d, J = 8.4 Hz, 1H), 6.28 (s, 1H), 4.01 - 4.95 (m, 1H), 3.68 (s, 3H), 3.38 - 2.99 (m, 11H), 2.55 (s, 3H), 2.40 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H).

[0322] Example 13: 3-(3,5'-Difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (Diastereomer 1)

[0323] Example 14: 3-(3,5'-Difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (Diastereomer 2)Step 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine

[0324] A mixture of 3-bromo-5-fluoro-2-methyl-pyridine (500 mg, 2.63 mmol), 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (735 mg, 2.89 mmol), Pd(dppf)Cl2*CH2CI2(430 mg, 526 pmol) and KOAc (775 mg, 7.89 mmol) in dioxane (10 mL) was degassed and purged with N2three times, and then the mixture was stirred at 70 °C for 16 hr. The reaction mixture was filtered and concentrated under reduced pressure to afford 5-fluoro-2- methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (623 mg, crude) as brown oil, which was used in the next step without purification.Step 2: Preparation of 5-bromo-3,5'-difluoro-2'-methyl-2,3'-bipyridine

[0325] A mixture of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (623 mg, 2.63 mmol), 2,5-dibromo-3-fluoro-pyridine (670 mg, 2.63 mmol), K2CO3(1.09 g, 7.88 mmol) and Pd(PPh3)4 (304 mg, 263 pmol) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2three times. The mixture was then stirred at 80 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 99:1 to 85:15) to afford 5-bromo-3,5'-difluoro-2'-methyl- 2,3'-bipyridine (410 mg, 54% yield) as a yellow oil. LCMS (ES ) m / z = 285.0 (M+H), tR= 0.633 min (Method C).Step 3: Preparation of 3,5'-difluoro-2'-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 2,3'-bipyridine

[0326] A mixture of 5-bromo-3,5'-difluoro-2'-methyl-2,3'-bipyridine (310 mg, 1.09 mmol), 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (333 mg, 1.31 mmol), Pd(dppf)CI2*CH2CI2(93 mg, 114 pmol), and KOAc (320 mg, 3.26 mmol) in dioxane (2 mL) was degassed and purged with N2three times. The resulting mixture was then stirred at 80 °C for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 5:1) to afford 3,5'-difluoro-2'-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 2,3'-bipyridine (360 mg, 99% yield) as yellow oil.XH NMR (400 MHz, CDCI3): 6 8.85 (s, 1H), 8.46 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.47 - 7.45 (m, 1H), 2.47 (s, 3H), 1.39 (s, 12H).Step 4: Preparation of 3-chloro-5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)- 2,7-dimethylisoquinolin-l(2H)-one

[0327] To a solution of (2-fluorophenyl)(methyl)(methylimino)-A6-sulfanone (224 mg, 1.20 mmol) and (R)-5-(l-aminoethyl)-3-chloro-2,7-dimethylisoquinolin-l(2H)-one (Intermediate 4) (200 mg, 798 pmol) in IPA (0.1 mL) was added DIEA (223 mg, 1.72 mmol) and 4A molecular sieves (50 mg). The mixture was stirred at 130 °C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE:EA = 1:1) to afford 3-chloro-5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-one (80 mg, 17% yield) as a yellow solid. LCMS (ES ) m / z = 418.1 (M+H), tR= 0.493 min (Method K).Step 5: Preparation of 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one

[0328] A mixture of 3-chloro-5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-one (230 mg, 550 pmol), 3,5'-difluoro-2'-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3'-bipyridine (150 mg, 452 pmol), 4-di-tert- butylphosphanyl-N,N-dimethyl-aniline palladium dichloride (39 mg, 55 pmol), and K3PO4(350 mg, 1.65 mmol) in dioxane (4 mL) and H2O (0.5 mL) was degassed and purged with N2three times. The mixture was stirred at 100 °C for 3 hr. The reaction mixture was then partitioned between H2O (10 mL) and EtOAc (10 mL). The organic phase was separated and dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE:EA = 1:2). Then the product was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 44%-74% B over 10 min) to afford 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5- ((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (75 mg, 22% yield) as a white solid. LCMS (ESP) m / z = 588.3 (M+H), tR= 0.534 min (Method C).Step 6: Preparation of 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (Diastereomer 1) and 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (Diastereomer 2)

[0329] 3-(3,5'-Difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (75 mg, 128 pmol) was separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10pm); mobile phase: [CO2-EtOH( 0.1% NH4OH)]; B%: 45%, isocratic elution mode) to afford 3-(3,5'-difluoro-2'- methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-one (Diastereomer 1) and 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5- yl)-5-((lR)-l-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)- one (Diastereomer 2) as white solids.

[0330] 3-(3,5'-Difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (Diastereomer 1) (30 mg). LCMS (ES ) m / z = 588.3 (M+H), tR= 0.531 min (Method C);XH NMR (400 MHz, CDCI3): 8 8.70 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.24 (s, 1H), 7.78 - 7.76 (m, 1H), 7.69 - 7.67 (m, 1H), 7.57 - 7.52 (m, 2H), 7.49 (d, J = 6.4 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.79 - 6.67 (m, 2H), 6.31 (d, J = 8.4 Hz, 1H), 5.05 - 4.98 (m, 1H), 3.56 (s, 3H), 3.14 (s, 3H), 2.81 (s, 3H), 2.57 (s, 3H), 2.45 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H).

[0331] 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((lR)-l-((2-(N,S- dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (Diastereomer 2) (37 mg). LCMS (ESP) m / z = 588.3 (M+H), tR= 0.540 min (Method C);XH NMR (400 MHz, CDCI3): 8 8.70 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.25 (s, 1H), 7.79 - 7.77 (m, 1H), 7.69 - 7.67 (m, 1H), 7.60 - 7.51 (m, 2H), 7.45 (d, J = 3.6 Hz, 1H), 7.25 - 7.20 (m, 1H), 6.81 - 6.73 (m, 2H), 6.32 (d, J = 8.4 Hz, 1H), 5.05 - 4.90 (m, 1H), 3.56 (s, 3H), 3.18 (s, 3H), 2.75 (s, 3H), 2.57 (s, 3H), 2.47 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H).

[0332] Example 15: (R)-5-(l-((6-chloro-2-(methylsulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-oneStep 1: Preparation of 6-chloro-3-fluoro-2-(methylthio)pyridine

[0333] To a solution of 2,6-dichloro-3-fluoro-pyridine (1 g, 6.02 mmol) in DMF (10 mL) was added sodium methanethiolate (500 mg, 7.13 mmol) at 0 °C and then the mixture was stirred at 25 °C for 2 hr. The reaction mixture was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 95:5) to afford 6-chloro-3-fluoro-2-(methylthio)pyridine (490 mg, 45% yield) as colorless oil.XH NMR (400 MHz, CDCI3): 6 7.22 - 7.17 (m, 1H), 7.01 - 6.97 (m, 1H), 2.59 (s, 3H).Step 2: 6-chloro-3-fluoro-2-(methylsulfonyl)pyridine

[0334] To a solution of 6-chloro-3-fluoro-2-(methylthio)pyridine (480 mg, 2.70 mmol) in EtOAc (10 mL) was added NaCIO (12.1 g, 162 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 2 hr. The reaction mixture was then partitioned between H2O (10 mL) and EtOAc (10 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-chloro-3-fluoro-2-(methylsulfonyl)pyridine (440 mg, crude) as a colorless oil, which was used for next step directly without purificaton. LCMS (ES ) m / z = 210.1 (M+H), tR= 0.422 min (Method C).Step 3: Preparation of (R)-5-(l-((6-chloro-2-(methylsulfonyl)pyridin-3-yl)amino)ethyl)-2,7- dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one

[0335] To a solution of (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (Intermediate 2) (100 mg, 261 pmol) and 6-chloro-3-fluoro-2- (methylsulfonyl)pyridine (110 mg, 523 pmol) in ACN (0.5 mL) was added triethylamine (79 mg, 785 pmol). The resuliting mixture was stirred at 80 °C for 12 hr. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 52%-82% B over 10 min) to afford (R)-5-(l-((6-chloro-2- (methylsulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (95 mg, 63% yield) as an off-white solid. LCMS (ES ) m / z = 572.3 (M+H), tR= 0.616 min (Method C);XH NMR (400 MHz, CDCI3): 68.12 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.13 - 7.01 (m, 2H), 6.60 (d, J = 9.2 Hz, 1H), 6.19 (s, 1H), 4.92 - 4.74 (m, 1H), 3.62 (s, 3H), 3.36 (s, 3H), 3.21 - 2.65 (m, 10H), 2.40 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H).

