Benzopyridinones and benzopyrimidinones as PI3K inhibitors

Abstract

General formula (1) TIFF2026528941000706.tif8965 [In the formula, R1~R8 and X1, X2, X3, and X4 are as defined.] Novel PI3K inhibitors are described, along with their manufacturing methods and use in the treatment of diseases associated with elevated or activated PI3K pathways.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under U.S. Provisional Application 63 / 532,175 filed on 11 / 2023 and U.S. Provisional Application 63 / 600,371 filed on 17 / November 2023, and incorporates the disclosures of these applications as a whole for all purposes herein. [Background technology]

[0002] Background of the Invention Phosphatidylinositol lipids (PIs) and their various phosphorylated variants are secondary messengers involved in diverse cellular vesicular transport and signaling processes. Phosphoinositide 3' kinases (PI3Ks) are a family of enzymes responsible for phosphorylation of the 3' hydroxyl position of the inositol ring of PIs. PI3Ks are subdivided into three classes depending on their structure and substrate. Class II PI3Ks (PI3K-C2α, PI3K-C2β, PI3K-C2γ) and Class III PI3Ks (vps34) are monomeric enzymes primarily associated with endocytosis and autophagy (Posor et al., Biochim Biophys Acta 2015, 1851, 794; Backer, Biochem J. 2016, 473, 2251). Class I PI3K is a heterodimer consisting of a catalytic kinase subunit (p110α, β, γ, δ) and one number-regulating subunit that determines its binding partner and intracellular localization. Class I PI3K is activated by interaction with receptor tyrosine kinases (RTKs), Ras-related GTPases, G protein-coupled receptors, and / or associated adapter proteins, and in its active form, it converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidyl 3,4,5-trisphosphate (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 pathway is associated with several proliferation-related roles and pathologies, including glucose regulation, cell survival, angiogenesis, and proliferation (Porta et al., Front Oncol. 2014, 4, 1), highlighting the role of class I PI3K as a key upstream regulator of these functions.

[0004] Class I PI3K is further subdivided into four isoforms (α, β, γ, and δ) based on the identity of catalytic (p110α, p110β, p110γ, or p110δ) and regulatory (p85α or its various splice variants, p85β, p55γ, or p101) subunits, which play different roles in cell physiology (Vanhaesebroeck et al., J Mol Med (Berl). 2016, 94, 5). PI3Kγ and PI3Kδ are expressed in most leukocytes and play important roles in pro-inflammatory pathways (Hawkins et. al., Biochimica et Biophysica Acta 2015, 1851, 882; Okkenhaug et al., Science 2002, 297, 1031; Ali et al., Nature 2004, 431, 1007). PI3Kα and PI3Kβ are expressed more eccentrically and share similar but not identical roles. For example, PI3Kα plays a non-redundant role in angiogenesis (Soler et al., J Exp Med. 2013, 210, 1937), while PI3Kβ is known to play a specific role 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 cancer. The PI3K pathway is hyperactivated through a variety of mechanisms, including activating mutations in PI3K isoforms, upregulation 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 encoding PI3Kα or mutations leading to upregulation of PI3Kα have been found to occur in many on-human cancers, including lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers (Goncalves et al., N Eng J Med. 2018, 379, 2052). In particular, PIK3CA, the gene encoding the p110α subunit of PI3Kα, is frequently mutated or amplified in a variety of tumor types. Missense mutations occur in all domains of p110α, but cluster in two 'hotspots', most commonly E542K and E545K in the helical domain and H1047R in the kinase domain. Helical domain mutations reduce p85-mediated inhibition of p110α or promote direct interaction between p110α and insulin receptor substrate 1 (IRS1)37, while kinase domain mutations enhance the interaction between p110α and lipid membranes, simultaneously upregulating signaling events. (Thorpe et al., Nat Rev Cancer 2015, 15, 7).

[0006] The development of PI3K pathway inhibitors is challenging because it is impossible to achieve doses sufficient to suppress tumors without adverse events. To date, PI3K inhibitors in clinical use (alpelisib, buparlisib, copanlisib, duvelisib, idelalisib, pictilisib, taselicib, and others) have caused dose-dependent adverse events such as hyperglycemia, rash, fatigue, and diarrhea, which are known on-target toxicities (Jiang et al., Mol Biol Rep. 2020, 47, 4587). Hyperglycemia is a result of the body's inability to produce or utilize enough insulin. The pancreas controls insulin release in response to changes in blood glucose levels, leading to glucose uptake by muscle and adipocytes when insulin levels are high, or gluconeogenesis by the liver when insulin levels are low. The tissue cell response to insulin requires PI3K signaling via the eccentrically expressed p110α subunit. As a result, targeted pan-PI3K inhibition interferes with tissue glucose metabolism, leading to insulin resistance (Hopkins et al., Nature 2018, 560, 499). To mitigate adverse events, selective PI3K isoform inhibitors have been developed. The severity of adverse events depends on the selective isoform; for example, PI3Kα inhibitors are associated with hyperglycemia and rash due to the role of the p110α subunit in the insulin response (Rugo et al., The Breast 2022, 61, 156). Similarly, the use of a selective PI3Kδ inhibitor (idelalisib) when the p110δ subunit is highly expressed in immune cells causes severe diarrhea and colitis. Inhibition with a dual inhibitor (taselicib), a potent PI3Kδ inhibitor with mild PI3Kα inhibition, results in gastrointestinal (GI) side effects, while no GI-related adverse events have been reported with a highly selective and potent PI3Kδ inhibitor (umbralicib) (Gadkar et al., CPT Pharmacometrics Syst Pharmacol. 2021, 11, 616). Such improvement in adverse events with highly isoform-selective and potent inhibitors demonstrates that toxicity mitigation strategies through the development of mutant-selective isoform inhibitors are promising for reducing toxicity severity.Furthermore, the selective inhibition of mutant PI3Kα isoforms beyond the wild type has minimal impact on PI3K signaling in healthy cells that only possess wild-type PI3Kα, can suppress cancer signaling, and can lead to a reduction in the toxicity associated with non-selective PI3K inhibition (Castel et al., Nat Cancer 2021 2, 587). Summary of the Invention Problems to be Solved by the Invention

[0007] Currently, there is interest in PI3K inhibitors for cancer treatment (WO2023 / 081209, WO2023 / 078401, WO2023 / 060262, WO2023 / 056407, WO2021 / 202964). However, there is a continuing need for novel, potent, and selective PI3K inhibitors as monotherapies or in combination therapies in cancer treatment. Means for Solving the Problems

[0008] Summary of the Invention One aspect of the present invention relates to formula (1) [Chemical Formula] [wherein: R1 is [Chemical Formula] selected from; each A is independently C1-C4 alkyl, fluoroalkyl, C3-C7 cycloalkyl, N(R a )2, (CH2) 0-5 -NR a -C(O)-C3-C7 cycloalkyl, (CH2) 1-5 -O-(CH2) 0-5 -C1-C4 alkyl, (CH2) 1-5 -O-C1-C3 cycloalkyl, (CH2) 1-5 -O-(CH2) 0-5 -CF3, (CH2) 1-5 -O-(CH2) 1-5-C1-C3 fluoroalkyl, (CH2) 0-5 -Aaryl, (CH2) 0-5 - Heteroaryl, (CH2) 0-5 - Heterocyclyl, (CH2) 0-5 -NR a -(CH2) 0-5 - Heteroaryl or (CH2) 0-5 -NR a -(CH2) 1-5 -N-heterocyclyl, where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl may be substituted or unsubstituted, or A and A may form a substituted or unsubstituted heterocyclyl ring together with the bonded -P(=O)- moiety; Each B is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, (CH2) 1-5 -OH, (CH2) 0-5 -N(R a )2, (CH2) 1-5 -NR a -C(O)-C3-C7 cycloalkyl, (CH2) 0-5 -Aaryl, (CH2) 0-5 - Heteroaryl, (CH2) 0-5 - Heterocyclyl, (CH2) 0-5 -C(O)-(CH2) 1-5 -O-C1-C4 alkyl, (CH2) 1-5 -NR a -(CH2) 0-5 - Heteroaryl or (CH2) 1-5 -NR a -(CH2) 2-5 -N-heterocyclyl, OC 1-5 -alkyl, OC 0-5 -Cycloalkyl, OC 0-5 -A heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are substituted or unsubstituted, or B and B may form a substituted or unsubstituted heterocyclyl ring with the -[O or NH]-P(=O)-O- moiety, or A and B may form a substituted or unsubstituted heterocyclyl ring with the -P(=O)-O- moiety; Each R a These are independently H, C1-C4 alkyl, C3-C7 cycloalkyl, C(O)C1-C3 alkyl, and (CH2) 1-5 -Fluoroalkyl, (CH2) 1-5 -OH, (CH2) 1-5 -NH2, (CH2) 1-5 -NH(C 1- C4 alkyl), (CH2) 1-5 -N(C 1- C4 alkyl)2 or C(O)-(CH2) 1-5 -O-C1-C3 alkyl, where alkyl and cycloalkyl are substituted or unsubstituted, or -S(=O)(A)(=NR a ) or -S(=O)(A)(NR a Regarding R a A may form a substituted or unsubstituted heterocyclyl ring with the atom it bonds to; R2 is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF3, CFH2, or CF2H, and when R2 is not H, the carbon atom bonded to R2 is a chiral center and exists as a (R)- and (S)-racemic mixture or (R)- or (S)-enantiomer; R3 is H or C1-C4 alkyl; R4 is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2, or CF2H; R6 is H, C1-C4 alkyl, C3-C7 cycloalkyl, heteroaromatic, CF3, CFH2, or CF2H; R7 is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2, or CF2H; Each R8 is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, CFH2, or CF2H; Each of X1, X2, X3, and X4 is independently N, CH, or substituted C; R5 is halogen; -O-L1-L2-L3-L4-L5-L6-L7-R9; -S-L1-L2-L3-L4-L5-L6-L7-R9; -S(O)-L1-L2-L3-L5-L6-L7-R9; -S(O)2-L1-L2-L3-L5-L6-L7-R9; -(NR 10 )-L1-L2-L3-L4-L5-L6-L7-R9; or -L8-L9-L 10 -L 11 -L 12 -R 14 And here: L1, L2, L3, L6, and L7 are each independent of (CHR 11 ), (CHR 11 -O), (CHR 11 -S), (C3-C7 cycloalkyl), (CH2) 1-4 or combination; L4 is C=O, C=S, or a bond; L5 is NR 10 , S, O or bond; R9 is H, C(=O)R 12 , C(=O)NR 12 R 13 , NR 12 R 13 , C(=O)OR 12 , C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or NR 10 When R9 and R 10 It may form a substituted or unsubstituted ring with the bonded nitrogen atom. The compound or its solvates, enantiomers, diastereomers, tautomers, polymorphs or isotope-labeled compounds, or pharmaceutically acceptable salts thereof. In exemplary embodiments, the ring is a 4- to 7-membered substituted or unsubstituted non-aromatic heterocyclic ring containing 0, 1 or 2 heteroatoms which may be N, O, S or Si (in addition to the nitrogen atom), provided that if the ring size is 4 or 5, the number of further heteroatoms is 0 or 1, and if the ring size is 6- to 7, the number of further heteroatoms is 0, 1 or 2, and if the ring is substituted, the substituents are CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxetane ring, or COR a (Here, R a is C1-C4 alkyl, O-C1-C4 alkyl, or NR b R c And here, R b and R c It contains, but is not limited to, one or more (which are independently H or C1-C4 alkyl groups); R 10 and R 11 Each of them is independently H or a C1-C4 alkyl group (e.g., CH3, CH2CH3, or CH(CH3)2), where the C1-C4 alkyl group is either unsubstituted or substituted; R 12 and R 13 Each of them is independently H, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted; or R 12 and R 13may form a substituted or unsubstituted ring together with the nitrogen atom to be bonded. In an exemplary embodiment, the ring is a 4- to 7-membered substituted or unsubstituted non-aromatic heterocyclic ring containing 0, 1 or 2 heteroatoms which may be N, O, S or Si (in addition to the nitrogen atom), provided that if the ring size is 4 or 5, the number of additional heteroatoms is 0 or 1, if the ring size is 6-7, the number of additional heteroatoms is 0, 1 or 2, and if the ring is substituted, the substituents are CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxetane ring, or COR a (where R a is C1-C4 alkyl, O-C1-C4 alkyl, or NR b R c and where R b and R c are independently H or C1-C4 alkyl), including but not limited to one or more of these; L8 is (CHR 15 ), (CHR 15 -O), (CHR 15 -S), (CHR 15 -NR 16 ), C=O, C=S or a bond; L9 is C3-C7 cycloalkyl, C(R 15 )=C(R 15 ), C≡C or a bond, optionally being part of a bridged, fused or spiro ring system; L 10 are independently (CHR 15 ), O, S, (NCR 15 ), N(C=O) or a bond; L 11 is (CHR 15 ), C=O, C=S or a bond; L 12 is H, (C3-C7 cycloalkyl), heterocyclyl, aryl, heteroaryl or a bond, where each of C3-C7 cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and C3-C7 cycloalkyl and / or heterocyclyl are optionally part of a bridged, fused or spiro ring system; R 14 H, CR 15 R 16 R 17 , OR 17 , SR 17 , NR 16 R 17 , C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted. R 15 and R 16 Each of them is independently H or C1-C3 alkyl; and Each R 17 R is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted; or R 16 and R 17 The substituents may form a substituted or unsubstituted ring with the bonded nitrogen atom. In exemplary embodiments, the ring is a 4- to 7-membered substituted or unsubstituted non-aromatic heterocyclic ring containing 0, 1 or 2 heteroatoms which may be N, O or S (in addition to the nitrogen atom), provided that if the ring size is 4 or 5, the number of further heteroatoms is 0 or 1, and if the ring size is 6- to 7, the number of further heteroatoms is 0, 1 or 2, and if the ring is substituted, the substituents may be Me, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxetane ring, or COR a (Here, R a is C1-C4 alkyl, O-C1-C4 alkyl, or NR b R c And here, R b and R c It contains, but is not limited to, one or more (which are independently H or C1-C4 alkyl groups); However, R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 When that is the case, L8, L9, L 10 , L 11 , L 12 and R 14 At least one of the atoms is a carbon-containing moiety, and R5 is directly bonded to the core structure by a carbon atom (benzopyridinone or benzopyrimidinone); Alternatively, R5 is a non-aromatic N-bonded heterocyclic ring. [ka] Herein, the heterocyclic ring is substituted or unsubstituted and optionally comprises further ring atoms selected from N, O, Si, and S, and optionally is bridging, condensed, or part of a spirocyclic system. In specific embodiments, the N-bonded heterocyclyl ring is 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-azadamantane.

[0009] In an exemplary embodiment, R5 is -(NR 10 )-L1-L2-L3-L4-L5-L6-L7-R9, where L1~L7, R9 and R 10 It is defined as follows.

[0010] In an exemplary embodiment, R5 is -O-L1-L2-L3-L4-L5-L6-L7-R9, where L1~L7 and R9 are as defined herein.

[0011] In exemplary embodiments, R5 is -S-L1-L2-L3-L4-L5-L6-L7-R9;-S(O)-L1-L2-L3-L5-L6-L7-R9; or -S(O)2-L1-L2-L3-L5-L6-L7-R9, where L1-L7 and R9 are as defined herein.

[0012] In exemplary embodiments, R9 is a 6-membered aryl ring; or a 5-6 membered heteroaryl ring containing 1-3 nitrogen atoms; or a non-aromatic 3-7 membered carbocyclic ring; or a non-aromatic 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, S, and Si (where the number of heteroatoms is 1 or 2 if the ring size is 4 or 5, and 1, 2, or 3 if the ring size is 6 or 7); or a C1-C6 alkyl group, where the aryl ring, heteroaryl ring, carbocyclic ring, heterocyclic ring, and C1-C6 alkyl group are unsubstituted or CH3, F, Cl, CF3, CF2H, CH2F, OCH3, -CH2CF3, cyclopropyl, -CN, N(CH3)2, oxetane ring, optionally phenyl or phenoxy groups substituted with 1-3 halogens (F, Cl, or Br) or CH3 groups, or COR a (Here, R a C1-C4 alkyl, O-C1-C4 alkyl or NR b R c And here, R b and R c It is independently substituted with one or more H or C1-C4 alkyl groups.

[0013] In an exemplary embodiment of R5, L8, L 10 and L 11 Each of these is a bond, while L9 is not a bond.

[0014] In an exemplary embodiment of R5, L8, L 10 and L 11 Each of these is a bond, and L9 is a cycloalkyl that is optionally crosslinked, condensed, or part of a spirocycle system.

[0015] In an exemplary embodiment of R5, L8, L 10 and L 11 Each of these is a bond, and L9 is a cycloalkyl group that is part of a cross-linking ring system.

[0016] In an exemplary embodiment of R5, L8, L10 and L 11 Each of these is a bond, and L9 is a cycloalkyl group that is part of a fused ring system.

[0017] In an exemplary embodiment of R5, L8, L 10 and L 11 Each of these is a bond, and L9 is a cycloalkyl group that is part of a spirocycle system.

[0018] In an exemplary embodiment of R5, L8, L 10 and L 11 Each of these is a bond, and L9 is C(R 15 )=C(R 15 )

[0019] In an exemplary embodiment of R5, L8, L 10 and L 11 Each of these is a bond, and L9 is C≡C.

[0020] In the exemplary embodiment of R5, L8, L9, L 10 and L 11 Each of them is a combination, L 12 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted.

[0021] In the exemplary embodiment of R5, L8, L9, L 10 and L 11 Each of them is a combination, L 12 R is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted. 14 H is H.

[0022] In the exemplary embodiment of R5, L8, L9, L 10 and L 11 Each of them is a combination, L 12R is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted. 14 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, where each of the C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is either unsubstituted or substituted.

[0023] In the exemplary embodiment of R5, L8, L9, L 10 and L 11 Each of them is a combination, L 12 R is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted. 14 -CR 14 R 15 R 16 That is the case.

[0024] In the exemplary embodiment of R5, L8, L9, L 10 and L 11 Each of them is a combination, L 12 R is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted. 14 は-OR 16 OR 17 That is the case.

[0025] In the exemplary embodiment of R5, L8, L9, L 10 and L 11 Each of them is a combination, L 12 R is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted. 14 Ha-SR 17 That is the case.

[0026] In the exemplary embodiment of R5, L8, L9, L 10 and L 11 Each of them is a combination, L 12 R is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted. 14 -NR 16 R 17 That is the case.

[0027] In this exemplary embodiment, R5 is [ka] And here, R d is H or CH3, and R e is a six-membered aromatic or heteroaromatic ring containing CH3, C3-C6 cycloalkyl, 0, 1 or 2 nitrogen atoms, and optionally substituted with CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CN or N(CH3)2, or R d and R e It may form a 4-7 membered non-aromatic heteroring with 1-2 heteroatoms that may be N or O together with the bonded nitrogen atom, provided that if the ring size is 4 or 5, the number of heteroatoms is 1, and if the ring size is 6-7, the number of heteroatoms is 1 or 2, where the ring is unsubstituted or CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxetane ring, or COR a (Here, R a is C1-C4 alkyl, O-C1-C4 alkyl, or NR b R c And here, R b and R c The substituents are substituted with one or more substituents (which are independently H or C1-C4 alkyl groups), but are not limited to these.

[0028] In this exemplary embodiment, R5 is an N-bonded non-aromatic heterocyclyl ring. [ka] Herein, the heterocyclyl ring is substituted or unsubstituted and optionally comprises one or more further atoms selected from N, O, Si, and S, and optionally is bridging, condensed, or part of a spiro-ring system. In specific embodiments, the N-bonded heterocyclyl ring is azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1,3,8-triazaspiro[4.5]-decan-4-one, or 1,4-dioxa-7-azaspiro[4.4]nonane.

[0029] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted and optionally contains one or more further atoms selected from N, O, Si, and S, and is not bridging, condensed, or part of a spiro-ring system.

[0030] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted and optionally contains one or more further atoms selected from N, O, Si, and S, and is bridging, condensed, or part of a spiro-ring system.

[0031] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted and does not contain further atoms selected from N, O, Si, and S, and is not bridging, condensed, or part of a spiro-ring system.

[0032] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted, does not contain further atoms selected from N, O, Si, and S, and is part of a bridging, condensed, or spiro-ring system.

[0033] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is not bridging, condensed, or part of a spiro-ring system.

[0034] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is bridging, condensed, or part of a spiro-ring system.

[0035] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is not bridging, condensed, or part of a spiro ring system.

[0036] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is bridging, condensed, or part of a spiro ring system.

[0037] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted and contains at least one further nitrogen ring atom and is not bridging, condensed, or part of a spiro-ring system.

[0038] In exemplary embodiments, the N-bonded non-aromatic heterocyclyl ring is substituted or unsubstituted and contains at least one further nitrogen ring atom and is bridging, condensed, or part of a spiro-ring system.

[0039] In exemplary embodiments of the compound of formula (1), R1 is [ka] Selected from, where A and B are as defined.

[0040] In exemplary embodiments of the compound of formula (1), R1 is [ka] Selected from, where A, B and R a It is defined as follows.

[0041] In exemplary embodiments of the compound of formula (1), R1 is [ka] Selected from, where B is defined as follows.

[0042] In exemplary embodiments of the compound of formula (1), R2 is CH3.

[0043] In exemplary embodiments of the compound of formula (1), R2 is CH2F.

[0044] In exemplary embodiments of the compound of formula (1), R3 is H.

[0045] In exemplary embodiments of the compound of formula (1), R4 is H or F.

[0046] In an exemplary embodiment, X1 is N, and X2 and X3 are independently CH or CF.

[0047] In an exemplary embodiment, X2 is N, and X1 and X3 are independently CH or CF.

[0048] In an exemplary embodiment, X3 is N, and X1 and X3 are independently CH or CF.

[0049] In this exemplary embodiment, X1 and X3 are N, and X2 is CH or CF.

[0050] In an exemplary embodiment, X1 and X2 are N, and X3 is CH or CF.

[0051] In an exemplary embodiment, X2 and X3 are N, and X1 is CH or CF.

[0052] In an exemplary embodiment, X1, X2, and X3 are N.

[0053] In exemplary embodiments, X1, X2, and X3 are independently CH or CF.

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

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

[0056] In an exemplary embodiment, X1 is N, X2 and X3 are independently CH or CF, and X4 is N.

[0057] In an exemplary embodiment, X2 is N, X1 and X3 are independently CH or CF, and X4 is N.

[0058] In an exemplary embodiment, X3 is N, X1 and X3 are independently CH or CF, and X4 is N.

[0059] In an exemplary embodiment, X1 and X3 are N, X2 is CH or CF, and X4 is N.

[0060] In an exemplary embodiment, X1 and X2 are N, X3 is CH or CF, and X4 is N.

[0061] In an exemplary embodiment, X2 and X3 are N, X1 is CH or CF, and X4 is N.

[0062] In this exemplary embodiment, X1, X2, and X3 are N, and X4 is N.

[0063] In this exemplary embodiment, X1, X2, and X3 are independently CH or CF, and X4 is N.

[0064] In an exemplary embodiment, X1 is N, X2 and X3 are independently CH or CF, and X4 is CH or CF.

[0065] In an exemplary embodiment, X2 is N, X1 and X3 are independently CH or CF, and X4 is CH or CF.

[0066] In an exemplary embodiment, X3 is N, X1 and X3 are independently CH or CF, and X4 is CH or CF.

[0067] In an exemplary embodiment, X1 and X3 are N, X2 is CH or CF, and X4 is CH or CF.

[0068] In an exemplary embodiment, X1 and X2 are N, X3 is CH or CF, and X4 is CH or CF.

[0069] In an exemplary embodiment, X2 and X3 are N, X1 is CH or CF, and X4 is CH or CF.

[0070] In an exemplary embodiment, X1, X2 and X3 are N, and X4 is CH or CF.

[0071] In an exemplary embodiment, X1, X2 and X3 are independently CH or CF, and X4 is CH or CF.

[0072] In an exemplary embodiment of the compound of formula (1), R5 is -O-L1-L2-L3-L4-L5-L6-L7-R9.

[0073] In an exemplary embodiment of the compound of formula (1), R5 is -S-L1-L2-L3-L4-L5-L6-L7-R9.

[0074] In an exemplary embodiment of the compound of formula (1), R5 is -S(O)-L1-L2-L3-L5-L6-L7-R9.

[0075] In an exemplary embodiment of the compound of formula (1), R5 is -S(O)2-L1-L2-L3-L5-L6-L7-R9.

[0076] In an exemplary embodiment of the compound of formula (1), R5 is -(NR 10 )-L1-L2-L3-L4-L5-L6-L7-R9.

[0077] In an exemplary embodiment of the compound of formula (1), R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 is.

[0078] In an exemplary embodiment of the compound of formula (1), R6 is CH3.

[0079] In an exemplary embodiment of the compound of formula (1), R7 is CH3.

[0080] In an exemplary embodiment of the compound of formula (1), each R8 is independently H or F.

