Benzopyridinones and benzopyrimidinones as PI3K inhibitors

Abstract

Novel PI3K inhibitors of general formula (1) wherein R1 to R8 and X1, X2, X3 and X4 are as defined, methods for their preparation and their use in the treatment of diseases associated with elevated or activated PI3K pathways are described.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 532,175, filed August 11, 2023, and U.S. Provisional Application No. 63 / 600,371, filed November 17, 2023, the disclosures of which are incorporated in their entirety for all purposes. Background Technology

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

[0003] High local concentrations of PIP3 promote the recruitment and activation of downstream signaling mates, including AKT and mTOR. Activation of the AKT / mTOR pathway is involved in several growth-related functions and pathologies, including glucose regulation, cell survival, angiogenesis, and proliferation (Porta et al., Front Oncol. 2014, 4, 1), demonstrating the role of class I PI3Ks as key upstream regulators of these functions.

[0004] Based on the characteristics of their catalytic subunits (p110α, p110β, p110γ, or p110δ) and regulatory subunits (p85α or its various splice variants p85β, p55γ, or p101), class I PI3Ks are further subdivided into four isoforms (α, β, γ, and δ), which play unique roles in cell physiology (Vanhaesebroeck et al., J Mol Med (Berl). 2016, 94, 5). PI3Kγ and PI3Kδ are mainly expressed in 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 β are more widely expressed and have similar but not identical roles. For example, PI3Kα has 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.). , NatRev 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 common events in human cancer. The PI3K pathway is overactivated 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 couples (Yang et al.). Mol Cancer2019, 18, 1). Mutations or mutations leading to PI3Kα upregulation have been found in genes encoding PI3Kα in many human cancers such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer (Goncalves et al., N Eng J Med. 2018, 379, 2052). In particular, the gene PIK3CA, which encodes the p110α subunit of PI3Kα, is frequently mutated or amplified in various tumor types. Missense mutations occur in all domains of p110α, but are mainly concentrated in two 'hotspots': most commonly E542K and E545K in the helical domain, and H1047R in the kinase domain. Mutations in the helical domain reduce the inhibition of p110α by p85 or promote the direct interaction of p110α with insulin receptor substrate 1 (IRS1)37, while mutations in the kinase domain increase the interaction of p110α with the lipid membrane, accompanied by upregulation of signal transduction events. (Thorpe et al., Nat Rev Cancer 2015, 15, 7).

[0006] The development of inhibitors targeting the PI3K pathway has been challenging because it is not possible to achieve sufficient tumor inhibition without adverse events. To date, clinically used PI3K inhibitors (alpelisib, buparlisib, copanlisib, duvelisib, idelalisib, pictilisib, taselisib, etc.) have caused dose-dependent adverse events such as hyperglycemia, rash, fatigue, and diarrhea (Jiang et al., Mol Biol Rep. 2020, 47, 4587), which are known on-target toxicities. Hyperglycemia is caused by insufficient insulin production or abnormal insulin utilization. The pancreas regulates insulin release in response to changes in blood glucose levels, resulting in glucose uptake by muscle and fat cells when insulin levels are high, or gluconeogenesis by the liver when insulin levels are low. The cellular response to insulin requires PI3K signaling via the widely expressed p110α subunit. Therefore, pan-PI3K inhibition of this target disrupts glucose metabolism in tissues, leading to insulin resistance (Hopkins et al., Nature 2018, 560, 499). To mitigate adverse events, selective PI3K subtype inhibitors have been developed. The severity of adverse events depends on the selected subtype; 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 selective PI3Kδ inhibitors (Adelaris), where the p110δ subunit is highly expressed in immune cells, can lead to severe diarrhea and colitis. Inhibition using a dual inhibitor (tacilisil) – a potent PI3Kδ inhibitor with moderate PI3Kα inhibition – resulted in gastrointestinal (GI) side effects, but no GI-related adverse events have been reported with the highly selective and potent PI3Kδ inhibitor (umbralisib) (Gadkar et al., CPT Pharmacometrics Syst Pharmacol. 2021, 11, 616). This phenomenon of mitigating adverse events with highly subtype-selective and potent inhibitors suggests that strategies to alleviate toxicity by developing mutation-selective subtype inhibitors are promising in reducing the severity of toxicity.Furthermore, selective inhibition of the mutant PI3Kα subtype, relative to the wild type, suppresses cancer signaling while having minimal effect on PI3K signaling in healthy cells carrying only wild-type PI3Kα, resulting in reduced toxicity associated with non-selective PI3K inhibition (Castel et al., Nat Cancer 20212, 587).

[0007] Currently, there is interest in developing PI3K inhibitors for cancer treatment (WO 2023 / 081209, WO 2023 / 078401, WO 2023 / 060262, WO2023 / 056407, WO 2021 / 202964). However, there remains a continued need for novel, potent, and selective PI3K inhibitors in cancer treatment, both as monotherapy and in combination therapy. Summary of the Invention

[0008] One aspect of the present invention is a compound of formula (1). Or its solvates, enantiomers, diastereomers, tautomers, polymorphs, or isotopically labeled compounds, or pharmaceutically acceptable salts thereof. in: R1 is selected from ; Each A is independently a 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 groups, (CH2) 0-5 -Aryl, (CH2) 0-5 -Heteroaryl, (CH2) 0-5 -Heterocyclic group, (CH2) 0-5 -NR a -(CH2) 0-5 -Heteroaryl or (CH2) 0-5 -NR a -(CH2) 1-5-N-heterocyclic group, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are substituted or unsubstituted, or alternatively, A and A together with the attached -P(=O)- portion may form a substituted or unsubstituted heterocyclic ring; 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 -Aryl, (CH2) 0-5 -Heteroaryl, (CH2) 0-5 -Heterocyclic group, (CH2) 0-5 -C(O)-(CH2) 1-5 -O-C1-C4 alkyl group, (CH2) 1-5 -NR a -(CH2) 0-5 -Heteroaryl or (CH2) 1-5 -NR a -(CH2) 2-5 -N-heterocyclic group, OC 1-5 -alkyl, OC 0-5 -cycloalkyl, OC 0-5 - Heterocyclic group, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are substituted or unsubstituted, or alternatively, B and B together with the attached -[O or NH]-P(=O)-O- portion can form a substituted or unsubstituted heterocyclic ring, or alternatively, A and B together with the attached -P(=O)-O- portion can form a substituted or unsubstituted heterocyclic ring; Each R a Independently, it can be H, C1-C4 alkyl, C3-C7 cycloalkyl, C(O)C1-C3 alkyl, or (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, wherein the alkyl and cycloalkyl groups are substituted or unsubstituted, or alternatively, for -S(=O)(A)(=NR) a ) or for -S(=O)(A)(NR a ), Ra A, together with the atoms it is attached to, can form substituted or unsubstituted heterocyclic rings; R2 is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF3, CFH2 or CF2H, and wherein R2 is not H, the carbon atom attached to R2 is a chiral center and exists as a racemic mixture of (R)- and (S)- or as an enantiomer of (R)- or (S)-. R3 is H or a C1-C4 alkyl group; 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 group, 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 a 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 , in: Each of L1, L2, L3, L6, and L7 is independently (CHR) 11 (CHR) 11 -O), (CHR) 11 -S), (C3-C7 cycloalkyl), (CH2) 1-4 OR key; L4 represents 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, heterocyclic, aryl, or heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted; or alternatively, when NR is present 10 At that time, R9 and R 10 Together with the attached nitrogen atom, a substituted or unsubstituted ring can be formed. In one exemplary embodiment, the ring is a 4- to 7-membered substituted or unsubstituted non-aromatic heterocyclic ring, containing 0, 1, or 2 heteroatoms (other than the nitrogen atom) that can be N, O, S, or Si, provided that if the ring size is 4 or 5, the number of additional heteroatoms will be 0 or 1, and if the ring size is 6 to 7, the number of additional heteroatoms will be 0, 1, or 2. If the ring is substituted, the substituents include, but are not limited to, CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxobutane ring, or COR. a One or more of them, where R a It is a C1-C4 alkyl, O-C1-C4 alkyl or NR b R c , where R b and R c Independently H or C1-C4 alkyl; R 10 and R 11 Each of them is independently H or a C1-C4 alkyl group (such as CH3, CH2CH3 or CH(CH3)2), wherein the C1-C4 alkyl group is unsubstituted or substituted; R 12 and R 13 Each of these is independently H, C1-C6 alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each of the C1-C6 alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted; or alternatively, R 12 and R 13Together with the attached nitrogen atom, a substituted or unsubstituted ring can be formed. In one exemplary embodiment, the ring is a 4- to 7-membered substituted or unsubstituted non-aromatic heterocyclic ring, containing 0, 1, or 2 heteroatoms (other than the nitrogen atom) that can be N, O, S, or Si, provided that if the ring size is 4 or 5, the number of additional heteroatoms will be 0 or 1, and if the ring size is 6 to 7, the number of additional heteroatoms will be 0, 1, or 2. If the ring is substituted, the substituents include, but are not limited to, CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxobutane ring, or COR. a One or more of them, where R a It is a C1-C4 alkyl, O-C1-C4 alkyl or NR b R c , where R b and R c Independently H or C1-C4 alkyl; L8 is (CHR) 15 (CHR) 15 -O), (CHR) 15 -S), (CHR) 15 -NR 16 ), C=O, C=S or bond; L9 is a C3-C7 cycloalkyl group (optionally part of a bridged ring, fused ring, or spirocyclic system), C(R 15 )=C(R 15 ), C≡C or key; L 10 Independently for (CHR) 15 ), O, S, (NCR) 15 ), N (C=O) or bond; L 11 For (CHR) 15 ), C=O, C=S or bond; L 12 The C3-C7 cycloalkyl, heterocyclic, aryl, heteroaryl or bond is H, (C3-C7 cycloalkyl), heterocyclic, aryl or heteroaryl, each of which is unsubstituted or substituted, and the C3-C7 cycloalkyl and / or heterocyclic is optionally part of a bridged ring, fused ring or spirocyclic system. R 14 For H, CR 15 R 16 R 17 OR 17 SR 17 NR 16 R 17The group comprises C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted. R 15 and R 16 Each of them is independently H or a C1-C3 alkyl group; and Each R 17 Independently, it is H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted; or alternatively, R 16 and R 17 Together with the attached nitrogen atom, a substituted or unsubstituted ring can be formed. In one exemplary embodiment, the ring is a 4- to 7-membered substituted or unsubstituted non-aromatic heterocyclic ring containing 0, 1, or 2 heteroatoms (other than the nitrogen atom) that can be N, O, or S, provided that if the ring size is 4 or 5, the number of additional heteroatoms will be 0 or 1, and if the ring size is 6 to 7, the number of additional heteroatoms will be 0, 1, or 2. If the ring is substituted, the substituents include, but are not limited to, Me, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxobutane ring, or COR. a One or more of them, where R a It is a C1-C4 alkyl, O-C1-C4 alkyl or NR b R c , where R b and R c Independently H or C1-C4 alkyl; The premise is that R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 At that time, L8, L9, L 10 L 11 L 12 and R 14 At least one of them is a carbon-containing part and R5 is directly connected to the core structure (benzopyridone or benzopyrimidinone) via carbon atoms; Or R5 is a non-aromatic N-linked heterocyclic ring. The heterocyclic ring is substituted or unsubstituted, optionally containing one or more additional ring atoms selected from N, O, Si, and S, and optionally is part of a bridged ring, fused ring, or spirocyclic system. In a particular embodiment, the N-linked heterocyclic base ring is a substituted or unsubstituted azacyclic butane, pyrrolidine, imidazoline, imidazoline, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1,4-dioxa-7-azaspiro[4.4]nonane, or 2-azaadamantane.

[0009] In one exemplary implementation, R5 is -(NR) 10 )-L1-L2-L3-L4-L5-L6-L7-R9, where L1 to L7, R9 and R 10 As defined.

[0010] In one exemplary implementation, R5 is -O-L1-L2-L3-L4-L5-L6-L7-R9, where L1 to L7 and R9 are as defined.

[0011] In one exemplary implementation, 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 to L7 and R9 are as defined.

[0012] In one exemplary embodiment, R9 is a 6-membered aryl ring; or a 5- to 6-membered heteroaryl ring containing 1 to 3 nitrogen atoms; or a non-aromatic 3- to 7-membered carbon ring; or a non-aromatic 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, S, and Si, provided that if the ring size is 4 or 5, the number of heteroatoms will be 1 or 2 and if the ring size is 6 or 7, the number of heteroatoms will be 1, 2, or 3; or a C1-C6 alkane. The alkyl group, wherein the aryl ring, heteroaryl ring, carbocyclic ring, heterocyclic ring, and C1-C6 alkyl group are unsubstituted or substituted by one or more of the following: CH3, F, Cl, CF3, CF2H, CH2F, OCH3, -CH2CF3, cyclopropyl, -CN, N(CH3)2, oxetane ring, phenyl or phenoxy group optionally substituted by 1 to 3 halogen (F, Cl, or Br) or CH3 groups, or COR a , where R a It is a C1-C4 alkyl, O-C1-C4 alkyl or NR b R c , where R b and R c It is independently H or C1-C4 alkyl.

[0013] In one exemplary implementation of R5, L8, L 10 and L 11 Each of the elements is a key and L9 is not a key.

[0014] In one exemplary implementation of R5, L8, L 10 and L 11 Each of them is a bond and L9 is a cycloalkyl group, which is optionally part of a bridged ring, fused ring, or spirocyclic system.

[0015] In one exemplary implementation of R5, L8, L 10 and L 11 Each of them is a bond and L9 is a cycloalkyl group, which is part of a bridged ring system.

[0016] In one exemplary implementation of R5, L8, L 10 and L 11 Each of them is a bond and L9 is a cycloalkyl group, which is part of a fused ring system.

[0017] In one exemplary implementation of R5, L8, L 10 and L 11 Each of them is a bond and L9 is a cycloalkyl group, which is part of a spirocyclic system.

[0018] In one exemplary implementation of R5, L8, L 10 and L 11 Each of them is a key and L9 is C(R) 15 )=C(R 15 ).

[0019] In one exemplary implementation of R5, L8, L 10 and L 11 Each of them is a key and L9 is C≡C.

[0020] In one exemplary implementation of R5, L8, L9, L 10 and L 11 Each of them is a key and L 12 It is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituted.

[0021] In one exemplary implementation of R5, L8, L9, L 10 and L 11 Each of them is a key and L 12It is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted, and R 14 For H.

[0022] In one exemplary implementation of R5, L8, L9, L 10 and L 11 Each of them is a key and L 12 It is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted, and R 14 It is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the C1-C6 alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituted.

[0023] In one exemplary implementation of R5, L8, L9, L 10 and L 11 Each of them is a key and L 12 It is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted, and R 14 For -CR 14 R 15 R 16 .

[0024] In one exemplary implementation of R5, L8, L9, L 10 and L 11 Each of them is a key and L 12 It is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted, and R 14 For -OR 16 or -OR 17 .

[0025] In one exemplary implementation of R5, L8, L9, L 10 and L 11 Each of them is a key and L 12 It is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted, and R 14 For -SR 17 .

[0026] In one exemplary implementation of R5, L8, L9, L 10 and L 11 Each of them is a key and L 12It is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted, and R 14 For -NR 16 R 17 .

[0027] In one exemplary implementation, R5 is , where R d It is H or CH3 and R e It is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen atoms, which may be optionally substituted by CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CN, or N(CH3)2, or R. d and R e Together with the attached nitrogen atom, a 4- to 7-membered non-aromatic heterocycle containing one to two heteroatoms that may be N or O can be formed, provided that if the ring size is 4 or 5, the number of heteroatoms will be 1, and if the ring size is 6 to 7, the number of heteroatoms will be 1 or 2, wherein the ring is unsubstituted or substituted by one or more of the following, including but not limited to: CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxobutane ring, or COR. a , where R a It is a C1-C4 alkyl, O-C1-C4 alkyl or NR b R c , where R b and R c It is independently H or C1-C4 alkyl.

[0028] In one exemplary embodiment, R5 is an N-linked non-aromatic heterocyclic base ring. The heterocyclic base ring is substituted or unsubstituted, optionally containing one or more additional atoms selected from N, O, Si, and S, and optionally is part of a bridged ring, fused ring, or spirocyclic system. In particular embodiments, the N-linked heterocyclic base ring is azacyclobutane, pyrrolidine, imidazoline, imidazoline, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2-oxa-7-azaspiro[3.5]nonane, 1,3,8-triazaspiro[4.5]decane-4-one, or 1,4-dioxa-7-azaspiro[4.4]nonane.

[0029] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si, and S, and is not part of a bridged ring, fused ring, or spirocyclic system.

[0030] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si, and S, and is part of a bridged ring, fused ring, or spirocyclic system.

[0031] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, contains no additional atoms selected from N, O, Si, and S, and is not part of a bridged ring, fused ring, or spirocyclic system.

[0032] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, contains no additional atoms selected from N, O, Si, and S, and is part of a bridged ring, fused ring, or spirocyclic system.

[0033] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is not part of a bridged ring, fused ring, or spirocyclic system.

[0034] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is part of a bridged ring, fused ring, or spirocyclic system.

[0035] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is not part of a bridged ring, fused ring, or spirocyclic system.

[0036] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is part of a bridged ring, fused ring, or spirocyclic system.

[0037] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is not part of a bridged ring, fused ring, or spirocyclic system.

[0038] In one exemplary embodiment, the N-linked non-aromatic heterocyclic base ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is part of a bridged ring, fused ring, or spirocyclic system.

[0039] In an exemplary embodiment of the compound of formula (1), R1 is selected from... Where A and B are as defined.

[0040] In an exemplary embodiment of the compound of formula (1), R1 is selected from... Among them, A, B and R a As defined.

[0041] In an exemplary embodiment of the compound of formula (1), R1 is selected from... Where B is as defined.

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

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

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

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

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

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

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

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

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

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

[0052] In one exemplary implementation, X1, X2, and X3 are N.

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

[0054] In one exemplary implementation, X4 is N.

[0055] In one exemplary implementation, X4 is CH or CF.

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

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

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

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

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

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

[0062] In one exemplary implementation, X1, X2, and X3 are N, and X4 is N.

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

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

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

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

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

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

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

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

[0071] In one exemplary implementation, 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 .

[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 one 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 selected from... Where A and B are as defined.

[0082] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, and R1 is selected from... Among them, A, B and R a As defined.

[0083] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, and R1 is selected from... Where B is as defined.