[0336] Example 16: (R)-5-(l-((6-ethynyl-2-(methylsulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-oneStep 1: Preparation of (R)-2,7-dimethyl-5-(l-((2-(methylsulfonyl)-6- ((trimethylsilyl)ethynyl)pyridin-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one

[0337] A mixture of (R)-5-(l-((6-chloro-2-(methylsulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3- (4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Example 15) (54 mg, 94 pmol), ethynyl(trimethyl)silane (93 mg, 944 pmol, 131 pL), Xphos-Pd-G4 (8 mg, 9.44 pmol), N- cyclohexyl-N-methyl-cyclohexanamine (55 mg, 283 pmol) in dioxane (1 mL) was degassed and purged with N2three times. The resulting mixture was stirred at 110 °C for 2 h. Then ethynyl(trimethyl)silane (93 mg, 944 pmol) was added and the mixture was stirred at 110 °C for another 12 hr under a nitrogen atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE:EA = 1:1) to afford (R)-2,7-dimethyl-5-(l-((2-(methylsulfonyl)-6- ((trimethylsilyl)ethynyl)pyridin-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (60 mg, 89% yield) as yellow oil. LCMS (ES ) m / z = 634.2 (M+H), tR= 0.729 min (Method E).Step 2: Preparation of (R)-5-(l-((6-ethynyl-2-(methylsulfonyl)pyridin-3-yl)amino)ethyl)-2,7- dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one

[0338] To a solution of (R)-2,7-dimethyl-5-(l-((2-(methylsulfonyl)-6-((trimethylsilyl)ethynyl)pyridin- 3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (55 mg, 86.8 pmol) in DMF (0.5 mL) was added CsF (26 mg, 174 pmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 150*25mm*10pm; mobile phase: [water(FA)-ACN]; gradient: 45%-75% B over 10 min) to afford (R)-5-(l-((6-ethynyl-2-(methylsulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (19 mg, 38% yield) as an off-white solid. LCMS (ES ) m / z = 562.3 (M+H), tR= 0.602 min (Method C);XH NMR (400 MHz, CDCI3): 68.12 (s, 1H), 7.42 (s, 1H), 7.26 - 7.16 (m, 2H), 6.55 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H), 4.95 - 4.77 (m, 1H), 3.62 (s, 3H), 3.39 (s, 3H), 3.15 - 2.71 (m, 11H), 2.39 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H).

[0339] Example 17: (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2- dihydroisoquinolin-5-yl)ethyl)amino)benzenesulfonamideStep 1: Preparation of 2-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide

[0340] To a stirred solution of 2-bromobenzenesulfonamide (2.5 g, 10.6 mmol) in DMF (50 mL) was added NaH (1.27 g, 31.7mmol, 60 wt%) at 0 °C under a nitrogen atmosphere. After the mixture was stirred for 30 min at 0 °C, SEM-CI (5.30 g, 31.7 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 4 h at room temperature under a nitrogen atmosphere. The reaction was quenched with water (50 mL) at 0 °C and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 10:1) to afford 2-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (4 g, 76% yield) as an oil.XH NMR (400 MHz, DMSO-ds) 88.12 - 8.08 (m, 1H), 7.82 -7.78 (m, 1H), 7.60 - 7.55 (m, 2H), 4.81 (s, 4H), 3.37 - 3.28 (m, 4H), 0.73 - 0.63 (m, 4H), 0.01 (s, 18H).Step 2: Preparation of (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2- dihydroisoquinolin-5-yl)ethyl)amino)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide

[0341] To a stirred solution of 2-bromo-N,N-bis((2- (trimethylsilyl)ethoxy)methyl)benzenesulfonamide (1.04 g, 2.09 mmol) and (R)-5-(l-aminoethyl)- 2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)isoquinolin-l(2H)-one (Intermediate 2) (400 mg, 1.05 mmol) in dioxane (10 mL) were added Pd2(dba)3(96 mg, 0.11 mmol), Cs2CO3(682 mg, 2.09 mmol) and Xantphos (121 mg, 0.21 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to afford (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2-dihydroisoquinolin-5- yl)ethyl)amino)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (250 mg, 30% yield) as an oil. MS (ES ) m / z = 796.2 [M-H]'.Step 3: Preparation of (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2- dihydroisoquinolin-5-yl)ethyl)amino)benzenesulfonamide

[0342] To a stirred solution of (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)-l,2-dihydroisoquinolin-5-yl)ethyl)amino)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (150 mg, 0.19 mmol) in THF (10 mL) was added TBAF (IM in THF, 1.88 mL, 1.88 mmol) dropwise at room temperature under a nitrogenatmosphere. The resulting mixture was stirred overnight at 50 °C. The reaction was then quenched with water (10 mL) at 0 °C and the mixture was extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (3 x 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions ( UV 254nm / 220nm Xselect CSH Prep C18 Column, 30*150 mm, 5pm; Water (0.1% FA), ACN 60 mL / min, 43% B to 68 % B in 10 min) to afford (R)-2- ((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2-dihydroisoquinolin-5- yl)ethyl)amino)benzenesulfonamide (66 mg, 65% yield) as a white solid. MS (ES+) m / z = 538.2 [M+H]+, tR= 0.977 min;XH NMR (400 MHz, DMSO-ds): 8 7.89 - 7.84 (m, 1H), 7.64 - 7.621 (m, 1H), 7.59 - 7.53 (m, 3H), 7.19 - 7.14 (m, 1H), 6.63 - 6.59 (m, 1H), 6.43 (s, 1H), 6.39 - 6.33 (m, 2H), 5.20 - 5.17 (m, 1H), 3.50 (s, 3H), 3.30 - 3.28 (m, 2H), 3.15 - 2.84 (m, 8H), 2.31 (s, 3H), 1.53 (d, J = 6.5 Hz, 3H).

[0343] Example 18: (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2- dihydroisoquinolin-5-yl)ethyl)amino)-N-methylbenzenesulfonamideStep 1: Preparation of 2-bromo-N-methyl-N-((2- (trimethylsilyl)ethoxy)methyl)benzenesulfonamide

[0344] A solution of 2-bromo-N-methylbenzenesulfonamide (700 mg, 2.80 mmol) in DMF (15 mL) was added NaH (244 mg, 5.60 mmol, 60 wt%) at 0 °C under a nitrogen atmosphere. After the mixture was stirred for 30 min at 0 °C, SEM-CI was added (607 mg, 3.64 mmol) at 0 °C. The mixture was then stirred for 5 h at room temperature. The reaction was quenched with water (10 mL) at room temperature and the mixture was extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA = 5:1) to afford 2-bromo-N-methyl-N-((2- (trimethylsilyl)ethoxy)methyl)benzenesulfonamide (650 mg, 61% yield) as a colorless oil.XH NMR(400 MHz, DMSO-c / g) 8 8.05 - 8.00 (m, 1H), 7.91 - 7.84 (m, 1H), 7.65 - 7.53 (m, 2H), 4.79 (s, 2H), 3.53 - 3.44 (m, 2H), 2.78 (s, 3H), 0.88 - 0.79 (m, 2H), 0.01 (s, 9H).Step 2: Preparation of (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)- l,2-dihydroisoquinolin-5-yl)ethyl)amino)-N-methyl-N-((2- (trimethylsilyl)ethoxy)methyl)benzenesulfonamide