[0081] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, and R1 is

Chemical formula

[0082] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, and R1 is

Chemical formula

[0083] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, and R1 is

Chemical formula

[0084] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, and R1 is [Chemical formula] selected from, where A and B are as defined, and R5 is an N - bonded heterocyclic 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), R2 is CH3 or CH2F, R3 is H, and R1 is [Chemical formula] selected from, where A, B and R a are as defined, and R5 is an N - bonded heterocyclic 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), R2 is CH3 or CH2F, R3 is H, and R1 is [Chemical formula] selected from, where B is as defined, and R5 is an N - bonded heterocyclic 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), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is [Chemical formula] selected from, where A and B are as defined.

[0088] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is [ka] Selected from, where A, B and R a It is defined as follows.

[0089] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is [ka] Selected from, where B is defined as follows.

[0090] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is [ka] R5 is selected from, where A and B are as defined, and R5 is an N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is either unsubstituted or substituted.

[0091] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is [ka] Selected from, where A, B and R a As defined, R5 is an N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, and piperidine, where each of these rings is either unsubstituted or substituted.

[0092] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is [ka] R5 is selected from, where B is as defined, and R5 is an N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is either unsubstituted or substituted.

[0093] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is [ka] Selected from, where A and B are as defined.

[0094] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is [ka] Selected from, where A, B and R a It is defined as follows.

[0095] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is [ka] Selected from, where B is defined as follows.

[0096] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is [ka] R5 is selected from, where A and B are as defined, and R5 is an N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is either unsubstituted or substituted.

[0097] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is [ka] Selected from, where A, B and R a As defined, R5 is an N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, and piperidine, where each of these rings is either unsubstituted or substituted.

[0098] In exemplary embodiments of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is [ka] R5 is selected from, where B is as defined, and R5 is an N-linked heterocyclyl ring selected from azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine and piperidine, where each of these rings is either unsubstituted or substituted.

[0099] In an exemplary embodiment, the compound of formula (1) is of formula (2) [ka] [During the ceremony: X1, X2, X3, R1 and R5 are defined as in the compound of formula (1), and The carbon atoms marked with an asterisk (*) are chiral centers and exist as (R)- and (S)-racemic mixtures or (R)- or (S)-enantiomers. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

[0100] In an exemplary embodiment, the compound of formula (1) is of formula (3) [ka] [During the ceremony: X1, X2, X3, R1 and R5 are defined as in the compound of formula (1), and The carbon atoms marked with an asterisk (*) are chiral centers and exist as (R)- and (S)-racemic mixtures or (R)- or (S)-enantiomers. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

[0101] In exemplary embodiments of the compound of formula (2) or formula (3), R1 is [ka] Selected from, where A and B are as defined in the compound of formula (1).

[0102] In exemplary embodiments of the compound of formula (2) or formula (3), R1 is [ka] Selected from, where A, B and R a This is defined as in the compound of formula (1).

[0103] In exemplary embodiments of the compound of formula (2) or formula (3), R1 is [ka] Selected from, where B is defined as in the compound of formula (1).

[0104] In exemplary embodiments of the compounds of formula (2) or formula (3), R5 is -O-L1-L2-L3-L4-L5-L6-L7-R9, where -O-L1-L2-L3-L4-L5-L6-L7-R9 is as defined in the compounds of formula (1).

[0105] In exemplary embodiments of the compounds of formula (2) or formula (3), R5 is -S-L1-L2-L3-L4-L5-L6-L7-R9, where -S-L1-L2-L3-L4-L5-L6-L7-R9 is as defined in the compounds of formula (1).

[0106] In exemplary embodiments of the compound of formula (2) or formula (3), R5 is -(NR 10 )-L1-L2-L3-L4-L5-L6-L7-R9, where -(NR 10 )-L1-L2-L3-L4-L5-L6-L7-R9 are defined in the compound of formula (1).

[0107] In exemplary embodiments of the compound of formula (2) or formula (3), R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 And here, -L8-L9-L 10 -L 11 -L 12 -R 14 This is defined as in the compound of formula (1).

[0108] In exemplary embodiments of the compound of formula (2) or formula (3), R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 And here, L8, L9, L 10 and L 11 L is a combination; 12is a (C3-C7 cycloalkyl), heterocyclyl, or heteroaryl, where each of the (C3-C7 cycloalkyl), heterocyclyl, or heteroaryl is substituted or unsubstituted; and R 14 is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is either unsubstituted or substituted.

[0109] In exemplary embodiments of the compound of formula (2) or formula (3), R1 is [ka] Selected from, where B is as defined in the compound of formula (1); R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 And here, L8, L9, L 10 and L 11 L is a combination; 12 is a (C3-C7 cycloalkyl), heterocyclyl, or heteroaryl, where each of the (C3-C7 cycloalkyl), heterocyclyl, or heteroaryl is substituted or unsubstituted; and R 14 is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is either unsubstituted or substituted.

[0110] In exemplary embodiments of the compound of formula (2) or formula (3), R1 is [ka] Selected from, where B is as defined in the compound of formula (1); R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 And here, L8, L9, L 10 and L 11 L is a combination; 12R is a (C3-C7 cycloalkyl), heterocyclyl, or heteroaryl, where each of the (C3-C7 cycloalkyl), heterocyclyl, or heteroaryl is substituted or unsubstituted; R 14 X1 is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is either unsubstituted or substituted; and one of X1 or X2 is N.

[0111] In exemplary embodiments of the compound of formula (2) or formula (3), R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 And here, L8, L9, L 10 and L 11 L is a combination; 12 R is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is substituted or unsubstituted; and R 14 is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is either unsubstituted or substituted.

[0112] In exemplary embodiments of the compound of formula (2) or formula (3), R1 is [ka] Selected from, where B is as defined in the compound of formula (1); R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 And here, L8, L9, L 10 and L 11 L is a combination; 12 R is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is substituted or unsubstituted; and R 14 is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is either unsubstituted or substituted.

[0113] In exemplary embodiments of the compound of formula (2) or formula (3), R1 is [ka] Selected from, where B is as defined in the compound of formula (1); R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 And here, L8, L9, L 10 and L 11 L is a combination; 12 R is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is substituted or unsubstituted; 14 X1 is a heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is either unsubstituted or substituted; and one of X1 or X2 is N.

[0114] In exemplary embodiments of the compounds of formula (2) or formula (3), R5 is an N-bonded non-aromatic heterocyclyl ring. [ka] And here, [ka] This is defined as in the compound of formula (1).

[0115] In exemplary embodiments of the compound of formula (2) or formula (3), X1 is N, and X2 and X3 are independently CH or CF.

[0116] In exemplary embodiments of the compound of formula (2) or formula (3), X2 is N, and X1 and X3 are independently CH or CF.

[0117] In exemplary embodiments of the compound of formula (2) or formula (3), X3 is N, and X1 and X3 are independently CH or CF.

[0118] In exemplary embodiments of the compound of formula (2) or formula (3), X1 and X3 are N, and X2 is CH or CF.

[0119] In exemplary embodiments of the compound of formula (2) or formula (3), X1 and X2 are N, and X3 is CH or CF.

[0120] In exemplary embodiments of the compound of formula (2) or formula (3), X2 and X3 are N, and X1 is CH or CF.

[0121] In exemplary embodiments of the compound of formula (2) or formula (3), X1, X2, and X3 are N.

[0122] In exemplary embodiments of the compound of formula (2) or formula (3), X1, X2, and X3 are independently CH or CF.

[0123] A certain aspect of the present invention is a pharmaceutical composition comprising any of the compounds of the present invention described herein (e.g., any of formulas (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 exemplary embodiments, a pharmaceutical composition comprising any of the compounds of the present invention described herein (e.g., any of formulas (1), (2), or (3)) or its solvates, enantiomers, diastereomers, tautomers, polymorphs, or isotope-labeled compounds, or pharmaceutically acceptable salts thereof, further comprises one or more anticancer agents.

[0125] Another aspect of the present invention is a method for treating a disease involving PI3K activity in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of any of the compounds of the present invention described herein (e.g., any of formulas (1), (2), or (3)) or its solvates, enantiomers, diastereomers, tautomers, polymorphs or isotope-labeled compounds, or pharmaceutically acceptable salts thereof.

[0126] In an exemplary embodiment, the disease being treated is cancer. In a specific embodiment, the disease is cancer carrying the PI3Kα H1047 mutation (e.g., H1047R). [Modes for carrying out the invention]

[0127] Detailed description of the invention As used herein, “at risk” refers to a medical condition or set of medical conditions exhibited by a patient that could make the patient more susceptible to a particular disease or suffering. For example, these conditions may result from influences including, but not limited to, behavioral, emotional, chemical, biochemical, or environmental influences.

[0128] The term "effective dose" as used herein refers to a pharmaceutical composition containing a specific amount of a therapeutic agent that achieves a clinically beneficial outcome (i.e., symptom relief). The toxicity and therapeutic efficacy of such a composition are, for example, measured in LD50. 50 (50% lethal dose in the population) and ED 50 The therapeutically effective dose (50% of the population) can be determined by standard drug procedures in cell cultures or experimental animals. The dose ratio between toxicity and therapeutic effect is the therapeutic index, or ratio LD50. 50 / ED 50 It can be expressed as follows. Compounds with a large therapeutic index are preferred. Data obtained from these cell culture assays and further animal studies can be used to calculate the dosage range for human use. The dosage of such compounds is preferably one with little or no toxicity. 50 It is within the circulating concentration range, including [the specified dose]. The dosage will vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0129] As used herein, the term “symptom” refers to any subjective or objective evidence of a disease or physical abnormality observed by a patient. For example, subjective evidence is usually based on the patient’s self-report and may include, but is not limited to, pain, headache, vision impairment, nausea and / or vomiting. Alternatively, objective evidence is usually medical test results and may include, but is not limited to, body temperature, complete blood count, lipid panel, thyroid panel, blood pressure, heart rate, electrocardiogram, whole-body imaging scan and other medical test results.

[0130] As used herein, the term “disease” refers to any dysfunction of a living animal or part of a normal state that interferes with or modifies the performance of a biological function. Typically manifested by differential signs and symptoms, diseases are usually responses to i) environmental factors (e.g., nutritional deficiencies, industrial hazards, or mechanisms); ii) specific infectious agents (e.g., helminths, bacteria, or viruses); iii) organism-specific defects (e.g., genetic abnormalities); and / or iv) combinations of these factors.

[0131] The terms “reduction,” “inhibition,” “reduction,” “suppression,” “reduction,” “prevention,” and their grammatical equivalents (including “lower,” “smaller,” etc.) are used in reference to the occurrence of any symptom in an untreated subject compared to a treated subject, indicating that the amount and / or intensity of the symptom in the treated subject is lower than in the untreated subject by any amount recognized as clinically relevant by any healthcare professional. In one embodiment, the amount and / or intensity of the symptom in the treated subject is at least 10%, at least 25%, at least 50%, at least 75%, and / or at least 90% lower than the amount and / or intensity of the symptom in the untreated subject.

[0132] The term "inhibitory compound" as used herein refers to any compound that can interact with a binding partner (i.e., attach, bind, etc.) under conditions that prevent the binding partner from responding to its native ligand. Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins / peptides.

[0133] The term "adhesion" as used herein refers to any interaction between a medium (or carrier) and a drug. Adhesion can be reversible or irreversible. Such adhesion includes, but is not limited to, covalent bonds, ionic bonds, van der Waals forces, or friction. A drug adheres to a medium (or carrier) if it is immersed, incorporated, coated, suspended, fermented, mixed, etc.

[0134] As used herein, the terms “drug” or “compound” refer to any pharmacologically active substance that can be administered to achieve a desired effect. Drugs or compounds may be synthetic or naturally occurring non-peptides, proteins or peptides, oligonucleotides or nucleotides, polysaccharides, or sugars.

[0135] As used herein, the terms “administer” or “to administer” refer to any method by which the composition is provided to a patient so that the composition may exert the intended effect in the patient. Exemplary methods of administration include direct mechanisms, such as topical tissue administration (i.e., extravascular administration, such as subcutaneous, intramuscular, or intraperitoneal), intravenous, oral ingestion, transdermal patch, topical, inhalation, and suppositories.

[0136] The term "patient" as used herein refers to a human or animal, and does not necessarily require hospitalization. For example, outpatients and residents of care facilities are considered "patients." Patients can be human or non-human animals of any age, and therefore include both adults and juveniles (i.e., children). The term "patient" is not intended to imply the need for medical treatment. Therefore, patients may be subjects of voluntary experiments, whether supporting clinical or basic scientific research.

[0137] As used herein, the term “subject” means, but is not limited to, humans (e.g., females or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other primates (e.g., monkeys); non-human mammals, e.g., cattle, pigs, horses, sheep, mice, goats, cats, dogs; and / or birds, e.g., chickens, ducks, and / or geese.

[0138] The term "affinity" used here refers to any attractive force that causes a substance or particle to be placed in a chemical combination and remain there. For example, an inhibitor compound with high affinity for a receptor is more effective than a low-affinity inhibitor in preventing the receptor from interacting with its native ligand.

[0139] The term "derived" as used herein refers to the source of a compound or sequence. In some respects, a compound or sequence may originate from an organism or a specific species. In other respects, a compound or sequence may originate from a larger complex or sequence.

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

[0141] The term "combination therapy" as used herein refers to a drug regimen of two or more different therapeutic agents administered over a period of time, where these therapeutic agents are administered together or separately. In some embodiments, 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 formulated as separate compositions or dosages so that they can be administered simultaneously or sequentially at various time intervals to the target that requires them.

[0143] The term "synergistic" or "synergistic" as used here refers to the phenomenon in which the combination of two therapeutic agents in combination therapy produces a greater result than the sum of the effects of each agent when administered individually.

[0144] The term "in vivo" used here refers to events that occur within the subject's body.

[0145] The term "in vitro" used here refers to an event that takes place outside of the subject.

[0146] The term "protein" as used herein refers to one of many naturally occurring, highly complex substances (e.g., enzymes or antibodies) that contain amino acid residues linked by peptide bonds and include carbon, hydrogen, nitrogen, oxygen, and typically sulfur. Generally, proteins contain hundreds of orders of magnitude more amino acids.

[0147] The term "peptide" as used here refers to any of the various amides derived from two or more amino acids, formed by the combination of an amino group and other carboxyl groups of an acid, and is usually obtained by partial hydrolysis of proteins. Generally, peptides contain tens of orders of magnitude of amino acids.

[0148] The terms "pharmaceutically acceptable" as used herein refer to molecules and compositions that, when administered to animals or humans, do not produce harmful, allergic, or other inappropriate reactions.

[0149] The term "pharmaceutically acceptable carrier" as used herein refers to any and all solvents or dispersion media, including but not limited to water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, coatings, isotonic and absorption retardants, liposomes, and commercial cleansers. Auxiliary bioactive components may also be incorporated into such carriers.

[0150] The term "pharmaceutically acceptable salt" as used herein refers to a salt that does not adversely affect the biological activity and properties of the compound, does not cause excessive toxicity, irritation, and / or allergic reactions, and is suitable for use in contact with the target tissue. pharmaceutically acceptable salts include those derived from appropriate 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, naphthalenesulfonic acid, lactic acid, succinic acid, oxalic acid, and stearic acid. In some cases, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group as described herein with a base to obtain salts such as ammonium salts, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), salts formed with organic bases, and amino acid salts. pharmaceutically acceptable salts derived from suitable 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, and aluminum. Organic bases capable of producing salts include, for example, primary, secondary, and tertiary amines.

[0151] The term “prodrug” as used herein refers to a compound disclosed in vivo or a compound converted to a pharmaceutically acceptable form of said compound. A prodrug may be inactive when administered to a subject but is converted to an active compound in vivo. In various cases, the physicochemical properties (e.g., bioavailability) and / or delivery properties of a prodrug are improved compared to the parent compound. Prodrugs are typically designed to enhance pharmaceutically and / or pharmacokinetic properties associated with the parent compound. Prodrug compounds often offer advantages in solubility, tissue compatibility, or release delay in a subject. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is cleaved when the prodrug is administered to a subject, forming a free hydroxyl, free amino, or free mercapto group, respectively. It is well known that prodrugs can be prepared from carboxylic acids, for example, in the form of carboxylate esters or thioesters.

[0152] The terms "purification" or "isolation" as used herein may refer to a composition (e.g., a peptide composition) that has been subjected to a process (e.g., fractionation) to remove various other components, and the composition substantially retains its expressed biological activity.

[0153] The term "sample" as used herein includes, for example, environmental and biological samples. Environmental samples include materials from the environment, such as soil and water. Biological samples include animals (e.g., humans), bodily fluids (e.g., blood, plasma, and serum), solids (e.g., feces), tissues, liquid foods (e.g., milk), and solid foods (e.g., plants). For example, a lung sample may be taken from bronchoalveolar lavage fluid (BAL) containing bodily fluids and cells derived from lung tissue. Biological samples may include cells, tissue extracts, bodily fluids, chromosomes or extrachromosomal elements isolated from cells, 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), etc.

[0154] The term "biologically active" as used herein refers to any molecule that possesses structural, regulatory, or biochemical function. For example, biological activity is determined, for instance, by the restoration of wild-type proliferation in cells lacking protein activity. Cells lacking protein activity can be produced in many ways (i.e., point mutations and frameshift mutations). Complementation is achieved by transfecting cells lacking protein activity with an expression vector expressing the protein, its derivatives, or a portion thereof.

[0155] The terms “label” or “detectable label” as used herein refer to any composition that is detectable by spectral, photochemical, biochemical, immunochemical, electrical, optical, or chemical means. Such labels include biotin for staining with labeled streptavidin conjugates, magnetic beads (e.g., Dynabeads), etc. (登録商標) ), fluorescent dyes (e.g., fluorescein, Texas Red) (登録商標) , rhodamine, green fluorescent protein, etc.), radiolabeled (for example, 3 H, 125 I, 35 S, 14 C, or 32 The labels include, but are not limited to, U.S. Patents 3,817,837;3,850,752;3,939,350;3,996,345;4,277,437;4,275,149;4,366,241 (all incorporated herein by reference). The labels intended in this invention can be detected by conventional means. For example, radioactive labels can be detected using photographic film or a scintillation counter, and fluorescent markers can be detected using a photodetector for detecting luminescence. Enzyme labels are typically detected by providing a substrate to the enzyme and detecting the reaction product produced by the enzyme's action on the substrate, and calorimetry labels are detected simply by the visualization of a colored label.

[0156] The term "conjugate" used here refers to any compound formed by the linkage of two or more parts.

[0157] As used herein, “part” or “group” refers to a molecular type designated by formula, chemical name, or structure, or a position. In the context of a particular embodiment, a conjugate contains one or more parts or chemical groups. This means that the formula of the part is substituted at a certain position so as to be linked and part of the molecular arrangement of the conjugate. Parts may be linked directly by covalent bonds, but it is not intended that the linkage of two or more parts must be directly linked to one another. A linking group, bridging group, or bonding group refers to any molecular arrangement that parts multiple parts by covalent bonds, such as, but not limited to, one or more amide groups. Furthermore, a conjugate may be unsubstituted, but a conjugate may have a variety of further substituents bonded to the linking group and / or to the part.

[0158] The terms "polymer" or "polymer group" as used herein refer to a chemical species or group consisting of repeatedly bonded portions. In a given embodiment, the number of repeating portions is preferably three or more, or more than ten. The bonded portions may have identical structures or their substructures may vary. A "monomer polymer" or "homopolymer" is a polymer containing the same repeating, asymmetric subunits. A "copolymer" is a polymer derived from two or more types of monomer species (i.e., two or more different chemically asymmetric subunits). A "block copolymer" is a polymer consisting of two or more types of polymer subunits linked by covalent bonds.

[0159] The term "substitution" as used herein refers to the substitution of at least one hydrogen atom in a molecular configuration by a substituent. The number of substituents present depends on the number of hydrogen atoms available for substitution and includes substitutions of more than one hydrogen atom bonded to a single atom (for example, a carbon or silicon atom that may be available for one, two, or three substitutions, or a nitrogen atom that may be available for one, two, or three substitutions, or an oxygen or sulfur atom that may be available for one substitution). In the case of an oxo substituent ("=O"), two hydrogen atoms are substituted (for example, when two hydrogen atoms of the central carbon atom in -CH2-CH2-CH3 are substituted, it provides -(CH2)-C(=O)-CH3 as the substituent). When substituted, one or more of the following groups are "substituents". Substituents include halogens (e.g., F, Cl, Br, I), hydroxy(OH), hydroxyalkyl (e.g., CH2-OH, CH(CH3)OH, C(CH3)2OH), oxo, cyano(CN), cyanoalkyl (e.g., CH2-CN, CH(CH3)CN, C(CH3)2CN), nitro(NO2), amino, alkylamino, dialkylamino, branched or unbranched alkyl (e.g., methyl, ethyl, propyl, isopropyl, sec-butyl, etc.), cycloalkyl (e.g., cyclopropyl), fluoroalkyl (e.g., CF3, CF2H, CH2F, CH2CF3, CH2CF2H, CHFCHF2, CF2CH2F, CF2CF3, CF2CH3, CF(CH3)2, CH2C) H2CF3, CF2CH2CF3, CF2CF2CF3, etc.) or more generally, haloalkyl (e.g., CH2Cl, CH(CH3)Br, etc.), O-alkyl (alkoxy) (e.g., OCH3, OCH2CH3, OCH(CH3)2, etc.), O-cycloalkyl (e.g., O-cyclopropyl), O-haloalkyl (e.g., OCF2H, OCFH2, OCF3, OCH2CF3, OCH2CF2H, OCHFCHF2, OCF2CH2F, OCF2CF3, OCF2CH3, OCF(CH3)2, OCH2CH2CF3, OCF2CH2CF3, OCF2CF2CF3 or OCH2Cl), O-aryl (e.g., O-phenyl), O-heteroaryl, O-heterocyclyl, (CH2) 1-3 -Cycloalkyl, (CH2) 1-3-Haloalkyl, (CH2) 1-3 - Heterocyclyl, (CH2) 1-3 -Aaryl, (CH2) 1-3 - Heteroaryl, thioalkyl (e.g., S-CH3), hydroxyalkyl (e.g., CH2OH), alkyl ether (e.g., CH2OCH3), alkynyl (e.g., -C≡CR) f ), alkenyl (e.g., -CR) f =CR f R g ), aryl (e.g., phenyl), arylalkyl (e.g., CH2Ph), heteroaryl (e.g., pyridyl or any 5-membered or 6-membered heteroaryl ring), heteroarylalkyl (e.g., CH2-pyridine), heterocyclyl, heterocycloalkyl and -NR f R g , -NR f C(=O)R g , -NR f C(=O)NR f NR g , -NR f -C(=O)OR f SO2R g -C(=O)R f , -C(=O)OR f -C(=O)(CH2) 1-3 R f -C(=O)O(CH2) 1-3 R f -C(=O)(CH(CH3))(CH2) 0-3 R f -C(=O)O(CH(CH3))(CH2) 0-3 R f -C(=O)(C(CH3)2)(CH2) 0-3 R f -C(=O)O(C(CH3)2)(CH2) 0-3 R f , -OR f -C(=O)NR f R g -OC(=O)NR f R g , -SR f -SOR f -S(=O)2R f-OS(=O)2R f -S(=O)OR f , and P(O)R f R g (Here, R f and R g Each of these substituents may be the same or different, and independently comprises, but is not limited to, 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. Furthermore, the substituents may be further substituted with one or more of the substituents such that the substituent can constitute, for example, a substituted alkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted heterocyclyl, or substituted heterocycloalkyl.

[0160] The term "unsubstituted" used here refers to any compound that does not contain any extra substituents attached to it. An unsubstituted compound is a compound whose chemical structure lacks extra substituents (for example, no non-hydrogen substituents). For example, unsubstituted proline is a proline amino acid, even if the amino group of proline can be considered to be disubstituted with an alkyl group.

[0161] In describing substituents with atoms on both sides, the term "bond" as used here refers to the absence of that substituent. For example, in the 4-atom sequence ABCD, if both B and C are listed as being bonded, the result is the 2-atom sequence AD. If only B is listed as being bonded, the result is the 3-atom sequence ACD.

[0162] The term "alkyl" as used herein refers to any linear or branched, acyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing 1 to 10 carbon atoms, while the term "lower alkyl" has the same meaning as alkyl except that it contains 1 to 3 carbon atoms. The term "higher alkyl" has the same meaning as alkyl except that it contains 4 to 10 carbon atoms. Representative saturated linear alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and n-nonyl, while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, and isopentyl. The methyl substituent used herein can be written as "CH3" or "Me" or as a terminal bond where no specific atom is indicated.

[0163] The term "cycloalkyl" used here refers to saturated and unsaturated cyclic alkyl groups. Typical saturated cyclic alkyl groups are C3-C 14 (For example, C3-C7) cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclododecyl; on the other hand, unsaturated cyclic alkyls include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadiene. Cyclic alkyls may also be referred to here as "homocycles" or "homocyclic rings."

[0164] The term "bicyclic compound" as used herein includes the "crosslinked," "condensed," and "spiro" compounds described herein.