[0084] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, and R1 is selected from... Wherein A and B are as defined, and R5 is an N-linked heterocyclic ring selected from azacyclobutane, pyrrolidine, imidazoline, imidazoline, piperazine, morpholine, thiomorpholine, and piperidine, wherein each of these rings is either 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 selected from... Among them, A, B and R a R5 is as defined, and is an N-linked heterocyclic ring selected from azacyclobutane, pyrrolidine, imidazoline, imidazoline, piperazine, morpholine, thiomorpholine, and piperidine, wherein each of these rings is either 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 selected from... Wherein B is as defined, and R5 is an N-linked heterocyclic ring selected from azacyclobutane, pyrrolidine, imidazoline, imidazoline, piperazine, morpholine, thiomorpholine, and piperidine, wherein each of these rings is either 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 selected from... Where A and B are as defined.

[0088] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is selected from... Among them, A, B and R a As defined.

[0089] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is selected from... Where B is as defined.

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

[0091] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is N, and R1 is selected from... Among them, A, B and R a R5 is as defined, and is an N-linked heterocyclic ring selected from azacyclobutane, pyrrolidine, imidazoline, imidazoline, piperazine, morpholine, thiomorpholine, and piperidine, wherein each of these rings is either unsubstituted or substituted.

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

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

[0094] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is selected from... Among them, A, B and R a As defined.

[0095] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is selected from... Where B is as defined.

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

[0097] In an exemplary embodiment of the compound of formula (1), R2 is CH3 or CH2F, R3 is H, X4 is CH or CF, and R1 is selected from... Among them, A, B and R a R5 is as defined, and is an N-linked heterocyclic ring selected from azacyclobutane, pyrrolidine, imidazoline, imidazoline, piperazine, morpholine, thiomorpholine, and piperidine, wherein each of these rings is either unsubstituted or substituted.

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

[0099] In one exemplary embodiment, the compound of formula (1) is the compound of formula (2). Or a solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof. in: X1, X2, X3, R1, and R5 are defined in the compounds as shown in formula (1), and Carbons marked with * are chiral centers and exist as a mixture of (R)- and (S)- racemic compounds or as (R)- or (S)- enantiomers.

[0100] In one exemplary embodiment, the compound of formula (1) is a compound of formula (3). Or a solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof. in: X1, X2, X3, R1, and R5 are defined in the compounds as shown in formula (1), and Carbons marked with * are chiral centers and exist as a mixture of (R)- and (S)- racemic compounds or as (R)- or (S)- enantiomers.

[0101] In an exemplary embodiment of a compound of formula (2) or formula (3), R1 is selected from... Where A and B are defined in the compounds of formula (1).

[0102] In an exemplary embodiment of a compound of formula (2) or formula (3), R1 is selected from... Among them, A, B and R a As defined in compounds of formula (1).

[0103] In an exemplary embodiment of a compound of formula (2) or formula (3), R1 is selected from... Where B is defined in the compound as in formula (1).

[0104] In an exemplary embodiment of a compound of formula (2) or formula (3), R5 is -O-L1-L2-L3-L4-L5-L6-L7-R9, wherein -O-L1-L2-L3-L4-L5-L6-L7-R9 is as defined in a compound of formula (1).

[0105] In an exemplary embodiment of a compound of formula (2) or formula (3), R5 is -S-L1-L2-L3-L4-L5-L6-L7-R9, wherein -S-L1-L2-L3-L4-L5-L6-L7-R9 is as defined in a compound of formula (1).

[0106] In an exemplary embodiment 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 compounds of formula (1).

[0107] In an exemplary embodiment of the compound of formula (2) or formula (3), R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 Among them, -L8-L9-L 10 -L 11 -L 12 -R 14 As defined in compounds of formula (1).

[0108] In an exemplary embodiment of the compound of formula (2) or formula (3), R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 Among them, L8, L9, L 10 and L 11 For key; L 12 It is a (C3-C7 cycloalkyl), heterocyclic, or heteroaryl group, wherein each of the (C3-C7 cycloalkyl), heterocyclic, or heteroaryl groups is substituted or unsubstituted; and R 14 It is a heterocyclic group or a heteroaryl group, wherein each of the heterocyclic group or heteroaryl group is either unsubstituted or substituted.

[0109] In an exemplary embodiment of a compound of formula (2) or formula (3), R1 is selected from... Where B is defined in the compound as in formula (1); R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 Among them, L8, L9, L 10 and L 11 For key; L 12 It is a (C3-C7 cycloalkyl), heterocyclic, or heteroaryl group, wherein each of the (C3-C7 cycloalkyl), heterocyclic, or heteroaryl groups is substituted or unsubstituted; and R 14 It is a heterocyclic group or a heteroaryl group, wherein each of the heterocyclic group or heteroaryl group is either unsubstituted or substituted.

[0110] In an exemplary embodiment of a compound of formula (2) or formula (3), R1 is selected from... Where B is defined in the compound as in formula (1); R5 is -L8-L9-L 10 -L 11 -L 12 -R 14Among them, L8, L9, L 10 and L 11 For key; L 12 It is a (C3-C7 cycloalkyl), heterocyclic, or heteroaryl group, wherein each of the (C3-C7 cycloalkyl), heterocyclic, or heteroaryl groups is substituted or unsubstituted; R 14 It is a heterocyclic group or a heteroaryl group, each of which is unsubstituted or substituted; and one of X1 or X2 is N.

[0111] In an exemplary embodiment of the compound of formula (2) or formula (3), R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 Among them, L8, L9, L 10 and L 11 For key; L 12 It is a heterocyclic group or a heteroaryl group, wherein each of the heterocyclic group or heteroaryl group is substituted or unsubstituted; and R 14 It is a heterocyclic group or a heteroaryl group, wherein each of the heterocyclic group or heteroaryl group is either unsubstituted or substituted.

[0112] In an exemplary embodiment of a compound of formula (2) or formula (3), R1 is selected from... Where B is defined in the compound as in formula (1), and R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 Among them, L8, L9, L 10 and L 11 For key; L 12 It is a heterocyclic group or a heteroaryl group, wherein each of the heterocyclic group or heteroaryl group is substituted or unsubstituted; and R 14 It is a heterocyclic group or a heteroaryl group, wherein each of the heterocyclic group or heteroaryl group is either unsubstituted or substituted.

[0113] In an exemplary embodiment of a compound of formula (2) or formula (3), R1 is selected from... Where B is defined in the compound as in formula (1), and R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 Among them, L8, L9, L 10 and L 11 For key; L12 It is a heterocyclic group or a heteroaryl group, wherein each of the heterocyclic group or heteroaryl group is substituted or unsubstituted; R 14 It is a heterocyclic group or a heteroaryl group, each of which is unsubstituted or substituted; and one of X1 or X2 is N.

[0114] In an exemplary embodiment of the compound of formula (2) or formula (3), R5 is an N-linked non-aromatic heterocyclic ring. ,in As defined in compounds of formula (1).

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

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

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

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

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

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

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

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

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

[0124] In one exemplary embodiment, a pharmaceutical composition comprising any compound of the present invention as described herein (such as any of formula (1), (2) or (3)) or its solvates, enantiomers, diastereomers, tautomers, polymorphs or isotopically labeled compounds, or pharmaceutically acceptable salts thereof, further comprises one or more anticancer agents.

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

[0126] In one exemplary embodiment, the disease to be treated is cancer. In a particular embodiment, the disease is cancer carrying a PI3Kα H1047 mutation (such as H1047R). Detailed Implementation

[0128] As used herein, the term "at risk of" refers to a medical condition or set of medical conditions that may make a patient susceptible to a particular disease or ailment. For example, these conditions may be caused by, but are not limited to, behavioral, emotional, chemical, biochemical, or environmental influences.

[0129] As used herein, the term "effective amount" refers to the specific amount of a pharmaceutical composition containing a therapeutic agent that achieves a clinically beneficial outcome (i.e., symptom relief). The LD50 can be determined, for example, in cell cultures or laboratory animals using standard pharmaceutical procedures. 50 (Dose lethal to 50% of the population) and ED 50 The toxicity and therapeutic efficacy of such compositions are determined by the dose that is therapeutically effective in 50% of the population. The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50. 50 / ED 50 Compounds exhibiting a large therapeutic index are preferred. Data obtained from these cell culture assays and additional animal studies can be used to determine dosage ranges for human use. The preferred dosages for such compounds include ED. 50 And within a range of circulating concentrations with very low or no toxicity. Dosage within this range varies depending on the dosage form used, patient sensitivity, and route of administration.

[0130] As used herein, the term "symptom" refers to any subjective or objective evidence observed by a patient regarding a disease or physical disorder. For example, subjective evidence is typically based on the patient's self-report and may include, but is not limited to, pain, headache, visual disturbances, nausea, and / or vomiting. Alternatively, objective evidence is typically the result of medical testing, including but not limited to body temperature, complete blood count, lipid profile, thyroid function, blood pressure, heart rate, electrocardiogram, tissue imaging scans, and other medical test results.

[0131] As used herein, the term “disease” refers to any impairment of the normal state of a living animal or part thereof that interrupts or alters the execution of vital functions. Diseases are typically manifested as obvious signs and symptoms and are usually a response to: i) environmental factors (such as malnutrition, industrial hazards, or climate); ii) specific infectious agents (such as worms, bacteria, or viruses); iii) inherent defects in the organism (such as genetic abnormalities); and / or iv) combinations of these factors.

[0132] The terms “reduce,” “inhibit,” “weaken,” “suppress,” “lower,” “prevent,” and their grammatical equivalents (including “lower,” “smaller,” etc.), when used to refer to any symptom presentation in an untreated subject relative to a treated subject, refer to any amount by which the number and / or severity of symptoms in the treated subject is lower than that in the untreated subject, as determined by any medically trained person to be clinically relevant. In one embodiment, the number and / or severity of symptoms in the treated subject is at least 10%, at least 25%, at least 50%, at least 75%, and / or at least 90% lower than that in the untreated subject.

[0133] As used herein, the term "inhibitory compound" refers to any compound that, under certain conditions, interacts with a binding partner (i.e., by attachment, binding, etc.) such that the binding partner no longer responds to its natural ligand. Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins / peptides.

[0134] As used herein, the term "attachment" refers to any interaction between a medium (or carrier) and a drug. Attachment can be reversible or irreversible. Such attachments include, but are not limited to, covalent bonding, ionic bonding, van der Waals forces, or frictional forces. If a drug is impregnated, incorporated into, coated with, suspended in, dissolved in, or mixed with a medium (carrier), then the drug is considered to be attached to that medium (or carrier).

[0135] As used herein, the terms "drug" or "compound" refer to any pharmaceutically active substance that can be administered to achieve the desired effect. A drug or compound can be synthetic or naturally occurring non-peptide, protein or peptide, oligonucleotide or nucleotide, polysaccharide or sugar.

[0136] As used herein, the terms “administered” or “administering” refer to any method of providing a composition to a patient so that the composition has its intended effect on that patient. An exemplary method of administration is by a direct mechanism, such as local tissue administration (i.e., extravascular administration, such as subcutaneous, intramuscular, or intraperitoneal), intravenous, oral ingestion, transdermal patch, topical, inhalation, suppository, etc.

[0137] As used herein, the term "patient" refers to a person or animal who does not require hospitalization. For example, outpatients and nursing home staff are "patients." A patient can be a person or non-human animal of any age and therefore includes adults and minors (i.e., children). The term "patient" is not intended to imply a need for medical treatment. Therefore, patients may voluntarily participate in experiments, whether clinical trials or experiments supporting basic scientific research.

[0138] As used herein, the term “subject” means (but is not limited to) humans (e.g., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or other primates (e.g., monkeys); non-human mammals such as cattle, pigs, horses, sheep, mice, goats, cats, dogs; and / or poultry such as chickens, ducks, and / or geese.

[0139] As used herein, the term "affinity" refers to any attractive force between substances or particles that allows them to enter and maintain a chemical bond. For example, an inhibitory compound with high affinity for a receptor will provide greater efficacy in preventing that receptor from interacting with its natural ligand than an inhibitor with low affinity.

[0140] As used herein, the term "derived from" refers to the origin of a compound or sequence. In one respect, a compound or sequence may originate from an organism or a particular species. In another respect, a compound or sequence may originate from a larger complex or sequence.

[0141] As used herein, the term “test compound” refers to any compound or molecule that is considered as an alternative to an inhibitory compound.

[0142] As used herein, the term "combination therapy" refers to a dosing regimen of two or more different therapeutic agents over a period of time, wherein the therapeutic agents are administered together or separately. In one embodiment, the combination therapy is a non-fixed combination.

[0143] As used herein, the term “non-fixed combination” refers to two or more different therapeutic agents formulated as separate compositions or dosage forms such that they can be administered simultaneously or sequentially at variable time intervals to a subject in need.

[0144] As used in this article, the term "synergistic" or "synergistic" refers to a phenomenon in which the combination of two therapeutic agents in combination therapy yields a greater measured result than the sum of the effects of each agent when administered alone.

[0145] As used in this article, the term "in vivo" refers to events that occur within the body of a subject.

[0146] As used in this article, the term "in vitro" refers to events that occur outside the subject's body.

[0147] As used herein, the term "protein" refers to any of the many naturally occurring, extremely complex substances (such as enzymes or antibodies) that contain amino acid residues linked by peptide bonds and contain carbon, hydrogen, nitrogen, oxygen, and usually sulfur. Typically, proteins contain hundreds of amino acids.

[0148] As used herein, the term "peptide" refers to any of the various amides derived from two or more amino acids through the combination of the amino group of one amino acid and the carboxyl group of another amino acid, and is typically obtained through the partial hydrolysis of proteins. Typically, peptides contain on the order of tens of amino acids.

[0149] As used herein, the terms “pharmaceutical acceptable” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse reactions, allergic reactions or other unexpected reactions when administered to animals or humans.

[0150] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents or dispersion media, including but not limited to water, ethanol, polyols (such as, for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, coating agents, isotonic agents and absorption delay agents, liposomes, commercially available detergents, etc. Co-active bioactive ingredients may also be incorporated into such carriers.

[0151] As used herein, the term "pharmaceutically acceptable salt" means a salt that does not adversely affect the biological activity and properties of a compound and is suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, and / or allergic reactions. Pharmaceutically acceptable salts include salts derived from suitable inorganic acids, organic acids, and bases, and include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, naphthalenesulfonic acid, lactic acid, succinic acid, oxalic acid, stearic acid, etc. In some cases, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group as described herein with a base to form a salt, 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 from 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 from which salts can be prepared include, for example, primary amines, secondary amines, and tertiary amines.

[0152] As used herein, the term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject but is converted in vivo to the active compound. In many cases, prodrugs have improved physicochemical properties (such as bioavailability) and / or delivery properties relative to the parent compound. Prodrugs are typically designed to enhance pharmaceutically and / or pharmacokinetic properties associated with the parent compound. Prodrug compounds often have advantages in terms of solubility, tissue compatibility, or delayed release in a subject. Prodrugs comprise compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, when the prodrug is administered to a subject, cleaves the bond to form a free hydroxyl, free amino, or free thiol group, respectively. Prodrugs are known to be prepared from carboxylic acids, in the form of, for example, carboxylic acid esters or thioesters.

[0153] As used herein, the terms “purified” or “isolated” may refer to a composition (such as, for example, a peptide composition) that has been treated (e.g., fractionated) to remove various other components and that the composition substantially retains its expressed biological activity.

[0154] As used herein, the term "sample" includes, for example, environmental samples and biological samples. Environmental samples include substances from the environment such as soil and water. Biological samples include animals (e.g., humans), fluids (e.g., blood, plasma, and serum), solids (e.g., feces), tissues, liquid foods (e.g., milk), and solid foods (e.g., vegetables). For example, lung samples can be collected via bronchoalveolar lavage (BAL), which contains fluids and cells derived from lung tissue. Biological samples may include cells, tissue extracts, body fluids, chromosomes or extrachromosomal elements isolated from cells, genomic DNA (in solution or bound to a solid carrier, such as for Southern blotting analysis), RNA (in solution or bound to a solid carrier, such as for Northern blotting analysis), cDNA (in solution or bound to a solid carrier), and the like.

[0155] As used herein, the term "bioactive" refers to any molecule that has a structural, regulatory, or biochemical function. For example, bioactivity can be determined, for instance, by the restoration of wild-type growth in cells lacking protein activity. Cells lacking protein activity can be generated by a variety of methods (i.e., point mutations and frameshift mutations, for example). Complementation is achieved by transfecting cells lacking protein activity with an expression vector expressing the protein, its derivatives, or a portion thereof.

[0156] As used herein, the term "label" or "detectable label" refers to any composition that can be detected by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, or chemical means. Such labels include biotin used for staining with labeled streptavidin conjugates; magnetic beads (e.g., Dynabeads) ® ); fluorescent dyes (e.g., fluorescein, Texas Red) ® Rhodamine, green fluorescent protein, etc.); radioactive labeling (e.g., 3 H, 125 I, 35 S, 14 C or 32P); enzymes (e.g., horseradish peroxidase, alkaline phosphatase, and other enzymes commonly used in ELISA); and colorimetric labels, such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads. Patents teaching the use of such labels include, but are not limited to, U.S. Patent Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241 (all of which are incorporated herein by reference in their entirety). The labels contemplated in this invention can be detected by conventional methods. For example, radioactive labels can be detected using photographic film or a scintillation counter, and fluorescent labels can be detected using a photodetector to detect the emitted light. Enzyme labels are typically detected by providing a substrate to the enzyme and detecting the reaction product produced by the enzyme acting on the substrate, while colorimetric labels can be detected simply by visually observing the colored label.

[0157] As used herein, the term "conjugate" refers to any compound formed by the connection of two or more parts.

[0158] As used herein, “part” or “group” refers to any type of molecular arrangement specified by a formula, chemical name, or structure. In the context of certain embodiments, a conjugate comprises one or more parts or chemical groups. This means that the formula of the part is substituted at a position to link and become part of the molecular arrangement of the conjugate. While the parts may be directly covalently linked, it is not intended that two or more parts must be directly linked to each other. Linking groups, crosslinking groups, or joining groups refer to any molecular arrangement that links the parts by covalent bonds, such as, but not limited to, one or more amide groups. Additionally, while conjugates may be unsubstituted, they may also have multiple additional substituents linked to the linking group and / or linked to the parts.

[0159] As used herein, "polymer" or "polymer group" refers to a chemical species or group consisting of repeating, linked portions. In some embodiments, it is preferred that the number of repeating portions is three or more, or greater than ten. The linking portions may be structurally identical or partially different. 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 polymer subunits linked by covalent bonds.