[0345] A mixture of 2-bromo-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (497 mg, 1.3 mmol), (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)isoquinolin-l(2H)-one (Intermediate 2) (200 mg, 0.52 mmol), Pd2(dba)3(48 mg, 0.052 mmol), Xantphos (61 mg, 0.11 mmol), and Cs2CO3(852 mg, 2.62 mmol) in dioxane (10 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure and the resulting residue was purified by prep-TLC (PE:EA = 1:1) to afford (R)-2-((l-(2,7- dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2-dihydroisoquinolin-5- yl)ethyl)amino)-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (150 mg, 42. % yield) as a light brown solid. MS (ES+) m / z = 682.3 [M+H]+.Step 3: Preparation of (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)- l,2-dihydroisoquinolin-5-yl)ethyl)amino)-N-m ethylbenzenesulfonamide

[0346] A mixture of afford (R)-2-((l-(2,7-dimethyl-l-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)- l,2-dihydroisoquinolin-5-yl)ethyl)amino)-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (150 mg, 0.22 mmol) and TBAF (2.2 mL, 2.2mmol) in THF (10 mL) was stirred for 20 h at 50 °C. The reaction was quenched with water (10 mL) at room temperature and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (3 x 15 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC (Column: XBridge Prep OBD C18 Column, 50*250 mm, 10pm; Mobile Phase A: Water (10 nmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 75% B in 20 min; Wave Length: 254 nm / 220 nm) to afford (R)-2-((l-(2,7-dimethyl-l- oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)-l,2-dihydroisoquinolin-5-yl)ethyl)amino)-N- methylbenzenesulfonamide (54 mg, 44%, yield) as a white solid.1H NMR (400 MHz, Methanol- d4): 8 8.02 - 7.97 (m, 1H), 7.68 - 7.66 (m, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.70 - 6.66 (m, 1H), 6.51 (s, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.17 - 5.16 (m, 1H), 3.66 (s, 3H), 3.26 - 3.25 (m, 2H), 3.20 - 2.88 (m, 8H), 2.57 (s, 3H), 2.38 (s, 3H), 1.65 (d, J = 6.7, 3H). MS (ES ) m / z = 550.4 [M- H]-.

[0347] Example 19: (R)-3,6-dimethyl-8-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)quinazolin-4(3H)-oneStep 1: Preparation of (R)-3,6-dimethyl-8-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(methylthio)quinazolin-4(3H)-one

[0348] To a stirred solution of (R)-8-(l-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)- one (Intermediate 6) (300 mg, 1.1 mmol) and l-iodo-2-methanesulfonylbenzene (321 mg, 1.1 mmol) in dioxane (10 mL) were added Cs2CO3(1.1 g, 3.4 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 (16 mg, 0.019 mmol) in portions at room temperature under argon atmosphere. The resulting mixture was stirred overnight at 100 °C. The reaction was then quenched with water (60 mL) at room temperature and the resulting mixture was extracted with EtOAc (2 x 60 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford (R)-3,6-dimethyl-8-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(methylthio)quinazolin-4(3H)-one (100 mg, 21% yield) as a light yellow solid.XH NMR (400 MHz, DMSO-ds): 87.81-7.76 (m, 1H), 7.66-7.58 (m, 2H), 7.36- 7.30 (m, 1H), 6.77-6.67 (m, 2H), 6.59 (d, J = 8.4 Hz, 1H), 5.53-5.41 (m, 1H), 3.53 (s, 3H), 3.20 (s, 3H), 2.68 (s, 3H), 2.36 (s, 3H), 1.63 (d, J = 6.6 Hz, 3H).Step 2: Preparation of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one

[0349] To a stirred solution of (R)-3,6-dimethyl-8-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-2- (methylthio)quinazolin-4(3H)-one (70 mg, 0.17 mmol) in THF (2 mL) was added oxone (169 mg, 1.0 mmol) in H2O (2 mL) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred for 1 h at room temperature and then was diluted with ice water (40 mL). The resulting mixture was extracted with EtOAc (2 x 40 mL) and the combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, (CH2CI2:MeOH = 10:1) to afford 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (40 mg, 55% yield) as a white solid. LCMS (ESP) m / z = 434.1 (M+H).Step 3: Preparation of (R)-3,6-dimethyl-8-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)quinazolin-4(3H)-one

[0350] A mixture of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (40 mg, 0.092 mmol) and l-(2,2,2- trifluoroethyl)piperazine (19 mg, 0.11 mmol) in NMP (2 mL) was stirred overnight at 130 °C. The mixture was then diluted with ice water (30 mL) and the resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, (PE:EA = 1:1) to afford (R)-2-hydroxy-3,6-dimethyl-8-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (35 mg, 8%) as a white solid.

[0351] A solution of (R)-2-hydroxy-3,6-dimethyl-8-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (35 mg, 0.090 mmol) and PyBOP (141 mg, 0.270 mmol) in DMF (2 mL) under an argon atmosphere was stirred at room temperature for 10 min. Then, DBU (69 mg, 0.45 mmol) and l-(2,2,2-trifluoroethyl)piperazine (23 mg, 0.14 mmol) were added in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature and then was diluted with ice water (20 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water, 5% to 95% gradient in 30 min; detector, UV 254 nm) to afford (R)-3,6- dimethyl-8-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)quinazolin-4(3H)-one (13 mg, 27% yield) as a white solid. LCMS (ES ) m / z = 538.2 [M+H];1H NMR (400 MHz, DMSO-ds): 8 7.76-7.20 (m, 1H), 7.64 - 7.54 (m, 2H), 7.37-7.29 (m, 1H), 6.77 (d, J = 7.0 Hz, 1H), 6.75 - 6.65 (m, 2H), 5.44-5.33 (m, 1H), 3.48 (s, 3H), 3.31 - 3.23 (m, 6H), 3.16 (s, 3H), 2.86-2.79 (m, 4H), 2.34 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H).

[0352] Example 85: (R)-3-(2-(5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-5-yl)-5-(l-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-oneStep 1: Preparation of (R)-3-chloro-5-(l-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-one

[0353] To a solution of (R)-5-(l-aminoethyl)-3-chloro-2,7-dimethylisoquinolin-l(2H)-one (Intermediate 4, 200 mg, 0.80 mmol) and l,4-difluoro-2-methylsulfonyl-benzene (200 mg, 1.04 mmol) in IPA (0.2 mL) was added 4A molecular sieves (100 mg) and DIEA (0.40 mL, 2.30 mmol). The mixture was stirred at 130 °C for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, PE:EA = 10:1 to 4:1) to give (R)-3-chloro-5-(l-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (170 mg, 50% yield) as a yellow solid. LCMS (ESP) m / z = 423.2 (M+H).Step 2: Preparation of (R)-3-(2-(5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-5- yl)-5-(l-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one

[0354] A mixture of (R)-3-chloro-5-(l-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-one (70 mg, 0.17 mmol), 7-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine (Intermediate 8, 81 mg, 0.25 mmol), mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l,l'- biphenyl)]palladium(ll) (cataCXium® A Pd G3) (12 mg, 0.017 mmol), Na2CO3(35 mg, 0.33 mmol) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged with N2three times. The mixture was then stirred at 100 °C for 1 h. The reaction mixture was then diluted with H2O (10 mL) and extracted with EA (10 mL x 3). The combined organics were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford (R)-3-(2-(5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-5-yl)-5-(l-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (30 mg, 30% yield) as a yellow solid. LCMS (ES ) m / z = 589.3 (M+H);XH NMR (400 MHz, CDCI3): 8 8.53 (s, 2H), 8.23-8.19 (m, 2H), 7.53 - 7.52 (m, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.01 - 6.93 (m, 1H), 6.60 (s, 1H), 6.52 (d, J = 5.2 Hz, 1H), 6.26 - 6.24 (m, 1H), 5.32 (s, 2H), 4.92 - 4.89 (m, 1H), 4.42 - 4.41 (m, 2H), 4.27 - 4.20 (m, 2H), 3.52 (s, 3H), 3.16 (s, 3H), 2.44 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H).