[0165] The terms “spiro” or “spirocyclic” as used herein refer to a chemical structure having at least two rings sharing one common atom. The rings may be cycloalkyl, heterocyclyl, or a combination thereof, and may contain one or more aryl or heteroaryl rings. Exemplary embodiments include 1,4-dioxaspiro[4.5]decane, oxazaspiro[3.4]octane, diazaspiro[3.4]octane, diazaspiro[2.5]octane, spirocyclic azetidine, and spirocyclic pyrrolidine and spirocyclic piperidine, 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 "crosslinked" as used herein refers to a compound containing two non-adjacent atoms common to two rings. Exemplary embodiments include, but are not limited to, norbornane, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, azabicyclo[3.1.0]hexane, 3,9-diazabicyclo[3.3.1]nonane, diazabicyclo[3.1.1]heptane, diazabicyclo[3.2.1]octane, 1,4-azabicyclo[2.2.1]heptane, 1,4-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.1]heptane, 1,4-diazabicyclo[2.2.2]octane, and other crosslinked piperazines and crosslinked piperidines.

[0167] The term "condensation" as used herein refers to polycyclic ring systems in which any two adjacent rings share exactly two adjacent atoms (ortho-condensation), and polycyclic ring systems in which a ring shares exactly two adjacent atoms with each of two or more rings in a continuous series of ortho-condensed rings (ortho- and peri-condensation). Exemplary embodiments include pentalene and dibenzoxepine (ortho-condensed) and pyrene (ortho- and peri-condensed). Ortho-condensed systems have an "n" common side and "2n" common atoms, while peri-condensed systems have an "n" common side and less than "2n" common atoms. Other exemplary condensed systems include condensed cyclopropyl rings, condensed aziridines, and condensed azetidines, when these rings are condensed with pyrrolidine rings, for example. Other examples include condensed pyrrolidine rings (e.g., octahydropyrrolo[3,4-c]pyrrole and octahydrocyclopenta[c]pyrrole), pyridine rings condensed with condensed pyridine rings, e.g., cycloalkyl (e.g., cyclopentane) or heterocyclyl (e.g., tetrahydrofuran or tetrahydropyran), or other condensed heteroaromatic rings (e.g., dihydro-5H-pyrazolo[5,1-b][1,3]oxazine and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine).

[0168] The terms “aromatic” or “aryl” as used herein refer to any aromatic carbocyclic substituent (i.e., one in which all ring atoms are carbon), such as but not limited to phenyl (from benzene), tolyl (from toluene), xylyl (from xylene), or polycyclic substituents (e.g., naphthyl (from naphthalene) and anthracenyl (from anthracene)).

[0169] The term "arylalkyl" as used herein refers to any alkyl having at least one alkyl hydrogen atom replaced by an aryl moiety, such as, but not limited to, benzyl, -(CH2)2phenyl, -(CH2)3phenyl, and -CH(phenyl)2.

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

[0171] The term "haloalkyl" as used herein refers to any alkyl group in which at least one hydrogen atom (and all hydrogen atoms) is replaced by a halogen atom, such as trifluoromethyl, dichloromethyl, difluoromethyl, monofluoromethyl, monobromomethyl, and 1,1,1-trifluoroethyl.

[0172] The term "aminoalkyl" used here refers, for example, -(CH2) 1-5 -NH2, -(CH2) 1-5 -NHCH3, -(CH2) 1-5 -N(CH3)2, -(CH2) 1-5 -NH-(CH2) 1-5 -N(CH3)2 refers to any alkyl group in which at least one hydrogen atom is replaced by a nitrogen atom.

[0173] The terms "heteroaromatic" or "heteroaryl" as used herein refer to any aromatic heterocyclic ring having 5 to 10 or more members, containing at least one heteroatom selected from nitrogen, oxygen, or sulfur, containing at least one carbon atom, and including, but not limited to, both monocyclic and bicyclic ring systems, where the nitrogen atom may be in an oxidized state. Heteroaryl rings can be bonded as substituents via ring heteroatoms or carbon atoms. Representative heteroaromatic compounds include 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-oxadi This includes, but is not limited to, azoles (1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazoles (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole), pyridazines, pyrimidines, pyrazines, 1,2,4-triazines, 1,3,5-triazines, triazolopyrazines, cinnoline, phthalazines, quinazoline, 1,8-naphthylpyridines, pyrido[3,2-d]pyrimidines, pyrido[4,3-d]pyrimidines, pyrido[3,4-b]pyrazines, pyrido[2,3-b]pyrazines, pteridines, triazolopyridines (e.g., [1,2,4]triazolo[4,3-a]pyridine), etc.

[0174] The term "heteroarylalkyl" used here refers to alkyl groups that have at least one alkyl hydrogen atom replaced by a heteroaryl moiety, such as -CH2 pyridinyl or -CH2 pyrimidinyl.

[0175] The terms "heterocycle," "heterocyclyl," or "heterocyclic ring" as used herein refer to a non-aromatic ring that is saturated or unsaturated and contains one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, phosphorus, and silicon, where each of the nitrogen, phosphorus, and sulfur heteroatoms may be in an oxidized state, each of the nitrogen and silicon heteroatoms may be substituted or unsubstituted, and the nitrogen heteroatom may optionally be quaternized, and include a bicyclic ring in which any of the above heterocycles is fused to an aryl or heteroaryl ring. Heterocyclic rings may be bonded as substituents via ring heteroatoms or carbon atoms. In various embodiments, the heterocycle comprises 3 to 14 or more ring atoms (e.g., a 3- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic ring), and includes 2H-azirine, azetidine, 2,3-dihydroazeto, 1,3-diazetidine, 2H-oxet, thietan, 2H-thieto, azetidine-2-one, morpholine, thiomorpholine, pyrrolidinone, pyrrolidinine, 2-pyrroline, 3-pyrroline, pyrazolidine, 2-pyrazolin, pyridazinone, pyrazinon, oxazolidine-2-one, 2-imidazoline, Imidazolidine, piperidine, oxopiperidine, tetrahydropyrimidinone, piperazine, oxopiperazine, diazepane, ethylene oxide (oxirane), ethyleneimine (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-1,4-azaphosfinan 4-oxide, oxadiazolon, dioxane (e.g., 1,4-dioxane and 1,3-dioxane), hydantoin, valerolactam, tetrahydrofuran, tetrahydropyran, 2H-pyran, 4H-pyran, thian, 2H-thiopyran, 1,3-dithian, 1,4-dithian, 1,3,5-trithian, pyrrolizidine, 1,4,5,6-tetrahydrocyclopenta[b]pyrrole, tetrahydropyridine, tetrahydropyrimidine, dihydropyridazine, 6-oxo-1,6-dihydropyridazine, 6-oxo-1,4-dihydropyridazine, 6-oxo-1,6-dihydropyrazine, 6-oxo-1,4-Dihydropyrazine, tetrahydrothiophene, tetrahydrothiopyran, tetrahydrotriazolopyrazine, tetrahydropyrazolopyridine, dihydrotriazolopyrazine, dihydropyrazolopyrazine, dihydroimidazopyrazine, indoline, isoindoline, decahydroisoquinoline, decahydroquinoline, 1,2,3,4-tetrahydroquinoline, 1,2-dihydroquinoline, 2H-benzo[e][1,3]oxazine, 2H-benzo[b][1,4]oxazine, quinoline-2(1H)-one, isoquinoline-1(2H)-one, quinuclidine, triethylenediamine, 1-azaadamantane, 2-azaadamantane, 2 This includes, but is not limited to, 3-dihydroazepine, 2,5-dihydroazepine, oxepane, azonanne, spiro[cyclobutane-1,3'-indole], 1-oxaspiro[4,5]decane, 1,6-dioxaspiro[3,4]octane, 2-oxa-7-azaspiro[3,5]nonane, 1,4-dioxa-7-azaspiro[4,4]nonane, 1,3-diazaspiro[4,4]-non-2-en-4-one, 2,9-diazaspiro[5,5]undecane-1-one, oxa-diazabicyclo[3.3.1]nonane, 8-azaspiro[4,5]decane-7,9-dione, 1,4-dithia-7-azaspiro[4,4]nonane, etc.

[0176] The term "heterocycloalkyl" used here refers to any alkyl group having at least one alkyl hydrogen atom replaced by a heterocycle, such as -CH2 morpholinyl.

[0177] The term "alkylamino" used herein includes, but is not limited to, methylamino, ethylamino, dimethylamino, and diethylamino, and refers to at least one alkyl moiety linked via a nitrogen bridge (i.e., -N-(alkyl) n Here, n = 1 or 2 (for example, alkylamino or dialkylamino).

[0178] The terms "alkyloxy" or "alkoxy" used herein refer to any alkyl moiety (i.e., -O-alkyl) linked via oxygen crosslinking, including but not limited to methoxy and ethoxy.

[0179] The term "thioalkyl" as used herein refers to any alkyl moiety (i.e., -S-alkyl) linked via a sulfur crosslink, including but not limited to methylthio and ethylthio.

[0180] The term "alkenyl" as used herein refers to an unbranched or branched hydrocarbon chain having one or more carbon-carbon double bonds, and may also be called an "unsaturated alkyl." The double bond of the alkenyl group may or may not be conjugated with other unsaturated groups. Suitable alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl. The alkenyl group may be unsubstituted or substituted with one or two suitable substituents.

[0181] The term "alkynyl" as used herein refers to an unbranched or branched hydrocarbon chain having one or more carbon-carbon triple bonds, and may also be called an "unsaturated alkyl." The triple bond of the alkynyl group may be conjugated or unconjugated with other unsaturated groups. Suitable alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. The alkynyl group may be unsubstituted or substituted with one or two suitable substituents.

[0182] The term "reactive group" used here refers to nucleophiles, electrophiles, or inherently reactive groups, i.e., groups that react in the presence of radicals. A nucleophile is a part of a molecule that forms a chemical bond with its reaction partner (electrophile) by donating both bonding electrons. Electrophiles accept these electrons. A nucleophile can participate in nucleophilic substitution, thereby being attracted to the complete or matching positive charge of an element and replacing the group it bonds to. Alternatively, a nucleophile can participate in the substitution of a carbonyl group. Carboxylic acids often become electrophilic by forming succinyl esters, and these esters react with aminoalkyls to form amides. Other common nucleophilic groups include thiolalkyls, hydroxylalkyls, primary and secondary amines, and carbon nucleophiles, such as enols and alkyl metal complexes. Other preferred methods for ligating proteins, oligosaccharides, and cells using reactive groups are disclosed (Lemieux et al., Trends in Biotechnology 1998, 16, 506, incorporated herein by reference in whole). Further preferred methods provide reactive groups for Staudinger ligation, i.e., the "Kick chemistry" of an azide-containing moiety and an alkynyl reactive group forming a triazole. Michael addition of a carbon nucleophilic enolate to an electrophilic carbonyl, or Schiff base formation of a nucleophilic primary or secondary amine to an aldehyde or ketone may also be utilized. Other conjugation methods 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 incorporated herein by reference in whole).

[0183] The term "biocompatibility" as used herein refers to any substance that does not induce a substantial adverse response in the host. It is always assumed that when an exogenous substance is introduced into a living organism, that substance may produce an immune response, such as an inflammatory response, that negatively affects the host. In the context of this invention, biocompatibility is evaluated according to the application for which it is designed: for example, a bandage is considered biocompatible with skin, while an implantable medical device is considered biocompatible with the internal tissues of the body. Preferably, biocompatible substances include, but are not limited to, biodegradable and biostable substances. If an implant containing such substance binds closely to the implant site in the host animal and the response is better than the tissue response recognized and established as appropriate for substances provided by ASTM, then no substantial adverse response occurs. ASTM subcommittee F04.16 on Biocompatibility Test Methods develops biocompatibility standards for medical and surgical materials and devices, including E1262-88, F612-20, F719-20e1, F720-17, F748-16, F749-20, F750-20, F756-17; F763-04, F813-20, F895-11, F981-04, and F1027. This includes 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, substances used in contact with blood flow must be made from materials that meet blood compatibility standards. One of these tests is damage to red blood cells, which can result in hemolysis, i.e., cell destruction, as described in F756-17 Standard Practice for Assessment of Hemolytic Properties of Materials.

[0184] As used herein, “bioactive substance” refers to any of a variety of chemical parts that bind to biomolecules such as, but not limited to, peptides, proteins, enzymes, receptors, substrates, lipids, antibodies, antigens, and nucleic acids. In one preferred embodiment, the bioactive substance is a biomolecule, but the bioactive substance is not intended to be limited to biomolecules. In another preferred embodiment, the bioactive substance provides hydrophobic, hydrophilic, or electrostatic interactions, such as polycarboxylic acids that are anionic at physiological pH. In another preferred embodiment, an alkaline growth factor (having an isoelectric point greater than 7) maintains a preferred electrostatic interaction with a polycarboxylate, which is subsequently released in a controlled and sustained manner.

[0185] "Cancer" is a term used to describe a physiological condition in mammals typically characterized by uncontrolled cell proliferation. Examples of cancer include, but are not limited to, carcinomas, lymphomas, leukemias, blastomas, and sarcomas. More specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), glioma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal cancers, renal cell carcinoma, kidney 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, gastric cancer, urothelial carcinoma (including locally advanced or metastatic urothelial carcinoma), bladder cancer, hepatocellular carcinoma, breast cancer, and head and neck cancers.

[0186] The term "stereoisomer" refers to a compound in which the atomic bonds are the same but the spatial arrangement of the atoms differs. Stereoiomers include cis-trans isomers, E and Z isomers, enantiomers, diastereomers, and atrop isomers. In the context of this invention, the term "enantiomerically pure" is interpreted to mean that the compound has an enantiomer excess of more than 95%, preferably more than 97%, with respect to the absolute configuration of the chiral center.

[0187] The present invention intends to encompass all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomer isomers, (D)-isomers, (L)-isomers, atrop isomers, tautomers, and racemic and other mixtures thereof, such as enantiomer or diastereomer-enriched compounds, all of which are within the scope of the invention. The present invention includes, in its definition, any such optically active or racemic mixture, as long as the compounds of the present invention as defined herein exist in an optically active or racemic state due to one or more chiral carbon atoms. The synthesis of optically active compounds can be carried out by standard techniques of organic chemistry well known in the art, such as synthesis from optically active starting materials or by resolution of racemic compounds. Similarly, the enantiomer or diastereomer purity of the compounds can also be evaluated using standard laboratory techniques.

[0188] The pharmaceutical compositions of the present invention may take any suitable form for a desired route of administration. When the composition is administered orally, any suitable orally deliverable dosage form may be used, for example, in the case of oral liquid formulations, water, glycol, oil, alcohol, etc., such as suspensions, syrups, elixirs, emulsions, and solutions; or in the case of powders, pills, capsules, and tablets, a solid carrier, such as starch, sugar, kaolin, diluents, lubricants, binders, disintegrants, etc. Tablets and capsules represent the most advantageous oral unit dosage forms because they are easy to administer. Compositions for injection or intravenous infusion are also provided in the form of solutions, suspensions, and emulsions. For non-enteral compositions, the carrier usually contains sterile water and / or other components that aid in dissolution. Solutions for injection are prepared with the carrier comprising a saline solution, a glucose solution, or a mixture of saline and glucose solutions. 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 transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, and optionally, may be combined with appropriate additives as needed, where the additives may facilitate the administration of the composition to the skin and / or facilitate the preparation of the composition to be delivered. These compositions can be administered in various ways, for example, as transdermal patches or ointments. Acid or base addition salts of the compounds of the present invention are typically more suitable for the preparation of aqueous compositions because they have increased water solubility than the corresponding neutral forms of the compounds.

[0189] The pharmaceutical composition of the present invention may contain one or more expanders, diluents, adjuvants, or other additives for promoting the preservation and / or administration of the active ingredients contained herein.

[0190] In exemplary embodiments, the pharmaceutical composition of the present invention may comprise one or more additional therapeutic agents, for example, to enhance efficacy or reduce undesirable side effects. In specific embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents useful for treating or preventing diseases directly or indirectly mediated by PI3K. Examples of such agents include, but are not limited to, agents for treating or preventing cancer, Huntington's disease, cystic fibrosis, hepatic fibrosis, renal fibrosis, pulmonary fibrosis, cutaneous fibrosis, rheumatoid arthritis, diabetes, or heart failure.

[0191] In certain embodiments, further therapeutic agents included are anticancer agents. Examples of anticancer agents include, but are not limited to, DNA-toxic cytotoxic drugs, alkylating agents, e.g., cyclophosphamide, dacarbazine, and cisplatin; antimetabolites, e.g., methotrexate, mercaptopurine, thioguanine, fluorouracil, and cytarabine; plant alkaloids, e.g., vinblastine and paclitaxel; antitumor antibiotics, e.g., doxorubicin, bleomycin, and mitomycin; hormones / antihormones, e.g., prednisone, tamoxifen, and flutamide; other types of anticancer agents, e.g., asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, and derivatives; colony-stimulating factors, amiphostine, camptothecin, topotecan; thalidomide analogs, e.g., lenalidomide; and proteasome inhibitors, e.g., velcade.

[0192] In other embodiments, the present invention provides a method for inhibiting or treating a disease resulting from abnormal cell proliferation and / or differentiation in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present invention. In one embodiment, the method for inhibiting or treating a disease comprises administering to a subject requiring such treatment a composition surrounding one or more compounds of the present invention and a pharmaceutically acceptable carrier in an effective amount. The composition to be administered may further include a therapeutic agent such as an anticancer agent.

[0193] The compounds of the present invention, as defined herein by their chemical structure and / or chemical name, are generally listed according to the IUPAC or CAS nomenclature system. Abbreviations familiar to those skilled in the art may be used. When a compound is described by both chemical structure and chemical name, and the chemical structure and chemical name are inconsistent, the chemical structure is intended to be the determinant of the compound's structure.

[0194] This invention includes compounds labeled with various radioactive or non-radioactive isotopes. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I), Carbon-14 ( 14 C), nitrogen-15( 15 N), sulfur-35( 35 S) and Chlorine-36 ( 36 The compounds of the present invention may contain, but are not limited to, Cl. In exemplary embodiments, one or more hydrogen atoms in the compounds of the present invention may be replaced with deuterium. In various embodiments, the compounds of the present invention contain at least one deuterium atom, or two or more deuterium atoms, or three or more deuterium atoms, etc. As described herein, the compounds of the present invention also contain tritium ( 3 H), Iodine-125( 125 I), and carbon-14 ( 14 Radiolabeling with radioactive isotopes such as C) is also possible. Radiolabeled compounds are useful as therapeutic or prophylactic agents, provide research reagents for assays, and / or provide diagnostic agents for techniques such as in vivo contrast imaging. Synthetic methods for incorporating isotopes into organic compounds are well known in this field.

[0195] In embodiments of the present invention, the compounds of the present invention as defined herein (e.g., any compound of formula (1), (2), (3), or (4)) or a pharmaceutically acceptable salt thereof exist as single enantiomers with an enantiomer excess (%ee) of ≥95%, e.g., ≥98%, e.g., ≥99%.

[0196] In embodiments of the present invention, the pharmaceutical composition comprises one of the compounds of the present invention as defined herein (e.g., a compound of formula I) or a pharmaceutically acceptable salt thereof, wherein the compound exists as a single enantiomer with an enantiomer excess (%ee) of ≥95%, e.g., ≥98%, e.g., ≥99%.

[0197] In exemplary embodiments of the present invention, the diseases or disorders treated with the compounds of the present invention are selected from congenital lipoma proliferation, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal cord syndromes (CLOVES), mosaic tissue hyperproliferative syndrome, venous malformations, and brain malformations associated with severe epilepsy or PIK3CA-associated hyperproliferative syndrome (Keppler-Noreuil et al., 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 present invention, the cancer to be treated is a cancer harboring the PI3K H1047 mutation (e.g., H1047R) (Thorpe et al., Nat Rev Cancer 2015, 15, 7).

[0199] The compounds of the present invention (defined, for example, by formulas (1) to (3)) are PI3Kα H1047R mutant selective inhibitors that typically exhibit greater selectivity for the H1047R mutant than the wild type. As such, these compounds can selectively reduce the amount of phosphorylated AKT (pAKT) and reduce proliferation, preferably across several tumor types, in PI3Kα H1047R mutant cell lines.

[0200] The combination of the PI3K H1047R mutant-selective inhibitors of the present invention (for example, defined by formulas (1) to (3)) with selective estrogen receptor degradation inducers (SERDs), such as but not limited to fulvestrant, elakestrant, camizestrant, or bepdegestrant, demonstrates a combination benefit leading to tumor regression in ER+ / PI3K H1047R mutant tumors, including but not limited to breast cancer xenograft T47D, at doses in which little or no regression is observed with any single agent.

[0201] The combination of the PI3K H1047R mutant-selective inhibitors of the present invention (e.g., defined by formulas (1) to (3)) with HER2 inhibitors such as tucatinib or trastuzumab, but not limited to these, demonstrates a combination benefit leading to tumor regression in ER- / HER2+ / PI3K H1047R mutant tumors, including but not limited to breast cancer xenograft HCC1954, at doses in which little or no regression is observed with either monotherapy.

[0202] The compound of the present invention represented by formula (1) is generally produced by the synthetic routes identified in schemes 1 to 16.

[0203] The substituted (hetero)aryl inputs required for the synthesis of the compound of formula (1) are commercially available or readily produced by the use of known synthetic chemical methods. For example, commercially available aminophenylphosphine oxide 1 can be used as a nucleophile in the synthetic scheme below, or can be converted to the corresponding iodide 2 for transition metal-mediated coupling via the Sandmeyer reaction under standard reaction conditions, as shown in Scheme 1. [ka]

[0204] The preparation of (hetero)aryl phosphate esters (e.g., dimethyl(2-bromophenyl)phosphonate 5) is achieved by copper oxide-mediated coupling of (hetero)arylboronic acid (e.g., 3) and dimethylphosphonate, which can provide a suitable coupling partner in transition metal-mediated coupling, Scheme 2. Such phosphate esters can be converted to alkyl phosphinates (e.g., 6) by reaction with a Grignard reagent, which are also suitable for use as coupling partners. [ka]

[0205] Are halogen-substituted (hetero)aryl sulfones and sulfonamides readily available from commercial sources (e.g., 7, where R respectively)? a It can be produced via (=CH3 or NH2) or known synthetic chemical methods, Scheme 3. For example, a benzenethiol, e.g. 8, may be alkylated with an alkyl halide (e.g., iodoethane) under basic conditions to give a thioether, e.g. 9. Subsequently, the thioether functional group is oxidized with one of several reagents (e.g., meta-chloroperoxybenzoic acid) to obtain an arylsulfone, e.g. 10. Alternatively, arylsulfone 10 may be obtained from the corresponding arylsulfinic acid 8 using an alkyl bromide or alkyl iodide in the presence of a suitable base (e.g., potassium carbonate). NThey can be produced via 2-alkylation. Heteroaryl sulfones (e.g., pyridyl sulfone 13) can be produced by the reaction of sodium methylsulfinate with 2-fluoro- or 2-chloropyridine (e.g., 11). The production of alkylaryl sulfones (e.g., 19 or 20) containing oxygen or nitrogen-bonded chains can be achieved from suitable halogenated methyl-substituted sulfones (e.g., 1-bromo-2-((chloromethyl)sulfonyl)benzene 16, but not limited to these). The synthesis of 16 can be achieved by alkylating aryl sulfinate 14 with bromochloromethane. Oxygen or nitrogen-bonded species inputs, 19 or 20, respectively, can be synthesized from 16 via alkylation of alcohol 17 or amine 18 in the presence of a suitable base (e.g., sodium hydride or potassium carbonate, but not limited to these). [ka]

[0206] A sulfoximine-containing input can be prepared from a thioether, Scheme 4. In the presence of a phenyliodonium reagent, a thioether-containing nitrobenzene (e.g., 21, but not limited to this) is reacted with ammonium carbamate to obtain a sulfoximine-containing intermediate, e.g., 22. The sulfoximine can be further functionalized optionally via an alkylation step to obtain a species, e.g., 23. By reduction of the nitro group of 23 (e.g., by iron in the presence of ammonium chloride), anilinosulfoximine 24 can be obtained. [ka]

[0207] The bicyclic core of the present invention can be synthesized by any of several ring expansion or cyclization methods. In Scheme 1, the synthesis of the isoquinolone core intermediate begins with a suitably substituted 2,3-dihydro-1H-inden-1-one 25. In the case of 25 where R7 is methyl and each R8 is hydrogen, this is commercially available. In other cases, the starting materials can be prepared via established methods known to those skilled in the art. Nitrosation of 25 to convert it to the oxime derivative 26 can be achieved using established methods (e.g., Touster, O.; Org. Reactions, VII, 1953, 327). A Beckmann rearrangement mediated by phosphorus pentachloride can convert 26 to 27 (Cushman, M.; Dekow, FW Tetrahedron 1978, 34(10), 1435-9). Alkylation of 27 with a suitable electrophile and base yields 28. If R6 is methyl, this is achieved by methyl iodide and a suitable base (e.g., sodium hydride). Other electrophilic substances and alkylating agents known to those skilled in the art may also be used. To convert bromide 28 to methyl ketone 29, a Still coupling reaction using a suitable tin reagent such as (α-ethoxyvinyl)-tributyltin, followed by acid hydrolysis, may be used (Sugiyama, et al., Bull. Chem. Soc. Jpn. 1987, 60(2), 767-768). Alternatively, the conversion from 28 to 29 can be achieved by other established methods, e.g., a Heck coupling reaction with a suitable enol-ether, followed by acid hydrolysis (Mingcui, L. et al., Org. Biomol. Chem., 2010, 8, 2012-2015). The reduction of ketone 29 to alcohol 30 can then be achieved using a suitable hydride reducing agent (e.g., sodium borohydride). It should be understood that, in addition to the method described in Scheme 1, there are other reported methods available for the production of isoquinolone and its derivatives, such as 27 or 28.For example: Li, B. et al., Tetrahedron Letters 2010, 51(29), 3748-3751; Wang, R.; et al., Organic & Biomolecular Chemistry 2011, 9(16), 5802-5808). [ka]