[0160] As used herein, the term "substituted" means that at least one hydrogen atom in the molecular arrangement is replaced 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 (e.g., in the case of a carbon or silicon atom, it can be monosubstituted, disubstituted, or trisubstituted; in the case of a nitrogen atom, it can be monosubstituted, disubstituted, or trisubstituted; or in the case of an oxygen or sulfur atom, it can be monosubstituted). In the case of an oxosubstituent ("=O"), two hydrogen atoms are replaced (when the two hydrogen atoms of the intermediate carbon atom in -CH2-CH2-CH3 are replaced, it provides, for example, -(CH2)-C(=O)-CH3 as a substituent). When substituted, one or more of the following groups are "substituents". Substituents include, but are not limited to, halogens (e.g., F, Cl, Br, I), hydroxyl (OH), hydroxyalkyl (e.g., CH2-OH, CH(CH3)OH, C(CH3)2OH), oxo, cyano (CN), cyanoalkyl (e.g., CH2-CN, CH(CH3)CN, C(CH3)2CN), nitro (NO2), amino, alkylamino, dialkylamino, branched or unbranched alkyl (e.g., methyl, ethyl, propyl, isopropyl, sec-butyl, etc.), cycloalkyl (e.g., cyclopropyl), fluoroalkyl (e.g., CF3, CF2H, CH2F, CH2CF3, CH2CF2H, CHFCHF2, CF2CH2F, CF2CF3, CF2CH3, CF(CH3)2, CH2CH2CF3, CF2CH2CF3, CF2CF2CF3, etc.), or more generally, haloalkyl (e.g., CH2Cl, CH(CH3)Br, etc.), O-alkyl (alkoxy) (e.g., OCH3, OCH2CH3, OCH(CH3)2, etc.), O-cycloalkyl (e.g., O-cyclopropyl), O-haloalkyl (e.g., OCF2H, OCFH2, OCF3, OCH2CF3, OCH2CF2H, OCFHFCHF2, OCF2CH2F, OCF2CF3, OCF2CH3, OCF(CH3)2, OCH2CH2CF3, OCF2CH2CF3, OCF2CF2CF3 or OCH2Cl), O-aryl (e.g., O-phenyl), O-heteroaryl, O-heterocyclic, (CH2) 1-3 -cycloalkyl, (CH2) 1-3 - Haloalkyl, (CH2) 1-3 -Heterocyclic group, (CH2) 1-3 -Aryl, (CH2) 1-3 - Heteroaryl, thioalkyl (e.g., S-CH3), hydroxyalkyl (e.g., CH2OH), alkyl ether (e.g., CH2OCH3), alkynyl (e.g., -C≡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- or 6-membered heteroaryl ring), heteroarylalkyl (e.g., CH2-pyridine), heterocyclic, heterocyclic alkyl, 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 , where each R f and R gThe substituents may be the same or different and independently hydrogen, alkyl (e.g., CH3), substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, heteroaryl, heteroaryl, or substituted heteroaryl. Furthermore, the above substituents may be further substituted by one or more of the above substituents, such that the substituents can constitute, for example, substituted alkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted heterocyclic, or substituted heterocyclic alkyl.

[0161] As used herein, the term "unsubstituted" refers to any compound that does not contain any additional substituents attached to it. An unsubstituted compound is defined as a compound with a chemical composition free of additional substituents (e.g., no non-hydrogen substituents). For example, unsubstituted proline is the proline amino acid, although the amino group of proline may be considered to be disubstituted by an alkyl group.

[0162] As used in this paper when describing substituents with atoms on both sides, the term "bond" refers to the absence of that substituent. For example, in the 4-atomic sequence ABCD, when both B and C are listed as bonds, the result is the 2-atomic sequence AD. If only B is listed as a bond, the result is the 3-atomic sequence ACD.

[0163] As used herein, the term "alkyl" refers to any straight-chain 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 but contains 1 to 3 carbon atoms. The term "higher alkyl" has the same meaning as alkyl but contains 4 to 10 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, etc., while saturated branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc. As used herein, a methyl substituent may be represented as "CH3" or "Me," or may be represented as a terminal bond without specific atomic identification.

[0164] As used herein, the term "cycloalkyl" refers to saturated and unsaturated cycloalkyl groups. Representative saturated cycloalkyl groups include, but are not limited to, C3-C64 cycloalkyl groups. 14 Cycloalkyl groups (such as C3-C7) include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, etc.; while unsaturated cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadiene, etc. Cycloalkyl groups are also referred to as "equivalent rings" or "allocyclic rings" in this document.

[0165] As used herein, the term "bicyclic compound" encompasses "bridging" compounds, "fused" compounds, and "spirocyclic" compounds as described herein.

[0166] As used herein, the term "spirocyclic" or "spirocyclic" refers to a chemical structure having at least two rings sharing a common atom. These rings may be cycloalkyl, heterocyclic, or combinations thereof, and may include one or more aryl or heteroaryl rings. Exemplary embodiments include 1,4-dioxaspiro[4.5]decane, oxa-azaspiro[3.4]octane, diazaspiro[3.4]octane, diazaspiro[2.5]octane, spirocyclic azacyclic butane, and spirocyclic pyrrolidine, as well as spirocyclic piperidine, wherein the other ring is a cycloalkyl (e.g., cyclobutane, cyclopentane, or cyclohexane) or a heterocyclic (e.g., piperidine, tetrahydropyran, tetrahydrofuran, azacyclic butane, or pyrrolidine).

[0167] As used herein, the term "bridged" refers to a compound containing two non-adjacent atoms common to two rings. Exemplary embodiments include, but are not limited to, norbornene, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, azabicyclo[3.1.0]hexane, 3,9-diazabicyclo[3.3.1]nonane, zabicyclo[3.1.1]heptane, zabicyclo[3.2.1]octane, 1,4-zabicyclo[2.2.1]heptane, 1,4-zabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.1]heptane, 1,4-diazabicyclo[2.2.2]octane, and other bridged piperazines and bridged piperidines.

[0168] As used herein, the term "fusion" refers to a polycyclic ring system in which any two adjacent rings share two and only two adjacent atoms (ortho-fusion) and a polycyclic ring system in which one ring shares two and only two adjacent atoms with each of two or more rings in a successive series of ortho-fused rings (ortho- and peri-fusion). Exemplary embodiments are cyclopentadiene and dibenzoxepine (ortho-fusion) and pyrene (ortho- and peri-fusion). Ortho-fused systems have "n" shared edges and "2n" shared atoms, while peri-fused systems have "n" shared edges and fewer than "2n" shared atoms. Other exemplary fusion systems include fused cyclopropyl rings, fused aziridines, and fused aziridines, such as when these rings are fused with pyrrolidine rings. Other examples include fused pyrrolidine rings (e.g., octahydropyrrolo[3,4-c]pyrrole and octahydrocyclopent[c]pyrrole), fused pyridine rings such as pyridine rings fused with cycloalkyl groups (e.g., cyclopentane) or heterocyclic groups (e.g., tetrahydrofuran or tetrahydropyran), or other fused heteroaromatic rings (e.g., dihydro-5H-pyrazolo[5,1-b][1,3]oxazine and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine).

[0169] As used herein, the term “aromatic” or “aryl” refers to any aromatic carbocyclic (i.e., all ring atoms are carbon) substituent, such as, but not limited to, phenyl (from benzene), tolyl (from toluene), xylyl (from xylene), or polycyclic systems (e.g., naphthyl (from naphthalene) and anthracene (from anthracene)).

[0170] As used herein, the term “arylalkyl” or “arylalkyl” means any alkyl group in which at least one alkyl hydrogen atom is replaced by an aryl moiety, such as, but not limited to, benzyl, -(CH2)2phenyl, -(CH2)3phenyl, -CH(phenyl)2, etc.

[0171] As used in this article, the term "halogen" refers to any fluorine, chlorine, bromine, or iodine component.

[0172] As used herein, the term "halogenated alkyl" refers to any alkyl group in which at least one hydrogen atom (and including all hydrogen atoms) has been replaced by a halogen atom, such as, for example, trifluoromethyl, dichloromethyl, difluoromethyl, monofluoromethyl, monobromomethyl, 1,1,1-trifluoroethyl, etc.

[0173] As used herein, the term "aminoalkyl" refers to any alkyl group in which at least one hydrogen atom has been replaced by a nitrogen atom, such as, for example, -(CH2). 1-5 -NH2、-(CH2) 1-5 -NHCH3, -(CH2) 1-5 -N(CH3)2、-(CH2) 1-5 -NH-(CH2) 1-5 -N(CH3)2, etc.

[0174] As used herein, the term "heteroaromatic" or "heteroaryl" refers to any aromatic heterocyclic ring having 5 to 10 or more members and having at least one heteroatom selected from nitrogen, oxygen, or sulfur and containing at least one carbon atom, including but not limited to monocyclic and bicyclic ring systems, wherein the nitrogen atom may be in an oxidized state. The heteroaryl ring may be connected as a substituent via a cyclic heteroatom or a carbon atom. Representative heteroaromatic compounds include, but are not limited to, furans, benzofurans, thiophenes, benzothiophenes, pyrroles, indoles, isoyindoles, indazoles, 7-azaindoles, 4-azaindoles, 5-azaindoles, 6-azaindoles, 7-azainazoles, pyridines, pyridones (e.g., 2-pyridone, 3-pyridone, or 4-pyridone), pyrimidinones, oxopyrazines, pyridine oxides, quinolines, isoquinolines, oxazoles, isoxazoles, benzoxazoles, pyrazoles, imidazoles, imidazopyrimidines, benzimidazoles, thiazoles, benzothiazoles, isothiazoles, 1,2,4-triazoles, 1,2,3-triazoles, tetrazolium, and oxadiazoles (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole). -Oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole), pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, triazolopyrazine, cyclophosphine, phthalazine, quinazoline, 1,8-naphthylpyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-b]pyrazine, pyrido[2,3-b]pyrazine, pteridine, triazolopyridine (e.g., [1,2,4]triazolo[4,3-a]pyridine), etc.

[0175] As used herein, the term “heteroarylalkyl” refers to any alkyl group in which at least one alkyl hydrogen atom is replaced by a heteroaryl moiety, such as -CH2pyridyl, -CH2pyrimidinyl, etc.

[0176] As used herein, the terms "heterocycle," "heterocyclic group," or "heterocyclic ring" refer to a saturated or unsaturated non-aromatic ring containing one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, phosphorus, and silicon, wherein each of the nitrogen, phosphorus, and sulfur heteroatoms may be in an oxidized state, each of the nitrogen and silicon heteroatoms may be substituted or unsubstituted, and the nitrogen heteroatomium may optionally be quaternized, and include bicyclic rings in which any of the aforementioned heterocycles is fused with an aryl or heteroaryl ring. Heterocyclic rings may be linked as substituents via cyclic heteroatoms or carbon atoms.In various embodiments, the heterocycle may contain 3 to 14 or more ring atoms (such as 3- to 7-membered monocyclic rings or 7- to 10-membered bicyclic rings) and includes, but is not limited to, 2H-aziropropane, azirobutane, 2,3-dihydroazirobutadiene, 1,3-diazacyclobutane, 2H-oxacyclobutene, thiohexacyclobutane, 2H-thiohexacyclobutene, azirobutane-2-one, morpholine, thiomorpholine, pyrrolidone, pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, pyrazolidine, 2-pyrazolidine, pyridazinone, pyrazinone, oxazolidine-2-one, 2-imidazoline, imidazoline, piperidine, oxoperidine, tetrahydropyrimidinone, piperazine, oxoperazine, diazacycloheptane, and ethylene oxide (oxacyclopropane). Ethyleneimine (azacyclopropane), 1,1-dioxoisothiazolidinyl, cyclothioethane (thiacyclopropane), oxacyclobutane, propylene oxide, 1,3-dioxolane, 1,2-oxothiacyclopentane, 1,3-oxothiacyclopentane, sulfolane, 2,4-thiazolidinedione, succinimide, 4-methyl-1,4-azaphosphonane 4-oxide, oxadiazolone, dioxane (e.g., 1,4-dioxane and 1,3-dioxane), hydantoin, valeramide, tetrahydrofuran, tetrahydropyran, 2H-pyran, 4H-pyran, thiazide, 2H-thiaran, 1,3-dithiazide, 1,4-dithiazide, 1,3,5-trithiazide, pyrrolizidine, 1,4,5,6-tetrahydrocyclopentan[b]pyridine 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, Tetrahydrothiaran, Tetrahydrotriazolopyrazine, Tetrahydropyrazolopyridine, Dihydrotriazolopyrazine, Dihydropyrazolopyrazine, Dihydroimidazopyrazine, Indoline, Isoindolin, 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, Quinine ring, Triethylenediamine, 1-Azametal Argonane, 2-azaadamantane, 2,3-dihydroazacycloheptatriene, 2,5-dihydroazacycloheptatriene, oxacycloheptaane, azacyclononane, 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-oxa-7-azaspiro[4,4]nonane, 1,3-azaspiro[4,4]non-2-en-4-one, 2,9-azaspiro[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.

[0177] As used herein, the term "heterocyclic alkyl" refers to any alkyl group in which at least one alkyl hydrogen atom is replaced by a heterocyclic alkyl group, such as -CH2morpholino.

[0178] As used herein, the term "alkylamino" refers to at least one alkyl moiety linked by a nitrogen bridge (i.e., -N-(alkyl)). n , where n = 1 or 2, such as alkylamino or dialkylamino), including but not limited to methylamino, ethylamino, dimethylamino, diethylamino, etc.

[0179] As used herein, the term "alkyloxy" or "alkoxy" refers to any alkyl moiety (i.e., -O-alkyl) connected by an oxygen bridge, such as, but not limited to, methoxy, ethoxy, etc.

[0180] As used herein, the term "thioalkyl" refers to any alkyl moiety (i.e., -S-alkyl) linked by a sulfur bridge, such as, but not limited to, methylthio, ethylthio, etc.

[0181] As used herein, the term "alkenyl" refers to an unbranched or branched hydrocarbon chain having one or more carbon-carbon double bonds and may also be referred to as an "unsaturated alkyl group." The double bond of an alkenyl group may be unconjugated or conjugated with another unsaturated group. Suitable alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-buten)-pentenyl. The alkenyl group may be unsubstituted or substituted with one or two suitable substituents.

[0182] As used herein, the term "alkynyl" refers to an unbranched or branched hydrocarbon chain having one or more carbon-carbon triple bonds and may also be referred to as an "unsaturated alkyl group." The triple bond of the alkynyl group may be unconjugated or conjugated with another unsaturated group. Suitable alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, 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.

[0183] As used herein, a “reactive group” refers to a nucleophile, electrophile, or radical-active group—that is, a group that reacts in the presence of a radical. A nucleophile is the part that forms a chemical bond with its reactive partner (electrophile) by donating two bonding electrons. The electrophile accepts these electrons. Nucleophiles can participate in nucleophilic substitution reactions, in which the nucleophile is attracted by all or part of the positive charge on an element and displaces the group it is bonded to. Alternatively, nucleophiles can also participate in substitution reactions of carbonyl groups. Carboxylic acids are often endowed with electrophilicity by producing succinyl esters and reacting these esters with aminoalkyl groups to form amides. Other common nucleophiles include thioalkyl, hydroxyalkyl, primary and secondary amines, and carbon nucleophiles such as enols and alkyl metal complexes. Other preferred methods for linking proteins, oligosaccharides, and cells using reactive groups have been disclosed (Lemieux et al., Trends in Biotechnology 1998, 16, 506, incorporated herein by reference in its entirety). In another preferred method, a reactive group for Staudinger linkage is provided, namely, a "click chemistry" reaction using a moiety containing an azide group and an alkynyl reactive group to form a triazole. Alternatively, Michael addition of a carbon nucleophile enol salt to an electrophilic carbonyl group or Schiff base formation of a nucleophilic primary or secondary amine with an aldehyde or ketone can be used. Other methods of bioconjugation are also provided (Hang et al., Accounts of Chemical Research 2001, 34, 727 and Kiick et al., Proc Natl Acad Sci US.A. 2002, 99, 19, both of which are incorporated herein by reference in their entirety).

[0184] As used herein, the term "biocompatibility" refers to any material that does not elicit a materially harmful reaction in the host. When a foreign body is introduced into a living organism, there is always a concern that it may induce an immune response, such as an inflammatory response, which could negatively impact the host. In the context of this invention, biocompatibility is evaluated based on the application the material is designed for: for example, bandages are considered biocompatible with skin, while implantable medical devices are considered biocompatible with the body's internal tissues. Preferably, biocompatible materials include, but are not limited to, biodegradable and biostable materials. No materially harmful reaction occurs if an implant containing such a material exhibits a close association with its implantation site in the host animal and responds better than the recognized and established appropriate tissue response elicited by materials provided in ASTM. ASTM Biocompatibility Testing Methods Subcommittee F04.16 has established 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, and F981- 04, F1027-86, F1408-20a, F1439-03, F1877-16, F1903-18, F1904-14, F1983-14, F1984-99, F2147-01, F2148-18, F2382-18, F2808-17, F1288-19, and F2909-19, each of which is incorporated herein by reference. For example, materials intended for use in contact with blood must be composed of materials that meet blood compatibility standards. One of these tests is the test for red blood cell damage, which may result in hemolysis, i.e., cell rupture, as described in F756-17, "Standard Practice for Assessment of Hemolytic Properties of Materials".

[0185] As used herein, "bioactive substance" refers to any of a variety of chemical fractions that will bind to biomolecules such as, but not limited to, peptides, proteins, enzymes, receptors, substrates, lipids, antibodies, antigens, and nucleic acids. In some preferred embodiments, the bioactive substance is a biomolecule, but this is not intended to limit the bioactive substance to biomolecules. In other preferred embodiments, the bioactive substance provides hydrophobic, hydrophilic, or electrostatic interactions, such as polycarboxylic acids that are anionic at physiological pH. In other preferred embodiments, basic growth factors (isoelectric point above 7) are retained via favorable electrostatic interactions with polycarboxylate salts and subsequently released in a controlled and sustained manner.

[0186] "Cancer" is a term used to refer to a physiological condition in mammals characterized by uncontrolled cell growth. 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), gliomas, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal cancer, 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, stomach cancer, urothelial carcinoma (including locally advanced or metastatic urothelial carcinoma), bladder cancer, hepatocellular carcinoma, breast cancer, and head and neck cancer.

[0187] The term "stereoisomer" refers to a compound having the same atomic bonds but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, diastereomers, and trans-block isomers. In the context of this invention, the term "enantiomerically pure" should be understood to mean that the compound in question is present in excess of more than 95%, preferably more than 97%, of its enantiomers with respect to the absolute configuration of its chiral center.

[0188] This disclosure covers all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, trans-isomers, tautomers, and racemates thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. As with respect to the compounds of the invention as defined herein, they may exist in an optically active or racemic form due to one or more asymmetric carbon atoms, and the invention includes any such optically active or racemic form in its definition. The synthesis of optically active compounds can be carried out using standard organic chemistry techniques known in the art, such as, for example, synthesis from optically active starting materials, or by resolution of racemic compounds. Similarly, the enantiomeric or diastereomeric purity of the compounds can be evaluated using standard laboratory techniques.