[0355] Example 86: (R)-3-(2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7- dimethyl-5-(l-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)isoquinolin-l(2H)-oneStep 1: Preparation of tert-butyl (R)-(l-(3-(2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4- yl)pyrimidin-5-yl)-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate

[0356] A mixture of (2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5-yl)boronic acid(Intermediate 9, 280 mg, 0.86 mmol), tert-butyl (R)-(l-(3-chloro-2,7-dimethyl-l-oxo-l,2- dihydroisoquinolin-5-yl)ethyl)carbamate (Intermediate 7, 300 mg, 0.86 mmol), mesylate[(di(l- adamantyl)-n-butylphosphine)-2-(2'-amino-l,l'- biphenyl)]palladium(ll) (cataCXium® A Pd G3) (62 mg, 0.086 mmol), K2CO3(355 mg, 2.57 mmol) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2three times. The mixture was then stirred at 100 °C for 1 h. The mixture was then filtered, and filtrate concentrated under reduced pressure affording a crude product. The crude product was purified by silica gel column chromatography (eluted with PE:EA from 1:0 to 1:1) to give tert-butyl (R)-(l-(3-(2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5-yl)- 2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate (400 mg, 70% yield) as a blackbrown solid. LCMS (ESP) m / z = 516.2 (M+H).Step 2: Preparation of (R)-5-(l-aminoethyl)-3-(2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4- yl)pyrimidin-5-yl)-2,7-dimethylisoquinolin-l(2H)-one

[0357] A solution of tert-butyl (R)-(l-(3-(2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5- yl)-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate (200 mg, 0.39 mmol) in a solution of HCI in dioxane (4 M, 2 mL) was prepared. The mixture was stirred at 25 °C for 0.3 h. The reaction was then concentrated under reduced pressure to give (R)-5-(l-aminoethyl)-3-(2- (l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethylisoquinolin-l(2H)-one hydrochloride (152 mg, 76% yield) as a brown solid. LCMS (ES ) m / z = 416.2 (M+H).Step 3: Preparation of (R)-3-(2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7- dimethyl-5-(l-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)isoquinolin-l(2H)-one

[0358] To a solution of (R)-5-(l-aminoethyl)-3-(2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4- yl)pyrimidin-5-yl)-2,7-dimethylisoquinolin-l(2H)-one (free base from the HCI salt reported in the previous step, generated via treating a 10:1 CH2CI2 / MeOH solution of the HCI salt with saturated aqueous NaHCO3, 150 mg, 0.36 mmol), 3-bromo-6-methyl-2-(trifluoromethyl)pyridine (130 mg, 0.54 mmol), (SP-4-l)-[l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H- imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (30 mg, 0.036 mmol), Cs2CO3(471 mg, 1.44 mmol) in dioxane (10 mL) was degassed and purged with N2three times. The mixture was then stirred at 90 °C for 1 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gelcolumn chromatography (eluted with PE:EA from 1:1 to 1:4) and then purified further by prep- HPLC to afford (R)-3-(2-(l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethyl- 5-(l-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)isoquinolin-l(2H)-one (24 mg, 11% yield) as a yellow solid. LCMS (ES ) m / z = 575.3 (M+H), tR=0 .517 min (Method X);XH NMR (400 MHz, DMSO-dg): 8 9.25 (s, 2H), 8.01 (s, 1H), 7.70 - 7.68 (m, 1H), 7.59 (s, 1H), 7.16 (s, 1H), 7.13 - 7.11 (m, 1H), 6.86 - 6.84 (m, 1H), 6.61 - 6.59 (m, 1H), 5.60 - 5.68 (m, 1H), 5.30 - 5.27 (m, 1H), 3.51 (s, 3H), 3.45 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H).

[0359] Example 87: (R)-5-(l-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinolin-l(2H)-oneStep 1: Preparation of l-bromo-2-(difluoromethyl)-3,4-difluorobenzene

[0360] To a stirred solution of 6-bromo-2,3-difluorobenzaldehyde (15.0 g, 67.8 mmol) in DCM (30 mL) was added DAST (21.9 g, 136 mmol) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 2 h and then quenched by the addition of ice water (400 mL) at 0 °C. The resulting mixture was then extracted with CH2CI2 (3 x 400 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 10:1) to afford l-bromo-2-(difluoromethyl)-3,4-difluorobenzene (11.0 g, 67 %yield) as an off-white oil.XH NMR (400 MHz, DMSO-ds) 8 7.73 - 7.63 (m, 2H), 7.45 - 7.14 (m, 1H).Step 2: Preparation of (R)-3-chloro-5-(l-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)- 2,7-dimethylisoquinolin-l(2H)-one

[0361] To a stirred solution of l-bromo-2-(difluoromethyl)-3,4-difluorobenzene (1.0 g, 4.1 mmol) and (R)-5-(l-Aminoethyl)-3-chloro-2,7-dimethylisoquinolin-l(2H)-one (Intermediate 4, 1.6 g, 6.1 mmol) in dioxane (10 mL) was added Cs2CO3(4.0 g, 12.3 mmol), XantPhos (0.48 g, 0.82 mmol) and Pd2(dba)3(0.4 g, 0.4 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred at 100 °C overnight. The reaction was diluted with ice water (50 mL) at 0 °C and then extracted with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 1:1) to afford (R)-3-chloro-5-(l-((2- (difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (960 mg, 56% yield) as a light-yellow oil. LCMS (ES ) m / z = 413 (M+H).Step 3: Preparation of (R)-5-(l-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7- dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l(2H)-one

[0362] To a stirred solution (R)-3-chloro-5-(l-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)- 2,7-dimethylisoquinolin-l(2H)-one (900 mg, 2.2 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (11.0 g, 43.6 mmol) in dioxane (10 mL) were added KOAc (642 mg, 6.5 mmol) and Pd(dppf)CI2(160 mg, 0.2 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The resulting mixture was then filtered, and the filter cake was washed with DCM (3 x 20 mL). The filtrate was then concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification. LCMS (ES ) m / z = 505 (M+H).Step 4: Preparation of (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((2-(difluoromethyl)-3,4- difluorophenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one

[0363] To a stirred solution (R)-5-(l-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7- dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l(2H)-one (900 mg, 1.8 mmol) and 2-bromo-5-iodopyrimidine (610 mg, 2.1 mmol) in dioxane (10 mL) and H2O (2 mL) were added Na2CO3(567 mg, 5.4 mmol) and Pd(PPh3)4 (206 mg, 0.2 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was then stirred at 90 °C overnight. The mixture was diluted with ice water (30 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to afford (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((2- (difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (450 mg, 47% yield) as a light-yellow solid. LCMS (ESP) m / z = 535 (M+H).Step 5: Preparation of (R)-5-(l-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7- dimethyl-3-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinolin-l(2H)-one

[0364] To a stirred solution of (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((2-(difluoromethyl)-3,4- difluorophenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (100 mg, 0.2 mmol) and 1- methyl-6-(trimethylstannyl)pyrazin-2-one (Intermediate 10, 102 mg, 0.3 mmol) in DMF (0.5 mL) were added mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(ll) (9.6 mg, 0.02 mmol) and tri-tert-butylphosphonium tetrafluoroborate (5.4 mg, 0.019 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was then stirred at 80 °C overnight. The mixture was diluted with ice water (30 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography and then prep-HPLC to afford (R)-5-(l-((2-(difluoromethyl)- 3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2- yl)pyrimidin-5-yl)isoquinolin-l(2H)-one (9.0 mg, 8.5% yield) as a light-yellow solid. LCMS (ES ) m / z = 565 (M+H);XH NMR (400 MHz, DMSO-ds): 89.32 (s, 2H), 8.21 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.66 - 7.36 (m, 2H), 7.28 - 7.14 (m, 2H), 6.17 - 6.08 (m, 2H), 5.26 - 5.15 (m, 1H), 3.62 (s, 3H), 3.47 (s, 3H), 2.41 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H).