[0208] In Scheme 6, alcohol 30 can be converted to amino derivative 33 by several different methods. The alcohol is first converted to an intermediate 31 having a leaving group, such as bromide or mesylate, using a generally known method. Compound 33 is obtained by nucleophilic substitution of 31. Alternatively, a Mitsunobu-type reaction is performed directly between (hetero)arylamine 32 and alcohol 30 to directly obtain compound 33. In some cases, the primary use of an activating group (e.g., 2,4-dinitrobenzenesulfonyl group) on the (hetero)arylamine functional group can accelerate the Mitsunobu reaction. The use of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and triphenylphosphine can also be used in the direct reaction of alcohol 30 with (hetero)arylamines (Shalit, T.; et al., Tetrahedron Letters 2010, 51, 5988-5991; Iranpoor, N.; et al., Tetrahedron 2009, 65, 3893-3899; Panday, SK, Mini-Reviews in Organic Chemistry 2019, 16(2), 127-140; Fukuyama, Tohru; et al., Tetrahedron Letters 1997, 38(33), 5831-5834). [ka]

[0209] The synthesis leading to the single enantiomer intermediate 38 is described in Scheme 7. This series of reactions utilizes the formation of a chiral sulfinylimine to control its stereochemistry. Such methods are widely reported. Ketone 28 can be converted to chiral sulfinyl-imine 34 by a known procedure, which can then be reduced to sulfinylamine 35 in a stereocontrolled manner 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). The use of the R isomer of the sulfinyl group generally yields the R,R-isomer of the product predominantly when 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 for imine reduction and can often enhance stereocontrol 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 situation in scheme 7 where the R2 portion is methyl, the benzyl stereocenter of 35 is effectively publicly labeled as the R isomer, as shown in the scheme. Another substitution pattern in R2 may formally change the stereocenter assignment of such an analog to S; however, even so, the relative configuration of such molecule 35 remains the same as when R2 is methyl. The major isomer can be separated from other trace isomers via standard chromatographic means. As shown in the references above, a wise selection of the sulfinyl-imine antipod and reducing agent may provide access to any antipod of the sulfinyl-amine. The sulfinyl-amine can be converted to a single enantiomer of chiralamine 36 using standard conditions (e.g., a dioxane solution of hydrogen chloride).Next, a (hetero)arylamine derivative 38 can be obtained by a standard coupling reaction of amine 36 and (hetero)aryl halide 37 (e.g., Ullmann coupling or Buchwald-Hartwig coupling for 37, Hal=I or Br) (Yang et al, Organic Process Research & Development 2022, 26(6), 1690-1750; Surry and Buchwald, Chemical Science 2011, 2(1), 27-50). Alternatively, the S of amine 36 and (hetero)aryl halide 37 can be obtained. N Ar reactions also yield intermediate 38, but input 37 must be sufficiently reactive (e.g., Hal=F or Cl and R1 being electron-withdrawing functional groups). [ka]

[0210] A final compound 40 can be prepared as outlined in Scheme 8. Intermediate 33 can be reacted with amine 39 under suitable Buchwald-Hartwig coupling conditions, where R' and R'' may be alkyl or aryl, or one of R' and R'' may be hydrogen. R' and R'' may be linked to form a ring. In some cases, the R' and / or R'' groups may be further assimilated before the subsequent steps. The racemic compound 40 can then be separated into individual enantiomers (41 and 42) using chiral chromatography (HPLC or SFC). [ka]

[0211] A single enantiomer 32 can be prepared from an enantiomerally pure intermediate 30 using chemistry similar to that shown in Scheme 8, as shown in Scheme 9. [ka]

[0212] In some cases, the reaction sequence may be adjusted as shown in Scheme 10. In this case, the Buchwald-Hartwig coupling of intermediate 35 and appropriately substituted amine 39 may yield 43. Then, the sulfinyl group is removed to obtain 44, followed by a Buchwald-Hartwig coupling with a (hetero)aryl halide (e.g., X=I or Br) to obtain a compound, e.g., 46. Alternatively, intermediate 44 may be coupled with an appropriately reactive (hetero)aryl halide 45 (e.g., X=F or Cl, where R1 is an electron-withdrawing group) and S N Compound 46 can be obtained by subjecting it to an Ar reaction. [ka]

[0213] Compounds having oxygen or sulfur coupling substitution from the 3-position of the isoquinolone ring can be prepared as shown in Scheme 11. Intermediate 38 can be subjected to a Buchwald-Hartwig coupling with a suitable sulfhydryl compound to obtain 48. Alternatively, intermediate 38 can be subjected to a suitable alcohol S N By subjecting the compound to an Ar reaction (which may be mediated by a base, such as sodium hydride), a compound, for example, 50, can be obtained. [ka]

[0214] When the substitution at position 3 of the isoquinolone ring is an alkyl or alkenyl group, these compounds can be prepared as shown in Scheme 12. Intermediate 33 can be subjected to a Suzuki coupling reaction (Stanforth, SP Tetrahedron 1998, 54(3 / 4), 263-303) with a suitable alkenyl boronate (or boronic acid) 51 to obtain 52. The racemic mixture 52 can then be subjected to chiral chromatography to obtain enantiomers 53 and 54. Alternatively, the double bond of 52 can be reduced under standard hydrogenation conditions (e.g., hydrogen and palladium catalyst). After chiral chromatography, enantiomers 55 and 56 can be obtained. When R and R' do not form a symmetrical configuration, further isomers may be obtained, which can also be separated by chromatography. [ka]

[0215] When the substitution at the 3-position of the isoquinolone group is an aryl or heteroaryl group, these types of compounds can be prepared by a method similar to that shown in Scheme 12. As described in Scheme 13, a Suzuki coupling reaction of 33 with a suitable aryl (or heteroaryl) borononate (or boronic acid) may yield enantiomers 57 and 58 after chiral separation. [ka]

[0216] Another method for the synthesis of aryl- or heteroaryl-substituted isoquinolones is described in Scheme 14. By Suzuki coupling of intermediate 35 with a suitable aryl or heteroaryl boronate (or boronic acid), followed by removal of the sulfinyl group, 59 can be obtained. By Ullmann or Buchwald-Hartwig coupling of 59 with (hetero)aryl halide 45, a compound, e.g., 60, can be obtained. Alternatively, 59 can be appropriately coupled with (hetero)aryl halide 45 (e.g., where X=F or Cl and R1 is an electron-withdrawing group)N Compound 60 can also be obtained by the Ar reaction. [ka]

[0217] The synthesis of benzopyrimidinone core-containing compounds can be recalled via known synthetic chemical techniques, Scheme 15. Starting with aminobenzoic acid 61, which is generally known or commercially available (e.g., from BLD Pharmatech Ltd.), the intermediate quinazoline-2,4-dione 62 can be produced under cyclization conditions. In exemplary embodiments where R6=H, cyclization can be achieved by treatment with urea at high temperature. In exemplary embodiments where R6=alkyl, cyclization can be achieved by a two-step method consisting of amide coupling with the corresponding alkylamine and HATU, followed by treatment with triphosgene. Chlorination of 62 can yield an intermediate of general structure 63. In exemplary embodiments, chlorination can be carried out by refluxing 62 in POCl3, followed by neutralization with an aqueous base (NaOH when R6=H, or NaHCO3 when R6=alkyl). The intermediate of general structure 64 is then S NIt is produced by Ar substitution. In an exemplary embodiment, 63 can be treated with an amine, amine hydrochloride, alcohol, or thiol (depending on whether R5 is an N-bond, O-bond, or S-bond, respectively) in a suitable solvent (e.g., ACN, NMP, or DMF, but not limited to these) at room temperature or, in an exemplary embodiment, at a high temperature (up to 140°C) to obtain an intermediate of general structure 64. Then, an intermediate of general structure 65 can be produced by carbonylation of 64. In an exemplary embodiment, the bromine substituent of 64 can be replaced with an acetyl group by treatment at a high temperature with tributyl(1-ethoxyvinyl)tin and a catalytic palladium species (e.g., Pd(PPh3)4 or PdCl2(PPh3)2, followed by hydrolysis with aqueous HCl to obtain ketone 65. Intermediate 65, when R3=H, can also be produced by formylation of 64 via various known methods (e.g., palladium-catalyzed carbonylation in the presence of H2, but not limited to this (Klaus, et al., Angew. Chem. Int. Ed. 2006, 45, 154), or cyanization followed by DIBAL reduction). Intermediate 65 can serve as a platform for further expansion of various R2 substitutions (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, alkyl, etc.) via various 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.). The alcohol intermediate of general structure 66 can be produced by reduction of 65. In an exemplary embodiment, the reduction was carried out by treating 65 with NaBH4 in the presence of MeOH. The conversion of general structures 67 and 68 of 66 to (hetero)arylamines can be carried out via reaction conditions similar to those described in schemes 6 to 14.

change

[0218] Another synthetic method to the single enantiomer benzopyrimidinone intermediate 71 is described in Scheme 16. This series of reactions utilizes the formation of a chiral sulfinylimine to establish the stereocenter of the subsequent synthetic product. Ketone 65 can be converted to the chiral sulfinyl-imine 69 via a known procedure, and then reduced to the sulfinylamine 70 in a stereocontrolled manner 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., J. Org. Chem. 2006, 71(18), 6859-6862). The use of the R isomer of the sulfinyl group 69 generally yields the predominant R,R-isomer of 70 when the reducing agent used is (for example) a mixture of sodium borohydride and cerium chloride heptahydrate. The use of this particular reducing system has been shown to be effective for imine reduction and can often enhance stereocontrol in similar reductions (Hua et al., Synthesis 1991, (11), 970-4; Zhu et al., J. Chem. Res. 2015, 39(7), 390-393). In scheme 16, where the R2 portion is methyl, the benzyl stereocenter of 35 is indeed formally labeled as the R isomer, as shown in the scheme. Another substitution pattern in R2 can formally change the stereocenter assignment of such analogs to S, however, even then, the relative configuration of such molecule 35 remains the same as when R2 is methyl. The major isomer can be separated from other trace isomers via standard chromatographic means. As shown in the previous references, a wise selection of the sulfinyl-imine antipod and reducing agent may provide access to any antipod of the sulfinyl-amine. Sulfinyl-amine 70 can be cleaved to a single enantiomer of chiral amine 71 using standard conditions (e.g., a dioxane solution of hydrogen chloride).Subsequently, a standard coupling reaction of amine 45 with aryl iodide or aryl bromide 45 (e.g., Ullmann coupling or Buchwald-Hartwig coupling) can yield the final compound 72 (Yang et al., Org. Process Res. & Dev. 2022, 26(6), 1690-1750; Surry and Buchwald, Chem. Sci. 2011, 2(1), 27-50). [ka]

[0219] The chemistry described in Schemes 1-16 illustrates various methods for synthesizing the compounds described. It should be understood that other variations of these methods may be used, and that the strict protecting groups, the specific transition metals used in the described reaction sequence or catalytic coupling reactions may be replaced with suitable substitutes known to those skilled in the art.

[0220] The following compound (1) represents various embodiments of the present invention: [ka] .

[0221] experiment All commercially available solvents and reagents were used as received. 1 ¹H NMR spectra were recorded using a Bruker Avance III HD 300 MHz or Bruker Avance III HD 400 MHz. MS samples were analyzed using a Shimadzu LCMS-2020 mass spectrometer employing electrospray ionization in both positive and negative modes. Samples were introduced into the mass spectrometer using chromatography. Unless otherwise specified in the experimental details, the purity of the final product was ≥90%. HPLC purity was measured using a Shimadzu Acquity HPLC system.

[0222] The following are acronyms used in the experimental section for well-known chemical solvents, reagents, parameters, and techniques: 1 1H NMR: Proton Nuclear Magnetic Resonance Spectroscopy ACN: Acetonitrile Acetic acid (ATOH) B2pin2: 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan BINAP:2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (Boc2)O: Ditert-butyl dicarbonate c-Bu: Cyclobutyl c-Pr:Cyclopropyl CDI: Carbonyldiimidazole CeCl3: Cerium(III) chloride CH2Cl2: Dichloromethane CH3I: Iodomethane CHCl3: Chloroform CO2: Carbon dioxide Cs2CO3: Cesium Carbonate CsF: Cesium Fluoride CuCl: Cuprous chloride DAST: Diethylaminosulfur trifluoride DBAD: Di-tert-butyl azodicarboxylate DBU:1,8-Diazabicyclo[5.4.0]undec-7-ene DCM: Dichloromethane DIBAL: Diisobutylaluminum hydride DIEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DTAD: Di-tert-butyl azodicarboxylate EA: Ethyl acetate ee: Enantiomer excess Et2O: Diethyl ether Et3N: Triethylamine Et3SiH: Triethylsilane æ:ethyl acetate EtOH: Ethanol FA: Formic acid h: time H2O: Water HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl: Hydrochloric acid Hex: Hexane HPLC: High-Performance Liquid Chromatography IPA: Isopropanol K2CO3: Potassium carbonate K3PO4: Potassium triphosphate KOAc: Potassium acetate LiOH: Lithium hydroxide mCPBA: Meth-chloroperoxybenzoic acid Me: Methyl MeCN: Acetonitrile MeOH: methanol mg: milligrams MgSO4: Magnesium sulfate min: minutes mL: milliliter MsCl: Methanesulfonyl chloride Ms2O: Methanesulfone anhydrous NaBH4: Sodium borohydride N2: Nitrogen NaCl: Sodium Chloride Na2CO3: Sodium carbonate NaH: Sodium hydride NaI: Sodium iodide NaOH: Sodium hydroxide NaHCO3: Sodium Bicarbonate NaH2PO4: Monosodium phosphate Na2SO3: Sodium sulfite Na2SO4: Sodium sulfate NH3: Ammonia NH4Cl: Ammonium chloride NH4HCO3: Ammonium bicarbonate NH4OH: Ammonium hydroxide (NH4)2CO3: Ammonium carbonate NMP: N-methylpyrrolidone Oxetane: A four-membered ring containing three carbon ring atoms and one oxygen ring atom. PBr3: Phosphorus tribromide PCl5: Phosphorus pentachloride Pd / C: Palladium / Carbon Pd-PEPPSI-IHeptCl 3-Chloropyridine:Dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) Pd(amphos)Cl2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd(dppf)Cl2:(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride PE: Petroleum ether POCl3: Phosphorus oxychloride PPh3: Triphenylphosphine Prep: preparative PyBOP: Benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate RuPhos:2-Dicyclohexylphosphino-2',6'-Diisopropoxybiphenyl RuPhos-Pd-G3: Methanesulfonate (2-dicyclohexylphosphinol-2',6'-di-isopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) SEM-Cl:2-(trimethylsilyl)ethoxymethylchloride SiO2: Silica T4P: 2,4,6-Tributyl-1,3,5,2,4,6-Trioxatriphosfinan 2,4,6-Trioxide TBAF: Tetrabutylammonium fluoride TBSCl:tert-butyldimethylsilyl chloride TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran Ti(OEt)4: Titanium (IV) Ethoxide Ti(Oi-Pr)4: Titanium(IV) Isopropoxide TLC: Thin-layer chromatography Xantphos:4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos-Pd-G4:(SP-4-3)-[Dicyclohexyl[2',4',6'-Tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15]

[0223] Intermediate 1: (R)-N-((R)-1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2-methylpropane-2-sulfinamide [ka]

[0224] Step 1: Preparation of 4-bromo-2-(hydroxy-0)-6-methyl-2,3-dihydro-1H-inden-1-one [ka] 4-bromo-6-methyl-2,3-dihydroinden-1-one (2 g, 8.89 mmol) was slowly added dropwise at 0°C to a solution of HCl (10 mL, 12 M) and Et2O (10 mL) while stirring. 3-methylbutyl nitrite (1.25 g, 10.66 mmol) was added dropwise. The resulting solution was stirred at room temperature for 4 hours. The mixture was cooled to 0°C, the precipitated solid was collected by filtration, and washed with H2O (3 × 50 mL). The resulting mixture was concentrated under vacuum. The crude organism was used directly in the next step without further purification. This yielded 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-1H-inden-1-one (1.5 g, 66% yield) as a grayish-white solid. MS: (ES + m / z = 254.1 [M+H] + .

[0225] Step 2: Production of 5-bromo-3-chloro-7-methyl-2H-isoquinoline-1-one [ka] To a solution of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-1H-inden-1-one (1.5 g, 5.90 mmol) in CHCl3 (30 mL) while stirring, PCl5 (2.46 g, 11.8 mmol) was slowly added at 0°C. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. To the crude organism, a solution of 1,4-dioxane in 4 M HCl (30 mL) was added. The resulting solution was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by grinding with 5:1 PE / siRNA to obtain 5-bromo-3-chloro-7-methyl-2H-isoquinoline-1-one (1 g, 61% yield) as a yellow solid. MS: (ES - ) m / z = 269.9 [M-1] - .

[0226] Step 3: 5-Bromo-3-chloro-2,7-dimethylisoquinoline-1-one [ka] To a 10 mL solution of 5-bromo-3-chloro-7-methyl-2H-isoquinoline-1-one (1.3 g, 4.77 mmol) in DMF (10 mL) while stirring, NaH (0.17 g, 7.16 mmol) was slowly added little by little at 0°C. The resulting solution was stirred at 0°C for 20 minutes. Iodomethane (0.81 g, 5.72 mmol) was slowly added dropwise at 0°C, and the resulting solution was stirred overnight at room temperature. The reaction was quenched with water (40 mL), and the resulting mixture was extracted with siRNA (3 × 50 mL). The combined organic layers were washed with brine (3 × 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 obtain 5-bromo-3-chloro-2,7-dimethylisoquinoline-1-one (900 mg, 65% yield) as a reddish-brown solid. MS: (ES + m / z = 286.0 [M+H] + .

[0227] Step 4: Production of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1-one [ka] A solution of 5-bromo-3-chloro-2,7-dimethylisoquinoline-1-one (2.6 g, 9.07 mmol), tributyl(1-ethoxyethenyl) stannan (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 and treated with aqueous 1N HCl (10 mL), and stirred for 15 minutes. The resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with water (3 × 60 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1-one (1.9 g, 83% yield) as a yellow solid. MS: ES + (m / z) = 250.1 [M+H] + .

[0228] Step 5: Preparation of (R,E)-N-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethylidene)-2-methylpropane-2-sulfinamide [ka] Ti(Oi-Pr)4 (55.78 g, 196.2 mmol) was added to a THF (200 mL) solution of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1-one (9.8 g, 39.2 mmol) and (R)-2-methylpropane-2-sulfinamide (23.78 g, 196.2 mmol) while stirring. 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 was washed with ethyl acetate (3 × 300 mL). The filtrate was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with H2O (3 × 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 obtain (R,E)-N-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (9g, 64% yield) as a yellow solid. MS: (ES + m / z = 353.1 [M+H] + .

[0229] Step 6: Preparation of (R)-N-((R)-1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2-methylpropane-2-sulfinamide [ka] NaBH4 (2.81 g, 74.4 mmol) was added at -78°C to a solution of (R,E)-N-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (10.5 g, 29.76 mmol) and CeCl3·7H2O (16.6 g, 44.6 mmol) in MeOH (120 mL) while stirring. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (150 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (2 × 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 further purified with HP-Flash (25%-55% ACN in H2O (0.1% FA) solution over 45 minutes) to obtain (R)-N-((R)-1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2-methylpropane-2-sulfinamide (6.5 g, 61% yield) as a grayish-white solid. MS: (ES + m / z = 355.0 [M+H] + .

[0230] Intermediate 2: (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka]

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

[0232] Step 2: Preparation of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] (R)-N-((R)-1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)-2-methylpropane-2-sulfinamide (3.6 g, 7.4 mmol) was added dropwise to a solution of (R)-N-((R)-1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)-2-methylpropane-2-sulfinamide (3.6 g, 7.4 mmol) in MeOH (37 mL) while stirring, with a solution of 4 M HCl with HCl (3.7 mL, 14.8 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was diluted with HCl (50 mL) and washed with saturated aqueous solution NaHCO3 (3 × 15 mL). The organic matter was then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to obtain (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(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-(1-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N-methylbenzamide [ka]

[0234] Step 1: Preparation of 2-amino-3-bromo-5-fluoro-N-methylbenzamide [ka] To a solution of 2-amino-3-bromo-5-fluorobenzoic acid (5 g, 21.4 mmol) in THF (50 mL), CDI (4.16 g, 25.6 mmol) was added at 25 °C. The mixture was then stirred at 70 °C for 1 hour, followed by the addition of methylamine hydrochloride (5.77 g, 85.5 mmol) and TEA (2.16 g, 21.4 mmol, 3 mL). The resulting mixture was stirred at 70 °C for 1 hour. The reaction was quenched with water (50 mL) and extracted with EA (50 mL x 3). The combined organic matter was 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 obtain 2-amino-3-bromo-5-fluoro-N-methylbenzamide (4.7 g, 89% yield) as a grayish-white solid. LCMS (ESI + m / z = 247.1 (M+H), t R = 0.491 minutes (Method C).

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

[0236] Step 3: Preparation of 2-amino-5-fluoro-3-(1-hydroxyethyl)-N-methylbenzamide [ka] 3-acetyl-2-amino-5-fluoro-N-methylbenzamide (2.5 g, 11.9 mmol) was dissolved in MeOH (30 mL) and NaBH4 (1.45 g, 38.3 mmol) was added at 0°C. The mixture was stirred at 25°C for 1 hour, and then quenched by adding saturated aqueous solution NH4Cl (10 mL) at 0°C. The resulting mixture was diluted with water (30 mL) and extracted with EA (20 mL x 3). The combined organic matter was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 0:1~4:1) to obtain 2-amino-5-fluoro-3-(1-hydroxyethyl)-N-methylbenzamide (3.6 g, 99% yield) as a yellow oil. LCMS (ESI + m / z = 195.0 (M+H - H2O), t R = 0.362 minutes (Method C).

[0237] Step 4: Preparation of 2-amino-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N-methylbenzamide [ka] 2-amino-5-fluoro-3-(1-hydroxyethyl)-N-methylbenzamide (3.6 g, 17.0 mmol) and imidazole (3.46 g, 50.9 mmol) were mixed in DCM (30 mL) and TBSCl (5.11 g, 33.9 mmol) in DMF (6 mL) at 0°C. The mixture was stirred at 25°C for 12 hours. 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 organic matter was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA = 1:0~10:1) to obtain 2-amino-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N-methylbenzamide (4 g, 72% yield) as a white solid. LCMS (ESI + m / z = 327.1 (M+H), tR = 0.623 minutes (Method C).

[0238] Intermediate 4: (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one [ka]

[0239] (R)-N-((R)-1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2-methylpropane-2-sulfinamide (intermediate 1) (12 g, 33.8 mmol) was dissolved in a 4 M HCl solution of dioxane (169 mL, 676 mmol). The mixture was stirred at 25°C for 1 hour 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 obtain (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (9.9 g, HCl salt) as a white solid. LCMS (ESI + ) m / z = 251.2 (M+H), t R = 0.413 minutes (Method C).

[0240] Intermediate 5: (R)-5-(1-aminoethyl)-3-chloro-7-fluoro-2-methylisoquinoline-1(2H)-one [ka]

[0241] This intermediate was prepared using a method similar to that described for intermediates 1 and 4, but with 4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one instead of 4-bromo-6-methyl-2,3-dihydro-1H-inden-1-one.

[0242] Intermediate 6: (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one [ka]

[0243] Step 1: Preparation of 8-bromo-3,6-dimethyl-2-thioxo-2,3-dihydroquinazoline-4(1H)-one [ka] Methyl isothiocyanate (19.0 g, 261 mmol) was added to a solution of 2-amino-3-bromo-5-methylbenzoic acid (30.0 g, 130 mmol) and TEA (45 mL, 326 mmol) in EtOH (500 mL) under an argon atmosphere at room temperature. The resulting mixture was stirred at 100°C for 4 hours. The mixture was then concentrated under reduced pressure. The residue was dissolved in Et2O (500 mL), the precipitated solid was collected by filtration, and washed with Et2O (2 × 300 mL) to obtain 8-bromo-3,6-dimethyl-2-thioxo-2,3-dihydroquinazoline-4(1H)-one (31.8 g, 85% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 7.79-7.69 (m, 1H), 7.73-7.70 (m, 1H), 3.66 (s, 3H), 2.33 (s, 3H).

[0244] Step 2: Production of 8-bromo-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one [ka] Dimethyl sulfate (5.9 g, 47.3 mmol) was added to a solution of 8-bromo-3,6-dimethyl-2-thioxo-2,3-dihydroquinazoline-4(1H)-one (9.0 g, 31.5 mmol) and NaOH (2.52 g, 63.1 mL) in DMF (90 mL) under a argon atmosphere at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then cooled to 0°C and quenched with ice water (50 mL). The resulting solid was washed with water (5 × 10 mL) and then dried under reduced pressure to obtain 8-bromo-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one (8.0 g, 85% yield) as a white solid. 1 ¹H NMR (300 MHz, chloroform-d): δ 7.99–7.91 (m, 1H), 7.83–7.76 (m, 1H), 3.60 (s, 3H), 2.73 (s, 3H), 2.46–2.40 (m, 3H).