[0189] The pharmaceutical compositions of the present invention can be in any form suitable for the intended route of administration. When the composition is intended for oral administration, any suitable oral delivery dosage form can be used, including but not limited to: water, glycols, oils, alcohols, etc. in the case of oral liquid formulations (such as suspensions, syrups, elixirs, emulsions, and solutions); or solid carriers such as starch, sugar, kaolin, diluents, lubricants, binders, disintegrants, etc. in the case of powders, pills, capsules, and tablets. Tablets and capsules are the most advantageous forms of oral dosage units due to their ease of administration. Injectable compositions or intravenous infusions are also provided in the form of solutions, suspensions, and emulsions. For parenteral compositions, the carrier typically contains sterile water and, possibly other ingredients that contribute to solubility. Injectable solutions can be prepared in which the carrier comprises an aqueous 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 glycerides of long-chain fatty acids, and mixtures of these oils with other oils. In compositions suitable for transdermal application, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, and optionally in combination with suitable additives as needed, wherein the additives facilitate application of the composition to the skin and / or facilitate the preparation of the composition to be delivered. These compositions can be applied in various ways, such as as transdermal patches or as ointments. Acid-addition or base-addition salts of the compounds of the present invention are generally more suitable for preparing aqueous compositions because their water solubility is higher than that of the corresponding neutral forms of the compounds.

[0190] The pharmaceutical compositions of the present invention may include one or more of fillers, diluents, adjuvants, mediators or other excipients to facilitate the storage and / or administration of the active ingredient contained therein.

[0191] In one exemplary embodiment, the pharmaceutical composition according to the invention may contain one or more additional therapeutic agents, for example, to increase efficacy or reduce adverse side effects. In a particular embodiment, the pharmaceutical composition further contains one or more additional therapeutic agents that can be used to treat or inhibit diseases directly or indirectly mediated by PI3K. Examples of such agents include, but are not limited to, agents for treating or inhibiting cancer, Huntington's disease, cystic fibrosis, liver fibrosis, kidney fibrosis, pulmonary fibrosis, skin fibrosis, rheumatoid arthritis, diabetes, or heart failure.

[0192] In one specific implementation, the additional therapeutic agent to be included is an anticancer agent. Examples of anticancer agents include, but are not limited to: DNA-damaging cytotoxic drugs; alkylating agents, such as cyclophosphamide, dacarbazine, and cisplatin; antimetabolites, such as methotrexate, mercaptopurine, thioguanine, fluorouracil, and cytarabine; plant alkaloids, such as vinblastine and paclitaxel; antitumor antibiotics, such as doxorubicin, bleomycin, and mitomycin; hormone / antihormone drugs, such as prednisone, tamoxifen, and flutamide; and other types of anticancer agents, such as asparaginase, rituximab, trastuzumab, imatinib, retinoic acid and its derivatives, colony-stimulating factors, amifostine, camptothecin, topotecan, thalidomide analogs (such as lenalidomide); and proteasome inhibitors, such as Velcade.

[0193] In another embodiment, the present invention provides a method for inhibiting or treating a disease caused by abnormal cell proliferation and / or differentiation in a subject with this need, comprising administering to the subject a therapeutically effective amount of one or more compounds according to the invention. In one embodiment, the method of inhibiting or treating the disease comprises administering to the subject with a composition comprising an effective amount of one or more compounds of the invention and a pharmaceutically acceptable carrier. The composition to be administered may also contain a therapeutic agent such as an anticancer agent.

[0194] The compounds of this invention are defined herein by their chemical structure and / or chemical name, and are generally listed according to the IUPAC or CAS nomenclature system. Abbreviations well known to those skilled in the art may be used. When a compound is referred to by both its chemical structure and chemical name, and the chemical structure conflicts with the chemical name, the chemical structure is intended to be used as the basis for determining the identity of the compound.

[0195] This invention includes compounds labeled with various radioactive or non-radioactive isotopes. Examples of atomic isotopes may include, but are not limited to, 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 Cl). In one exemplary embodiment, one or more hydrogen atoms in the compounds of the present invention may be replaced by deuterium. In various embodiments, the compounds of the present invention comprise 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 may also be subjected to radioactive isotopes such as tritium (Cl). 3 H), Iodine-125 ( 125 I) and carbon-14 (14 C) Radiolabeling. Radiolabeled compounds can be used as therapeutic or preventative agents, provided as research reagents for purposes such as assays, and / or as diagnostic agents for techniques such as in vivo imaging. Synthetic methods for introducing isotopes into organic compounds are well known in the art.

[0196] In one embodiment of the invention, the compound of the invention as defined herein (such as any of formula (1), (2), (3) or (4)) or a pharmaceutically acceptable salt thereof, is present as a single enantiomer in an enantiomer excess (% ee) ≥ 95%, such as ≥ 98%, such as ≥ 99%.

[0197] In one embodiment of the invention, the pharmaceutical composition comprises a compound of the invention as defined herein (such as a compound of formula (I)) or a pharmaceutically acceptable salt thereof, wherein the compound is present as a single enantiomer with an enantiomer excess (% ee) ≥ 95%, such as ≥ 98%, such as ≥ 99%.

[0198] In one exemplary embodiment of the invention, the disease or condition to be treated with the compounds of the invention is selected from congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndromes (CLOVES), mosaic tissue overgrowth syndrome, venous malformations, and brain malformations associated with severe epilepsy or PIK3CA-associated overgrowth syndrome (PROS) (Keppler-Noreuil et al.). , Am J Med Genet A. 2015, 167A, 287; Kurek et al., Am. J. Hum. Genet. 2012, 90, 1108).

[0199] In one exemplary embodiment of the invention, the cancer to be treated is a cancer carrying a PI3K H1047 mutation (such as H1047R) (Thorpe et al., Nat Rev Cancer 2015, 15, 7).

[0200] The compounds of the present invention (such as those defined by formulas (1) to (3)) are generally selective inhibitors of the PI3Kα H1047R mutation, exhibiting higher selectivity for the H1047R mutation than for the wild type. Therefore, these compounds can selectively reduce the amount of phosphorylated AKT (pAKT) and decrease proliferation in PI3Kα H1047R mutant cell lines, preferably covering several tumor types.

[0201] The PI3K H1047R mutation selective inhibitors of the present invention (such as those defined by formulas (1) to (3)) combined with selective estrogen receptor degraders (SERDs) (such as, but not limited to, fulvestrant, elacestrant, carizestrant, or vepdegestrant) can demonstrate a combination benefit leading to tumor regression in ER+ / PI3K H1047R mutant tumors (such as, but not limited to, the breast cancer xenograft model T47D) at doses where regression is barely observable or not observable with monotherapy.

[0202] The present invention’s selective inhibitors of PI3K H1047R mutations (such as those defined by formulas (1) to (3)) combined with HER2 inhibitors (such as, but not limited to, tucatinib or trastuzumab) can demonstrate a combination benefit leading to tumor regression in ER- / HER2+ / PI3K H1047R mutant tumors (such as, but not limited to, the breast cancer xenograft model HCC1954) at doses at which regression is barely observable or not observable when administered as monotherapy.

[0203] The compounds of formula (1) of the present invention can generally be prepared according to the synthetic routes determined in schemes 1-16.

[0204] The substituted (hetero)aryl starting materials required for the synthesis of compound (1) are either commercially available or readily prepared using known synthetic chemistry methods. For example, commercially available aminophenylphosphine oxide 1 can be used as a nucleophile in the synthetic schemes described later; or, it can be converted to the corresponding iodide 2 via the Sandmeyer reaction under standard reaction conditions for use in transition metal-mediated coupling reactions, as shown in Scheme 1.

[0205] The preparation of heteroaryl phosphates (e.g., dimethyl (2-bromophenyl)phosphonate 5) can be achieved via a copper oxide-mediated coupling reaction of heteroarylboronic acid (e.g., 3) with dimethyl phosphonate, thereby providing a suitable coupling partner in transition metal-mediated coupling reactions, as shown in Scheme 2. Such phosphates can be converted to alkylphosphinates (e.g., 6) by reaction with a Grignard reagent, which are also suitable as coupling partners.

[0206] Halogen-substituted (hetero)aryl sulfones and sulfonamides are readily available from commercial sources (e.g., 7, where R, respectively). a= CH3 or NH2), or can be prepared by known synthetic chemical methods, as shown in Scheme 3. For example, thiophenols such as 8 can be alkylated with a haloalkane (e.g., iodoethane) under basic conditions to provide thioethers such as 9. Subsequently, the thioether functional group can be oxidized with any of a number of reagents (e.g., m-chloroperoxybenzoic acid) to provide aryl sulfones, such as 10. Alternatively, aryl sulfone 10 can be prepared from the corresponding aryl sulfinic acid 8 via alkyl bromide or alkyl iodide in the presence of a suitable base (e.g., potassium carbonate). N 2. Alkylation is used to prepare heteroaryl sulfones. Heteroaryl sulfones (e.g., pyridyl sulfone 13) can be prepared by reacting sodium methyl sulfinate with 2-fluoropyridine or 2-chloropyridine (such as 11). The preparation of alkylaryl sulfones containing oxygen or nitrogen linkages (such as 19 or 20) can be achieved from suitable halomethyl-substituted sulfones (e.g., but not limited to 1-bromo-2-((chloromethyl)sulfonyl)benzene 16). The synthesis of 16 can be achieved by alkylating aryl sulfinate 14 with bromochloromethane. Oxygen or nitrogen linkage starting materials (19 or 20, respectively) can be synthesized by alkylating 16 with alcohol 17 or amine 18 in the presence of a suitable base (e.g., but not limited to sodium hydride or potassium carbonate).

[0207] The starting material containing sulfoxide imine can be prepared from thioethers, as shown in Scheme 4. A thioether-containing nitrobenzene (e.g., but not limited to 21) can be reacted with ammonium carbamate in the presence of a phenyl iodide reagent to give an intermediate containing sulfoxide imine, such as 22. This sulfoxide imine can optionally be further functionalized via an alkylation step to give species such as 23. Reduction of the nitro group of 23 (e.g., reduction with iron in the presence of ammonium chloride) can give aniline sulfoxide imine 24.

[0208] The bicyclic core of the present invention can be synthesized by any of a variety of ring-expansion or cyclization methods. In Scheme 1, the synthesis of the isoquinolone core intermediate can be achieved from appropriately substituted 2,3-dihydro-1 H-Indene-1-one 25 is the starting material. For 25, where R7 is methyl and each R8 is hydrogen, the compound is commercially available. In other cases, the starting material can be prepared by existing methods known to those skilled in the art. Nitrosation of 25 to convert to oxime derivative 26 can be achieved by existing methods (see, for example, Touster, O.; Org. Reactions, VII, 1953, 327). Phosphorus pentachloride-mediated Beckmann rearrangement can convert 26 to 27 (Cushman, M.; Dekow, FW Tetrahedron 1978, 34(10), 1435-9). Alkylation of 27 with a suitable electrophile and base will give 28. In the case where R6 is methyl, this can be achieved with iodomethane and a suitable base (such as sodium hydride). Other electrophiles and alkylating agents known to those skilled in the art can also be used. To convert bromide 28 to methyl ketone 29, a suitable tin reagent such as ( (-ethoxyvinyl)-tributyltin undergoes Stille coupling followed by acid hydrolysis (Sugiyama et al., Bull. Chem. Soc. Jpn. 1987, 60(2), 767-768). Alternatively, the conversion of 28 to 29 can be achieved by other existing methods, such as Heck coupling using a suitable enol ether followed by acid hydrolysis (Mingcui, L. et al., Org. Biomol. Chem., 2010, 8, 2012–2015). Ketone 29 can then be reduced to alcohol 30 using a suitable hydride reducing agent (such as sodium borohydride). It should be understood that other reported methods, besides those described in Scheme 1, can be used to prepare isoquinolones such as 27 or 28 and their derivatives. 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).

[0209] In scheme 6, alcohol 30 can be converted to amino derivative 33 by a number of different methods. First, the alcohol can be converted to an intermediate 31 with a leaving group such as a bromo group or a methanesulfonate ester using commonly known methods. Nucleophilic substitution of intermediate 31 yields compound 33. An alternative is to directly give compound 33 by reacting (hetero)arylamine 32 with the Mitsunobu form of alcohol 30. In some cases, the temporary use of an activating group (such as a 2,4-dinitrobenzenesulfonyl group) on the (hetero)arylamine functional group can promote the Mitsunobu reaction. In the direct reaction of alcohol 30 with (hetero)arylamines, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and triphenylphosphine (Shalit, T. et al., Tetrahedron Letters 2010, 51, 5988–5991; Iranpoor, N. et al., Tetrahedron 2009, 65, 3893–3899; Pandy, SK, Mini-Reviews in Organic Chemistry 2019, 16(2), 127-140; Fukuyama, Tohru et al., Tetrahedron Letters 1997, 38(33), 5831-5834) can also be used.

[0210] Scheme 7 illustrates the synthesis of a single enantiomer intermediate 38. The reaction sequence utilizes the formation of a chiral sulfinimide to control the stereochemistry. Such methods have been widely reported. Ketone 28 can be converted to a chiral sulfinimide 34 via a known procedure, which can then be stereocontrolled reduced to sulfinamide 35 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). By using the R isomer of the sulfinyl group, typically when the reducing agent used is, for example, a mixture of sodium borohydride and cerium chloride heptahydrate, the R,R-isomer of the product is mainly generated. It has been shown that this particular reduction system is effective in reducing imines and generally provides enhanced stereocontrol in similar reduction reactions (Hua et al., Synthesis 1991, (11), 970-4; Zhu et al., Journal of Chemical Research 2015, 39(7), 390-393). In Scheme 7, when R2 is methyl, the benzylic stereocenter of 35 is indeed formally labeled as the R isomer as indicated in the scheme. Different substitution modes within R2 may formally change the stereocenter assignment of such analogs 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 the minor isomers using standard chromatographic methods. As demonstrated in the aforementioned references, careful selection of the enantiomers of the sulfinimide and the reducing agent yields either enantiomer of the sulfinamide. Using standard conditions (such as hydrogen chloride in dioxane), the sulfinamide can be cleaved into a single enantiomer of the chiral amine 36. Standard coupling reactions of the amine 36 with (hetero)aryl halide 37 (such as Ullmann coupling or Buchwald-Hartwig coupling when Hal = I or Br in 37) then yield the (hetero)aryl amine derivative 38 as a result (Yang et al., Organic Process Research & Development 2022, 26(6), 1690-1750; Surry and Buchwald, Chemical Science 2011, 2(1), 27-50).Alternatively, if the starting material 37 is sufficiently reactive (e.g., Hal = F or Cl and R1 is an electron-withdrawing functional group), then the S between the amine 36 and the (hetero)aryl halide 37 is... N Ar reactions can also produce intermediate 38.

[0211] Certain final compounds 40 can be prepared as described in Scheme 8. Intermediate 33 can be reacted with amine 39 under suitable Buchwald-Hartwig coupling conditions, wherein R' and R" can be alkyl or aryl, or one of R' and R" can be hydrogen. R' and R" can also be linked to form a ring. In some cases, the R' and / or R" groups can be further carefully modified prior to subsequent steps. The racemic compound 40 can then be isolated as its individual enantiomers (41 and 42) using chiral chromatography (HPLC or SFC).

[0212] The single enantiomer 32 can be prepared directly from the enantiomeric pure intermediate 30 using a chemical method similar to that shown in Scheme 8, as shown in Scheme 9.

[0213] In some cases, the reaction sequence can be adjusted as shown in Scheme 10. In this case, Buchwald-Hartwig coupling of intermediate 35 with a suitably substituted amine 39 can give 43. Removal of the sulfinyl group to give 44, followed by Buchwald-Hartwig coupling with a (hetero)aryl halide (e.g., X = I or Br) to give compounds such as 46. Alternatively, intermediate 44 can undergo S-reaction with a suitably reactive (hetero)aryl halide 45 (e.g., X = F or Cl and R1 is an electron-withdrawing group). N Ar reaction yielded compound 46.

[0214] Substituted compounds having an oxygen or sulfur linkage at the 3-position of the isoquinolone ring can be prepared as shown in Scheme 11. Intermediate 38 can be Buchwald-Hartwig coupled with a suitable thiol compound to give 48. Alternatively, intermediate 38 can be S-coupled with a suitable alcohol. N Ar reaction (which can be mediated by a base such as sodium hydride) to give compounds such as 50.

[0215] These compounds can be prepared as shown in Scheme 12, provided that the 3-position of the isoquinolone ring is substituted with an alkyl or alkenyl group. Intermediate 33 can be subjected to a Suzuki coupling reaction with a suitable alkenyl-boronate (or boric acid) 51 (Stanforth, SP Tetrahedron 1998, 54(3 / 4), 263-303) to give 52. Racemic product 52 can then be subjected to chiral chromatographic separation to give enantiomers 53 and 54. Alternatively, the double bond of 52 can be reduced under standard hydrogenation conditions (e.g., hydrogen and palladium catalyst). This, after chiral chromatographic separation, gives enantiomers 55 and 56. Other isomers may be produced where R and R' do not form a symmetrical arrangement, and these isomers can also be separated by chromatography.

[0216] In the case where the 3-position of the isoquinolone group is substituted with an aryl or heteroaryl group, these types of compounds can be prepared by a method similar to that shown in Scheme 12. As illustrated in Scheme 13, the Suzuki coupling reaction between 33 and a suitable aryl (or heteroaryl) borate ester (or boric acid) can give enantiomers 57 and 58 after chiral separation.

[0217] Scheme 14 illustrates an alternative mode for synthesizing aryl-substituted or heteroaryl-substituted isoquinolones. The Suzuki coupling reaction between intermediate 35 and a suitable aryl or heteroaryl borate ester (or borate) yields 59 after the removal of the sulfinyl group. The Ullmann or Buchwald-Hartwig coupling between 59 and (hetero)aryl halide 45 yields compounds such as 60. Alternatively, 59 can undergo an S-reaction with a suitable (hetero)aryl halide 45 (e.g., X = F or Cl and R1 is an electron-withdrawing group). N Ar reaction also yielded compound 60.