[0365] Example 88: (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2- (l-methyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinolin-l(2H)-oneStep 1: Preparation of (R)-3-chloro-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-oneTo a stirred solution / mixture of (R)-5-(l-Aminoethyl)-3-chloro-2,7-dimethylisoquinolin-l(2H)-one (Intermediate 4, 1 g, 4.0 mmol) and 4-fluoro-l-iodo-2-(trifluoromethyl)benzene (1.73 g, 5.98 mmol) and Cs2CO3(3.90 g, 12.0 mmol) and RuPhos (744 mg, 1.60 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3(730 mg, 0.80 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was then stirred at 100 °C for 2 h. The mixture was then diluted with ice water (50 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 5:1) to afford (R)-3-chloro-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin- l(2H)-one (600 mg, 36% yield) as a white solid. LCMS (ES ) m / z = 413 (M+H).

[0366] To a stirred solution / mixture of (R)-5-(l-Aminoethyl)-3-chloro-2,7-dimethylisoquinolin- l(2H)-one (Intermediate 4, 1 g, 4.0 mmol) and 4-fluoro-l-iodo-2-(trifluoromethyl)benzene (1.73 g, 5.98 mmol) and Cs2CO3(3.90 g, 12.0 mmol) and RuPhos (744 mg, 1.60 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3(730 mg, 0.80 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was then stirred at 100 °C for 2 h. The mixture was then diluted with ice water (50 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 5:1) to afford (R)-3-chloro-5-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (600 mg, 36% yield) as a white solid. LCMS (ES ) m / z = 413 (M+H).Step 2: Preparation of (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l(2H)-one

[0367] To a stirred solution / mixture of (R)-3-chloro-5-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (600 mg, 1.45 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (738 mg, 2.91 mmol) and KOAc (428 mg, 4.36 mmol) in dioxane (10 mL) were added Pd(dppf)CI2(213 mg, 0.29 mmol) dropwise at room temperature under an argon atmosphere. The resulting mixture was stirred at 110 °C overnight. The mixture was then filtered and concentrated under reduced pressure to afford a crude product that was used in the next step directly without characterization or further purification. LCMS (ESP) m / z = 505 (M+H).Step 3: Preparation of (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one

[0368] To a stirred mixture of crude (R)-3-chloro-5-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (600 mg, 1.19 mmol) and 2-bromo-5-iodopyrimidine (508 mg, 1.79 mmol) in dioxane (4 mL) and H2O was added Pd(PPh3)4 (137 mg, 0.12 mmol) and Na2CO3(378 mg, 3.57 mmol) under an argon atmosphere. The resulting mixture was stirred at 110 °C for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2CI2:MeOH = 5:1) to afford (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-one (450 mg, 71% yield) as a light-yellow solid. LCMS (ES ) m / z = 535.1 (M+H).Step 4: Preparation of (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinolin-l(2H)-one

[0369] To a stirred mixture of (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (50 mg, 0.093 mmol) and l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazin-2-one (Intermediate 11, 66 mg, 0.28 mmol) and Pd(dppf)CI2(34 mg, 0.046 mmol) and Cs2CO3(91 mg, 0.28 mmol) in DMF (2mL) was added CuCI (18 mg, 0.19 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred at 60 °C for 1 h, diluted with ice water (30 mL) at 0 °C, and then extracted with EtOAc (3 x 30 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to afford (R)-5-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6-dihydropyrazin-2- yl)pyrimidin-5-yl)isoquinolin-l(2H)-one (9.4 mg, 18% yield) as a brown solid. LCMS (ES ) m / z = 565.2 (M+H);XH NMR (400 MHz, DMSO-ds): 8 9.32 (s, 2H), 8.21 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.78 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.19 (s, 1H), 7.16 (s, 1H), 6.51 - 6.43 (m, 1H), 5.39 (d, J = 6.2 Hz, 1H), 5.31 - 5.23 (m, 1H), 3.62 (s, 3H), 3.47 (s, 3H), 2.39 (s, 3H), 1.55 (d, J = 6.6 Hz, 3H).

[0370] Example 89: (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2- (l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinolin-l(2H)-oneStep 1: Preparation of tert-butyl (R)-(l-(2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6- dihydropyridazin-4-yl)pyrimidin-5-yl)-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate

[0371] To a solution of (2-(l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)pyrimidin-5-yl)boronic acid(Intermediate 12, 516 mg, 2.22 mmol) and tert-butyl (R)-(l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate (Intermediate 7 , 600 mg, 1.71 mmol) in dioxane (12 mL) and H2O (1 mL) was added Na2CO3(363 mg, 3.42 mmol) and mesylate[(di(l-adamantyl)-n- butylphosphine)-2-(2'-amino-l,l'- biphenyl)]palladium(ll) (cataCXium® A Pd G3) (125 mg, 0.17 mmol). The reaction mixture was stirred at 90 °C for 2 h under a N2atmosphere. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, eluted with PE:EA from 1:0 to 1:1) to give tertbutyl (R)-(l-(2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)pyrimidin-5-yl)-l-oxo- l,2-dihydroisoquinolin-5-yl)ethyl)carbamate (250 mg, 29% yield) as a yellow solid. LCMS (ES ) m / z = 503.1 (M+H).Step 2: Preparation of (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6- dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinolin-l(2H)-one hydrochloride

[0372] A mixture of tert-butyl (R)-(l-(2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6-dihydropyridazin-4- yl)pyrimidin-5-yl)-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate (250 mg, 0.50 mmol) in a solution of HCI in dioxane (2 M, 6 mL, 12 mmol) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give (R)-5-(l-aminoethyl)-2,7-dimethyl-3- (2-(l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinolin-l(2H)-one hydrochloride (218 mg, 93% yield) was as a yellow solid. LCMS (ESP) m / z = 403.1 (M+H).Step 3: Preparation of (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl- 3-(2-(l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinolin-l(2H)-one

[0373] To a mixture of (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(2-(l-methyl-6-oxo-l,6- dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinolin-l(2H)-one hydrochloride (70 mg, 0.16 mmol) and l-bromo-4-fluoro-2-(trifluoromethyl)benzene (78 mg, 0.32 mmo) in dioxane (2 mL) was added (SP-4-l)-[l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2- ylidene]dichloro(2-methylpyridine)palladium (13 mg, 0.016 mmol) and Cs2CO3(130 mg, 0.40 mmol) in one portion at 25°C under a N2atmosphere. The mixture was then stirred at 100 °C for 16 h. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 x 2 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to afford (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3- (2-(l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinolin-l(2H)-one (19 mg, 21% yield) as a yellow solid. LCMS (ESP) m / z = 565.2 (M+H);XH NMR (400 MHz, CDCI3): 6 9.01 (s, 2H), 8.80 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.22 - 7.19 (m, 1H), 6.92 - 6.85 (m, 1H), 6.74 (s, 1H), 6.26 - 6.19 (m, 1H), 4.95 - 4.89 (m, 1H), 4.61-4.57 (m, 1H), 3.90 (s, 3H), 3.54 (s, 3H), 2.47 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H).

[0374] Example 90: (R)-2,7-dimethyl-3-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-oneStep 1: Preparation of 5-bromo-2'-methyl-2,5'-bipyrimidine

[0375] A mixture of (2-methylpyrimidin-5-yl)boronic acid (460 mg, 3.3 mmol), 5-bromo-2-iodo- pyrimidine (1 g, 3.5 mmol), Pd(dppf)Cl2*CH2Cl2 (287 mg, 0.35 mmol) and Na2CO3(744 mg, 7.0 mmol) in dioxane (20 mL) and H2O (4 mL) was degassed and purged with N2three times. The mixture was then stirred at 90 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate 300 mL (3 x 100 mL). The combined organics were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product. The crude product was purified by silica gel column chromatography (eluted with PE:EA from 10:1 to 3:1) to afford 5-bromo-2'-methyl-2,5'- bipyrimidine (410 mg, 46% yield) as a white solid. LCMS (ES ) m / z = 251.2 (M+H).Step 2: Preparation of 2'-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5'- bipyrimidine