[0245] Step 3: Production of 8-acetyl-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one [ka] To a mixture of 8-bromo-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one (7.1 g, 23.7 mmol) and tributyl(1-ethoxyethenyl) stannane (10.3 g, 28.5 mmol) in a 1,4-dioxane solution (100 mL) while stirring, tetrakis(triphenylphosphine)palladium(O) (2.7 g, 2.4 mmol) was added gradually at room temperature under an argon atmosphere. The resulting mixture was stirred overnight at 100 °C. The mixture was then cooled to 0 °C. 14.4 mL of 1N aqueous HCl (0) was added gradually at 0 °C for 5 minutes. The resulting mixture was then stirred at room temperature for 1 hour and then diluted with ice water (50 mL). The mixture was then extracted with ELISA (3 × 50 mL) and the organic matter was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (increasing PE:EA = 1:0 to 5:1 over 30 minutes) to obtain 8-acetyl-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one (4.0 g, 64% yield) as a white solid. 1 ¹H NMR (300 MHz, chloroform-d): δ 8.22–8.15 (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).

[0246] Step 4: Preparation of (R,E)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazoline-8-yl)ethylidene)-2-methylpropane-2-sulfinamide [ka] 8-Acetyl-3,6-dimethyl-2-(methylthio)quinazoline-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 at 0°C with ice and salt (400 mL). The resulting mixture was filtered, and the filter cake was washed with ELISA (2 × 200 mL). The resulting filtrate was extracted with ELISA (2 × 400 mL). The combined organic matter was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude organism was used directly in the next step without further purification. LCMS (ESI + m / z = 366.0 (M+H) + .

[0247] Step 5: Preparation of (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazoline-8-yl)ethyl)-2-methylpropane-2-sulfinamide [ka] To a solution of (R,E)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (50 g, 137 mmol) and CeCl3·7H2O (76.5 g, 205 mmol) in MeOH (400 mL) while stirring, NaBH4 (12.9 g, 342 mmol) was gradually added under an argon atmosphere at -78 °C. The resulting mixture was stirred for 2 hours at -78 °C to room temperature. The reaction was quenched at 0 °C with saturated aqueous solution NH4Cl (800 mL). The resulting mixture was then extracted with CH2Cl2 (3 × 800 mL). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous MeCN (10 mmol / L NH4HCO3), 40% to 95% gradient over 30 minutes; detector, UV 254 nm) to obtain (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazoline-8-yl)ethyl)-2-methylpropane-2-sulfinamide (42.6 g, 85% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ values: 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).

[0248] Step 6: Production of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one [ka] To an ethyl acetate solution of a mixture of (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (4 g, 10.9 mmol) being stirred, aqueous 8N HCl (50 mL) was gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched at 0°C with ice and salt (60 mL). The resulting mixture was extracted with ethyl acetate (3 × 60 mL). The aqueous layer was adjusted to pH 10 by adding concentrated NH4OH. The resulting mixture was extracted with dimethyl chloride (2 × 50 mL). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one (2.8 g, 97% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 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)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate [ka]

[0250] (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4, 3g, 12.0 mmol), DIEA (1.55g, 12.0 mmol), and (Boc)2O (3.92g, 18.0 mmol) were mixed in THF (30 mL) and stirred at 25°C for 0.5 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was ground in PE (50 mL) at 25°C for 30 minutes to obtain tert-butyl (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (3.4 g, 81% yield) as a bright yellow solid. LCMS (ESI + m / z = 351.2 (M+H).

[0251] Intermediate 8: 7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine [ka]

[0252] Step 1: Preparation of 7-(5-bromopyrimidine-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine [ka] 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (926 mg, 7.46 mmol) and 5-bromo-2-fluoropyrimidine (1.1 g, 6.22 mmol) were dissolved in DMSO (10 mL), to which DIEA (3.25 mL, 18.7 mmol) was added. The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was then diluted with H2O (100 mL) and extracted with 1:3 IPA:DCM (50 mL x 3). The combined organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude organism was ground in 10:1 PE:EA (20 mL), the resulting solid was recovered by filtration, and the filter cake was washed with PE (20 mL) to obtain 7-(5-bromopyrimidine-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1.5 g, 85% yield) as a grayish-white solid. LCMS (ESI + m / z = 281.1 (M+H).

[0253] Step 2: Preparation of 7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine [ka] A 10 mL solution of dioxane containing a mixture of 7-(5-bromopyrimidine-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 2.13 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (813 mg, 3.20 mmol), KOAc (314 mg, 3.20 mmol), and Pd(dppf)Cl2·CH2Cl2 (174 mg, 0.21 mmol) was deoxygenated three times and purged with N2. The mixture was then stirred at 90°C for 2 hours. The reaction mixture was filtered, and the filtrate was used directly. LCMS (ESI + m / z = 329.2 (M+H).

[0254] Intermediate 9: (2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)boronic acid [ka]

[0255] Step 1: Preparation of 4-bromo-1,3-dimethylpyridine-2(1H)-one [ka] To a solution of 4-bromo-3-methylpyridine-2(1H)-one (900 mg, 4.79 mmol) in DMF (15 mL), K2CO3 (1.98 g, 14.4 mmol) and iodomethane (1.02 g, 7.18 mmol) were added. The mixture was stirred at 25°C for 8 hours. The mixture was diluted with water (50 mL) and then extracted three times with DCM (25 mL each). The combined organic matter was washed with brine (4 × 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-bromo-1,3-dimethylpyridine-2(1H)-one (1 g, 93% yield) as a white solid. LCMS (ESI + m / z = 202.0 (M+H).

[0256] Step 2: Preparation of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one [ka] To a solution of a mixture of 4-bromo-1,3-dimethylpyridine-2(1H)-one (950 mg, 4.70 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.39 g, 9.40 mmol) in dioxane (20 mL), KOAc (1.38 g, 14.1 mmol) and Pd(dppf)Cl2 (344 mg, 0.47 mmol) were added. The resulting mixture was deoxygenated three times and purged with N2. The mixture was then heated to 100°C and stirred for 1 hour. Next, the reaction mixture was concentrated under reduced pressure to obtain 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (crude yield of 3g) as a black-brown solid, which was used in the next step without further purification. LCMS (ESI + m / z = 250.2 (M+H).

[0257] Step 3: Production of 4-(5-bromopyrimidine-2-yl)-1,3-dimethylpyridine-2(1H)-one [ka] To a solution of a mixture of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (1.17 g, 4.70 mmol) and 5-bromo-2-iodopyrimidine (1.61 g, 5.64 mmol) in dioxane (10 mL) and H2O (1 mL), K2CO3 (1.95 g, 14.1 mmol) and Pd(dppf)Cl2 (344 mg, 0.47 mmol) were added. The resulting mixture was degassed three times and purged with N2. The mixture was heated to 100°C, stirred for 2 hours, then filtered, the filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Crude organisms were purified by silica gel column chromatography (eluting with PE:EA 1:1 to 1:2) to obtain 4-(5-bromopyrimidine-2-yl)-1,3-dimethylpyridine-2(1H)-one (900 mg, 61% yield) as a brown solid. LCMS (ESI +m / z = 280.0 (M+H).

[0258] Step 4: Production of (2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)boronic acid [ka] To a solution of a mixture of 4-(5-bromopyrimidine-2-yl)-1,3-dimethylpyridine-2(1H)-one (300 mg, 1.07 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (544 mg, 2.14 mmol) in dioxane (10 mL), KOAc (315 mg, 3.21 mmol) and Pd(dppf)Cl2 (78 mg, 0.11 mmol) were added. The resulting mixture was degassed three times and purged with N2. The mixture was then heated to 100°C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain (2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)boronic acid (520 mg, crude yield) as a black-brown solid, which was used directly without further purification. LCMS (ESI + m / z = 246.1 (M+H).

[0259] Intermediate 10: 1-methyl-6-(trimethylstannyl)pyrazine-2(1H)-one [ka]

[0260] Step 1: Production of 6-bromo-1-methylpyrazine-2-one [ka] To a solution of 6-bromo-1H-pyrazine-2-one (6 g, 34.3 mmol) in DMF (60 mL), K2CO3 (14.2 g, 103 mmol) was added at room temperature under a nitrogen atmosphere. Iodomethane (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 hour. The reaction product was then diluted with ice water (100 mL) at 0°C, and the resulting mixture was extracted with siRNA (3 × 100 mL). The combined organic matter was then washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting at PE:EA = 1:1) to obtain 6-bromo-1-methylpyrazine-2-one (3 g, 46% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.96 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 3.63 - 3.51 (m, 3H).

[0261] Step 2: Production of 1-methyl-6-(trimethylstannyl)pyrazine-2(1H)-one [ka] To a solution of 6-bromo-1-methylpyrazine-2-one (2.0 g, 13.8 mmol) in dioxane (20 mL), Pd(PPh3)4 (3.19 g, 2.7 mmol) was added at room temperature under an argon atmosphere, followed by the dropwise addition of hexamethyldistannan (13.6 g, 41.5 mmol) with stirring. The resulting mixture was stirred overnight at 100°C. The reaction was then quenched by adding ice water (50 mL) at 0°C, and the resulting mixture was extracted with SiO2 (3 × 50 mL). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain 1-methyl-6-(trimethylstannyl)pyrazine-2-one (700 mg, 18% yield) as a bright yellow oil. LCMS (ESI + m / z = 274.7 (M+H).

[0262] Intermediate 11: 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-one [ka]

[0263] To a THF (5 mL) solution of a mixture of 6-bromo-1-methylpyrazine-2-one (intermediate 10, step 1, 200 mg, 1.06 mmol) and bis(pinacorato)diborone (403 mg, 1.59 mmol) being stirred, n-BuLi (0.63 mL, 1.59 mmol) was added gradually under an argon atmosphere at -78°C. The resulting mixture was stirred at -78°C for 5 hours. The reaction was quenched by adding EtOH (20 mL) at 0°C, and the resulting mixture was concentrated under reduced pressure to obtain 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-one (200 mg, 80% crude yield) as a white solid. The crude product was used directly without further purification. LCMS (ESI + m / z = 237.0 (M+H).

[0264] Intermediate 12: (2-(1-methyl-6-oxo-1,6-dihydropyridazine-4-yl)pyrimidine-5-yl)boronic acid [ka]

[0265] Step 1: Production of 5-chloro-2-methylpyridazine-3(2H)-one [ka] Iodomethane (13.1 g, 91.9 mmol) was added to a solution of 5-chloropyridazine-3(2H)-one (6 g, 46.0 mmol) and Cs2CO3 (15 g, 46 mmol) in DMF (150 mL). The reaction mixture was stirred at 30°C for 8 hours. The reaction mixture was then diluted with H2O (150 mL) and extracted with ELISA (3 × 120 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (eluting with PE:EA = 1:1) to obtain 5-chloro-2-methylpyridazine-3(2H)-one (5.2 g, 74% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 3.76 (s, 3H).

[0266] Step 2: Production of (1-methyl-6-oxo-1,6-dihydropyridazine-4-yl)boronic acid [ka] To a solution of 5-chloro-2-methylpyridazine-3(2H)-one (2.0 g, 13.8 mmol) and XPhos (1.32 g, 2.77 mmol) in dioxane (50 mL), KOAc (2.72 g, 27 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (7.03 g, 27 mmol) and Pd2(dba)3 (1.27 g, 1.38 mmol) were added. The reaction mixture was stirred at 90°C for 4 hours under an N2 atmosphere. The reaction mixture was then concentrated to obtain a residue, which was diluted with H2O (50 mL) and siRNA (3 × 40 mL). Next, the aqueous phase was freeze-dried to obtain (1-methyl-6-oxo-1,6-dihydropyridazine-4-yl)boronic acid (2.3 g, crude product) as a white solid, which was used directly in the next step without further purification. LCMS (ESI + m / z = 155.0 (M+H).

[0267] Step 3: Production of 5-(5-bromopyrimidine-2-yl)-2-methylpyridazine-3(2H)-one [ka] (1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)boronic acid (1.5 g, 9.74 mmol) and 5-bromo-2-iodopyrimidine (2.78 g, 9.74 mmol) were dissolved in dioxane (30 mL) and H2O (3 mL). K2CO3 (2.69 g, 19.5 mmol) and Pd(dppf)Cl2 (713 mg, 0.97 mmol) were added to these solutions. The reaction mixture was stirred at 90°C for 1 hour under an N2 atmosphere. The reaction mixture was then diluted with H2O (10 mL) and extracted with ELISA (3 × 20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was ground in PE:EA = 5:1 (50 mL) to obtain 5-(5-bromopyrimidine-2-yl)-2-methylpyridazine-3(2H)-one (1.2 g, 40% yield) as a yellow solid. LCMS (ESI + m / z = 266.9 (M+H).

[0268] Step 4: Production of (2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)boronic acid [ka] KOAc (551 mg, 5.62 mmol) and Pd(dppf)Cl2 (137 mg, 0.19 mmol) were added to a 20 mL solution of 5-(5-bromopyrimidine-2-yl)-2-methylpyridazine-3(2H)-one (0.50 g, 1.87 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (713 mg, 2.81 mmol) in dioxane (20 mL). The reaction mixture was stirred at 90 °C for 2 hours under an N2 atmosphere. The reaction mixture was then filtered, and the filter cake was rinsed with Â(3 × 30 mL). Next, the filtrate was concentrated to obtain (2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)boronic acid (400 mg, crude product) as a gray solid, which was used in the next step without further purification. LCMS (ESI + m / z = 232.9 (M+H).

[0269] Intermediate 13: 1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2(1H)-one [ka]

[0270] Step 1: Production of 3-(benzyloxy)-5-chloro-2-methylpyrazine [ka] 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 small increments under a nitrogen atmosphere at 0°C. After 30 minutes, benzyl alcohol (4.98 g, 46.0 mmol) was added at 0°C. The resulting mixture was then stirred at room temperature for 2 hours. The reaction was quenched by adding water (100 mL) at 0°C. The resulting mixture was extracted with diethyl ether (3 × 200 mL). The combined organic matter was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 3-(benzyloxy)-5-chloro-2-methylpyrazine (5.1 g, crude yield) as a yellow oil. LCMS (ESI + m / z = 235.1 (M+H).

[0271] Step 2: Production of 6-chloro-3-methylpyrazine-2-ol [ka] To a toluene (50 mL) solution of 3-(benzyloxy)-5-chloro-2-methylpyrazine (8 g, 49.0 mmol) while stirring, BBr3 (1.0 M dichloromethane solution, 147 mL, 147 mmol) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C for 1 hour. The reaction was quenched with MeOH at 0°C, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting at CH2Cl2:MeOH = 5:1) to obtain 6-chloro-3-methylpyrazine-2-ol as a white solid (3.7 g, 75% yield). LCMS (ESI + m / z = 145.2 (M+H).

[0272] Step 3: Production of 6-chloro-1,3-dimethylpyrazine-2(1H)-one [ka] To a 20 mL solution of 6-chloro-3-methylpyrazine-2-ol (2 g, 13.8 mmol) and K2CO3 (5.74 g, 41.5 mmol) in DMF (20 mL) while stirring, iodomethane (3.93 g, 27.7 mmol) was gradually added at 0°C under a nitrogen atmosphere. The resulting mixture was then stirred at room temperature for 1 hour. The reaction was then quenched by adding water (100 mL) at 0°C. The resulting mixture was extracted with SiO2 (3 × 100 mL). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting at PE:EA = 1:1) to obtain 6-chloro-1,3-dimethylpyrazine-2(1H)-one (1 g, crude yield) as an oil. LCMS (ESI + m / z = 159.2 (M+H).

[0273] Step 4: Production of 1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2(1H)-one [ka] 6-chloro-1,3-dimethylpyrazine-2-one (200 mg, 1.26 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.6 g, 6.31 mmol) were added to a solution of 1,4-dioxane (2 mL) while stirring. Pd(dppf)Cl2·CH2Cl2 (103 mg, 0.13 mmol) and KOAc (371 mg, 3.78 mmol) were added at room temperature. The resulting mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with 1,4-dioxane (2 mL). The filtrate was concentrated and used directly without further purification. LCMS: (ESI + m / z = 251.4(M+H). [Examples]

[0274] Example 1: (R)-5-(1-((2-(ethylsulfonyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka]

[0275] Step 1: Production of (2-bromophenyl)(ethyl)sulfane [ka] To a solution of 2-bromobenzenethiol (2.7 g, 14.3 mmol) in acetone (10 mL), K2CO3 (1.97 g, 28.6 mmol) was added, followed by iodoethane (4.45 g, 28.6 mmol). The solution was then stirred at 50°C for 12 hours. The solution was partitioned into 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 obtain (2-bromophenyl)(ethyl)sulfan (3 g, 96% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 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).

[0276] Step 2: Production of 1-bromo-2-(ethylsulfonyl)benzene [ka] To a 20 mL solution of (2-bromophenyl)(ethyl)sulfan in DCM, m-CPBA (4.8 g, 23.7 mmol, 85% purity) was added at 0°C, and the mixture was stirred at 25°C for 1 hour. 30 mL of Na₂SO₃ solution was added to the mixture, and it was extracted using 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 = 1:0~10:1) to obtain 1-bromo-2-(ethylsulfonyl)benzene (2.2 g, 89% yield) as a colorless oil. LCMS (ESI + ) m / z = 249.0 (M+H), t R = 0.500 minutes (Method C).

[0277] Step 3: Production of (R)-5-(1-((2-(ethylsulfonyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] To a solution of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (intermediate 2) (50 mg, 131 μmol) and 1-bromo-2-(ethylsulfonyl)benzene (100 mg, 401 μmol) in toluene (3 mL), Cs2CO3 (128 mg, 392 μmol) and RuPhos-Pd-G3 (22 mg, 26.2 μmol) were added, and the mixture was stirred at 105 °C for 12 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, and water (5 mL) was added. The mixture was then extracted with ethyl acetate (5 mL x 3), the combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA = 1:2) to obtain a brown oily substance. Next, the oily substance was further purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 65%~75%B over 10 minutes), and the eluent was freeze-dried to obtain (R)-5-(1-((2-(ethylsulfonyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (12.5 mg, 8% yield) as a yellow solid. LCMS (ESI + ) m / z = 551.2 (M+H), t R = 0.592 minutes (Method C); 1 H NMR (400 MHz, DMSO-d6): δ 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-(1-((2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka]

[0279] Step 1: Production of (2-bromophenyl)(chloromethyl)sulfane [ka] To a solution of 1-bromo-2-methylsulfanylbenzene (500 mg, 2.46 mmol) in DCM (6 mL), NCS (362 mg, 2.71 mmol) was gradually added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered through a short silica pad and eluted with DCM (20 mL). The solvent was removed under reduced pressure to obtain (2-bromophenyl)(chloromethyl)sulfan (550 mg, crude) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 7.65 - 7.57 (m, 2H), 7.41 - 7.33 (m, 1H), 7.21 - 7.14 (m, 1H), 5.02 (s, 2H).

[0280] Step 2: Production of (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)sulfane [ka] To a solution of 2,2,2-trifluoroethanol (569 mg, 5.68 mmol) in DMF (2 mL), NaH (129 mg, 3.22 mmol, 60% purity) was added. The mixture was stirred under a nitrogen atmosphere at 0°C for 1.5 hours, followed by NaI (284 mg, 1.89 mmol) and (2-bromophenyl)(chloromethyl)sulfan (450 mg, 1.89 mmol). The mixture was then warmed to 25°C and stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was quenched at 0°C under a nitrogen atmosphere with saturated aqueous solution NH4Cl (20 mL). The mixture was extracted with ₹ (20 mL x 3), 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®; 10g SepaFlash® Silica Flash Column, 100% PE eluent, 60 mL / min) to obtain (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)sulfan (500 mg, crude) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 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).

[0281] Step 3: Production of 1-bromo-2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)benzene [ka] (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)sulfan (550 mg, 1.83 mmol) was dissolved in DCM (8 mL) and m-CPBA (1.11 g, 5.48 mmol, 85% purity) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was then quenched with saturated Na₂SO₃ (60 mL) and extracted with DCM (30 mL x 3). The combined organic phase was 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®; 10g SepaFlash® Silica Flash Column, 0-20% EA / PE eluent, gradient @ 60 mL / min) to obtain 1-bromo-2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)benzene (480 mg, 79% yield) as a colorless oil. LCMS (ESI + ) m / z = 354.9 / 356.9 (M+Na), t R = 0.781 minutes (Method E).

[0282] Step 4: Preparation of (R)-2,7-dimethyl-5-(1-((2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] A toluene (1 mL) solution of a mixture of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (intermediate 2) (50 mg, 131 μmol), 1-bromo-2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)benzene (152 mg, 458 μmol), Cs2CO3 (170 mg, 523 μmol), and RuPhos-Pd-G3 (109 mg, 131 μmol) was degassed three times, purged with N2, and then stirred under a nitrogen atmosphere at 110°C for 12 hours. The mixture was then filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by preparative TLC (SiO2, PE:EA=2:1) ​​to obtain the crude product, which was then further purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 60%~90% B over 10 minutes) and preparative HPLC (column: WWaters xbridge 150×25mm×10μm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 60%~80% B over 8 minutes) to obtain a yellow solid, which was further purified by SFC (column: DAISEL Chiralcel) Purified using OJ-H (250mm x 30mm, 5μm); mobile phase: [CO2-EtOH (0.1%NH3·H2O)]; B%: 20%, fixed composition elution mode), (R)-2,7-dimethyl-5-(1-((2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (18.36 mg, 22% yield) as a white solid. LCMS (ESI + ) m / z = 635.3 (M+H), t R = 0.606 minutes (Method C); 1H NMR (400 MHz, DMSO-d6): δ 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[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (enantiomer 1)

[0284] Example 4: 6-Fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (enantiomer 2) [ka]

[0285] Step 1: Preparation of N-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-6-(methylcarbamoyl)phenyl)-3-(4-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxamide [ka] To a solution of 2-amino-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N-methylbenzamide (intermediate 3) (500 mg, 1.53 mmol) and 3-(4-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (347 mg, 1.68 mmol) in 10 mL of ethyl acetate, T4P (3.31 g, 4.59 mmol, 50% purity) and pyridine (606 mg, 7.66 mmol) were added. The mixture was then stirred at 25°C for 3 hours. The reaction mixture was partitioned into H2O (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain N-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-6-(methylcarbamoyl)phenyl)-3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-carboxamide (800 mg, crude) as a grayish-white solid. LCMS (ESI + ) m / z = 515.3 (M+H), t R = 0.735 minutes (Method C). Step 2: Preparation of 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazoline-4(3H)-one [ka]

[0286] N-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-6-(methylcarbamoyl)phenyl)-3-(4-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxamide (750 mg, 1.46 mmol) was dissolved in DMF (10 mL) and K2CO3 (604 mg, 4.37 mmol) was added. The mixture was stirred at 90°C for 12 hours. The reaction mixture was partitioned into H2O (50 mL) and ELISA (50 mL). The organic phase was separated, washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:0~93:7) to obtain 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazoline-4(3H)-one (670 mg, 92% yield) as a white solid. LCMS (ESI + m / z = 497.3 (M+H), t R = 0.920 minutes (Method D).

[0287] Step 3: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-8-(1-hydroxyethyl)-3-methylquinazoline-4(3H)-one [ka] 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazoline-4(3H)-one (620 mg, 1.25 mmol) was dissolved in THF (5 mL) and TBAF (1 M, 2.5 mL) was added. The mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was then partitioned into H₂O (20 mL) and ELISA (20 mL). The organic phase was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:0~4:1) to obtain 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-8-(1-hydroxyethyl)-3-methylquinazoline-4(3H)-one (410 mg, 85% yield) as a white solid. LCMS (ESI + ) m / z = 383.3 (M+H), t R = 1.044 minutes (Method E).

[0288] Step 4: Preparation of 8-(1-bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazoline-4(3H)-one [ka] 6-Fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-8-(1-hydroxyethyl)-3-methylquinazoline-4(3H)-one (320 mg, 837 μmol) was added to a 5 mL solution of DCM with PBr3 (453 mg, 1.67 mmol) at 0°C. The mixture was stirred at 0°C for 0.5 hours. The reaction was then quenched with H2O (10 mL) at 0°C, and the mixture was adjusted to pH 7 with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with 3 x 5 mL DCM solutions. The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium 2SO4, and then concentrated under reduced pressure to obtain 8-(1-bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazoline-4(3H)-one (300 mg, crude) as a white solid. LCMS (ESI + ) m / z = 445.1 (M+H), t R = 0.709 minutes (Method C).

[0289] Step 5: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one [ka] 2-methylsulfonylaniline (230 mg, 1.34 mmol) was dissolved in DMF (5 mL) and NaH (90 mg, 2.25 mmol, 60% purity) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. 8-(1-bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazoline-4(3H)-one (350 mg, 786 μmol) was added to the mixture and stirred at 25°C for another 0.5 hours. The reaction mixture was quenched by adding saturated NH4Cl solution (50 mL) at 0°C and then extracted with ELISA (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water (FA)-ACN]; gradient: 58%~88% B over 10 minutes) to obtain 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (110 mg, 26% yield) as a white solid. LCMS (ESI + ) m / z = 536.3 (M+H), t R = 0.736 minutes (Method C).