[0218] The synthesis of compounds containing a benzopyrimidinone core can be achieved using known synthetic chemistry techniques, as shown in Scheme 15. Starting with aminobenzoic acid 61, which is generally known or commercially available (such as from BLD Pharmatech Ltd.), the intermediate quinazoline-2,4-dione 62 can be generated under cyclization conditions. In an exemplary embodiment, when R6 = H, cyclization can be achieved by treatment with urea at elevated temperatures. In an exemplary embodiment, when R6 = alkyl, cyclization can be carried out via a two-step process: first, amide coupling with the corresponding alkylamine and HATU, followed by treatment with triphosgene. Chlorination of 62 can yield an intermediate of general formula 63. In an exemplary embodiment, chlorination can be achieved by reflux of 62 in POCl3, followed by neutralization with an aqueous alkaline solution (NaOH when R6 = H, or alternatively, NaHCO3 when R6 = alkyl). Then, it can be further processed by S... N Ar substitution reaction generates an intermediate of general formula 64. In an exemplary embodiment, an amine, amine hydrochloride, alcohol, or thiol (depending on the desired R5) is used. N -connected, O -Connected or not S -The connecting part), in some embodiments, treatment of 63 in a suitable solvent (e.g., but not limited to ACN, NMP, or DMF) at room temperature with the addition of a suitable base (e.g., but not limited to DIEA, K2CO3, or NaH) or at elevated temperatures (up to 140°C) in some embodiments yields an intermediate of general formula 64. An intermediate of general formula 65 can then be generated by carbonylation of 64. In some exemplary embodiments, ketone 65 is obtained by treating 64 at elevated temperatures with tributyl(1-ethoxyvinyl)tin and a catalytic palladium species (e.g., but not limited to Pd(PPh3)4 or PdCl2(PPh3)2), followed by hydrolysis with an aqueous HCl solution to replace the bromine substituent of 64 with an acetyl group. When R3 = H, intermediate 65 can also be obtained by various known methods (e.g., but not limited to palladium-catalyzed carbonylation in the presence of H2 (Klaus et al.)). , 64 is produced by formylation of 64 (Angew. Chem. Int. Ed. 2006, 45, 154) or by cyanation followed by reduction with DIBAL. Intermediate 65 can serve as a platform for 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; et al.) further extend to a wide variety of R2 substitutions (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, alkyl, etc.). Alcohol intermediates of general formula 66 can be prepared by reduction of 65. In one exemplary embodiment, this reduction is carried out by treating 65 with NaBH4 in MeOH. The conversion of 66 to (hetero)arylamines of general formulas 67 and 68 can be achieved under reaction conditions similar to those described in schemes 6-14.

[0219] Scheme 16 illustrates an alternative synthetic approach for producing a single enantiomer of benzopyrimidinone intermediate 71. This reaction sequence utilizes the formation of a chiral sulfinyl imide to establish the stereocenter of the subsequent synthetic product. Ketone 65 can be converted to chiral sulfinyl imide 69 via a known procedure, which can then be stereocontrolled reduced to sulfinamide 70 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 R isomer with sulfinyl group 69 typically yields the R,R-isomer with 70 primarily when the reducing agent used is, for example, a mixture of sodium borohydride and cerium chloride heptahydrate. It has been shown that this particular reduction system is effective for reducing imines and generally provides enhanced stereocontrol in similar reduction reactions (Hua et al.). , Synthesis 1991, (11), 970-4; Zhu et al. ,J. Chem. Res. 2015, 39(7), 390-393). In Scheme 16, where R2 is methyl, the benzylic stereocenter of 35 is indeed formally labeled as the R isomer as indicated in the scheme. Different substitution modes within R2 may formally change the stereocenter assignment of such analogs 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 the minor isomers using standard chromatographic methods. As demonstrated in the aforementioned references, careful selection of the enantiomers of sulfinimide and the reducing agent yields any enantiomer of sulfinamide. Using standard conditions (such as hydrogen chloride in dioxane), sulfinamide 70 can be cleaved into a single enantiomer of chiral amine 71. Then, the standard coupling reaction of amine 45 with aryl iodine or aryl bromide 45 (such as Ullmann coupling or Buchwald-Hartwig coupling) yields the final compound 72 as a result (Yang et al.). , Org.Process Res.&Dev.2022, 26(6), 1690-1750; Surry and Buchwald, Chem. Sci.2011, 2(1), 27-50).

[0220] The chemical reactions illustrated in schemes 1 to 16 demonstrate various synthetic modes of the compounds. It should be understood that other variations may be employed on these modes, and the exact protecting groups, the sequence of the listed reactions, or the specific transition metals used in the catalytic coupling reactions may be replaced with suitable substitutes known to those skilled in the art.

[0221] The following compounds of formula (1) represent various embodiments of the present invention: .

[0222] experiment All commercially available solvents and reagents are used in the receiving state. 1 ¹H NMR spectra were recorded using a Bruker Avance III HD 300 MHz or Bruker Avance III HD 400 MHz. MS analysis was performed on a Shimadzu LCMS-2020 mass spectrometer equipped with an electrospray ionization source, operating in both positive and negative ion modes. Samples were introduced into the mass spectrometer using chromatographic methods. Unless otherwise specified in the experimental details, all final products were ≥ 90% pure. HPLC purity was measured on a Shimadzu Acquity HPLC system.

[0223] The following are abbreviations for well-known chemical solvents, reagents, parameters, and techniques used in the experimental section: 1 H NMR: Proton nuclear magnetic resonance spectrum ACN: Acetonitrile AcOH: Acetic acid B2pin2: 4,4,5,5-Tetramethyl-2-(tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (Boc2)O: Ditert-butyl dicarbonate c-Bu: Cyclobutyl c-Pr: Cyclopropyl CDI: Carbonyldiimidazole CeCl3: Cerium(III) trichloride CH2Cl2: Dichloromethane CH3I: Iodomethane CHCl3: Chloroform CO2: Carbon dioxide Cs2CO3: Cesium carbonate CsF: Cesium fluoride CuCl: Cuprous chloride DAST: Diethylaminosulfonium trifluoride DBAD: Di-tert-butyl azodicarbonate 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 azodicarbonate EA: Ethyl acetate ee: enantiomer excess Et2O: Diethyl ether Et3N: Triethylamine Et3SiH: Triethylsilane EtOAc: Ethyl acetate EtOH: Ethanol FA: Formic acid h: hours 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: Isopropyl alcohol K2CO3: Potassium carbonate K3PO4: Tripotassium phosphate KOAc: Potassium acetate LiOH: Lithium hydroxide m CPBA: m-chloroperoxybenzoic acid Me: Methyl MeCN: Acetonitrile MeOH: Methanol mg: milligram MgSO4: Magnesium sulfate min: minutes mL: milliliters MsCl: Methanesulfonyl chloride Ms2O: Mesylate anhydride NaBH4: Sodium borohydride N2: Nitrogen gas NaCl: Sodium chloride Na2CO3: Sodium carbonate NaH: Sodium hydride NaI: Sodium iodide NaOH: Sodium hydroxide NaHCO3: Sodium bicarbonate NaH2PO4: Sodium monophosphate Na2SO3: Sodium sulfite Na2SO4: Sodium sulfate NH3: ammonia NH4Cl: Ammonium chloride NH4HCO3: Ammonium bicarbonate NH4OH: Ammonium hydroxide (NH4)2CO3: Ammonium carbonate NMP: N -Methylpyrrolidone Oxycyclic butane: a 4-membered ring containing 3 carbon ring atoms and 1 oxygen ring atom. PBr3: Phosphorus tribromide PCl5: Phosphorus pentachloride Pd / C: Palladium supported on carbon Pd-PEPPSI-IHeptCl 3-Chloropyridine: Dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-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: Tetra(triphenylphosphine)palladium(0) Pd2(dba)3:tris(dibenzylacetone)dipalladium(0) PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride PE: Petroleum ether POCl3: Phosphorus oxychloride PPh3: Triphenylphosphine prep: preparative PyBOP: Benzotriazol-1-yloxytripyrrolidine hexafluorophosphate RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl RuPhos-Pd-G3: Methanesulfonyloxy(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride SiO2: Silicon dioxide T4P: 2,4,6-Tributyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide TBAF: Tetrabutylammonium fluoride TBSCl: tert-butyldimethylsilyl chloride TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran Ti(OEt)4: Titanium ethoxide (IV) Ti(Oi-Pr)4: Titanium isopropoxide (IV) TLC: Thin-layer chromatography Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene Xphos-Pd-G4:(SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonyloxy-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium Intermediate 1: (R)-N-((R)-1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2-methylpropane-2-sulfinamide Step 1: Preparation of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-1H-inden-1-one 3-Methylbutyl nitrite (1.25 g, 10.66 mmol) was slowly added dropwise to a stirred solution of 4-bromo-6-methyl-2,3-dihydro-1H-indone (2 g, 8.89 mmol) in HCl (10 mL, 12 M) and Et₂O (10 mL). The resulting solution was stirred at room temperature for 4 hours. The mixture was cooled to 0°C, and the precipitated solid was collected by filtration and washed with H₂O (3 x 50 mL). The resulting mixture was concentrated under vacuum. The crude product was used directly in the next step without further purification. This yielded 1.5 g, 66% yield, of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-1H-indone as a grayish-white solid. MS: (ES) + m / z = 254.1 [M+H] + .

[0224] Step 2: Preparation of 5-bromo-3-chloro-7-methyl-2H-isoquinoline-1-one PCl5 (2.46 g, 11.8 mmol) was slowly added in portions to a stirred solution of 1.5 g (5.90 mmol) of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-1H-indene-1-one in 30 mL of CHCl3 at 0 °C. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. 4 M HCl (30 mL) in 1,4-dioxane was added to the crude product. The resulting solution was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by grinding with PE / EtOAc in a 5:1 ratio to give 1 g (61% yield) of 5-bromo-3-chloro-7-methyl-2H-isoquinoline-1-one as a yellow solid. MS: (ES) - m / z = 269.9[M-1] - .

[0225] Step 3: 5-Bromo-3-chloro-2,7-dimethylisoquinoline-1-one NaH (0.17 g, 7.16 mmol) was slowly added in portions to a stirred solution of 5-bromo-3-chloro-7-methyl-2H-isoquinoline-1-one (1.3 g, 4.77 mmol) in DMF (10 mL) at 0 °C. The resulting solution was stirred at 0 °C for 20 min. 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 mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4:1) to give 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] + .

[0226] Step 4: Preparation of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1-one A mixture of 5-bromo-3-chloro-2,7-dimethylisoquinoline-1-one (2.6 g, 9.07 mmol), tributyl(1-ethoxyvinyl)stanane (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 nitrogen atmosphere. The reaction mixture was cooled to room temperature, treated with 1 N HCl aqueous solution (10 mL), and stirred for 15 min. The resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (3 x 60 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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] + .

[0227] Step 5: Preparation of (R,E)-N-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethylene)-2-methylpropane-2-sulfinamide Ti(Oi-Pr)₄ (55.78 g, 196.2 mmol) was added to a stirred 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) in THF (200 mL). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was quenched with a saturated aqueous sodium chloride solution (200 mL). The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3 x 300 mL). The filtrate was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with H₂O (3 x 200 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3:2) to give (R,E)-N-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (9 g, yield 64%) as a yellow solid. MS: (ES) + m / z = 353.1 [M+H] + .

[0228] 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 NaBH4 (2.81 g, 74.4 mmol) was added to a stirred solution of (R,E)-N-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethylene)-2-methylpropane-2-sulfinamide (10.5 g, 29.76 mmol) and CeCl3•7H2O (16.6 g, 44.6 mmol) in MeOH (120 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (150 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:2) and then further purified by HP-Flash chromatography (25%-55% ACN / H2O (0.1% FA), 45 min) to give (R)-N-((R)-1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2-methylpropane-2-sulfinamide (6.5 g, yield 61%) as a grayish-white solid. MS: (ES) + m / z = 355.0[M+H] + .

[0229] Intermediate 2: (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Step 1: Preparation of (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 Under a nitrogen atmosphere at room temperature, Pd2(dba)3 (0.77 g, 0.85 mmol), Cs2CO3 (5.51 g, 16.9 mmol), and RuPhos (0.79 g, 1.69 mmol) were added to a stirred solution of (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) in dioxane (60 mL). The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The mixture was filtered, and the filter cake was washed with EtOAc (50 mL x 2). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 2:1) to give (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, yield 87%) as a yellow oil. MS: (ES) + m / z = 487.3 [M+H] + .

[0230] Step 2: Preparation of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one At room temperature, 4 M HCl (3.7 mL, 14.8 mmol) in EtOAc was added dropwise to a stirred solution of (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, 7.4 mmol) in MeOH (37 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 aqueous solution (3 x 15 mL). The organic layer was then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give (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), a yellow solid. MS: (ES + ) m / z = 383.2 [M+H]+ .

[0231] Intermediate 3: 2-amino-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N-methylbenzamide Step 1: Preparation of 2-amino-3-bromo-5-fluoro-N-methylbenzamide CDI (4.16 g, 25.6 mmol) was added to a solution of 2-amino-3-bromo-5-fluorobenzoic acid (5 g, 21.4 mmol) in THF (50 mL) 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 layers were washed with water (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA = 1:0 to 1:1) to give 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 min (Method C).

[0232] Step 2: Preparation of 3-acetyl-2-amino-5-fluoro-N-methylbenzamide Pd(PPh3)4 (1.73 g, 1.50 mmol) was added to a solution of 2-amino-3-bromo-5-fluoro-N-methylbenzamide (3.7 g, 15.0 mmol) and tributyl(1-ethoxyvinyl)stanane (7.45 g, 20.6 mmol) in dioxane (40 mL) under a nitrogen atmosphere. The mixture was then stirred at 100 °C for 15 h. The solution was then cooled to 0 °C and 1 M HCl aqueous solution (5 mL) was added. The mixture was then stirred at 0 °C for 30 min. A saturated KF aqueous solution (50 mL) was then added. The reaction mixture was then diluted with H2O (50 mL) and EA (50 mL) and stirred at 20 °C for 1 h. The mixture was filtered and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE:EA = 1:0 to 0:1) to give 2.5 g (79% yield) of 3-acetyl-2-amino-5-fluoro-N-methylbenzamide as a yellow solid. LCMS (ESI) + m / z = 211.2 (M+H), t R = 0.514 min (Method C).

[0233] Step 3: Preparation of 2-amino-5-fluoro-3-(1-hydroxyethyl)-N-methylbenzamide NaBH4 (1.45 g, 38.3 mmol) was added to a solution of 3-acetyl-2-amino-5-fluoro-N-methylbenzamide (2.5 g, 11.9 mmol) in MeOH (30 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour and then quenched by adding saturated NH4Cl aqueous solution (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 layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 0:1 to 4:1) to give 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 min (Method C).

[0234] Step 4: Preparation of 2-amino-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-N-methylbenzamide A solution of TBSCl (5.11 g, 33.9 mmol) in DMF (6 mL) was added to a solution of 2-amino-5-fluoro-3-(1-hydroxyethyl)-N-methylbenzamide (3.6 g, 17.0 mmol) and imidazole (3.46 g, 50.9 mmol) in DCM (30 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. 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 organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA = 1:0 to 10:1) to give 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), t R = 0.623 min (Method C).

[0235] Intermediate 4: (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one To a solution of (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), 4 M HCl in dioxane was added (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 give (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 min (Method C).

[0236] Intermediate 5: (R)-5-(1-aminoethyl)-3-chloro-7-fluoro-2-methylisoquinoline-1(2H)-one The intermediate was prepared using a method similar to that described for intermediates 1 and 4, wherein 4-bromo-6-fluoro-2,3-dihydro-1H-indone was used instead of 4-bromo-6-methyl-2,3-dihydro-1H-indone.

[0237] Intermediate 6: (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one Step 1: Preparation of 8-bromo-3,6-dimethyl-2-thiooxo-2,3-dihydroquinazolin-4(1H)-one Methyl isothiocyanate (19.0 g, 261 mmol) was added to a mixture of 2-amino-3-bromo-5-methylbenzoic acid (30.0 g, 130 mmol) and TEA (45 mL, 326 mmol) in EtOH (500 mL) at room temperature under an argon atmosphere. 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), and the precipitated solid was collected by filtration and washed with Et2O (2 x 300 mL) to give 31.8 g (85% yield) of 8-bromo-3,6-dimethyl-2-thiooxo-2,3-dihydroquinazoline-4(1H)-one as a brown solid. 1 H NMR (400 MHz, DMSO- d 6): 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).

[0238] Step 2: Preparation of 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one Dimethyl sulfate (5.9 g, 47.3 mmol) was added in portions to a stirred mixture of 8-bromo-3,6-dimethyl-2-thiooxo-2,3-dihydroquinazolin-4(1H)-one (9.0 g, 31.5 mmol) and NaOH (2.52 g, 63.1 mmol) in DMF (90 mL) under an 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 x 10 mL) and then dried under reduced pressure to give 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (8.0 g, 85% yield) as a white solid. 1 H 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).

[0239] Step 3: Preparation of 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one Tetra(triphenylphosphine)palladium(O) (2.7 g, 2.4 mmol) was added in portions to a stirred mixture of 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (7.1 g, 23.7 mmol) and tributyl(1-ethoxyvinyl)stanane (10.3 g, 28.5 mmol) in 1,4-dioxane (100 mL) under an argon atmosphere at room temperature. The resulting mixture was stirred overnight at 100 °C. The mixture was then cooled to 0 °C. A 1 N HCl aqueous solution (14.4 mL) was added in portions at 0 °C over 5 minutes. The resulting mixture was then stirred at room temperature for 1 hour and diluted with ice water (50 mL). The mixture was then extracted with EtOAc (3 x 50 mL), and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA increased from 1:0 to 5:1 within 30 minutes) to give 4.0 g of 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (64% yield) as a white solid. 1 H 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).

[0240] Step 4: Preparation of (R,E)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-sulfinamide 8-Acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (10 g, 38.1 mmol), (R)-2-methylpropane-2-sulfinamide (9.23 g, 76.2 mmol), and Ti(OEt)4 (21.7 g, 95.3 mmol) were combined in THF (200 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred overnight at 80 °C. The reaction was quenched at 0 °C with ice and salt (400 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (2 x 200 mL). The filtrate was extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) + m / z = 366.0 (M+H) + .

[0241] Step 5: Preparation of (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide NaBH4 (12.9 g, 342 mmol) was added in portions to a stirred mixture of (R,E)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-sulfinamide (50 g, 137 mmol) and CeCl3•7H2O (76.5 g, 205 mmol) in MeOH (400 mL) at -78 °C under an argon atmosphere. The resulting mixture was stirred from -78 °C to room temperature for 2 hours. The reaction was quenched at 0 °C with a saturated aqueous solution of NH4Cl (800 mL). The mixture was then extracted with CH2Cl2 (3 x 800 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 40% to 95% gradient over 30 min; detector, UV 254 nm) to give (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (42.6 g, 85% yield) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 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).

[0242] Step 6: Preparation of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one Under a nitrogen atmosphere, at room temperature, 50 mL of 8 N HCl aqueous solution was added in portions to a stirred 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) in EtOAc. 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 EtOAc (3 x 60 mL). The aqueous layer was adjusted to pH 10 by adding concentrated NH4OH. The resulting mixture was extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (2.8 g, 97% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6): 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).