[0376] A mixture of 5-bromo-2'-methyl-2,5'-bipyrimidine (200 mg, 0.80 mmol), 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (303 mg, 1.19 mmol), KOAc (235 mg, 2.39 mmol) and Pd(dppf)Cl2*CH2CI2(65 mg, 0.080 mmol) in dioxane (5 mL) was degassed and purged with N2three times. The mixture was then stirred at 80 °C for 12 h. The mixture was then concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (eluted with PE:EA = 0 / 1) to give 2'- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine (340 mg, crude yield) as a black-brown solid which was used as is in the next step without further purification. LCMS (ESP) m / z = 217.3 (M+H, boric acid).Step 3: Preparation of (R)-2,7-dimethyl-3-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one

[0377] A mixture of 2'-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine (58 mg, 0.24 mmol), (R)-3-chloro-2,7-dimethyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (Example 7, Step 1, 50 mg, 0.12 mmol), Cs2CO3(193 mg, 0.59 mmol) and bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(ll) (10 mg, 0.012 mmol) in dioxane (10 mL) in a sealable vessel was degassed and purged with nitrogen three times. The mixture was then stirred at 120 °C for 12 h. The reaction mixture was concentrated under reduced pressure to givethe crude product. The crude product was filtered through silica gel (eluted with MeOH) to give a residue which was purified further by prep-HPLC to give (R)-2,7-dimethyl-3-(2'-methyl-[2,5'- bipyrimidin]-5-yl)-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (46 mg, 36% yield) as a white solid. LCMS (ES ) m / z = 541.2 (M+H);XH NMR (400 MHz, DMSO-ds): 8 9.59 (s, 2H), 9.28 (s, 2H), 8.04 (s, 1H), 7.64-7.62 (m, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.35 - 7.26 (m, 1H), 7.16 (s, 1H), 6.75-6.72 (m, 1H), 6.65 (d, J = 5.6 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.38 - 5.24 (m, 1H), 3.47 (s, 3H), 3.26 (s, 3H), 2.75 (s, 3H), 2.41 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H).

[0378] Example 91: (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(l-(2- methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)isoquinolin-l(2H)-oneStep 1: Preparation of 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one

[0379] A mixture of 4-iodo-lH-pyridazin-6-one (697 mg, 3.14 mmol), (2-methylpyrimidin-5- yl)boronic acid (1.3 g, 9.42 mmol), Cu(OAc)2(5.71 g, 31.4 mmol), and pyridine (2.49 g, 31.4 mmol) in dichloroethane (10 mL) was degassed and purged with O2three times. The mixture was then stirred at 60 °C for 12 hours under an O2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (eluted with PE:EA = 1:0 to 72:28) to afford 5-iodo-2-(2-methylpyrimidin-5- yl)pyridazin-3(2H)-one (1.3 g, 87% yield) as yellow solid. LCMS (ESP) m / z = 314.9 (M+H).Step 2: Preparation of (l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)boronic acid

[0380] A mixture of 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one (500 mg, 1.59 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (809 mg, 3.18 mmol), KOAc (469 mg, 4.78 mmol), and Pd(dppf)CI2(116 mg, 0.16 mmol) in dioxane (3 mL) was degassed and purged with N2three times. The mixture was then stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give (l-(2- methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)boronic acid (500 mg, crude yield) as a brown oil, which was used into the next step without further purification. LCMS (ES ) m / z = 233.0 (M+H), tR= 0.338 min (Method AJ).Step 3: Preparation of tert-butyl (R)-(l-(2,7-dimethyl-3-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6- dihydropyridazin-4-yl)-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate

[0381] A mixture of (l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)boronic acid (500 mg, 1.59 mmol), tert-butyl (R)-(l-(3-chloro-2,7-dimethyl-l-oxo-l,2-dihydroisoquinolin-5- yl)ethyl)carbamate (Intermediate 7, 447 mg, 1.27 mmol), mesylate[(di(l-adamantyl)-n- butylphosphine)-2-(2'-amino-l,l'- biphenyl)]palladium(ll) (cataCXium® A Pd G3) (116 mg, 0.16 mmol) and K2CO3(660 mg, 4.77 mmol) in dioxane (5 mL) and H2O (0.5 mL) was degassed and purged with N2three times. The mixture was then stirred at 100 °C for 0.5 h. The reaction was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with PE:EA = 1:0, then DCM:MeOH = 95:5) to afford tert-butyl (R)-(l-(2,7-dimethyl-3-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate (420 mg, 44% yield) as a yellow solid. LCMS (ES ) m / z = 503.3 (M+H).Step 4: Preparation of (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(l-(2-methylpyrimidin-5-yl)-6-oxo- l,6-dihydropyridazin-4-yl)isoquinolin-l(2H)-one hydrochloride

[0382] To a solution of tert-butyl (R)-(l-(2,7-dimethyl-3-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6- dihydropyridazin-4-yl)-l-oxo-l,2-dihydroisoquinolin-5-yl)ethyl)carbamate (400 mg, 0.80 mmol) in DCM (0.5 mL) was added a solution of HCI in dioxane (4 M, 4.0 mL, 16 mmol). The mixture was stirred at 25°C for 1 h and then concentrated under reduced pressure to give (R)-5-(l- aminoethyl)-2,7-dimethyl-3-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4- yl)isoquinolin-l(2H)-one hydrochloride (400 mg, crude yield) as a yellow solid that was used in the next step without further purification. LCMS (ESP) m / z = 403.2 (M+H).Step 5: Preparation of (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6-dihydropyridazin-4-yl)isoquinolin-l(2H)-one

[0383] A mixture of (R)-5-(l-aminoethyl)-2,7-dimethyl-3-(l-(2-methylpyrimidin-5-yl)-6-oxo-l,6- dihydropyridazin-4-yl)isoquinolin-l(2H)-one hydrochloride (200 mg, 0.46 mmol), l-bromo-4- fluoro-2-(trifluoromethyl)benzene (166 mg, 0.68 mmol), [l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-l-ium-l-yl)palladium (38 mg, 0.046 mmol) and Cs2CO3(742 mg, 2.28 mmol) in dioxane (2 mL) was degassed and purged with N2three times. The mixture was then stirred at 100 °C for 4 h. The reaction mixture was then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by prep-TLC (silica gel, eluted with PE:EA = 1:2) and then by prep-HPLC to give (R)-5- (l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(l-(2-methylpyrimidin-5-yl)- 6-oxo-l,6-dihydropyridazin-4-yl)isoquinolin-l(2H)-one (94 mg, 37% yield) as a yellow solid. LCMS (ESP) m / z = 565.3 (M+H);XH NMR (400 MHz, CDCI3): 6 9.13 (s, 2H), 8.23 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.24 - 7.17 (m, 2H), 6.92 - 6.85 (m, 1H), 6.83 (s, 1H), 6.21 - 6.19 (m, 1H), 5.02 - 4.87 (m, 1H), 4.60 (br d, J = 3.2 Hz, 1H), 3.61 (s, 3H), 2.85 (s, 3H), 2.47 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H).

[0384] Example 92: (R)-3-(5-(2,7-dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-l-oxo-l,2- dihydroisoquinolin-3-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxideStep 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine

[0385] A solution of 3-bromo-5-fluoro-2-methylpyridine (200 mg, 1.05 mmol) in dioxane (3 mL) was treated with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (401 mg, 1.58 mmol) at room temperature, followed by the addition of KOAc (155 mg, 1.58 mmol) and Pd(dppf)CI2*CH2CI2(86 mg, 0.11 mmol). The resulting mixture was stirred at100 °C for 0.5 h under a nitrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ES+) m / z = 238.1 (M+H).Step 2: Preparation of 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine

[0386] A solution 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 (3 mL) and H2O (0.6 mL) was treated with 5-bromo-2-iodopyrimidine (240 mg, 0.84 mmol) at room temperature followed by the addition of Pd(PPh3)4 (97 mg, 0.084 mmol) and Na2CO3(179 mg, 1.69 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was then filtered, and the filter cake was washed with EtOAc (2 x 10 mL). After further dilution with ethyl acetate, the filtrate was washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (eluted with EA) to afford 5-bromo-2-(5-fluoro-2- methylpyridin-3-yl)pyrimidine (100 mg, 46%) as an off-white solid. LCMS (ES ) m / z = 268.0 (M+H).Step 3: Preparation of 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide

[0387] A solution of 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine (110 mg, 0.41 mmol) in DCM (2 mL) was treated with m-CPBA (106 mg, 0.615 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by prep-TLC (eluted with EA) to afford 3-(5-bromopyrimidin-2-yl)-5-fluoro- 2-methylpyridine 1-oxide (50 mg, 43%) as an off-white solid. LCMS (ESP) m / z = 286.0 (M+H, bromine isotope).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

[0388] A solution of 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridin-l-ium-l-olate (200 mg, 0.704 mmol) in dioxane (3 mL) was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (268 mg, 1.06 mmol) at room temperature, followed by the addition of Pd(dppf)CI2(52 mg, 0.070 mmol) and KOAc (137 mg, 1.41 mmol). The resulting mixture was stirred at 100 °C for 1 h and then filtered. The filtrate was then concentrated under reduced pressure and the crude product was used in the next step directly without further purification. LCMS (ES ) m / z = 332.1 (M+H).Step 5: Preparation of (R)-3-(5-(2,7-dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)-l- oxo-1, 2-dihydroisoquinolin-3-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide

[0389] A solution of 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin- 2-yl)pyridine 1-oxide (300 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was treated with (R)-3-chloro- 2,7-dimethyl-5-(l-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinolin-l(2H)-one (Example 7, Step 1, 367 mg, 0.91 mmol), Na2CO3(192 mg, 1.81 mmol) and H2O (1.0 mL) at room temperature, followed by the addition of Pd(PPh3)4 (105 mg, 0.091 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with 1,4-dioxane (3 x 10 mL). The filtrate was then concentrated under reduced pressure. The residue was dissolved in EtOAc (60 mL), washed with brine (2 x 20mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford (R)-3-(5-(2,7-dimethyl-5-(l-((2- (methylsulfonyl)phenyl)amino)ethyl)-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrimidin-2-yl)-5-fluoro- 2-methylpyridine 1-oxide (11 mg, 2% yield) as an off-white solid. LCMS (ES ) m / z = 574.4 (M+H); XH NMR (400 MHz, DMSO-ds): 8 9.32 (s, 2H), 8.82-8.79 (m, 1H), 8.05 (s, 1H), 7.78-7.75 (m, 1H), 7.68-7.58 (m, 2H), 7.35-7.28 (m, 1H), 7.17 (s, 1H), 6.76-6.73 (m, 1H), 6.66 (d, J = 5.6 Hz, 1H), 6.48 (d, J = 8.5 Hz, 1H), 5.35-5.28 (m, 1H), 3.48 (s, 3H), 3.27 (s, 3H), 2.61 (s, 3H), 2.41 (s, 3H), 1.56 (d, J = 6.5 Hz, 3H).

[0390] Example 93: (R)-3-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-5-(l-((4- fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-oneStep 1: Preparation of (R)-3-chloro-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-one

[0391] To a stirred solution of (R)-5-(l-Aminoethyl)-3-chloro-2,7-dimethylisoquinolin-l(2H)-one (Intermediate 4, 1 g, 4.0 mmol) and 4-fluoro-l-iodo-2-(trifluoromethyl)benzene (1.73 g, 5.98 mmol) in 1,4-dioxane (10 mL) were added RuPhos (0.37 g, 0.80 mmol), Pd2(dba)3(0.37 g, 0.40mmol) and Cs2CO3(3.90 g, 12.0 mmol) at room temperature. The resulting mixture was then stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) at 0 °C and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by trituration with MeCN (30 mL) to afford (R)-3-chloro-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7- dimethylisoquinolin-l(2H)-one (460 mg, 55% yield) as a grey solid. LCMS (ES ) m / z = 413.1 (M+H).Step 2: Preparation of (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l(2H)-one

[0392] To a stirred solution of (R)-3-chloro-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)- 2,7-dimethylisoquinolin-l(2H)-one (400 mg, 0.97 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane in 1,4-dioxane (5 mL) were added Pd(dppf)CI2(71 mg, 0.097 mmol) and KOAc (285 mg, 2.91 mmol). The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was then filtered, the filter cake was washed with DCM (2 x 20 mL), and the filtrate was concentrated under reduced pressure to afford (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l(2H)-one (400 mg, crude yield) as a brown oil, which was used as is directly in the next step without further purification. LCMS (ESP) m / z = 505.2 (M+H).Step 3: Preparation of (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one

[0393] To a stirred solution of (R)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7- dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l(2H)-one (400 mg, 0.79 mmol) in dioxane (10 mL) and H2O (2 mL) was added 2-bromo-5-iodopyrimidine (226 mg, 0.79 mmol), Pd(PPh3)4 (92 mg, 0.079 mmol) and Na2CO3(252 mg, 2.38 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (eluted with PE:EA = 1:1) to afford (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((4-fluoro-2- (trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (190 mg, 35% yield) as a light-yellow solid. LCMS: (ES ) m / z = 535.1 (M+H).Step 4: Preparation of (R)-3-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one

[0394] To a stirred solution of (R)-3-(2-bromopyrimidin-5-yl)-5-(l-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (200 mg, 0.37 mmol) and l,3-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazin-2-one (Intermediate 14,140 mg, 0.56 mmol) in H2O (0.5 mL) and 1,4-dioxane (2 mL) were added Na2CO3(119 mg, 1.12 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) at room temperature. The resulting mixture was stirred at 90 °C for an additional 2 h under a nitrogen atmosphere. The reaction was then quenched by the addition of water (5 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep- HPLC to afford (R)-3-(2-(l,5-dimethyl-6-oxo-l,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-5-(l-((4- fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinolin-l(2H)-one (4.3 mg, 2% yield) as a light-yellow solid. LCMS (ES ) m / z = 579.3 (M+H);1H NMR (400 MHz, Methanol-d4): 8 9.20 (s, 2H), 8.15 (s, 1H), 7.82 (s, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.25-7.22 (m, 1H), 7.18 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.44-6.42 (m, 1H), 5.27-5.16 (m, 1H), 5.01 (s, 1H), 3.79 (s, 3H), 3.58 (s, 3H), 2.52 (s, 3H), 2.46 (s, 3H), 1.64 (d, J = 6.6 Hz, 3H).

[0395] Examples 20 to 84, 94 to 955, 964, 967, 986, 989, 1022, 1025, 1044 to 1060, 1062, 1068, 1071, and 1072 appear in Tables 1 and 2 below and were prepared in manners similar to that described above for Examples 1 to 19 and 85 to 93. If not specified otherwise, each depicted chiral center exists as a (R)- and (S)-racemic mixture or separately as the (R)- or (S)- enantiomer. Each compound appearing in Table 1 is identified by both a chemical structure and a name, but the chemical structure should be afforded more weight regarding the representation of the compound.Table 1. Examples 20 to 84 and 94 to 11709££92VTable 2. LCMS and NMR Spectra of Selected Examples from Table 1Assays and Compound Testing

[0396] In vitro cell proliferation: determination of EC50 values for inhibition of proliferation in T47D cells expressing mutant PI3Ka (H1047R) mutation and SKBR3 cells express WT PI3Ka.

[0397] T47D or SKBR3 cells were trypsinized, resuspended in culture media and seeded onto assay ready plates. T47D culture media consisted of RPMI, 10% FBS and Insulin (0.2 units / mL). SKBR3 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 370Celsius and 5% CO2. After 72 hours, cells were equilibrated at room temperature for 15 minutes. 30 uL of CellTiter-Glo reagent is added to the plate, which is then shaken for 30 minutes at temperature at 300-500 rpm. Cells are then read on an Envision plate reader. The percentage of inhibition of proliferation was calculated using the following formula: %l nhibition = 100 x (LumD- LumSamPie) / (LumD-Luminh), where D is obtained from cells treated with 0.1% DMSO only; Inh is obtained from cells treated with lOuM 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

[0398] For EC50 values shown in Table 2, "A" refers to 1 nM < EC50 < 500 nM; "B" refers to 500 nM< EC50 < 2 pM; "C" refers to 2 pM < EC50 < 15 pM; and "D" refers to an EC50 > 15 pM.Table 3. Cellular proliferation data

[0399] In vitro cell pAKT: determination of IC50 values for inhibition of phosphorylation of AKT (pAKT) in T47D cells expressing mutant PI3Ka (H1047R) mutation and SKBR3 cells express WT PI3Ka.