[0290] Step 6: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (enantiomer 1) and (S)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (enantiomer 2) [ka] The enantiomer of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (110 mg, 205 μmol) was separated by SFC (neutral conditions: column: DAISEL Chiralpak IC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 40%, fixed composition elution mode) and isolated as a white solid.

[0291] 6-Fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (enantiomer 1) (48.8 mg). LCMS (ESI + ) m / z = 536.3 (M+H), t R = 0.666 minutes (Method C); 1 H NMR (400 MHz, CDCl3): δ 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[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (enantiomer 2) (52.6 mg). LCMS (ESI + ) m / z = 536.3 (M+H), t R = 0.671 minutes (Method C); 1H NMR (400 MHz, CDCl3): δ 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-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one

[0294] Example 6: (R)-4,7-difluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one [ka]

[0295] Step 1: Preparation of (R)-3-chloro-7-fluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one [ka] To a solution of (R)-5-(1-aminoethyl)-3-chloro-7-fluoro-2-methylisoquinoline-1(2H)-one (intermediate 5) (300 mg, 1.18 mmol) and 1-bromo-2-methylsulfonylbenzene (554 mg, 2.36 mmol) in toluene (3 mL), Cs2CO3 (1.15 g, 3.53 mmol), Pd2(dba)3 (108 mg, 118 μmol), and RuPhos (55 mg, 118 μmol) were added. The mixture was stirred at 110 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by column chromatography (SiO2, PE:EA = 100:1~5:1) to obtain (R)-3-chloro-7-fluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (160 mg, 29% yield) as a yellow solid. LCMS (ESI + ) m / z = 409.0 (M+H), t R = 1.009 minutes (Method E).

[0296] Step 2: Preparation of (R)-7-fluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one [ka] (R)-3-chloro-7-fluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (150 mg, 367 μmol) and 1-(2,2,2-trifluoroethyl)piperazine (124 mg, 734 μmol) were dissolved in dioxane (2 mL), to which Cs2CO3 (359 mg, 1.10 mmol) and RuPhos-Pd-G3 (31 mg, 37 μmol) were added. The mixture was stirred at 130 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (Phenomenex luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 48%~78%B over 10 minutes) to obtain (R)-7-fluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (40 mg, 19% yield) as a white solid. LCMS (ESI + ) m / z = 541.2 (M+H), t R = 0.570 minutes (Method C); 1 H NMR (400 MHz, CDCl3): δ 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).

[0297] Step 3: Preparation of (R)-4,7-difluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] (R)-7-fluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (25 mg, 46 μmol) in ACN (2 mL) solution, SelectFluor TM (49 mg, 139 μmol), Et3SiH (8.1 mg, 69 μmol), and Pd(PPh3)4 (53 mg, 46 μmol) were added. The mixture was stirred at 50°C for 2 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 47%~77% B over 10 minutes) to obtain (R)-4,7-difluoro-2-methyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (17 mg, 62% yield) as a yellow solid. LCMS (ESI + ) m / z = 559.2 (M+H), t R = 0.920 minutes (Method E); 1 H NMR (400 MHz, CDCl3): δ 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-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)isoquinoline-1(2H)-one [ka]

[0299] Step 1: Production of (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one [ka] A toluene (6 mL) solution of a mixture of 1-bromo-2-methylsulfonylbenzene (619 mg, 2.63 mmol), (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4) (330 mg, 1.32 mmol), Pd2(dba)3 (121 mg, 131 μmol), RuPhos (123 mg, 263 μmol), and Cs2CO3 (1.29 g, 3.95 mmol) was degassed three times, purged with N2, and then the mixture was stirred under a nitrogen atmosphere at 110°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1~3:1) to obtain (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (180 mg, 29% yield) as a yellow solid. LCMS (ESI + ) m / z = 405.2 (M+H), t R = 0.597 minutes (Method C).

[0300] Step 2: Preparation of (R)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine-4-yl)isoquinoline-1(2H)-one [ka] The mixture of (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (170 mg, 420 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridine (183 mg, 630 μmol), Pd(dppf)Cl2·CH2Cl2 (69 mg, 84 μmol), and Na2CO3 (134 mg, 1.26 mmol) was degassed three times with a solution of dioxane (4 mL) and H2O (0.5 mL), purged with N2, and then stirred under a nitrogen atmosphere at 90°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1-2:1) to obtain (R)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine-4-yl)isoquinoline-1(2H)-one (150 mg, 60% yield) as a yellow solid. LCMS (ESI + ) m / z = 534.2 (M+H), t R = 0.902 minutes (Method E).

[0301] Step 3: Production of (R)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)isoquinoline-1(2H)-one [ka] To a solution of 10% Pd / C (60 mg, 56 μmol) in MeOH (5 mL), (R)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine-4-yl)isoquinoline-1(2H)-one (140 mg, 262 μmol) was added under a nitrogen atmosphere. The suspension was degassed three times and purged with H2. The mixture was stirred at 25°C for 12 hours under H2 (15 psi). Then, 20% Pd(OH)2 / C (37 mg, 52.5 μmol) was added to the mixture and stirred at 50°C for another hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 48%~78%B over 10 minutes) to obtain (R)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)isoquinoline-1(2H)-one (51 mg, 36% yield) as a grayish-white solid. LCMS (ESI + ) m / z = 536.3 (M+H), t R = 0.555 minutes (Method C); 1 H NMR (400 MHz, CDCl3): δ 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-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 1)

[0303] Example 9: 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 2) [ka] s

[0304] Step 1: Preparation of (2-fluorophenyl)(imino)(methyl)-λ6-sulfanone [ka] To a solution of 1-fluoro-2-methylsulfanylbenzene (2 g, 14.1 mmol) in MeOH (50 mL), (NH4)2CO3 (2.03 g, 21.1 mmol) and (bis(acetoxy)iodo)benzene (11.3 g, 35.2 mmol) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 1:1) to obtain (2-fluorophenyl)(imino)(methyl)-λ6-sulfanone (2.4 g, 98% yield) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3): δ 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).

[0305] Step 2: Preparation of (2-fluorophenyl)(methyl)(methylimino)-λ6-sulfanone [ka] (2-fluorophenyl)(imino)(methyl)-λ6-sulfanone (1 g, 5.77 mmol) was dissolved in DMF (10 mL) and NaH (700 mg, 17.50 mmol, 60% purity) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. Then CH3I (4.56 g, 32.1 mmol) was added to the mixture and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (50 mL) at 0°C. The resulting mixture was then extracted with RINKAN (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 obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1~5:1) to obtain (2-fluorophenyl)(methyl)(methylimino)-λ6-sulfanone (950 mg, 87% yield) as a yellow solid. LCMS (ESI + ) m / z = 188.1 (M+H), t R = 0.387 minutes (Method L).

[0306] Step 3: Preparation of 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one [ka] (2-fluorophenyl)(methyl)(methylimino)-λ6-sulfanone (147 mg, 784 μmol) and (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (intermediate 2) (100 mg, 261 μmol) were dissolved in IPA (0.1 mL), to which DIEA (371 mg, 2.87 mmol, 0.5 mL) and 4 Å molecular sieves (100 mg) were added at 25 °C. The mixture was then stirred at 110 °C for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 44%~74%B over 10 minutes) to obtain 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (50 mg, 34% yield) as a yellow solid. LCMS (ESI + ) m / z = 550.3 (M+H), t R = 0.549 minutes (Method E); 1 H NMR (400 MHz, CDCl3): δ 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).

[0307] Step 4: Preparation of 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 1) and 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 2) [ka] 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (50 mg, 91 μmol) was injected into SFC (neutral conditions; column: DAISEL Chiralcel) The mixture was purified using OD-H (250 mm × 30 mm, 5 μm); mobile phase: [CO2-EtOH]; B%: 35%, fixed composition elution mode) to obtain 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 1) and 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 2) as yellow solids.

[0308] 5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 1) (19 mg). LCMS (ESI + ) m / z = 550.3 (M+H), t R = 0.519 minutes (Method C);1 H NMR (400 MHz, CDCl3): δ 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-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 2) (18 mg). LCMS (ESI + ) m / z = 550.3 (M+H), t R = 0.513 minutes (Method C); 1 H NMR (400 MHz, CDCl3): δ 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-((1R)-1-((6-methyl-2-(S-methylsulfonimidoyl)pyridine-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka]

[0311] Step 1: Production of 3-fluoro-6-methyl-2-(methylthio)pyridine [ka] Sodium methanethiolate (489 mg, 6.97 mmol) was added at 0°C to a solution of 2,3-difluoro-6-methylpyridine (900 mg, 6.97 mmol) in DMF (10 mL). The mixture was stirred at 25°C for 0.5 hours. The reaction was quenched with water (10 mL) and extracted with EA (20 mL x 3). The organic phases were combined, 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 obtain 3-fluoro-6-methyl-2-(methylthio)pyridine (700 mg, 60% yield) as a white oil. LCMS (ESI + ) m / z = 158.1 (M+H), t R = 0.849 minutes (Method E).

[0312] Step 2: Preparation of (3-fluoro-6-methylpyridine-2-yl)(imino)(methyl)-λ6-sulfanone [ka] (NH4)2CO3 (596 mg, 6.2 mmol) was added to a solution of 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). The mixture was stirred at 25°C for 12 hours and then concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (PE:EA = 1:0, 0:1) to obtain (3-fluoro-6-methylpyridine-2-yl)(imino)(methyl)-λ6-sulfanone (630 mg, 72% yield) as a yellow oil. LCMS (ESI + ) m / z = 188.9 (M+H), t R = 0.248 minutes (Method E).

[0313] Step 3: Preparation of 2,7-dimethyl-5-((1R)-1-((6-methyl-2-(S-methylsulfonimidoyl)pyridine-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] (3-fluoro-6-methylpyridine-2-yl)(imino)(methyl)-λ6-sulfanone (148 mg, 784 μmol) and (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (intermediate 2) (100 mg, 261 μmol) were dissolved in IPA (0.5 mL), to which DIEA (371 mg, 2.87 mmol, 0.5 mL) and 4 Å molecular sieve (80 mg) were added. The mixture was stirred at 130 °C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 43%~73%B over 10 minutes) to obtain 2,7-dimethyl-5-((1R)-1-((6-methyl-2-(S-methylsulfonimidoyl)pyridine-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (54 mg, 36% yield) as a yellow solid. LCMS (ESI + ) m / z = 551.1 (M+H), t R = 0.922 minutes (Method E); 1 H NMR (400 MHz, CDCl3): δ 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-(1-((2-(((1-methyl-1H-pyrazole-4-yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka]

[0315] Step 1: Production of 4-(((2-fluorophenyl)thio)methyl)-1-methyl-1H-pyrazole [ka] To a solution of 4-(chloromethyl)-1-methylpyrazole hydrochloride (300 mg, 1.80 mmol) in DMF (5 mL), K2CO3 (496 mg, 3.59 mmol) and 2-fluorobenzenethiol (230 mg, 1.80 mmol) were added. The mixture was stirred at 60°C for 12 hours. The reaction mixture was partitioned into H2O (50 mL) and siRNA (50 mL). The organic phase was separated, washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1~4:1) to obtain 4-(((2-fluorophenyl)thio)methyl)-1-methyl-1H-pyrazole (340 mg, 85% yield) as a colorless oil. LCMS (ESI + ) m / z = 222.9 (M+H), t R = 0.500 minutes (Method C).

[0316] Step 2: Production of 4-(((2-fluorophenyl)sulfonyl)methyl)-1-methyl-1H-pyrazole [ka] 340 mg, 1.53 mmol of 4-(((2-fluorophenyl)thio)methyl-1-methyl-1H-pyrazole was added to a 5 mL solution of DCM with m-CPBA (620 mg, 3.05 mmol, 85% purity) at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding aqueous Na2SO3 at 25°C. The mixture was then diluted with H2O (10 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with saturated NaHCO3 solution (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1~1:1) to obtain 4-(((2-fluorophenyl)sulfonyl)methyl-1-methyl-1H-pyrazole (360 mg, 92% yield) as a colorless oil. LCMS (ESI + ) m / z = 255.1 (M+H), t R = 0.516 minutes (Method C).

[0317] Step 3: Preparation of (R)-2,7-dimethyl-5-(1-((2-(((1-methyl-1H-pyrazole-4-yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] A solution of 4-(((2-fluorophenyl)sulfonyl)methyl)-1-methyl-1H-pyrazole (133 mg, 523 μmol), (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (intermediate 2) (100 mg, 261 μmol), DIEA (371 mg, 2.87 mmol, 0.5 mL), and 4Å molecular sieve (50 mg) in IPA (0.1 mL) was degassed three times and purged with N2. The mixture was stirred under a nitrogen atmosphere at 130 °C for 6 hours. The reaction mixture was dissolved in ACN (2 mL), filtered, and the filtrate was obtained. The filtrate was separated and purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 45%~75%B over 10 minutes) to obtain (R)-2,7-dimethyl-5-(1-((2-(((1-methyl-1H-pyrazole-4-yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (83 mg, 51% yield) as a white solid. LCMS (ESI + ) m / z = 617.3 (M+H), t R = 0.593 minutes (Method C); 1 H NMR (400 MHz, CDCl3): δ 8.11 (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-methylpyridine-3-yl)piperazine-1-yl)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one [ka]

[0319] Step 1: Preparation of tert-butyl 4-(5-fluoro-2-methylpyridine-3-yl)piperazine-1-carboxylate [ka] To a toluene (30 mL) solution of 3-bromo-5-fluoro-2-methylpyridine (1.9 g, 10.0 mmol) and tert-butyl piperazine-1-carboxylate (2.79 g, 15.0 mmol), Cs2CO3 (9.77 g, 30.0 mmol), BINAP (623 mg, 1.0 mmol), and Pd(OAc)2 (224 mg, 1.0 mmol) were added, and the mixture was stirred under a nitrogen atmosphere at 80°C for 12 hours. The solution was filtered through a Celite pad, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, PE:EA = 75:25~50:50) to obtain tert-butyl 4-(5-fluoro-2-methylpyridine-3-yl)piperazine-1-carboxylate (2.5 g, 76% yield) as a yellow solid. LCMS (ESI + ) m / z = 296.3 (M+H), t R = 0.514 minutes (Method C).

[0320] Step 2: Preparation of 1-(5-fluoro-2-methylpyridine-3-yl)piperazine [ka] To a solution of tert-butyl 4-(5-fluoro-2-methylpyridine-3-yl)piperazine-1-carboxylate (2.5 g, 8.46 mmol) in DCM (9 mL), TFA (4.61 g, 40.4 mmol) was added at 0°C, and the solution was stirred at 25°C for 1 hour. The solution was concentrated to obtain the crude product. The crude product was dissolved in MeOH (10 mL), and the pH was adjusted to 8 by adding aqueous ammonia. The solution was purified by preparative HPLC (column: Kromasil Eternity XT 250 × 80 mm × 10 μm; mobile phase: [water (NH4OH)-ACN]; gradient: 1% to 31% B over 20 minutes), and the eluent was freeze-dried to obtain 1-(5-fluoro-2-methylpyridine-3-yl)piperazine (0.8 g, 48% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ: 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).

[0321] Step 3: Preparation of (R)-3-(4-(5-fluoro-2-methylpyridine-3-yl)piperazin-1-yl)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one [ka] A 10 mL solution of (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (Example 7, Step 1) (0.2 g, 301 μmol), 1-(5-fluoro-2-methylpyridine-3-yl)piperazine (0.2 g, 1.02 mmol), Cs2CO3 (982 mg, 3.01 mmol), and BINAP-Pd-G3 (30 mg, 30 μmol) in dioxane (10 mL) was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The solution was filtered through a Celite pad, and the filtrate was concentrated. The residue was purified by preparative TLC (PE:EA = 1:4) to obtain a yellow oily substance. Next, the yellow oily substance was further purified by preparative HPLC (column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 48%~78%B over 10 minutes), and the eluent was freeze-dried to obtain (R)-3-(4-(5-fluoro-2-methylpyridine-3-yl)piperazin-1-yl)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (64 mg, 37% yield) as a yellow solid. LCMS (ESI + ) m / z = 564.2 (M+H), t R = 0.937 minutes (Method E); 1 H NMR (400 MHz, CDCl3): δ 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'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 1)

[0323] Example 14: 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 2) [ka]

[0324] Step 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] A 10 mL solution of dioxane containing a mixture of 3-bromo-5-fluoro-2-methylpyridine (500 mg, 2.63 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (735 mg, 2.89 mmol), Pd(dppf)Cl2·CH2Cl2 (430 mg, 526 μmol), and KOAc (775 mg, 7.89 mmol) was degassed three times, purged with N2, and then the mixture was stirred at 70°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (623 mg, crude) as a brown oily substance, which was used in the next step without purification.

[0325] Step 2: Preparation of 5-bromo-3,5'-difluoro-2'-methyl-2,3'-bipyridine [ka] A mixture of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (623 mg, 2.63 mmol), 2,5-dibromo-3-fluoropyridine (670 mg, 2.63 mmol), K2CO3 (1.09 g, 7.88 mmol), and Pd(PPh3)4 (304 mg, 263 μmol) was degassed three times with dioxane (10 mL) and H2O (1 mL) solutions and purged with N2. The mixture was then stirred at 80°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 99:1~85:15) to obtain 5-bromo-3,5'-difluoro-2'-methyl-2,3'-bipyridine (410 mg, 54% yield) as a yellow oil. LCMS (ESI + ) m / z = 285.0 (M+H), t R = 0.633 minutes (Method C).

[0326] Step 3: Preparation of 3,5'-difluoro-2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3'-bipyridine [ka] A 2 mL solution of dioxane containing 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-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (333 mg, 1.31 mmol), Pd(dppf)Cl2·CH2Cl2 (93 mg, 114 μmol), and KOAc (320 mg, 3.26 mmol) was degassed three times and purged with N2. The resulting mixture was then stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 5:1) to obtain 3,5'-difluoro-2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3'-bipyridine (360 mg, 99% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 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).

[0327] Step 4: Production of 3-chloro-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] (2-fluorophenyl)(methyl)(methylimino)-λ6-sulfanone (224 mg, 1.20 mmol) and (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4) (200 mg, 798 μmol) were dissolved in IPA (0.1 mL), to which DIEA (223 mg, 1.72 mmol) and 4 Å molecular sieves (50 mg) were added. The mixture was stirred at 130 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, PE:EA=1:1) to obtain 3-chloro-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (80 mg, 17% yield) as a yellow solid. LCMS (ESI + ) m / z = 418.1 (M+H), t R = 0.493 minutes (Method K).

[0328] Step 5: Preparation of 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] A mixture of 3-chloro-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (230 mg, 550 μmol), 3,5'-difluoro-2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3'-bipyridine (150 mg, 452 μmol), 4-di-tert-butylphosphanyl-N,N-dimethylaniline palladium dichloride (39 mg, 55 μmol), and K3PO4 (350 mg, 1.65 mmol) was degassed three times in a solution of dioxane (4 mL) and H2O (0.5 mL) and purged with N2. The mixture was stirred at 100°C for 3 hours. Next, the reaction mixture was partitioned into H2O (10 mL) and siRNA (10 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, PE:EA = 1:2). The organism was then purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 44%~74% B over 10 minutes) to obtain 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (75 mg, 22% yield) as a white solid. LCMS (ESI + ) m / z = 588.3 (M+H), t R = 0.534 minutes (Method C).

[0329] Step 6: Preparation of 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 1) and 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 2) [ka] 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (75 mg, 128 μmol) was fed to SFC (column: DAIEL Chiralcel) Separation was performed using OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH4OH)]; B%: 45%, fixed composition elution mode) to obtain 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 1) and 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 2) as white solids.

[0330] 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 1) (30 mg). LCMS (ESI +) m / z = 588.3 (M+H), t R = 0.531 minutes (Method C); 1 H NMR (400 MHz, CDCl3): δ 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'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonimidoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 2) (37 mg). LCMS (ESI + ) m / z = 588.3 (M+H), t R = 0.540 minutes (Method C); 1H NMR (400 MHz, CDCl3): δ 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-(1-((6-chloro-2-(methylsulfonyl)pyridine-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka]

[0333] Step 1: Production of 6-chloro-3-fluoro-2-(methylthio)pyridine [ka] Sodium methanethiolate (500 mg, 7.13 mmol) was added at 0°C to a solution of 2,6-dichloro-3-fluoropyridine (1 g, 6.02 mmol) in DMF (10 mL), and the mixture was then stirred at 25°C for 2 hours. The reaction mixture was partitioned into H2O (50 mL) and siRNA (50 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1~95:5) to obtain 6-chloro-3-fluoro-2-(methylthio)pyridine (490 mg, 45% yield) as a colorless oil.1 H NMR (400 MHz, CDCl3): δ 7.22 - 7.17 (m, 1H), 7.01 - 6.97 (m, 1H), 2.59 (s, 3H).

[0334] Step 2: 6-Chloro-3-fluoro-2-(methylsulfonyl)pyridine [ka] 6-chloro-3-fluoro-2-(methylthio)pyridine (480 mg, 2.70 mmol) was dissolved in 10 mL of ethyl acetate, to which NaClO (12.1 g, 162 mmol) was added at 25°C. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was then partitioned into H2O (10 mL) and ethyl acetate (10 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 6-chloro-3-fluoro-2-(methylsulfonyl)pyridine (440 mg, crude) as a colorless oil, which was used in the next step without purification. LCMS (ESI + ) m / z = 210.1 (M+H), t R = 0.422 minutes (Method C).

[0335] Step 3: Production of (R)-5-(1-((6-chloro-2-(methylsulfonyl)pyridine-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (intermediate 2) (100 mg, 261 μmol) and 6-chloro-3-fluoro-2-(methylsulfonyl)pyridine (110 mg, 523 μmol) were dissolved in ACN (0.5 mL) to which triethylamine (79 mg, 785 μmol) was added. The resulting mixture was stirred at 80°C for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water (FA)-ACN]; gradient: 52%~82% B over 10 minutes) to obtain (R)-5-(1-((6-chloro-2-(methylsulfonyl)pyridine-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (95 mg, 63% yield) as a grayish-white solid. LCMS (ESI + ) m / z = 572.3 (M+H), t R = 0.616 minutes (Method C); 1 H NMR (400 MHz, CDCl3): δ 8.12 (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-(1-((6-ethynyl-2-(methylsulfonyl)pyridine-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka]

[0337] Step 1: Preparation of (R)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)-6-((trimethylsilyl)ethynyl)pyridine-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] A mixture of (R)-5-(1-((6-chloro-2-(methylsulfonyl)pyridine-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (Example 15) (54 mg, 94 μmol), ethinyl(trimethyl)silane (93 mg, 944 μmol, 131 μL), Xphos-Pd-G4 (8 mg, 9.44 μmol), and N-cyclohexyl-N-methyl-cyclohexanamine (55 mg, 283 μmol) was degassed three times in a 1 mL solution of dioxane and purged with N2. The resulting mixture was stirred at 110°C for 2 hours. Then ethinyl(trimethyl)silane (93 mg, 944 μmol) was added, and the mixture was stirred under a nitrogen atmosphere at 110°C for another 12 hours. Next, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, PE:EA = 1:1) to obtain (R)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)-6-((trimethylsilyl)ethynyl)pyridine-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (60 mg, 89% yield) as a yellow oil. LCMS (ESI + ) m / z = 634.2 (M+H), t R = 0.729 minutes (Method E).

[0338] Step 2: Preparation of (R)-5-(1-((6-ethynyl-2-(methylsulfonyl)pyridine-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)isoquinoline-1(2H)-one [ka] (R)-2,7-dimethyl-5-(1-((2-(methylsulfonyl)-6-((trimethylsilyl)ethynyl)pyridine-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (55 mg, 86.8 μmol) was added to a solution of DMF (0.5 mL) with CsF (26 mg, 174 μmol). The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water (FA)-ACN]; gradient: 45%~75% B over 10 minutes) to obtain (R)-5-(1-((6-ethynyl-2-(methylsulfonyl)pyridine-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (19 mg, 38% yield) as a grayish-white solid. LCMS (ESI + ) m / z = 562.3 (M+H), t R = 0.602 minutes (Method C); 1 H NMR (400 MHz, CDCl3): δ 8.12 (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-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzenesulfonamide [ka]

[0340] Step 1: Preparation of 2-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] To a 50 mL solution of 2-bromobenzenesulfonamide (2.5 g, 10.6 mmol) in DMF while stirring, NaH (1.27 g, 31.7 mmol, 60 wt%) was added at 0°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 30 minutes, and then SEM-Cl (5.30 g, 31.7 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was quenched with water (50 mL) at 0°C, and the aqueous phase was extracted with siRNA (3 × 50 mL). The combined organic matter was washed with brine (3 × 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 (elution at PE:EA = 10:1) to obtain 2-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (4 g, 76% yield) as an oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 - 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).

[0341] Step 2: Preparation of (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] To a 10 mL solution of 2-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (1.04 g, 2.09 mmol) and (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (intermediate 2) (400 mg, 1.05 mmol) in dioxane (10 mL) while stirring, Pd2(dba)3 (96 mg, 0.11 mmol), Cs2CO3 (682 mg, 2.09 mmol), and Xantphos (121 mg, 0.21 mmol) were added 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 ELISA. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2-dihydroisoquinoline-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 [MH] - .