[0243] Intermediate 7: (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)tert-butyl carbamate A solution of (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4, 3 g, 12.0 mmol), DIEA (1.55 g, 12.0 mmol), and (Boc)₂O (3.92 g, 18.0 mmol) in THF (30 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was then concentrated under reduced pressure to give a crude product. This crude product was milled with PE (50 mL) at 25 °C for 30 min to give (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate tert-butyl ester (3.4 g, yield 81%) as a pale yellow solid. LCMS (ESI) + m / z = 351.2 (M+H).

[0244] Intermediate 8: 7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Step 1: Preparation of 7-(5-bromopyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine DIEA (3.25 mL, 18.7 mmol) was added to a solution of 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) in DMSO (10 mL). The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was then diluted with H₂O (100 mL) and extracted with a 1:3 IPA:DCM mixture (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was ground with PE:EA (20 mL) at a ratio of 10:1. The solid was collected by filtration, and the filter cake was washed with PE (20 mL) to give 1.5 g (85% yield) of 7-(5-bromopyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine as a grayish-white solid. LCMS (ESI) + m / z = 281.1 (M+H).

[0245] Step 2: Preparation of 7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine A mixture of 7-(5-bromopyrimidin-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-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentanane (813 mg, 3.20 mmol), KOAc (314 mg, 3.20 mmol), and Pd(dppf)Cl2•CH2Cl2 (174 mg, 0.21 mmol) in dioxane (10 mL) was deoxygenated and purged three times 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).

[0246] Intermediate 9: (2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)boronic acid Step 1: Preparation of 4-bromo-1,3-dimethylpyridin-2(1H)-one To a solution of 4-bromo-3-methylpyridin-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 time). The combined organic layers were washed with brine (4 x 40 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 4-bromo-1,3-dimethylpyridin-2(1H)-one (1 g, 93% yield) as a white solid. LCMS (ESI) + m / z = 202.0 (M+H).

[0247] Step 2: Preparation of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-2(1H)-one KOAc (1.38 g, 14.1 mmol) and Pd(dppf)Cl2 (344 mg, 0.47 mmol) were added to a mixture of 4-bromo-1,3-dimethylpyridin-2(1H)-one (950 mg, 4.70 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (2.39 g, 9.40 mmol) in dioxane (20 mL). The resulting mixture was degassed and purged three times with N2. The mixture was then heated to 100 °C and stirred for 1 hour. The reaction was then concentrated under reduced pressure to give 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridin-2(1H)-one (3 g, crude yield), a dark brown solid, which was used in the next step without further purification. LCMS (ESI) + m / z = 250.2 (M+H).

[0248] Step 3: Preparation of 4-(5-bromopyrimidin-2-yl)-1,3-dimethylpyridin-2(1H)-one To a mixture of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyridin-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 and purged three times with N₂. The mixture was heated to 100 °C and stirred for 2 hours, then filtered and the filtrate was dried over anhydrous Na₂SO₄. The filtrate was then filtered again and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluting with PE:EA from 1:1 to 1:2) to give 900 mg (61% yield) of a brown solid, 4-(5-bromopyrimidin-2-yl)-1,3-dimethylpyridin-2(1H)-one. LCMS (ESI) + m / z = 280.0 (M+H).

[0249] Step 4: Preparation of (2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)boronic acid KOAc (315 mg, 3.21 mmol) and Pd(dppf)Cl2 (78 mg, 0.11 mmol) were added to a mixture of 4-(5-bromopyrimidin-2-yl)-1,3-dimethylpyridin-2(1H)-one (300 mg, 1.07 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (544 mg, 2.14 mmol) in dioxane (10 mL). The resulting mixture was degassed and purged three times with N2. The mixture was then heated to 100 °C and stirred for 1 hour. The reactants were concentrated under reduced pressure to give (2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)boronic acid (520 mg, crude yield), a dark brown solid, which was used directly without further purification. LCMS (ESI) + m / z = 246.1 (M+H).

[0250] Intermediate 10: 1-Methyl-6-(trimethyltinyl)pyrazine-2(1H)-one Step 1: Preparation of 6-bromo-1-methylpyrazin-2-one Under a nitrogen atmosphere, K₂CO₃ (14.2 g, 10⁻³ mmol) was added to a solution of 6-bromo-1H-pyrazin-2-one (6 g, 34.3 mmol) in DMF (60 mL) at room temperature. 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 mixture was then diluted with ice water (100 mL) at 0 °C and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 1:1) to give 6-bromo-1-methylpyrazin-2-one (3 g, 46% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6): δ 7.96 (d,J = 2.2 Hz, 1H), 7.62 (d, J =2.2 Hz, 1H), 3.63 – 3.51 (m, 3H).

[0251] Step 2: Preparation of 1-methyl-6-(trimethylsilyl)pyrazine-2(1H)-one Pd(PPh3)4 (3.19 g, 2.7 mmol) was added to a solution of 6-bromo-1-methylpyrazin-2-one (2.0 g, 13.8 mmol) in dioxane (20 mL) at room temperature under an argon atmosphere, followed by dropwise addition of hexamethyldistinane (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 mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give 1-methyl-6-(trimethylsilyl)pyrazin-2-one (700 mg, 18% yield) as a pale yellow oil. LCMS (ESI) + m / z = 274.7 (M+H).

[0252] Intermediate 11: 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazin-2-one Under an argon atmosphere at -78 °C, n-BuLi (0.63 mL, 1.59 mmol) was added in portions to a stirred mixture of 6-bromo-1-methylpyrazin-2-one (intermediate 10, step 1, 200 mg, 1.06 mmol) and bis(pinacol)diborone (403 mg, 1.59 mmol) in THF (5 mL). 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 mixture was concentrated under reduced pressure to give 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazin-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).

[0253] Intermediate 12: (2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)boronic acid Step 1: Preparation of 5-chloro-2-methylpyridazine-3(2H)-one Iodomethane (13.1 g, 91.9 mmol) was added to a solution of 5-chloropyridazin-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 EtOAc (3 x 120 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. This residue was purified by silica gel chromatography (eluting with PE:EA = 1:1) to give 5-chloro-2-methylpyridazin-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).

[0254] Step 2: Preparation of (1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)boronic acid To a solution of 5-chloro-2-methylpyridazin-3(2H)-one (2.0 g, 13.8 mmol) and XPhos (1.32 g, 2.77 mmol) in dioxane (50 mL), KOAc (2.72 g, 27.7 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (7.03 g, 27.7 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 a nitrogen atmosphere. The reaction mixture was then concentrated to obtain a residue, which was diluted with H2O (50 mL) and EtOAc (3 x 40 mL). The aqueous phase was then freeze-dried to obtain (1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)boronic acid (2.3 g, crude product) as a white solid, which was used as is in the next step without further purification. LCMS (ESI) + m / z = 155.0 (M+H).

[0255] Step 3: Preparation of 5-(5-bromopyrimidin-2-yl)-2-methylpyridazine-3(2H)-one To a solution of (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) 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. The reaction mixture was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was then diluted with H₂O (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na₂SO₄, filtered, and concentrated to give the residue. The residue was ground with PE:EA = 5:1 (50 mL) to give 1.2 g (40% yield) of 5-(5-bromopyrimidin-2-yl)-2-methylpyridazine-3(2H)-one as a yellow solid. LCMS (ESI) + m / z = 266.9 (M+H).

[0256] Step 4: Preparation of (2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)boronic acid To a solution of 5-(5-bromopyrimidin-2-yl)-2-methylpyridazin-3(2H)-one (0.50 g, 1.87 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (713 mg, 2.81 mmol) in dioxane (20 mL), KOAc (551 mg, 5.62 mmol) and Pd(dppf)Cl2 (137 mg, 0.19 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was then filtered, and the filter cake was washed with EtOAc (3 x 30 mL). The filtrate was then concentrated to obtain (2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)boronic acid (400 mg, crude) as a gray solid, which was used in the next step without further purification. LCMS (ESI) + m / z = 232.9. (M+H).

[0257] Intermediate 13: 1,3-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazin-2(1H)-one Step 1: Preparation of 3-(benzyloxy)-5-chloro-2-methylpyrazine A solution of 3,5-dichloro-2-methylpyrazine (5 g, 30.7 mmol) in THF (60 mL) was treated fractionally with NaH (1.1 g, 46.0 mmol) at 0 °C under a nitrogen atmosphere. 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 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 3-(benzyloxy)-5-chloro-2-methylpyrazine (5.1 g, crude yield) as a yellow oil. LCMS (ESI) + m / z = 235.1 (M+H).

[0258] Step 2: Preparation of 6-chloro-3-methylpyrazine-2-ol BBr3 (1.0 M, in dichloromethane, 147 mL, 147 mmol) was added dropwise to a stirred solution of 3-(benzyloxy)-5-chloro-2-methylpyrazine (8 g, 49.0 mmol) in toluene (50 mL) under a nitrogen atmosphere at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour. The reaction was quenched with MeOH at 0 °C, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with CH2Cl2:MeOH = 5:1) to give 6-chloro-3-methylpyrazin-2-ol (3.7 g, 75% yield) as a white solid. LCMS (ESI) + m / z = 145.2 (M+H).

[0259] Step 3: Preparation of 6-chloro-1,3-dimethylpyrazine-2(1H)-one Iodomethane (3.93 g, 27.7 mmol) was added fractionally to a stirred 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) under a nitrogen atmosphere at 0 °C. 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 EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 1:1) to give 6-chloro-1,3-dimethylpyrazine-2(1H)-one (1 g, crude yield) as an oil. LCMS (ESI) + m / z = 159.2 (M+H).

[0260] Step 4: Preparation of 1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazin-2(1H)-one Pd(dppf)Cl2•CH2Cl2 (103 mg, 0.13 mmol) and KOAc (371 mg, 3.78 mmol) were added to a stirred solution of 6-chloro-1,3-dimethylpyrazin-2-one (200 mg, 1.26 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (1.6 g, 6.31 mmol) in 1,4-dioxane (2 mL). The resulting mixture was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The 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). Example

[0262] Example 1: (R)-5-(1-((2-(ethylsulfonyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Step 1: Preparation of (2-bromophenyl)(ethyl)thion K₂CO₃ (1.97 g, 28.6 mmol) was added to a solution of 2-bromothiophenol (2.7 g, 14.3 mmol) in acetone (10 mL), followed by iodoethane (4.45 g, 28.6 mmol). The solution was then stirred at 50 °C for 12 hours. The solution was partitioned between ethyl acetate (20 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to give (2-bromophenyl)(ethyl)thione (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).

[0263] Step 2: Preparation of 1-bromo-2-(ethylsulfonyl)benzene m-CPBA (4.8 g, 23.7 mmol, 85% purity) was added to a solution of (2-bromophenyl)(ethyl)thione (2 g, 9.2 mmol) in DCM (20 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 hour. Na₂SO₃ solution (30 mL) was added to the mixture, and extraction was performed using DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, PE:EA = 1:0 to 10:1) to give 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 min (Method C).

[0264] Step 3: Preparation of (R)-5-(1-((2-(ethylsulfonyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one 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 a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and water (5 mL) was added. The mixture was then extracted with ethyl acetate (5 mL x 3), the combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA = 1:2) to obtain a brown oil. This oil was then further purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10 μm; mobile phase: [water(FA)-ACN]; gradient: 65%-75% B over 10 minutes) and the eluent was lyophilized to give a yellow solid (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, yield 8%). LCMS (ESI) + m / z = 551.2 (M+H), t R =0.592 min (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).

[0265] Example 2: (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 Step 1: Preparation of (2-bromophenyl)(chloromethyl)thione NCS (362 mg, 2.71 mmol) was added fractionally to a solution of 1-bromo-2-methylthioalkylbenzene (500 mg, 2.46 mmol) in DCM (6 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered through a short silica gel sieve and eluted with DCM (20 mL). The solvent was removed under reduced pressure to give (2-bromophenyl)(chloromethyl)thione (550 mg, crude product) 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).

[0266] Step 2: Preparation of (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)thion 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 at 0 °C under nitrogen for 1.5 h, followed by the addition of NaI (284 mg, 1.89 mmol) and (2-bromophenyl)(chloromethyl)thione (450 mg, 1.89 mmol). The mixture was then warmed to 25 °C and stirred under nitrogen for 12 h. The reaction mixture was quenched at 0 °C under nitrogen with a saturated aqueous solution of NH4Cl (20 mL). The mixture was extracted with EtOAc (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 rapid silica gel chromatography (ISCO®; 10 g SepaFlash®Silica Flash Column, 100% PE eluent, 60 mL / min) to give (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)thione (550 mg, crude product) as a colorless oil. 1H 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).

[0267] Step 3: Preparation of 1-bromo-2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)benzene m-CPBA (1.11 g, 5.48 mmol, 85% purity) was added to a solution of (2-bromophenyl)((2,2,2-trifluoroethoxy)methyl)thione (550 mg, 1.83 mmol) in DCM (8 mL) 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 phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, eluent 0-20% EA / PE, gradient, 60 mL / min) to give 1-bromo-2-(((2,2,2-trifluoroethoxy)methyl)sulfonyl)benzene (480 mg, yield 79%) as a colorless oil. LCMS (ESI) + ) m / z = 354.9 / 356.9 (M+Na), t R = 0.781 min (Method E).

[0268] 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)piperazin-1-yl)isoquinoline-1(2H)-one 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) in toluene (1 mL) was degassed and purged three times with N₂. The mixture was then stirred at 110 °C for 12 hours under a nitrogen atmosphere. 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 a crude product. This crude product was then further purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; gradient: 60%-90% B within 10 min) and preparative HPLC (column: Waters xbridge 150*25mm*10μm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 60%-80% B within 8 min) to obtain a yellow solid. This solid was then purified by SFC (column: DAICELCHIRALCEL OJ-H (250mm*30mm, 5μm); mobile phase: [CO2-EtOH (0.1%)). [NH3•H2O]; B%: 20%, isocratic elution mode) Further purification of the yellow solid yielded (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 (18.3 mg, yield 22%), a white solid. LCMS (ESI) + ) m / z = 635.3 (M+H), t R = 0.606 min (Method C); 1 H 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 = 8.4Hz, 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).

[0269] Example 3: 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (enantiomer 1) Example 4: 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (enantiomer 2) 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 T4P (3.31 g, 4.59 mmol, 50% purity) and pyridine (606 mg, 7.66 mmol) were added 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 EtOAc (10 mL). The mixture was then stirred at 25 °C for 3 hours. The reaction mixture was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain N-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-6-(methylcarbamoyl)phenyl)-3-(4-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxamide (800 mg, crude product), a grayish-white solid. LCMS (ESI) + ) m / z = 515.3 (M+H), t R =0.735 min (Method C).

[0270] Step 2: Preparation of 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazolin-4(3H)-one K₂CO₃ (604 mg, 4.37 mmol) was added to a solution of 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) in DMF (10 mL). The mixture was stirred at 90 °C for 12 hours. The reaction mixture was partitioned between H₂O (50 mL) and EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:0 to 93:7) to give 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazolin-4(3H)-one (670 mg, 92% yield) as a white solid. LCMS (ESI) + m / z = 497.3 (M+H), tR = 0.920 min (Method D).

[0271] Step 3: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-8-(1-hydroxyethyl)-3-methylquinazolin-4(3H)-one TBAF (1 M, 2.5 mL) was added to a solution of 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazolin-4(3H)-one (620 mg, 1.25 mmol) in THF (5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was then partitioned between H2O (20 mL) and EtOAc (20 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:0 to 4:1) to give 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-8-(1-hydroxyethyl)-3-methylquinazolin-4(3H)-one (410 mg, 85% yield) as a white solid. LCMS (ESI) + ) m / z = 383.3 (M+H), t R =1.044 min (Method E).

[0272] Step 4: Preparation of 8-(1-bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazolin-4(3H)-one PBr3 (453 mg, 1.67 mmol) was added to a solution of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-8-(1-hydroxyethyl)-3-methylquinazolin-4(3H)-one (320 mg, 837 μmol) in DCM (5 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The reaction was then quenched with H2O (10 mL) at 0 °C and the mixture was adjusted to pH 7 with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na₂SO₄, and then concentrated under reduced pressure to give 8-(1-bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazolin-4(3H)-one (300 mg, crude) as a white solid. LCMS (ESI) + ) m / z = 445.1 (M+H), t R = 0.709 min (Method C).

[0273] Step 5: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one NaH (90 mg, 2.25 mmol, 60% purity) was added to a solution of 2-methylsulfonylaniline (230 mg, 1.34 mmol) in DMF (5 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. 8-(1-bromoethyl)-6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methylquinazolin-4(3H)-one (350 mg, 786 μmol) was added to the mixture, and the mixture was stirred again at 25 °C for 0.5 h. The reaction mixture was quenched by adding saturated NH4Cl solution (50 mL) at 0 °C, and then extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex luna C18150*25mm*10μm; mobile phase: [water(FA)-ACN]; gradient: 58%-88% B over 10 minutes) to give a white solid 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (110 mg, yield 26%). LCMS (ESI) + ) m / z = 536.3 (M+H), t R = 0.736 min (Method C).

[0274] Step 6: Preparation of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-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-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (enantiomer 2) The enantiomers of 6-fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (110 mg, 205 μmol) were separated as white solids by SFC (neutral conditions; column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 40%, isocratic elution mode).

[0275] 6-Fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (enantiomer 1) (48.8 mg). LCMS (ESI) + ) m / z = 536.3(M+H), t R = 0.666 min (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).

[0276] 6-Fluoro-2-(3-(4-fluorophenyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (enantiomer 2) (52.6 mg). LCMS (ESI) + ) m / z = 536.3(M+H), t R = 0.671 min (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).

[0277] Example 5: (R)-7-fluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Example 6: (R)-4,7-difluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Step 1: Preparation of (R)-3-chloro-7-fluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one 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 to remove the solvent. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 5:1) to give (R)-3-chloro-7-fluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (160 mg, yield 29%) as a yellow solid. LCMS (ESI) + m / z = 409.0 (M+H), t R =1.009 min (Method E).

[0278] Step 2: Preparation of (R)-7-fluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Cs₂CO₃ (359 mg, 1.10 mmol) and RuPhos-Pd-G₃ (31 mg, 37 μmol) were added to a solution of (R)-3-chloro-7-fluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (150 mg, 367 μmol) and 1-(2,2,2-trifluoroethyl)piperazine (124 mg, 734 μmol) in dioxane (2 mL). The mixture was stirred at 130 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Phenomenex Luna C18150*25mm*10μm; mobile phase: [water(FA)-ACN]; gradient: 48%-78% B over 10 minutes) to give (R)-7-fluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (40 mg, yield 19%) as a white solid. LCMS (ESI) + m / z = 541.2 (M+H), t R = 0.570 min (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).