[0400] T47D or SKBR3 cells were trypsinized, resuspended in culture media and seeded onto assay ready plates. T47D culture media consisted of RPMI, 10% FBS and Insulin (0.2 units / mL). SKBR3 culture media consisted of McCoy's 5a and 10% FBS. Cells were seeded at a density of 5000 cells / well and dispensed in 12.5 p.L 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 is used to stamp plates at 12.5 nL of compound or DMSO. Cells were grown for 6 hours at 370Celsius and 5% CO2. After 6 hours, 4 p.L of Lysis buffer reagent was added to the plate, which was then centrifuged for 1 minute at 1000 rpm. Then the plate was incubated at room temperature for 30 minutes. After 30 minutes, 4 p.L of antibody mix containing Eu Cryptate, d2 Cryptate, and detection buffer, was added to the plate. The plate was centrifuged for 1 minute at 1000 rpm and then incubated overnight at room temperature. The plate was read on an Envision plate reader using the HTRF protocol. The percentage of inhibition of AKT phosphorylation was calculated using the following formula: %l nhibition = 100 x (pAKTHC - pAKTSample) / (pAKTHC -pAKTLC)), where pAKTHC is obtained from cells treated with 0.1% DMSO only; pAKTLC is obtained from cells treated with lOuM Alpelisib. 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)).Reagent table

[0401] For IC50 values shown in Table 3, "A" refers to 1 nM < IC50 < 500 nM; "B" refers to 500 nM <IC50 < 2 pM; "C" refers to 2 pM < IC50 < 15 pM; and "D" refers to an IC50 > 15 pM.Table 4. Cellular pAKT dataReferences

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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:Ri is selected fromeach A is independently C1-C4 alkyl, fluoroalkyl, C3-C7 cycloalkyl, N(Ra)2, (CH2)o-5-NRa-C(0)-C3-C7cycloalkyl, (CH2)I-5-0-(CH2)O-5-CI-C4 alkyl, (CH2)I-5-O-CI-C3cycloalkyl, (CH2)I-5-0-(CH2)O-5-CF3, (CH2)I- 5-O-(CH2)I-5-CI-C3fluoroalkyl, (CH2)o-s-aryl, (CH2)o-5-heteroaryl, (CH2)o-5-heterocyclyl, (CH2)o-s-NRa- (CH2)o-5-heteroaryl or (CH2)o-5-NRa-(CH2)i-5-N-heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, 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-C7cycloalkyl, (CH2)I-5-OH, (CH2)o-s-N(Ra)2, (CH2)i-5-NRa- C(O)-C3-C7cycloalkyl, (CHzJo-s-aryl, (CH2)o-5-heteroaryl, (CH2)o-5-heterocyclyl, (CH2)O-5-C(0)-(CH2)I-5- O-C1-C4 alkyl, (CH2)i-5-NRa-(CH2)o-5-heteroaryl or (CH2)i-5-NRa-(CH2)2-5-N-heterocyclyl, O-Ci-5-alkyl, O-Co-5-cycloalkyl, O-Co-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, C3-C7 cycloalkyl, C(O)Ci-C3alkyl, (CH2)i-5-fluoroalkyl, (CH2)I-5-OH, (CH2)I-5-NH2, (CH2)I.5-NH(CI.C4alkyl), (CH2)I.5-N(CI.C4alkyl)2or C(O)-(CH2)I-5-O-CI-C3alkyl, where the alkyl and cycloalkyl are substituted or unsubstituted, or alternatively, for -S(=O)(A)(=NRa) or for -S(=O)(A)(NRa), Raand A together with the attached atoms, may form a substituted or unsubstituted heterocyclyl ring;R2is H, Ci-C4alkyl, C3-C7 cycloalkyl, CF3, CFH2or CF2H, 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 Ci-C4alkyl;R4is H, Ci-C4alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H;Re is H, Ci-C4alkyl, C3-C7 cycloalkyl, heteroaromatic, CF3, CFH2or CF2H;R7is H, Ci-C4alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H; each Rs is independently H, Ci-C4alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2or CF2H; each of Xi, X2and X3is independently N, CH or substituted C;X4is CH or substituted C;Rs is halogen;wherein: each of Li, L2, L3, Lsand L7is independently (CHRH), (CHRn-O), (CHRH-S), (C3-C7 cycloalkyl), (CH2)I-4or a bond;U is C=O, C=S or a bond;L5is NR10, S, O or a bond;R9is H, C(=0)Ri2, C(=O)NRi2Ri3, NR12R13, C(=O)ORI2, Ci-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively when NR10 is present, R9and Rio together with the attached nitrogen atom may form a substituted or unsubstituted ring; each of Rio and Rn 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 Ri2and Ri3is independently H, Ci-C6alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively, Ri2and Ri3together with the attached nitrogen atom may form a substituted or unsubstituted ring;Ls is (CHR15), (CHR15-O), (CHR15-S), (CHRI5-NRI6), C=O, C=S or a bond;L9is C3-C7 cycloalkyl that is optionally part of a bridged, fused or spiro ring system, C(Ri5)=C(Ri5), C=C 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-C7 cycloalkyl), heterocyclyl, aryl, heteroaryl or a bond, where each of the C3-C7 cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and the C3-C7 cycloalkyl and / or heterocyclyl is optionally part of a bridged, fused or spiro ring system;R14 is H, CR15R16R17, OR17, SR17, NRi6Ri7, CI-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, each of Ri5and RiSis independently H or C1-C3 alkyl; and each R17 is independently H, Ci-C6alkyl, Ci-C6fluoroalkyl, Ci-C6aminoalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-C6alkyl, Ci-C6fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or alternatively, RiSand Ri7together with the attached nitrogen atom may form a substituted or unsubstituted ring, with the proviso that when R5iRi4, at least one of Lg, L9, Lio, Ln, Li2and Ri4is a carbon-containing moiety and R5is directly attached to the (isoquinolone) core structure by a carbon atom;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.

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 -( N RIO)-LI-L2-L3-L4-L5-L6-L7-R9, where Li to L7, R9 and Rio 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-LI-L2“L3-L4-L5-L6-I_7-R9,’ -S(O)-LI-L2“L3-L5-L6-I_7-R9,’ or -S(O)2“LI-L2“L3-L5-L6-I_7-R9, where Li to L7 and R9 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 Lgto L12 and Ri4are 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 Ri is selected fromwherein A and B are as defined in claim 1.

8. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Ri is selected fromwherein A, B and Raare as defined in claim 1.

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

10. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein X4is CH or CF.

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

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

13. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Xi is N, and X2and X3are independently CH or substituted C.

14. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein X2is N, and Xi and X3are independently CH or substituted C.

15. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein X3is N, and Xi and X3are independently CH or substituted C.

16. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Xi and X3are N, and X2is CH or substituted C.

17. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Xi and X2are N, and X3is CH or substituted C.

18. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein X2and X3are N, and Xi is CH or substituted C.

19. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein Xi, X2and X3are N.

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 Xi, X2and X3are independently CH or substituted C.

21. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3 or CH2F, R3is H and X4is N.

22. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and X4is CH or CF.

23. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and R5is24. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and R5is -O25. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and R5is -S-L26. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R2is CH3or CH2F, R3is H and R5is -(NRioJ27. The compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein X4is CH, R2is CH3or CH2F, R3is H and R5is28. 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:Xi, X2, X3, Ri and R5are defined as in 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.

29. The compound according to claim 28 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein each of Xi, X2and X3is independently CH or CF.

30. A pharmaceutical composition comprising the compound of any one of claims 1 to 29 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition according to claim 30, further comprising one or more anticancer agents.

32. The pharmaceutical composition according to claim 31, 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.

33. 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 29 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the disease is cancer.

35. The method of claim 33, 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).

36. The method of claim 33, wherein the disease is a cancer bearing a PI3Ka H1047R mutation.

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