[0342] Step 3: Preparation of (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzenesulfonamide [ka] To a solution of (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (150 mg, 0.19 mmol) in THF (10 mL), TBAF (1 M in THF, 1.88 mL, 1.88 mmol) was added dropwise at room temperature under a nitrogen atmosphere. 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 ELISA (3 × 20 mL). The combined organic matter was washed with brine (3 × 15 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude organism was purified by preparative HPLC under the following conditions (UV 254nm / 220nm Xselect CSH Prep C18 column, 30×150mm, 5μm; water (0.1% FA), ACN 60 mL / min, 43%B~68%B over 10 minutes) to obtain (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzenesulfonamide (66 mg, 65% yield) as a white solid. + m / z = 538.2 [M+H] + , t R = 0.977 minutes; 1 H NMR (400 MHz, DMSO-d6): δ 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-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-N-methylbenzenesulfonamide [ka]

[0344] Step 1: Preparation of 2-bromo-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] To a solution of 2-bromo-N-methylbenzenesulfonamide (700 mg, 2.80 mmol) in DMF (15 mL), NaH (244 mg, 5.60 mmol, 60 wt%) was added at 0°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 30 minutes, and then SEM-Cl (607 mg, 3.64 mmol) was added at 0°C. The mixture was then stirred at room temperature for 5 hours. The reaction was quenched with water (10 mL) at room temperature, and the mixture was extracted with siRNA (3 × 20 mL). The combined organic matter was washed with brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=5:1) to obtain 2-bromo-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (650 mg, 61% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0345] Step 2: Preparation of (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] A 10 mL solution of dioxane containing a mixture of 2-bromo-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (497 mg, 1.3 mmol), (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(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) was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (PE:EA=1:1) to obtain (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2-dihydroisoquinoline-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] + .

[0346] Step 3: Preparation of (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-N-methylbenzenesulfonamide [ka] A mixture of (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (150 mg, 0.22 mmol) and TBAF (2.2 mL, 2.2 mmol) in a solution of THF (10 mL) was stirred at 50°C for 20 hours. The reaction was quenched with water (10 mL) at room temperature, and the resulting mixture was extracted with ELISA (3 × 20 mL). The combined organic matter was washed with brine (3 × 15 mL) and then dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude organism was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 50 × 250 mm, 10 μm; mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45%B to 75%B over 20 minutes; wavelength: 254 nm / 220 nm) to obtain (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-N-methylbenzenesulfonamide (54 mg, 44%, yield) as a white solid. 1 H NMR (400 MHz, methanol-d4): δ 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 [MH] - .

[0347] Example 19: (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinazoline-4(3H)-one [ka]

[0348] Step 1: Production of (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(methylthio)quinazoline-4(3H)-one [ka] To a 10 mL solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazoline-4(3H)-one (intermediate 6) (300 mg, 1.1 mmol) and 1-iodo-2-methanesulfonylbenzene (321 mg, 1.1 mmol) in dioxane (10 mL) while stirring, Cs2CO3 (1.1 g, 3.4 mmol) and [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloroimidazole-2-ylidene]-dichloro-(2-methylpyridine-1-ium-1-yl)palladium (16 mg, 0.019 mmol) were gradually added at room temperature under an 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 SiO2CO3 (2 × 60 mL). The combined organic matter was 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 obtain (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(methylthio)quinazoline-4(3H)-one (100 mg, 21% yield) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.81-7.76 (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).

[0349] Step 2: Production of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one [ka] To a solution of (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(methylthio)quinazoline-4(3H)-one (70 mg, 0.17 mmol) in THF (2 mL) while stirring, a solution of oxone (169 mg, 1.0 mmol) in H2O (2 mL) was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 1 hour and then diluted with ice water (40 mL). The resulting mixture was extracted with SiO2 (2 × 40 mL), the combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to obtain 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (40 mg, 55% yield) as a white solid. LCMS (ESI + m / z = 434.1 (M+H).

[0350] Step 3: Production of (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinazoline-4(3H)-one [ka] A solution of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (40 mg, 0.092 mmol) and 1-(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 SiO (2 × 30 mL). The combined organic matter was 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 obtain (R)-2-hydroxy-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (35 mg, 8%) as a white solid.

[0351] A solution of (R)-2-hydroxy-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazoline-4(3H)-one (35 mg, 0.090 mmol) and PyBOP (141 mg, 0.270 mmol) in DMF (2 mL) was stirred at room temperature for 10 minutes under an argon atmosphere. Then, DBU (69 mg, 0.45 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (23 mg, 0.14 mmol) were added gradually at room temperature. The resulting mixture was stirred at room temperature for 3 hours and then diluted with ice water (20 mL). The resulting mixture was extracted with ELISA (2 × 20 mL). The combined organic matter was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN aqueous solution, 5% to 95% gradient over 30 minutes; detector, UV 254 nm) to obtain (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinazoline-4(3H)-one (13 mg, 27% yield) as a white solid. LCMS (ESI + m / z = 538.2 [M+H]; 1 H NMR (400 MHz, DMSO-d6): δ 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-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)pyrimidine-5-yl)-5-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka]

[0353] Step 1: Preparation of (R)-3-chloro-5-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4, 200 mg, 0.80 mmol) and 1,4-difluoro-2-methylsulfonylbenzene (200 mg, 1.04 mmol) were dissolved in IPA (0.2 mL), to which 4 Å molecular sieves (100 mg) and DIEA (0.40 mL, 2.30 mmol) were added. The mixture was stirred at 130 °C for 12 hours. 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 obtain (R)-3-chloro-5-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (170 mg, 50% yield) as a yellow solid. LCMS (ESI + m / z = 423.2 (M+H).

[0354] Step 2: Preparation of (R)-3-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)pyrimidine-5-yl)-5-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] (R)-3-chloro-5-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (70 mg, 0.17 mmol), 7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (intermediate 8, 81 mg, 0.25 mmol), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II)(cataCXium(registered trademark) A A mixture of PdG3 (12 mg, 0.017 mmol) and Na2CO3 (35 mg, 0.33 mmol) was degassed three times in a solution of dioxane (2 mL) and H2O (0.2 mL) and purged with N2. The mixture was then stirred at 100°C for 1 hour. The reaction mixture was then diluted with H2O (10 mL) and extracted with EA (10 mL x 3). The combined organic matter was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC to obtain (R)-3-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)pyrimidine-5-yl)-5-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (30 mg, 30% yield) as a yellow solid. LCMS (ESI + m / z = 589.3 (M+H); 1H NMR (400 MHz, CDCl3): δ 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-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethyl-5-(1-((6-methyl-2-(trifluoromethyl)pyridine-3-yl)amino)ethyl)isoquinoline-1(2H)-one [ka]

[0356] Step 1: Preparation of tert-butyl (R)-(1-(3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate [ka] A mixture of (2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)boronic acid (intermediate 9, 280 mg, 0.86 mmol), tert-butyl (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl) carbamate (intermediate 7, 300 mg, 0.86 mmol), mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A PdG3) (62 mg, 0.086 mmol), and K2CO3 (355 mg, 2.57 mmol) was degassed three times with a solution of dioxane (5 mL) and H2O (1 mL) and purged with N2. Next, the mixture was stirred at 100°C for 1 hour. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting with PE:EA 1:0 to 1:1) to obtain tert-butyl (R)-(1-(3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (400 mg, 70% yield) as a black to brown solid. LCMS (ESI + m / z = 516.2 (M+H).

[0357] Step 2: Preparation of (R)-5-(1-aminoethyl)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethylisoquinoline-1(2H)-one [ka] A solution of tert-butyl (R)-(1-(3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (200 mg, 0.39 mmol) in a HCl dioxane solution (4 M, 2 mL) was prepared. The mixture was stirred at 25°C for 0.3 hours. The reaction product was then concentrated under reduced pressure to obtain (R)-5-(1-aminoethyl)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethylisoquinoline-1(2H)-one hydrochloride (152 mg, 76% yield) as a brown solid. LCMS (ESI + m / z = 416.2 (M+H).

[0358] Step 3: Production of (R)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethyl-5-(1-((6-methyl-2-(trifluoromethyl)pyridine-3-yl)amino)ethyl)isoquinoline-1(2H)-one [ka] (R)-5-(1-aminoethyl)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethylisoquinoline-1(2H)-one (free base from the HCl salt described in the previous step, 10:1 ratio of the HCl salt) The product was produced by treating a CH2Cl2 / MeOH solution with saturated aqueous NaHCO3 (150 mg, 0.36 mmol), 3-bromo-6-methyl-2-(trifluoromethyl)pyridine (130 mg, 0.54 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (30 mg, 0.036 mmol), and Cs2CO3 (471 mg, 1.44 mmol) in a 10 mL dioxane solution. The solution was degassed three times and purged with N2. The mixture was then stirred at 90°C for 1 hour. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Crude organisms were purified by silica gel column chromatography (eluting in PE:EA 1:1 to 1:4), and then further purified by preparative HPLC to obtain (R)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridine-4-yl)pyrimidine-5-yl)-2,7-dimethyl-5-(1-((6-methyl-2-(trifluoromethyl)pyridine-3-yl)amino)ethyl)isoquinoline-1(2H)-one (24 mg, 11% yield) as a yellow solid. LCMS (ESI + ) m / z = 575.3 (M+H), t R = 0.517 minutes (Method X); 1H NMR (400 MHz, DMSO-d6): δ 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-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one [ka]

[0360] Step 1: Preparation of 1-bromo-2-(difluoromethyl)-3,4-difluorobenzene [ka] To a 30 mL solution of 6-bromo-2,3-difluorobenzaldehyde (15.0 g, 67.8 mmol) in DCM, DAST (21.9 g, 136 mmol) was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 2 hours, then quenched by adding 400 mL of ice water at 0°C. The resulting mixture was then extracted with CH2Cl2 (3 × 400 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting at PE:EA = 10:1) to obtain 1-bromo-2-(difluoromethyl)-3,4-difluorobenzene (11.0 g, 67% yield) as a grayish-white oil. 1H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.63 (m, 2H), 7.45 - 7.14 (m, 1H).

[0361] Step 2: Preparation of (R)-3-chloro-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] To a 10 mL solution of 1-bromo-2-(difluoromethyl)-3,4-difluorobenzene (1.0 g, 4.1 mmol) and (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4, 1.6 g, 6.1 mmol) in dioxane, Cs2CO3 (4.0 g, 12.3 mmol), XantPhos (0.48 g, 0.82 mmol), and Pd2(dba)3 (0.4 g, 0.4 mmol) were added at room temperature under an argon atmosphere. The resulting mixture was stirred overnight at 100 °C. The reaction product was diluted with ice water (50 mL) at 0 °C and then extracted with SiO2 (3 × 50 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting at PE:EA = 1:1) to obtain (R)-3-chloro-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (960 mg, 56% yield) as a bright yellow oil. LCMS (ESI + ) m / z = 413 (M+H).

[0362] Step 3: Production of (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1(2H)-one [ka] To a 10 mL solution of (R)-3-chloro-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (900 mg, 2.2 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (11.0 g, 43.6 mmol) in dioxane (10 mL) while stirring, KOAc (642 mg, 6.5 mmol) and Pd(dppf)Cl2 (160 mg, 0.2 mmol) were added gradually at room temperature under an argon atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. The resulting mixture was then filtered, and the filter cake was washed with DCM (3 × 20 mL). The filtrate was then concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification. LCMS (ESI + ) m / z = 505 (M+H).

[0363] Step 4: Preparation of (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] To a solution of (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1(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), Na2CO3 (567 mg, 5.4 mmol) and Pd(PPh3)4 (206 mg, 0.2 mmol) were gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was then stirred overnight at 90°C. The mixture was diluted with ice water (30 mL) at 0°C, and the resulting mixture was extracted with ELISA (3 × 30 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (450 mg, 47% yield) as a bright yellow solid. LCMS (ESI + ) m / z = 535 (M+H).

[0364] Step 5: Production of (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one [ka] To a 0.5 mL solution of (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (100 mg, 0.2 mmol) and 1-methyl-6-(trimethylstannyl)pyrazine-2-one (intermediate 10, 102 mg, 0.3 mmol) in DMF (0.5 mL), mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (9.6 mg, 0.02 mmol) and tri-tert-butylphosphonium tetrafluoroborate (5.4 mg, 0.019 mmol) were gradually added at room temperature under an argon atmosphere. The resulting mixture was then stirred overnight at 80°C. The mixture was diluted with ice water (30 mL) at 0°C, and the resulting mixture was extracted with ELISA (3 × 30 mL). The combined organic matter was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography, followed by preparative HPLC, to obtain (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one (9.0 mg, 8.5% yield) as a bright yellow solid. LCMS (ESI + ) m / z = 565 (M+H); 1 H NMR (400 MHz, DMSO-d6): δ 9.32 (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-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one [ka] Step 1: Preparation of (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] Pd2(dba)3 (730 mg, 0.80 mmol) was gradually added to a solution / mixture in a 1,4-dioxane solution (10 mL) containing (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4, 1 g, 4.0 mmol), 4-fluoro-1-iodo-2-(trifluoromethyl)benzene (1.73 g, 5.98 mmol), Cs2CO3 (3.90 g, 12.0 mmol), and RuPhos (744 mg, 1.60 mmol) while stirring, under an argon atmosphere at room temperature. The resulting mixture was then stirred at 100 °C for 2 hours. The mixture was then diluted with ice water (50 mL) at 0 °C, and the resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting at PE:EA = 5:1) to obtain (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (600 mg, 36% yield) as a white solid. LCMS (ESI + ) m / z = 413 (M+H).

[0366] Pd2(dba)3 (730 mg, 0.80 mmol) was gradually added to a solution / mixture in a 1,4-dioxane solution (10 mL) containing (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4, 1 g, 4.0 mmol), 4-fluoro-1-iodo-2-(trifluoromethyl)benzene (1.73 g, 5.98 mmol), Cs2CO3 (3.90 g, 12.0 mmol), and RuPhos (744 mg, 1.60 mmol) while stirring, under an argon atmosphere at room temperature. The resulting mixture was then stirred at 100 °C for 2 hours. The mixture was then diluted with ice water (50 mL) at 0 °C, and the resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting at PE:EA = 5:1) to obtain (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (600 mg, 36% yield) as a white solid. LCMS (ESI + ) m / z = 413 (M+H).

[0367] Step 2: Preparation of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1(2H)-one [ka] Pd(dppf)Cl2 (213 mg, 0.29 mmol) was added dropwise to a solution / mixture of (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (600 mg, 1.45 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (738 mg, 2.91 mmol), and KOAc (428 mg, 4.36 mmol) in dioxane (10 mL) while stirring, under an argon atmosphere at room temperature. The resulting mixture was stirred overnight at 110 °C. The mixture was then filtered and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without characterization or further purification. LCMS (ESI + ) m / z = 505 (M+H).

[0368] Step 3: Preparation of (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] To a solution of a mixture of crude (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (600 mg, 1.19 mmol) and 2-bromo-5-iodopyrimidine (508 mg, 1.79 mmol) in dioxane (4 mL) and H2O, Pd(PPh3)4 (137 mg, 0.12 mmol) and Na2CO3 (378 mg, 3.57 mmol) were added under an argon atmosphere. The resulting mixture was stirred at 110°C for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with CH2Cl2:MeOH = 5:1) to obtain (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (450 mg, 71% yield) as a bright yellow solid. LCMS (ESI + m / z = 535.1 (M+H).

[0369] Step 4: Production of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one [ka] CuCl (18 mg, 0.19 mmol) was gradually added to a solution of (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (50 mg, 0.093 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-one (intermediate 11 mg, 66 mg, 0.28 mmol) and a mixture of Pd(dppf)Cl2 (34 mg, 0.046 mmol) and Cs2CO3 (91 mg, 0.28 mmol) in DMF (2 mL) while stirring, under an argon atmosphere at room temperature. The resulting mixture was stirred at 60°C for 1 hour, diluted with ice water (30 mL) at 0°C, and then extracted with ELISA (3 × 30 mL). The combined organic matter was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one (9.4 mg, 18% yield) as a brown solid. LCMS (ESI + m / z = 565.2 (M+H); 1 H NMR (400 MHz, DMSO-d6): δ 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-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one [ka]

[0371] Step 1: Preparation of tert-butyl (R)-(1-(2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate [ka] (2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)boronic acid (intermediate 12, 516 mg, 2.22 mmol) and tert-butyl (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (intermediate 7, 600 mg, 1.71 mmol) were added to a solution of dioxane (12 mL) and H2O (1 mL) with Na2CO3 (363 mg, 3.42 mmol) and mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A PdG3) (125 mg, 0.17 mmol). The reaction mixture was stirred at 90°C for 2 hours under an N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (eluting silica gel, PE:EA 1:0~1:1) to obtain tert-butyl (R)-(1-(2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (250 mg, 29% yield) as a yellow solid. LCMS (ESI +m / z = 503.1 (M+H).

[0372] Step 2: Preparation of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazine-4-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one hydrochloride [ka] A mixture of tert-butyl (R)-(1-(2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (250 mg, 0.50 mmol) was stirred in a HCl dioxane solution (2 M, 6 mL, 12 mmol) at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one hydrochloride as a yellow solid. LCMS (ESI + m / z = 403.1 (M+H).

[0373] Step 3: Preparation of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one [ka] To a 2 mL solution of dioxane containing a mixture of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazine-4-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one hydrochloride (70 mg, 0.16 mmol) and 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (78 mg, 0.32 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (13 mg, 0.016 mmol) and Cs2CO3 (130 mg, 0.40 Next, the mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 × 2 mL). The combined organic phase was washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidine-5-yl)isoquinoline-1(2H)-one (19 mg, 21% yield) as a yellow solid. LCMS (ESI + m / z = 565.2 (M+H); 1 H NMR (400 MHz, CDCl3): δ 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'-bipyrimidine]-5-yl)-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one [ka]

[0375] Step 1: Production of 5-bromo-2'-methyl-2,5'-bipyrimidine [ka] A mixture of (2-methylpyrimidine-5-yl)boronic acid (460 mg, 3.3 mmol), 5-bromo-2-iodopyrimidine (1 g, 3.5 mmol), Pd(dppf)Cl2·CH2Cl2 (287 mg, 0.35 mmol), and Na2CO3 (744 mg, 7.0 mmol) was degassed three times in a solution of dioxane (20 mL) and H2O (4 mL), and purged with N2. The mixture was then stirred at 90°C for 3 hours. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate 300 mL (3 × 100 mL). The combined organic matter was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude organism was purified by silica gel column chromatography (eluting with PE:EA 10:1~3:1) to obtain 5-bromo-2'-methyl-2,5'-bipyrimidine (410 mg, 46% yield) as a white solid. LCMS (ESI + m / z = 251.2 (M+H).

[0376] Step 2: Preparation of 2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine [ka] A 5 mL solution of dioxane containing 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-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (303 mg, 1.19 mmol), KOAc (235 mg, 2.39 mmol), and Pd(dppf)Cl2·CH2Cl2 (65 mg, 0.080 mmol) was degassed three times and purged with N2. The mixture was then stirred at 80°C for 12 hours. The mixture was then concentrated under reduced pressure to obtain the crude product. The crude organism was purified by silica gel column chromatography (eluting at PE:EA=0 / 1) to obtain 2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine (340 mg, crude yield) as a black-brown solid, which was used directly in the next step without further purification. LCMS (ESI + ) m / z = 217.3 (M+H, boric acid).

[0377] Step 3: Production of (R)-2,7-dimethyl-3-(2'-methyl-[2,5'-bipyrimidine]-5-yl)-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one [ka] A 10 mL solution of dioxane containing a mixture of 2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5'-bipyrimidine (58 mg, 0.24 mmol), (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(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(II) (10 mg, 0.012 mmol) was degassed three times and purged with nitrogen. The mixture was then stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. Crude organisms were eluted with silica gel (eluted with MeOH) to obtain a residue, which was further purified by preparative HPLC to obtain (R)-2,7-dimethyl-3-(2'-methyl-[2,5'-bipyrimidine]-5-yl)-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (46 mg, 36% yield) as a white solid. LCMS (ESI + m / z = 541.2 (M+H); 1 H NMR (400 MHz, DMSO-d6): δ 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-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)isoquinoline-1(2H)-one [ka]

[0379] Step 1: Production of 5-iodo-2-(2-methylpyrimidine-5-yl)pyridazine-3(2H)-one [ka] A solution of a mixture of 4-iodo-1H-pyridazin-6-one (697 mg, 3.14 mmol), (2-methylpyrimidine-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 three times and purged with O2. The mixture was then stirred at 60°C for 12 hours under an O2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (eluting at PE:EA = 1:0 to 72:28) to obtain 5-iodo-2-(2-methylpyrimidine-5-yl)pyridazin-3(2H)-one (1.3 g, 87% yield) as a yellow solid. LCMS (ESI + m / z = 314.9 (M+H).

[0380] Step 2: Production of (1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)boronic acid [ka] A 3 mL solution of dioxane containing a mixture of 5-iodo-2-(2-methylpyrimidine-5-yl)pyridazin-3(2H)-one (500 mg, 1.59 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (809 mg, 3.18 mmol), KOAc (469 mg, 4.78 mmol), and Pd(dppf)Cl2 (116 mg, 0.16 mmol) was degassed three times and purged with N2. The mixture was then stirred at 100°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain (1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)boronic acid (500 mg, crude yield) as a brown oily substance, which was used in the next step without further purification. LCMS (ESI + ) m / z = 233.0 (M+H), t R = 0.338 minutes (Method AJ).

[0381] Step 3: Production of tert-butyl (R)-(1-(2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate [ka] A mixture of (1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)boronic acid (500 mg, 1.59 mmol), tert-butyl (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl) carbamate (intermediate 7, 447 mg, 1.27 mmol), mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A PdG3) (116 mg, 0.16 mmol), and K2CO3 (660 mg, 4.77 mmol) was degassed three times and purged with N2. Next, the mixture was stirred at 100°C for 0.5 hours. The reaction product was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1:0, followed by elution with DCM:MeOH=95:5) to obtain tert-butyl (R)-(1-(2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (420 mg, 44% yield) as a yellow solid. LCMS (ESI + m / z = 503.3 (M+H).

[0382] Step 4: Production of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)isoquinoline-1(2H)-one hydrochloride [ka] A solution of tert-butyl (R)-(1-(2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (400 mg, 0.80 mmol) in DCM (0.5 mL) was mixed with a 4 M, 4.0 mL, 16 mmol solution of dioxane in HCl. The mixture was stirred at 25°C for 1 hour, then concentrated under reduced pressure to obtain (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)isoquinoline-1(2H)-one hydrochloride (400 mg, crude yield) as a yellow solid, which was used in the next step without further purification. LCMS (ESI + m / z = 403.2 (M+H).

[0383] Step 5: Preparation of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)isoquinoline-1(2H)-one [ka] A 2 mL solution of dioxane containing a mixture of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)isoquinoline-1(2H)-one hydrochloride (200 mg, 0.46 mmol), 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (166 mg, 0.68 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloroimidazole-2-ylidene]-dichloro-(2-methylpyridine-1-ium-1-yl)palladium (38 mg, 0.046 mmol), and Cs2CO3 (742 mg, 2.28 mmol) was degassed three times and purged with N2. The mixture was then stirred at 100°C for 4 hours. Next, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (eluting with silica gel, PE:EA = 1:2) and then by preparative HPLC to obtain (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidine-5-yl)-6-oxo-1,6-dihydropyridazine-4-yl)isoquinoline-1(2H)-one (94 mg, 37% yield) as a yellow solid. LCMS (ESI + m / z = 565.3 (M+H); 1 H NMR (400 MHz, CDCl3): δ 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-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrimidine-2-yl)-5-fluoro-2-methylpyridine 1-oxide [ka]

[0385] Step 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] 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-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (401 mg, 1.58 mmol) at room temperature, followed by the addition of KOAc (155 mg, 1.58 mmol) and Pd(dppf)Cl2·CH2Cl2 (86 mg, 0.11 mmol). The resulting mixture was stirred under a nitrogen atmosphere at 100°C for 0.5 hours. The resulting mixture was filtered and concentrated under reduced pressure. The crude organism was used directly in the next step without further purification. LCMS (ES + m / z = 238.1 (M+H).

[0386] Step 2: Production of 5-bromo-2-(5-fluoro-2-methylpyridine-3-yl)pyrimidine [ka] A solution of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (200 mg, 0.84 mmol) in dioxane (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 hours under a nitrogen atmosphere. The mixture was then filtered, and the filter cake was washed with ethyl acetate (2 × 10 mL). After further dilution with ethyl acetate, the filtrate was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (elution with EA) to obtain 5-bromo-2-(5-fluoro-2-methylpyridine-3-yl)pyrimidine (100 mg, 46%) as a grayish-white solid. LCMS (ESI + m / z = 268.0 (M+H).