[0279] Step 3: Preparation of (R)-4,7-difluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one To a solution of (R)-7-fluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (25 mg, 46 μmol) in ACN (2 mL), SelectFluor™ (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 purified by preparative HPLC (Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; gradient: 47%-77%B over 10 minutes) to give (R)-4,7-difluoro-2-methyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (17 mg, yield 62%) as a yellow solid. LCMS (ESI) + m / z = 559.2 (M+H), t R = 0.920 min (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).

[0280] Example 7: (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)isoquinoline-1(2H)-one Step 1: Preparation of (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one 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) in toluene (6 mL) was degassed and purged three times with N2. The mixture was then stirred at 110 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 3:1) to give (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (180 mg, yield 29%) as a yellow solid. LCMS (ESI) + m / z = 405.2 (M+H), t R = 0.597 min (Method C).

[0281] Step 2: Preparation of (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)isoquinoline-1(2H)-one A mixture of (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (170 mg, 420 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-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) in dioxane (4 mL) and H2O (0.5 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 2:1) to give (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-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 min (Method E).

[0282] Step 3: Preparation of (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)isoquinoline-1(2H)-one (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)isoquinoline-1(2H)-one (140 mg, 262 μmol) was added to a mixture of 10% Pd / C (60 mg, 56 μmol) in MeOH (5 mL) under a nitrogen atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C for 12 h under H2 (15 psi). Then, 20% Pd(OH)2 / C (37 mg, 52.5 μmol) was added to the mixture and stirred again at 50 °C for 1 h. 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 give (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)isoquinoline-1(2H)-one (51 mg, yield 36%) as a grayish-white solid. LCMS (ESI) + ) m / z = 536.3 (M+H), t R = 0.555 min (Method C); 1 HNMR (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).

[0283] Example 8: 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 1) Example 9: 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 2) Step 1: Preparation of (2-fluorophenyl)(imino)(methyl)-λ6-sulfone To a solution of 1-fluoro-2-methylthioalkylbenzene (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 give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 1:1) to give (2-fluorophenyl)(imino)(methyl)-λ6-sulfone (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).

[0284] Step 2: Preparation of (2-fluorophenyl)(methyl)(methylimino)-λ6-sulfone NaH (700 mg, 17.50 mmol, 60% purity) was added to a solution of (2-fluorophenyl)(imino)(methyl)-λ6-sulfone (1 g, 5.77 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, CH3I (4.56 g, 32.1 mmol) was added to the mixture and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched by adding a saturated aqueous solution of NH4Cl (50 mL) at 0 °C. The resulting mixture was then extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE:EA = 100:1 to 5:1) to give (2-fluorophenyl)(methyl)(methylimino)-λ6-sulfone (950 mg, yield 87%) as a yellow solid. LCMS (ESI) + m / z = 188.1 (M+H), t R =0.387 min (method L).

[0285] Step 3: Preparation of 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one DIEA (371 mg, 2.87 mmol, 0.5 mL) and 4 Å molecular sieve (100 mg) were added to a solution of (2-fluorophenyl)(methyl)(methylimino)-λ6-sulfone (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) in IPA (0.1 mL) 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 give a yellow solid 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (50 mg, yield 34%). LCMS (ESI) + ) m / z = 550.3 (M+H), t R =0.549 min (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 = 4.0Hz, 3H), 2.39(d, J = 6.0 Hz, 3H), 1.62 - 1.60 (m, 3H).

[0286] Step 4: Preparation of 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)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-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 2) 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (50 mg, 91 μm) was purified by SFC (neutral conditions; column: DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 μm); mobile phase: [CO2-EtOH]; B%: 35%, isocratic elution mode). μmol) yielded 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)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-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (diastereomer 2) as yellow solids.

[0287] 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)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 min (Method C); 1H 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).

[0288] 5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)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 min (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).

[0289] Example 10: 2,7-Dimethyl-5-((1R)-1-((6-methyl-2-(S-methylsulfonylimideyl)pyridin-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Step 1: Preparation of 3-fluoro-6-methyl-2-(methylthio)pyridine Sodium methanethiol (489 mg, 6.97 mmol) was added to a solution of 2,3-difluoro-6-methylpyridine (900 mg, 6.97 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. 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 residue was purified by silica gel chromatography (PE:EA = 1:0, 10:1) to give 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 min (Method E).

[0290] Step 2: Preparation of (3-fluoro-6-methylpyridin-2-yl)(imino)(methyl)-λ6-sulfone To a mixture of 3-fluoro-6-methyl-2-(methylthio)pyridine (650 mg, 4.13 mmol) and (acetoxy(phenyl)-iodoalkyl)acetate (3.33 g, 10.3 mmol) in MeOH (5 mL), (NH4)2CO3 (596 mg, 6.2 mmol) was added. The mixture was stirred at 25 °C for 12 hours and then concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE:EA = 1:0, 0:1) to give (3-fluoro-6-methylpyridin-2-yl)(imino)(methyl)-λ6-sulfone (630 mg, 72% yield) as a yellow oil. LCMS (ESI) + ) m / z = 188.9 (M+H), t R = 0.248 min (Method E).

[0291] Step 3: Preparation of 2,7-dimethyl-5-((1R)-1-((6-methyl-2-(S-methylsulfonylimideyl)pyridin-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one To a solution of (3-fluoro-6-methylpyridin-2-yl)(imino)(methyl)-λ6-sulfone (148 mg, 784 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) in IPA (0.5 mL), 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 give 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 min) to give a yellow solid of 2,7-dimethyl-5-((1R)-1-((6-methyl-2-(S-methylsulfonyliminoyl)pyridin-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (54 mg, yield 36%). LCMS (ESI) + ) m / z = 551.1 (M+H), t R = 0.922 min (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 = 5.2Hz, 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 = 6.8Hz, 3H).

[0292] Example 11: (R)-2,7-dimethyl-5-(1-((2-(((1-methyl-1H-pyrazol-4-yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Step 1: Preparation of 4-(((2-fluorophenyl)thio)methyl)-1-methyl-1H-pyrazole 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-fluorothiophenol (230 mg, 1.80 mmol) were added. The mixture was stirred at 60 °C for 12 hours. The reaction mixture was partitioned between H₂O (50 mL) and EtOAc (50 mL). The organic phase was separated, washed with brine (20 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, PE:EA = 100:1 to 4:1) to give 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 min (Method C).

[0293] Step 2: Preparation of 4-(((2-fluorophenyl)sulfonyl)methyl)-1-methyl-1H-pyrazole m-CPBA (620 mg, 3.05 mmol, 85% purity) was added to a solution of 4-(((2-fluorophenyl)thio)methyl)-1-methyl-1H-pyrazole (340 mg, 1.53 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by adding an aqueous solution of 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 a saturated NaHCO₃ solution (30 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, PE:EA = 100:1 to 1:1) to give 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 min (Method C).

[0294] Step 3: Preparation of (R)-2,7-dimethyl-5-(1-((2-(((1-methyl-1H-pyrazol-4-yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one A mixture 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 and purged three times with N2. The mixture was stirred at 130 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was dissolved in ACN (2 mL) and filtered to obtain the filtrate. The filtrate 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 give (R)-2,7-dimethyl-5-(1-((2-(((1-methyl-1H-pyrazol-4-yl)methyl)sulfonyl)phenyl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (83 mg, yield 51%) as a white solid. LCMS (ESI) + ) m / z = 617.3 (M+H), t R = 0.593 min (Method C); 1 H NMR (400MHz, 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).

[0295] Example 12: (R)-3-(4-(5-fluoro-2-methylpyridin-3-yl)piperazin-1-yl)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one Step 1: Preparation of tert-butyl 4-(5-fluoro-2-methylpyridin-3-yl)piperazine-1-carboxylate To a solution of 3-bromo-5-fluoro-2-methylpyridine (1.9 g, 10.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (2.79 g, 15.0 mmol) in toluene (30 mL), 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 at 80 °C for 12 hours under a nitrogen atmosphere. The solution was filtered through a diatomaceous earth filter and the filtrate was concentrated. The residue was purified by column chromatography (SiO₂, PE:EA = 75:25 to 50:50) to give 4-(5-fluoro-2-methylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 76% yield) as a yellow solid. LCMS (ESI) + ) m / z = 296.3 (M+H), t R = 0.514 min (Method C).

[0296] Step 2: Preparation of 1-(5-fluoro-2-methylpyridin-3-yl)piperazine TFA (4.61 g, 40.4 mmol) was added to a solution of tert-butyl 4-(5-fluoro-2-methylpyridin-3-yl)piperazine-1-carboxylate (2.5 g, 8.46 mmol) in DCM (9 mL) 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 ammonia. The solution was purified by preparative HPLC (column: Kromasil Eternity XT 250*80mm*10μm; mobile phase: [water (NH4OH)-ACN]; gradient: 1%-31% B over 20 min) and the eluent was lyophilized to give 1-(5-fluoro-2-methylpyridin-3-yl)piperazine (0.8 g, yield 48%) 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).

[0297] Step 3: Preparation of (R)-3-(4-(5-fluoro-2-methylpyridin-3-yl)piperazin-1-yl)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one A solution of (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (Example 7, Step 1) (0.2 g, 301 μmol), 1-(5-fluoro-2-methylpyridin-3-yl)piperazine (0.2 g, 1.02 mmol), Cs₂CO₃ (982 mg, 3.01 mmol), and BINAP-Pd-G₃ (30 mg, 30 μmol) in dioxane (10 mL) was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The solution was filtered through a diatomaceous earth pad and the filtrate was concentrated. The residue was purified by preparative-TLC (PE:EA = 1:4) to give a yellow oil. The yellow oil was then further purified by preparative HPLC purification (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; gradient: 48%-78% B over 10 minutes) and the eluent was lyophilized to obtain a yellow solid (R)-3-(4-(5-fluoro-2-methylpyridin-3-yl)piperazin-1-yl)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one (64 mg, yield 37%). LCMS (ESI) + m / z = 564.2 (M+H), t R = 0.937 min (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).

[0298] Example 13: 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 1) Example 14: 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridine]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 2) Step 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine 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-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (735 mg, 2.89 mmol), Pd(dppf)Cl2•CH2Cl2 (430 mg, 526 μmol), and KOAc (775 mg, 7.89 mmol) in dioxane (10 mL) was degassed and purged three times 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 give 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (623 mg, crude) as a brown oil, which was used in the next step without further purification.

[0299] Step 2: Preparation of 5-bromo-3,5'-difluoro-2'-methyl-2,3'-bipyridine A mixture of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-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) in dioxane (10 mL) and H₂O (1 mL) was degassed and purged three times with N₂. The mixture was then stirred at 80 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE:EA = 99:1 to 85:15) to give 5-bromo-3,5'-difluoro-2'-methyl-2,3'-bipyridine (410 mg, yield 54%) as a yellow oil. LCMS (ESI) + ) m / z= 285.0 (M+H), t R = 0.633min (Method C).

[0300] Step 3: Preparation of 3,5'-difluoro-2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3'-bipyridine 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-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (333 mg, 1.31 mmol), Pd(dppf)Cl2•CH2Cl2 (93 mg, 114 μmol), and KOAc (320 mg, 3.26 mmol) in dioxane (2 mL) was degassed and purged three times 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 give 3,5'-difluoro-2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-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).

[0301] Step 4: Preparation of 3-chloro-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one To a solution of (2-fluorophenyl)(methyl)(methylimino)-λ6-sulfone (224 mg, 1.20 mmol) and (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4) (200 mg, 798 μmol) in IPA (0.1 mL), DIEA (223 mg, 1.72 mmol) and 4 Å molecular sieve (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 give the residue. The residue was purified by preparative TLC (SiO2, PE:EA = 1:1) to give 3-chloro-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)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 min (method K).

[0302] Step 5: Preparation of 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one A mixture of 3-chloro-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)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-dioxaborhexacyclopentan-2-yl)-2,3'-bipyridine (150 mg, 452 μmol), 4-di-tert-butylphosphoalkyl-N,N-dimethylanilinepalladium dichloride (39 mg, 55 μmol), and K3PO4 (350 mg, 1.65 mmol) in dioxane (4 mL) and H2O (0.5 mL) was degassed and purged three times with N2. The mixture was stirred at 100 °C for 3 hours. The reaction mixture was then partitioned between H2O (10 mL) and EtOAc (10 mL). The organic phase was separated and dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative-TLC (SiO2, PE:EA = 1:2). The product was then purified by preparative-HPLC (FA conditions; column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; gradient: 44%-74% B over 10 min) to give 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (75 mg, yield 22%) as a white solid. LCMS (ESI + ) m / z = 588.3 (M+H), t R = 0.534 min (Method C).

[0303] Step 6: Preparation of 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 1) and 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 2) 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (75 mg, 128 μm) was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH4OH)]; B%: 45%, isocratic elution mode) (SFC column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH4OH)]; B%: 45%, isocratic elution mode). μmol) yielded 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonyliminoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 1) and 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridin]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonyliminoyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (diastereomer 2) as white solids.

[0304] 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridinyl]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)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 min (Method C); 1 H NMR (400 MHz, CDCl3): δ8.70 (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).

[0305] 3-(3,5'-difluoro-2'-methyl-[2,3'-bipyridinyl]-5-yl)-5-((1R)-1-((2-(N,S-dimethylsulfonylimideyl)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 min (Method C); 1 H NMR (400 MHz, CDCl3): δ8.70 (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).

[0306] Example 15: (R)-5-(1-((6-chloro-2-(methanesulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Step 1: Preparation of 6-chloro-3-fluoro-2-(methylthio)pyridine Sodium methanethiol (500 mg, 7.13 mmol) was added to a solution of 2,6-dichloro-3-fluoropyridine (1 g, 6.02 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was partitioned between H₂O (50 mL) and EtOAc (50 mL). The organic phase was separated, washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, PE:EA = 100:1 to 95:5) to give 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).

[0307] Step 2: 6-Chloro-3-fluoro-2-(methylsulfonyl)pyridine NaClO (12.1 g, 162 mmol) was added to a solution of 6-chloro-3-fluoro-2-(methylthio)pyridine (480 mg, 2.70 mmol) in EtOAc (10 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was then partitioned between H2O (10 mL) and EtOAc (10 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-chloro-3-fluoro-2-(methylsulfonyl)pyridine (440 mg, crude) as a colorless oil, which was used directly in the next step without purification. LCMS (ESI) + ) m / z = 210.1 (M+H), t R = 0.422 min (Method C).

[0308] Step 3: Preparation of (R)-5-(1-((6-chloro-2-(methanesulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Triethylamine (79 mg, 785 μmol) was added 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) (100 mg, 261 μmol) and 6-chloro-3-fluoro-2-(methanesulfonyl)pyridine (110 mg, 523 μmol) in ACN (0.5 mL). The resulting mixture was stirred at 80 °C for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure to give 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 give (R)-5-(1-((6-chloro-2-(methanesulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (95 mg, yield 63%) as a grayish-white solid. LCMS (ESI) + ) m / z = 572.3 (M+H), t R = 0.616 min (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).

[0309] Example 16: (R)-5-(1-((6-ethynyl-2-(methanesulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one Step 1: Preparation of (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)-6-((trimethylsilyl)ethynyl)pyridin-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one A mixture of (R)-5-(1-((6-chloro-2-(methanesulfonyl)pyridin-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), ethynyl(trimethyl)silane (93 mg, 944 μmol, 131 μL), Xphos-Pd-G4 (8 mg, 9.44 μmol), and N-cyclohexyl-N-methyl-cyclohexylamine (55 mg, 283 μmol) in dioxane (1 mL) was degassed and purged three times with N2. The resulting mixture was stirred at 110 °C for 2 hours. Then, ethynyl(trimethyl)silane (93 mg, 944 μmol) was added, and the mixture was stirred again at 110 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was then 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 give (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)-6-((trimethylsilyl)ethynyl)pyridin-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 min (Method E).

[0310] Step 2: Preparation of (R)-5-(1-((6-ethynyl-2-(methanesulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one CsF (26 mg, 174 μmol) was added to a solution of (R)-2,7-dimethyl-5-(1-((2-(methanesulfonyl)-6-((trimethylsilyl)ethynyl)pyridin-3-yl)amino)ethyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (55 mg, 86.8 μmol) in DMF (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. 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 give (R)-5-(1-((6-ethynyl-2-(methanesulfonyl)pyridin-3-yl)amino)ethyl)-2,7-dimethyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)isoquinoline-1(2H)-one (19 mg, yield 38%) as a grayish-white solid. LCMS (ESI) + ) m / z = 562.3 (M+H), t R = 0.602 min (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).

[0311] Example 17: (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzenesulfonamide Step 1: Preparation of 2-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide NaH (1.27 g, 31.7 mmol, 60 wt%) was added to a stirred solution of 2-bromobenzenesulfonamide (2.5 g, 10.6 mmol) in DMF (50 mL) under a nitrogen atmosphere at 0 °C. After stirring the mixture at 0 °C for 30 min, 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 h. The reaction was quenched with water (50 mL) at 0 °C, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 10:1) to give 2-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (4 g, 76% yield) as oil. 1 H NMR (400 MHz, DMSO- d 6) 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).

[0312] Step 2: Preparation 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,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide) Under a nitrogen atmosphere at room temperature, Pd2(dba)3 (96 mg, 0.11 mmol), Cs2CO3 (682 mg, 2.09 mmol), and Xantphos (121 mg, 0.21 mmol) were added to a stirred 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). The resulting mixture was stirred overnight at 100 °C. The mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give (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, yield 30%) as oil. MS (ES) - m / z = 796.2 [MH] - .

[0313] Step 3: Preparation 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)benzenesulfonamide Under a nitrogen atmosphere at room temperature, TBAF (1M, in THF, 1.88 mL, 1.88 mmol) was added dropwise to a stirred solution 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,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (150 mg, 0.19 mmol) in 10 mL of THF. The resulting mixture was stirred overnight at 50 °C. The reaction was then quenched with water (10 mL) at 0 °C and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 15 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (UV 254nm / 220nm X select CSH Prep C18 Column, 30*150 mm, 5μm; water (0.1% FA), ACN 60 mL / min, 43% B to 68% B over 10 min) to give (R)-2-((1-(2,7-dimethyl-1-oxo-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzenesulfonamide (66 mg, 65% yield) as a white solid. MS (ES) + m / z = 538.2 [M+H] + , t R = 0.977 min; 1 H NMR (400 MHz, DMSO- d 6): δ7.89 – 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).

[0314] Example 18: (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 Step 1: Preparation of 2-bromo-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide NaH (244 mg, 5.60 mmol, 60 wt%) was added to a solution of 2-bromo-N-methylbenzenesulfonamide (700 mg, 2.80 mmol) in DMF (15 mL) at 0 °C under a nitrogen atmosphere. After stirring the mixture at 0 °C for 30 min, SEM-Cl (607 mg, 3.64 mmol) was added at 0 °C. The mixture was then stirred at room temperature for 5 h. The reaction was quenched with water (10 mL) at room temperature and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA = 5:1) to give 2-bromo-N-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (650 mg, 61% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO- d 6) 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).