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

[0388] Step 4: Preparation of 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl)pyridine 1-oxide [ka] A solution of 3-(5-bromopyrimidine-2-yl)-5-fluoro-2-methylpyridine-1-ium-1-oleate (200 mg, 0.704 mmol) in dioxane (3 mL) was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (268 mg, 1.06 mmol) at room temperature, followed by the addition of Pd(dppf)Cl2 (52 mg, 0.070 mmol) and KOAc (137 mg, 1.41 mmol). The resulting mixture was stirred at 100°C for 1 hour and then filtered. The filtrate was then concentrated under reduced pressure and used directly in the next step without further purification of the crude organism. LCMS (ESI) + m / z = 332.1 (M+H).

[0389] Step 5: Preparation of (R)-3-(5-(2,7-dimethyl-5-(1-((2-(methylsulfonylphenyl)phenyl)amino)ethyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrimidine-2-yl)-5-fluoro-2-methylpyridine 1-oxide [ka] A solution of 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl)pyridine 1-oxide (300 mg, 0.91 mmol) in a 1,4-dioxane solution (5 mL) was treated with (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)isoquinoline-1(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 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filter cake was washed with 1,4-dioxane (3 × 10 mL). The filtrate was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL), washed with brine (2 × 20 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude organism was purified by preparative HPLC to obtain (R)-3-(5-(2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrimidine-2-yl)-5-fluoro-2-methylpyridine 1-oxide (11 mg, 2% yield) as a grayish-white solid. LCMS (ESI + m / z = 574.4 (M+H); 1 H NMR (400 MHz, DMSO-d6): δ 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-(1,5-dimethyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka]

[0391] Step 1: Preparation of (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] To a solution of 1,4-dioxane solution (10 mL) containing 4-fluoro-1-iodo-2-(trifluoromethyl)benzene (1.73 g, 5.98 mmol) and 4-dioxane solution (10 mL), RuPhos (0.37 g, 0.80 mmol), Pd2(dba)3 (0.37 g, 0.40 mmol), and Cs2CO3 (3.90 g, 12.0 mmol) were added at room temperature. The resulting mixture was then stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction was quenched by adding water (20 mL) at 0 °C, and the resulting mixture was extracted with ELISA (3 × 30 mL). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by grinding with MeCN (30 mL) to obtain (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (460 mg, 55% yield) as a gray solid. LCMS (ESI + m / z = 413.1 (M+H).

[0392] Step 2: Preparation of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1(2H)-one [ka] Pd(dppf)Cl2 (71 mg, 0.097 mmol) and KOAc (285 mg, 2.91 mmol) were added to a 1,4-dioxane (5 mL) solution of (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (400 mg, 0.97 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan while stirring. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. Next, the resulting mixture was filtered, the filter cake was washed with DCM (2 × 20 mL), and the filtrate was concentrated under reduced pressure to obtain (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1(2H)-one (400 mg, crude yield) as a brown oily substance, which was used directly in the next step without further purification. LCMS (ESI + m / z = 505.2 (M+H).

[0393] Step 3: Preparation of (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] To a solution of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1(2H)-one (400 mg, 0.79 mmol) in dioxane (10 mL) and H2O (2 mL) while stirring, 2-bromo-5-iodopyrimidine (226 mg, 0.79 mmol), Pd(PPh3)4 (92 mg, 0.079 mmol), and Na2CO3 (252 mg, 2.38 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 hours. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (eluting with PE:EA = 1:1) to obtain (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (190 mg, 35% yield) as a bright yellow solid. LCMS: (ESI + ) m / z = 535.1(M+H).

[0394] Step 4: Preparation of (R)-3-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] To a stirring solution of (R)-3-(2-bromopyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (200 mg, 0.37 mmol) and 1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-one (intermediate 14, 140 mg, 0.56 mmol) in H2O (0.5 mL) and 1,4-dioxane (2 mL), Na2CO3 (119 mg, 1.12 mmol) and Pd (PPh-3 )4 (43 mg, 0.037 mmol) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 90°C for a further 2 hours. The reaction was then quenched by adding water (5 mL) at 0°C. The resulting mixture was extracted with ELISA (3 × 5 mL). The combined organic matter was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude organism was purified by preparative HPLC to obtain (R)-3-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyrazine-2-yl)pyrimidine-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (4.3 mg, 2% yield) as a bright yellow solid. LCMS (ESI + m / z = 579.3 (M+H); 1 H NMR (400 MHz, methanol-d4): δ 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 20-84, 94-955, 964, 967, 986, 989, 1022, 1025, 1044-1060, 1062, 1068, 1071, and 1072 are shown in Tables 1 and 2 below, and Examples 1-19 and 85-93 were prepared by similar methods as described above. Unless otherwise noted, each chiral center described exists separately as a (R)- and (S)-racemic mixture or (R)- or (S)-enantiomer. Each compound shown in Table 1 is identified by both its chemical structure and name, but more emphasis should be placed on the chemical structure when describing the compound. [Table 16] Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 Table 71 Table 72 Table 73 Table 74 Table 75 Table 76 Table 77 Table 78 Table 79 Table 80 Table 81 Table 82 Table 83 Table 84 Table 85 Table 86 Table 87 Table 88 Table 89 Table 90 Table 91 Table 92 Table 93 Table 94 Table 95 Table 96 Table 97 Table 98 Table 99 Table 100 Table 101 Table 102 Table 103 Table 104 Table 105 Table 106 Table 107 Table 108 Table 109 Table 110 Table 111 Table 112 Table 113 Table 114 Table 115 Table 116 Table 117 Table 118 Table 119 Table 120 Table 121 Table 122 Table 123 Table 124 Table 125 Table 126 Table 127 Table 128 Table 129 Table 130 Table 131 Table 132 Table 133 Table 134 Table 135 Table 136 Table 137 Table 138 Table 139 Table 140 Table 141 Table 142 Table 143 Table 144 Table 145 Table 146 Table 147 Table 148 Table 149 Table 150 Table 151 Table 152 Table 153 Table 154 Table 155 Table 156 Table 157 Table 158 Table 159 Table 160 Table 161 Table 162 Table 163 Table 164 Table 165 Table 166 Table 167 Table 168 Table 169 Table 170 Table 171 Table 172 Table 173 Table 174 Table 175 Table 176 Table 177 Table 178 Table 179 Table 180 Table 181 Table 182 Table 183 Table 184 Table 185 Table 186 Table 187 Table 188 Table 189 Table 190 Table 191 Table 192 Table 193 Table 194 Table 195 Table 196 Table 197 Table 198 Table 199 Table 200 Table 201 Table 202 Table 203 Table 204 Table 205 Table 206 Table 207 Table 208 Table 209 Table 210 Table 211 Table 212 Table 213 Table 214 Table 215 Table 216 Table 217 Table 218 Table 219 Table 220 Table 221 Table 222 Table 223 Table 224 Table 225 Table 226 Table 227 Table 228 Table 229 Table 230 Table 231 Table 232 Table 233 Table 234 Table 235 Table 236 Table 237 Table 238 Table 239 Table 240 Table 241 Table 242 Table 243 Table 244 Table 245 Table 246 Table 247 Table 248 Table 249 Table 250 Table 251 Table 252 Table 253 Table 254 Table 255 Table 256 Table 257 Table 258 Table 259 Table 260 Table 261 Table 262 Table 263 Table 264 Table 265 Table 266 Table 267 Table 268 Table 269 Table 270 Table 271 Table 272 Table 273 Table 274 Table 275 Table 276 Table 277 Table 278 Table 279 Table 280 Table 281 Table 282 Table 283 Table 284 Table 285 Table 286 Table 287 Table 288 Table 289 Table 290 Table 291 Table 292 Table 293 Table 294 Table 295 Table 296 Table 297 Table 298 Table 299 Table 300 Table 301 Table 302 Table 303 Table 304 Table 305 Table 306 Table 307 Table 308 Table 309 Table 310 Table 311 Table 312 Table 313 Table 314 Table 315 Table 316 Table 317 Table 318 Table 319 Table 320 Table 321 Table 322 Table 323 Table 324 Table 325 Table 326 Table 327 Table 328 Table 329 Table 330 Table 331 Table 332 Table 333 Table 334 Table 335 Table 336 Table 337 Table 338 Table 339 Table 340 Table 341 Table 342 Table 343 Table 344 Table 345 Table 346 Table 347 Table 348 Table 349 Table 350 Table 351 Table 352 Table 353 Table 354 Table 355 Table 356 Table 357 Table 358 Table 359 Table 360 Table 361 Table 362 Table 363 Table 364 Table 365 Table 366 Table 367 Table 368 Table 369 Table 370 Table 371 Table 372 Table 373 Table 374 Table 375 Table 376 Table 377 Table 378 Table 379 Table 380 Table 381 Table 382 Table 383 Table 384 Table 385 Table 386 Table 387 Table 388 Table 389 Table 390 Table 391 Table 392 Table 393 Table 394 Table 395 Table 396 Table 397 Table 398 Table 399 Table 400 Table 401 Table 402 Table 403 Table 404 Table 405 Table 406 Table 407 Table 408 Table 409 Table 410 Table 411 Table 412 Table 413 Table 414 Table 415 Table 416 Table 417 Table 418 Table 419 Table 420 Table 421 Table 422 Table 423 Table 424 Table 425 Table 426 Table 427 Table 428 Table 429 Table 430

[0396] Assays and compound testing In vitro cell proliferation: Emission control of T47D cells expressing the mutant PI3Ka(H1047R) mutation and SKBR3 cells expressing WT PI3Ka. 50 Value determination

[0397] T47D or SKBR3 cells were trypsinized, resuspended in culture medium, and seeded in assay-ready plates. T47D culture medium consisted of RPMI, 10% FBS, and insulin (0.2 units / mL). SKBR3 culture medium consisted of McCoys 5a and 10% FBS. Cells were seeded at a density of 1,500 cells / well, and 50 μL was distributed into 384-well assay-ready plates (Corning, 89089-790). The assay-ready plates were pre-stamped with 10 dilutions of the target compound and controls. Echo655 was used to stamp with 40 nL of the compound or DMSO. Cells were cultured for 72 hours at 37°C and 5% CO2. After 72 hours, cells were equilibrated at room temperature for 15 minutes. 30 μL of CellTiter-Glo reagent was added to the plate, and then the plate was shaken at 300-500 rpm for 30 minutes. The cells were then read using an Envision plate reader. The percentage of growth inhibition was calculated using the following formula: % inhibition = 100 × (Lum D -Lum サンプル ) / (Lum D -Lum Inh (In the formula, D is obtained from cells treated with 0.1% DMSO alone; Inh is obtained from cells treated with 10 μM alperisib). Effective concentration (EC) to achieve 50% inhibition of proliferation. 50 ) is expressed using Xlfit(v5.3.1.3), equation 201: Y = base + (top - base) / (1 + 10^((LogEC 50 The calculation is performed by curve fitting using (-X) × (HillSlope). [Table 431]

[0398] Table 2 shows the EC 50Regarding the value, 'A' is 1nM <EC 50 <500nM; "B" is 500nM <EC 50 <2μM; "C" is 2μM <EC 50 <15μM is the definition; and "D" is EC 50 This refers to 15 μM. [Table 432] [Table 433] [Table 434] [Table 435] [Table 436] [Table 437] [Table 438] [Table 439] [Table 440] [Table 441] [Table 442] [Table 443] [Table 444] [Table 445] [Table 446] Table 447 Table 448 Table 449 Table 450 Table 451 Table 452 Table 453 Table 454

[0399] IC on phosphorylation inhibition of AKT (pAKT) in in vitro cells: T47D cells expressing the PI3Ka(H1047R) mutant and SKBR3 cells expressing WT PI3Ka. 50 Value determination

[0400] T47D or SKBR3 cells were trypsinized, resuspended in culture medium, and seeded in assay-ready plates. T47D culture medium consisted of RPMI, 10% FBS, and insulin (0.2 units / mL). SKBR3 culture medium consisted of McCoy's 5a and 10% FBS. Cells were seeded at a density of 5000 cells / well, and 12.5 μL was distributed into 384-well assay-ready plates (Perkin Elmer, 6008238). The assay-ready plates were pre-stamped with 10 dilutions of the target compound and controls. Echo655 was used to stamp with 12.5 nL of the compound or DMSO. Cells were grown for 6 hours at 37°C and 5% CO2. After 6 hours, 4 μL of lysis buffer reagent was added to the plate, and then the plate was centrifuged at 1000 rpm for 1 minute. The plate was then incubated at room temperature for 30 minutes. After 30 minutes, an antibody mix containing 4 μL of Eu Cryptate, d2 Cryptate, and detection buffer was added to the plate. The plate was centrifuged at 1000 rpm for 1 minute and then incubated overnight at room temperature. The plate was read using an Envision plate reader with the HTRF protocol. The AKT phosphorylation inhibition percentage was calculated using the following formula: % inhibition = 100 × (pAKTHC - pAKT sample) / (pAKTHC - pAKTLC) (wherein pAKTHC is obtained from cells treated with 0.1% DMSO only; pAKTLC is obtained from cells treated with 10 μM alperisib). 50 (The concentration that achieves 50% inhibition of pAKT) is calculated using Xlfit(v5.3.1.3), equation 201: Y = base + (peak - base) / (1 + 10^((LogIC) 50 The calculation is performed by curve fitting using (-X) × (HillSlope). [Table 455]

[0401] Table 3 shows the ICs 50 Regarding the value, 'A' is 1nM <IC 50 <500nM; "B" is 500nM <IC 50<2μM; "C" is 2μM <IC 50 <15μM refers to IC; and "D" is IC 50 This refers to 15 μM. [Table 456] [Table 457] [Table 458] [Table 459] [Table 460] [Table 461] [Table 462] [Table 463] [Table 464] [Table 465] [Table 466] [Table 467] [Table 468] [Table 469] [Table 470] [Table 471] Table 472 Table 473 Table 474 Table 475 Table 476 Table 477 Table 478 Table 479 Table 480 Table 481 Table 482 Table 483 Table 484 Table 485

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Claims

1. Formula (1) 【Chemistry 1】 [In the ceremony: R １ teeth 【Chemistry 2】 Selected from; Each A is independently C １ -C ４ alkyl, fluoroalkyl, C ３ -C ７ cycloalkyl, N(R ａ ) ２ , (CH ２ ) ０－５ -NR ａ -C(O)-C ３ -C ７ cycloalkyl, (CH ２ ) １－５ -O-(CH ２ ) ０－５ -C １ -C ４ alkyl, (CH ２ ) １－５ -O-C １ -C ３ cycloalkyl, (CH ２ ) １－５ -O-(CH ２ ) ０－５ -CF ３ , (CH ２ ) １－５ -O-(CH ２ ) １－５ -C １ -C ３ fluoroalkyl, (CH ２ ) ０－５ -aryl, (CH ２ ) ０－５ -heteroaryl, (CH ２ ) ０－５ -heterocyclyl, (CH ２ ) ０－５ -NR ａ -(CH ２ ) ０－５ -heteroaryl or (CH ２ ) ０－５ -NR ａ -(CH ２ ) １－５ -N-heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted, or A and A may together with the -P(=O)- moiety to which they are attached form a substituted or unsubstituted heterocyclic ring; Each B is independently H, C １ -C ４ Alkyl, C ３ -C ７ Cycloalkyl, (CH ２ ) １－５ -OH, (CH ２ ) ０－５ -N(R ａ ) ２ , (CH ２ ) １－５ -NR ａ -C(O)-C ３ -C ７ Cycloalkyl, (CH ２ ) ０－５ - Aryl, (CH ２ ) ０－５ - Heteroaryl, (CH ２ ) ０－５ - Heterocyclyl, (CH ２ ) ０－５ -C(O)-(CH ２ ) １－５ -O-C １ -C ４ Alkyl, (CH ２ ) １－５ -NR ａ -(CH ２ ) ０－５ - Heteroaryl or (CH ２ ) １－５ -NR ａ -(CH ２ ) ２－５ -N-heterocyclyl, O-C １－５ -Alkyl, O-C ０－５ -Cycloalkyl, O-C ０－５ -A heterocyclyl, where the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are substituted or unsubstituted, or B and B may form a substituted or unsubstituted heterocyclyl ring with the bonded -[O or NH]-P(=O)-O- moiety, or A and B may form a substituted or unsubstituted heterocyclyl ring with the bonded -P(=O)-O- moiety; Each R ａ is independently H, C １ -C ４ alkyl, C ３ -C ７ cycloalkyl, C(O)C １ -C ３ alkyl, (CH ２ ) １－５ -fluoroalkyl, (CH ２ ) １－５ -OH, (CH ２ ) １－５ -NH ２ , (CH ２ ) １－５ -NH(C １－ C​​​​​​​​​​​​​​​​​​​​​​​​​​ R ２ H, C １ -C ４ Alkyl, C ３ -C ７ Cycloalkyl, CF ３ CFH ２ or CF ２ H and R ２ When it is not H, R ２ The carbon atom bonded to it is a chiral center and exists as a (R)- and (S)-racemic mixture or as a (R)- or (S)-enantiomer; R ３ is H or C １ -C ４ It is alkyl; R ４ H, C １ -C ４ Alkyl, C ３ -C ７ Cycloalkyl, halogen, CN, CF ３ OCF ３ CFH ２ or CF ２ It is H; R ６ H, C １ -C ４ Alkyl, C ３ -C ７ Cycloalkyl, heteroaromatic, CF ３ CFH ２ or CF ２ It is H; R ７ H, C １ -C ４ Alkyl, C ３ -C ７ Cycloalkyl, halogen, CN, CF ３ OCF ３ CFH ２ or CF ２ It is H; Each R ８ H and C are independent. １ -C ４ Alkyl, C ３ -C ７ Cycloalkyl, halogen, CN, CF ３ OCF ３ CFH ２ or CF ２ It is H; X １ , X ２ and X ３ Each of them is independently N, CH, or substituted C; X ４ is CH or substituted C; R ５ teeth halogen; -O-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ ; -S-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ ; -S(O)-L １ -L ２ -L ３ -L ５ -L ６ -L ７ -R ９ ; -S(O) ２ -L １ -L ２ -L ３ -L ５ -L ６ -L ７ -R ９ ; -(NR １０ )-L １ -8 ２ -8 ３ -8 ４ -8 ５ -8 ６ -8 ７ -2 ９ ;または -L ８ -L ９ -L １０ -L １１ -L １２ -R １４ And here: L １ , L ２ , L ３ , L ６ and L ７ Each of them is independent (CHR １１ ), (CHR １１ -O), (CHR １１ -S), (C ３ -C ７ Cycloalkyl), (CH ２ ) １－４ or combination; L ４ C=O, C=S, or bond; L ５ NR １０ , S, O or bond; R ９ H, C(=O)R １２ , C(=O)NR １２ R １３ , NR １２ R １３ , C(=O)OR １２ , C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C １ -C ６ Alkyl, C １ -C ６ Each of the fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted; or NR １０ When R exists, ９ and R １０ It may form a substituted or unsubstituted ring with the nitrogen atom it bonds to; R １０ and R １１ Each of them is independently H or C １ -C ４ Alkyl (e.g., CH ３ ,CH ２ CH ３ or CH(CH ３ ) ２ ) and here, C １ -C ４ Alkyl groups are either unsubstituted or substituted; R １２ and R １３ Each of these is independently H, C １ -C ６ Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C １ -C ６ Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is either unsubstituted or substituted; or, R １２ and R １３ It may form a substituted or unsubstituted ring with the nitrogen atom it bonds to; L ８ (CHR １５ ), (CHR １５ -O), (CHR １５ -S), (CHR １５ -NR １６ ), C=O, C=S or bond; L ９ C is, if desired, cross-linked, condensed, or part of a spiro ring system. ３ -C ７ Cycloalkyl, C(R １５ ) = C(R １５ ), C≡C or bond; L １０ (CHR) １５ ), O, S, (NCR １５ ), N(C=O) or bond; L １１ (CHR １５ ), C=O, C=S or bond; L １２ H, (C ３ -C ７ Cycloalkyl), heterocyclyl, aryl, heteroaryl, or bond, where C ３ -C ７ Each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be unsubstituted or substituted, and C ３ -C ７ Cycloalkyl and / or heterocyclyls are optionally crosslinked, condensed, or part of a spirocycle system; R １４ H, CR １５ R １６ R １７ , OR １７ , SR １７ , NR １６ R １７ , C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C １ -C ６ Alkyl, C １ -C ６ Each of the fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds may be unsubstituted or substituted. R １５ and R １６ Each of them is independently H or C １ -C ３ It is alkyl; and Each R １７ H and C are independent. １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ It is an aminoalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are either unsubstituted or each is substituted; or, R １６ and R １７ It may form a substituted or unsubstituted ring with the nitrogen atom it bonds to. However, R ５ ga-L ８ -L ９ -L １０ -L １１ -L １２ -R １４ When L ８ , L ９ , L １０ , L １１ , L １２ and R １４ At least one of them is a carbon-containing part, R ５ It is directly bonded to the (isoquinolone) core structure by carbon atoms; or R ５ This is a non-aromatic N-bonded heterocyclic ring. 【Transformation 3】 Here, the heterocyclic ring is substituted or unsubstituted and optionally contains further ring atoms selected from N, O, Si, and S, and optionally is bridging, condensed, or part of a spirocyclic system. Compounds thereof or their solvates, enantiomers, diastereomers, tautomers, polymorphs or isotope-labeled compounds, or pharmaceutically acceptable salts thereof.

2. R ５ But - (NR １０ )-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ And here, L １ ~L ７ , R ９ and R １０ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof as defined herein.

3. R ５ ga-O-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ And here, L １ ~L ７ and R ９ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof as defined herein.

4. R ５ ga-S-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ ;-S(O)-L １ -L ２ -L ３ -L ５ -L ６ -L ７ -R ９ ; or -S(O) ２ -L １ -L ２ -L ３ -L ５ -L ６ -L ７ -R ９ And here, L １ ~L ７ and R ９ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof as defined herein.

5. R ５ ga-L ８ -L ９ -L １０ -L １１ -L １２ -R １４ And here, L ８ ~L １２ and R １４ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof as defined herein.

6. R ５ non-aromatic N-bonded heterocyclyl ring 【Chemistry 4】 The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the heterocyclyl ring is substituted or unsubstituted and optionally comprises one or more further ring atoms selected from N, O, Si and S, and optionally is bridging, condensed or part of a spiro-ring system.

7. R １ but 【Transformation 5】 A compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof, selected from, where A and B are as defined in claim 1.

8. R １ but 【Transformation 6】 Selected from, where A, B and R ａ A compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof as defined in claim 1.

9. R １ but 【Transformation 7】 A compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof, selected from, where B is as defined in claim 1.

10. X ４ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, wherein is CH or CF.

11. R ２ ga CH ３ or CH ２ F is the compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R ３ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, wherein the compound is H.

13. X １ N is X ２ and X ３ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein is independently CH or substituted C.

14. X ２ N is X １ and X ３ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein is independently CH or substituted C.

15. X ３ N is X １ and X ３ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein is independently CH or substituted C.

16. X １ and X ３ N is X ２ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, wherein is CH or substituted C.

17. X １ and X ２ N is X ３ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, wherein is CH or substituted C.

18. X ２ and X ３ N is X １ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, wherein is CH or substituted C.

19. X １ , X ２ and X ３ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, wherein N is present.

20. X １ , X ２ and X ３ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein is independently CH or substituted C.

21. R ２ ga CH ３ or CH ２ F is R ３ H is X ４ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, wherein N is present.

22. R ２ ga CH ３ or CH ２ F is R ３ H is X ４ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, wherein is CH or CF.

23. R ２ ga CH ３ or CH ２ F is R ３ H is R ５ ga-L ８ -L ９ -L １０ -L １１ -L １２ -R １４ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, or a pharmaceutically acceptable salt thereof.

24. R ２ ga CH ３ or CH ２ F is R ３ H is R ５ ga-O-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, or a pharmaceutically acceptable salt thereof.

25. R ２ ga CH ３ or CH ２ F is R ３ H is R ５ ga-S-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, or a pharmaceutically acceptable salt thereof.

26. R ２ ga CH ３ or CH ２ F is R ３ H is R ５ But - (NR １０ )-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, or a pharmaceutically acceptable salt thereof.

27. X ４ CH is, R ２ ga CH ３ or CH ２ F is R ３ H is R ５ ga-L ８ -L ９ -L １０ -L １１ -L １２ -R １４ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound according to claim 1, or a pharmaceutically acceptable salt thereof.

28. The compound of formula (1) is the compound of formula (2) 【Transformation 8】 [In the ceremony: X １ , X ２ , X ３ , R １ and R ５ This is as defined in the compound of formula (1), and The carbon atoms marked with an asterisk (*) are chiral centers and exist as (R)- and (S)-racemic mixtures or (R)- or (S)-enantiomers. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof according to claim 1.

29. X １ , X ２ and X ３ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 28, wherein each of is independently CH or CF.

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

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

32. The pharmaceutical composition according to claim 31, wherein one or more anticancer 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, amiphostine, camptothecin, topotecan, thalidomide, lenalidomide, CDK inhibitors, and proteasome inhibitors.

33. A method for treating a disease involving PI3K activity in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29.

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

35. The method according to claim 33, wherein the disorder is a congenital lipoma proliferation, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome (CLOVES), mosaic tissue hyperproliferation syndrome, venous malformation, and a brain malformation associated with severe epilepsy or PIK3CA-associated hyperproliferation syndrome.

36. The method according to claim 33, wherein the disease is a cancer that harbors the PI3KαH1047R mutation.

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