[0315] Step 2: Preparation 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 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) in dioxane (10 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative-TLC (PE:EA = 1:1) to give (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, yield 42%), as a light brown solid. MS (ES) + m / z = 682.3 [M+H] + .

[0316] Step 3: Preparation 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-methylbenzenesulfonamide 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 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 EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 15 mL) and then dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by 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 min; 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, yield 44%) as a white solid. 1 H NMR (400 MHz, methanol-) d 4): 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] - .

[0317] Example 19: (R)-3,6-dimethyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinazolin-4(3H)-one Step 1: Preparation of (R)-3,6-dimethyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-2-(methylthio)quinazolin-4(3H)-one Under an argon atmosphere and at room temperature, Cs₂CO₃ (1.1 g, 3.4 mmol) and [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-yl]-dichloro-(2-methylpyridin-1-onthium-1-yl)palladium (16 mg, 0.019 mmol) were added in portions to a stirred solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-dimethyl-2-yl]-2-dichloro-2-yl]-2-dichloro-2-yl]-2-methylpyridin-1-onthium-1-yl)palladium. The resulting mixture was stirred overnight at 100 °C. The reaction was then quenched with water (60 mL) at room temperature and the mixture was extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give (R)-3,6-dimethyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-2-(methylthio)quinazolin-4(3H)-one (100 mg, yield 21%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6): 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 = 6.6Hz, 3H).

[0318] Step 2: Preparation of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one Oxone (169 mg, 1.0 mmol) was added dropwise to a stirred solution of (R)-3,6-dimethyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-2-(methylthio)quinazolin-4(3H)-one (70 mg, 0.17 mmol) in THF (2 mL) 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 mixture was extracted with EtOAc (2 x 40 mL), the combined organic layers were 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 give 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (40 mg, 55% yield) as a white solid. LCMS (ESI) + ) m / z = 434.1 (M+H).

[0319] Step 3: Preparation of (R)-3,6-dimethyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinazolin-4(3H)-one A mixture of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-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 extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give (R)-2-hydroxy-3,6-dimethyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (35 mg, 8%) as a white solid.

[0320] A solution of (R)-2-hydroxy-3,6-dimethyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)quinazolin-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 min at room temperature. Then, DBU (69 mg, 0.45 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (23 mg, 0.14 mmol) were added in portions at room temperature. The resulting mixture was stirred at room temperature for 3 h and then diluted with ice water (20 mL). The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (column, C18 silica gel; mobile phase, MeCN / water, 5% to 95% gradient over 30 min; detector, UV 254 nm) to give (R)-3,6-dimethyl-8-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinazolin-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- d 6): δ7.76-7.20 (m, 1H), 7.64 – 7.54 (m, 2H),7.37-7.29 (m, 1H), 6.77 (d, J = 7.0Hz, 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).

[0321] Example 85: (R)-3-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-5-yl)-5-(1-((4-fluoro-2-(methanesulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one Step 1: Preparation of (R)-3-chloro-5-(1-((4-fluoro-2-(methanesulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one To a solution of (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4, 200 mg, 0.80 mmol) and 1,4-difluoro-2-methylsulfonyl-benzene (200 mg, 1.04 mmol) in IPA (0.2 mL), 100 mg of 4 Å molecular sieve and DIEA (0.40 mL, 2.30 mmol) were added. The mixture was stirred at 130 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, PE:EA = 10:1 to 4:1) to give (R)-3-chloro-5-(1-((4-fluoro-2-(methanesulfonyl)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).

[0322] Step 2: Preparation of (R)-3-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-5-yl)-5-(1-((4-fluoro-2-(methanesulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one p-(R)-3-chloro-5-(1-((4-fluoro-2-(methanesulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (70 mg, 0.17 mmol), 7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (intermediate 8, 81 mg, 0.25 mmol), methanesulfonate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3) (12 mg, 0.017 mmol), Na2CO3 (35 mg, 0.33 mmol) The mixture of 1 mmol) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged three times 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 layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC to give (R)-3-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-5-yl)-5-(1-((4-fluoro-2-(methanesulfonyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (30 mg, yield 30%) as a yellow solid. LCMS (ESI) + m / z = 589.3 (M+H); 1 H 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).

[0323] Example 86: (R)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethyl-5-(1-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)isoquinoline-1(2H)-one Step 1: Preparation of (R)-(1-(3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)tert-butyl carbamate The mixture of (2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)boronic acid (intermediate 9, 280 mg, 0.86 mmol), (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate tert-butyl ester (intermediate 7, 300 mg, 0.86 mmol), methanesulfonate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3) (62 mg, 0.086 mmol), K2CO3 (355 mg, 2.57 mmol) in dioxane (5 mL) and H2O (1 mL) was degassed and purged three times with N2. The mixture was then stirred at 100°C for 1 hour. The mixture was then 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 from 1:0 to 1:1) to give (R)-(1-(3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (400 mg, 70% yield), as a dark brown solid. LCMS (ESI) + m / z = 516.2 (M+H).

[0324] Step 2: Preparation of (R)-5-(1-aminoethyl)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethylisoquinoline-1(2H)-one A solution of (R)-(1-(3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (200 mg, 0.39 mmol) in HCl / dioxane solution (4 M, 2 mL) was prepared. The mixture was stirred at 25 °C for 0.3 h. The reaction was then concentrated under reduced pressure to give (R)-5-(1-aminoethyl)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-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).

[0325] Step 3: Preparation of (R)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethyl-5-(1-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)isoquinoline-1(2H)-one p-(R)-5-(1-aminoethyl)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethylisoquinoline-1(2H)-one (from the free base of the HCl salt reported in the previous step, generated by treating a 10:1 CH2Cl2 / MeOH solution of the HCl salt with a saturated NaHCO3 aqueous solution, 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-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (30 mg, 0.036 mmol), Cs2CO3 (471 The solution of (mg, 1.44 mmol) in dioxane (10 mL) was degassed and purged three times 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 give the crude product. The crude product was purified by silica gel column chromatography (eluting with PE:EA from 1:1 to 1:4) and then further purified by preparative HPLC to give (R)-3-(2-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-2,7-dimethyl-5-(1-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)amino)ethyl)isoquinoline-1(2H)-one (24 mg, yield 11%) as a yellow solid. LCMS (ESI) + m / z = 575.3 (M+H), t R =0.517 min (method X); 1 H NMR (400 MHz, DMSO- d 6): δ9.25 (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).

[0326] Example 87: (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinoline-1(2H)-one Step 1: Preparation of 1-bromo-2-(difluoromethyl)-3,4-difluorobenzene DAST (21.9 g, 136 mmol) was added dropwise to a stirred solution of 6-bromo-2,3-difluorobenzaldehyde (15.0 g, 67.8 mmol) in DCM (30 mL) under an argon atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 2 h and then quenched by adding ice water (400 mL) at 0 °C. The mixture was then extracted with CH2Cl2 (3 x 400 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 10:1) to give 1-bromo-2-(difluoromethyl)-3,4-difluorobenzene (11.0 g, 67% yield) as a grayish-white oil. 1 HNMR (400 MHz, DMSO- d 6) δ 7.73 – 7.63 (m, 2H), 7.45 – 7.14 (m, 1H).

[0327] Step 2: Preparation of (R)-3-chloro-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one Under an argon atmosphere at room temperature, 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 to a stirred 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 (10 mL). The resulting mixture was stirred overnight at 100 °C. The reaction mixture was diluted with ice water (50 mL) at 0 °C and then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 1:1) to give (R)-3-chloro-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (960 mg, yield 56%) as a pale yellow oil. LCMS (ESI) + m / z = 413 (M+H).

[0328] Step 3: Preparation of (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)isoquinoline-1(2H)-one Under an argon atmosphere at room temperature, KOAc (642 mg, 6.5 mmol) and Pd(dppf)Cl2 (160 mg, 0.2 mmol) were added fractionally to a stirred 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-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (11.0 g, 43.6 mmol) in dioxane (10 mL). The resulting mixture was stirred at 90 °C for 2 hours. The mixture was then filtered, and the filter cake was washed with DCM (3 x 20 mL). The filtrate was then concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification. LCMS (ESI + ) m / z = 505 (M+H).

[0329] Step 4: Preparation of (R)-3-(2-bromopyrimidin-5-yl)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one Under a nitrogen atmosphere at room temperature, Na₂CO₃ (567 mg, 5.4 mmol) and Pd(PPh₃)₄ (206 mg, 0.2 mmol) were added in portions to a stirred solution of (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborheocyton-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). The resulting mixture was then stirred overnight at 90 °C. The mixture was diluted with ice water (30 mL) at 0 °C and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give (R)-3-(2-bromopyrimidin-5-yl)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (450 mg, 47% yield) as a pale yellow solid. LCMS (ESI) + )m / z = 535 (M+H).

[0330] Step 5: Preparation of (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinoline-1(2H)-one Under an argon atmosphere at room temperature, methanesulfonyl[(tri-tert-butylphosphine)-2-(2H)-one (100 mg, 0.2 mmol) and 1-methyl-6-(trimethylmethylenetinyl)pyrazin-2-one (intermediate 10, 102 mg, 0.3 mmol) were added in portions to a stirred solution of (R)-3-(2-bromopyrimidin-5-yl)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)-amino)-2-one (intermediate 10, 102 mg, 0.3 mmol) in DMF (0.5 mL) with added at least twice the amount of added attenuated temperature. The resulting mixture was then stirred overnight at 80 °C. The mixture was diluted with ice water (30 mL) at 0 °C and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography followed by preparative-HPLC to give (R)-5-(1-((2-(difluoromethyl)-3,4-difluorophenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinoline-1(2H)-one (9.0 mg, yield 8.5%) as a pale yellow solid. LCMS (ESI) + ) m / z = 565 (M+H); 1 H NMR (400 MHz, DMSO- d 6): 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).

[0331] Example 88: (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinoline-1(2H)-one Step 1: Preparation of (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one Pd2(dba)3 (730 mg, 0.80 mmol) was added in portions to a stirred solution / mixture of (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) in 1,4-dioxane (10 mL) at room temperature under an argon atmosphere. 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 extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 5:1) to give (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (600 mg, yield 36%) as a white solid. LCMS (ESI) + m / z = 413 (M+H).

[0332] Pd2(dba)3 (730 mg, 0.80 mmol) was added in portions to a stirred solution / mixture of (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) in 1,4-dioxane (10 mL) at room temperature under an argon atmosphere. 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 extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 5:1) to give (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (600 mg, yield 36%) as a white solid. LCMS (ESI) + m / z = 413 (M+H).

[0333] 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-dioxaborhecyclopentan-2-yl)isoquinoline-1(2H)-one Pd(dppf)Cl2 (213 mg, 0.29 mmol) was added dropwise to a stirred 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-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (738 mg, 2.91 mmol) and KOAc (428 mg, 4.36 mmol) in dioxane (10 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred overnight at 110 °C. The mixture was then filtered and concentrated under reduced pressure to give a crude product, which was used directly in the next step without characterization or further purification. LCMS (ESI) + m / z = 505 (M+H).

[0334] Step 3: Preparation of (R)-3-(2-bromopyrimidin-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one Pd(PPh3)4 (137 mg, 0.12 mmol) and Na2CO3 (378 mg, 3.57 mmol) were added to a stirred 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 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 give (R)-3-(2-bromopyrimidin-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (450 mg, yield 71%) as a pale yellow solid. LCMS (ESI) + m / z = 535.1 (M+H).

[0335] Step 4: Preparation of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-5-yl)isoquinoline-1(2H)-one CuCl (18 mg, 0.19 mmol) was added in portions to a stirred mixture of (R)-3-(2-bromopyrimidin-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (50 mg, 0.093 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazin-2-one (intermediate 11, 66 mg, 0.28 mmol), Pd(dppf)Cl2 (34 mg, 0.046 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in DMF (2 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred at 60°C for 1 hour, diluted with ice water (30 mL) at 0°C, and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-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 (400MHz, DMSO- d 6): 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 = 1.8Hz, 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).

[0336] 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)pyrimidin-5-yl)isoquinoline-1(2H)-one Step 1: Preparation of (R)-(1-(2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)tert-butyl carbamate To a solution of (2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)boronic acid (intermediate 12, 516 mg, 2.22 mmol) and (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate tert-butyl (intermediate 7, 600 mg, 1.71 mmol) in dioxane (12 mL) and H₂O (1 mL), Na₂CO₃ (363 mg, 3.42 mmol) and methanesulfonate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3) (125 mg, 0.17 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was then concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (silica gel, eluted with PE:EA from 1:0 to 1:1) to give (R)-(1-(2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate tert-butyl ester (250 mg, yield 29%) as a yellow solid. LCMS (ESI) + m / z = 503.1 (M+H).

[0337] Step 2: Preparation of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinoline-1(2H)-one hydrochloride A mixture of (R)-(1-(2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate tert-butyl (250 mg, 0.50 mmol) in HCl / dioxane solution (2 M, 6 mL, 12 mmol) was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinoline-1(2H)-one hydrochloride (218 mg, 93% yield) as a yellow solid. LCMS (ESI) + m / z = 403.1(M+H).

[0338] 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)pyrimidin-5-yl)isoquinoline-1(2H)-one Under a nitrogen atmosphere at 25 °C, (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-pyrimidin-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) in dioxane (2 mL) were added in a single batch to a mixture of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazol-2-yl)benzene (78 mg, 0.32 mmol) in dioxane (2 mL). The mixture was then 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 phases were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative-HPLC to give (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(2-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrimidin-5-yl)isoquinoline-1(2H)-one (19 mg, 21% yield) as a yellow solid. LCMS (ESI) + m / z = 565.2 (M+H); 1H 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).

[0339] Example 90: (R)-2,7-dimethyl-3-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one Step 1: Preparation of 5-bromo-2'-methyl-2,5'-bipyrimidine A mixture of (2-methylpyrimidin-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) in dioxane (20 mL) and H2O (4 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with 300 mL (3 x 100 mL) of ethyl acetate. The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluting with PE:EA from 10:1 to 3:1) to give 5-bromo-2'-methyl-2,5'-bipyrimidine (410 mg, yield 46%) as a white solid. LCMS (ESI) + m / z = 251.2 (M+H).

[0340] Step 2: Preparation of 2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,5'-bipyrimidine 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-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (303 mg, 1.19 mmol), KOAc (235 mg, 2.39 mmol), and Pd(dppf)Cl2•CH2Cl2 (65 mg, 0.080 mmol) in dioxane (5 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C for 12 hours. The mixture was then concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluting with PE:EA = 0 / 1) to give 2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,5'-bipyrimidine (340 mg, crude yield) as a brownish-black solid, which was used as is in the next step without further purification. LCMS (ESI) + m / z = 217.3 (M+H, boric acid).

[0341] Step 3: Preparation of (R)-2,7-dimethyl-3-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)isoquinoline-1(2H)-one In a sealable container, a mixture of 2'-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2,5'-bipyrimidine (58 mg, 0.24 mmol), (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methanesulfonyl)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) in dioxane (10 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 120 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was filtered through silica gel (eluted with MeOH) to obtain a residue, which was further purified by preparative HPLC to give (R)-2,7-dimethyl-3-(2'-methyl-[2,5'-bipyrimidin]-5-yl)-5-(1-((2-(methanesulfonyl)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- d 6): 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).

[0342] Example 91: (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)isoquinoline-1(2H)-one Step 1: Preparation of 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one A mixture of 4-iodo-1H-pyridazin-6-one (697 mg, 3.14 mmol), (2-methylpyrimidin-5-yl)boronic acid (1.3 g, 9.42 mmol), Cu(OAc)₂ (5.71 g, 31.4 mmol), and pyridine (2.49 g, 31.4 mmol) in dichloroethane (10 mL) was degassed and purged three times 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 give a residue. The residue was purified by silica gel chromatography (eluting with PE:EA = 1:0 to 72:28) to give 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one (1.3 g, 87% yield) as a yellow solid. LCMS (ESI) + m / z = 314.9 (M+H).

[0343] Step 2: Preparation of (1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)boronic acid A mixture of 5-iodo-2-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one (500 mg, 1.59 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (809 mg, 3.18 mmol), KOAc (469 mg, 4.78 mmol), and Pd(dppf)Cl2 (116 mg, 0.16 mmol) in dioxane (3 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give (1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)boronic acid (500 mg, crude yield) as a brown oil, which was used in the next step without further purification. LCMS (ESI) + m / z = 233.0 (M+H), t R = 0.338 min (method AJ).

[0344] Step 3: Preparation of (R)-(1-(2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)tert-butyl carbamate A mixture of (1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)boronic acid (500 mg, 1.59 mmol), (R)-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate tert-butyl (intermediate 7, 447 mg, 1.27 mmol), methanesulfonate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3) (116 mg, 0.16 mmol), and K2CO3 (660 mg, 4.77 mmol) in dioxane (5 mL) and H2O (0.5 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C for 0.5 h. The reaction mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with PE:EA = 1:0, then DCM:MeOH = 95:5) to give (R)-(1-(2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate tert-butyl ester (420 mg, yield 44%) as a yellow solid. LCMS (ESI) + m / z = 503.3 (M+H).

[0345] Step 4: Preparation of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)isoquinoline-1(2H)-one hydrochloride A solution of HCl in dioxane (4 M, 4.0 mL, 16 mmol) was added to a solution of (R)-(1-(2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)carbamate (400 mg, 0.80 mmol) in DCM (0.5 mL). The mixture was stirred at 25 °C for 1 hour and then concentrated under reduced pressure to give (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-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).

[0346] Step 5: Preparation of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)isoquinoline-1(2H)-one A mixture of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-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-dichloro-imidazol-2-yl]-dichloro-(2-methylpyridin-1-onthiol-1-yl)palladium (38 mg, 0.046 mmol), and Cs₂CO₃ (742 mg, 2.28 mmol) in dioxane (2 mL) was degassed and purged three times with N₂. The mixture was then stirred at 100 °C for 4 hours. The reaction mixture was then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative-TLC (silica gel, eluted with PE:EA = 1:2) and then by preparative-HPLC to give (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(1-(2-methylpyrimidin-5-yl)-6-oxo-1,6-dihydropyridazin-4-yl)isoquinoline-1(2H)-one (94 mg, yield 37%) 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).

[0347] Example 92: (R)-3-(5-(2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide Step 1: Preparation of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine 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-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (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 at 100 °C for 0.5 h under a nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ES) + m / z = 238.1 (M+H).

[0348] Step 2: Preparation of 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine A solution of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-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 EtOAc (2 x 10 mL). After further dilution with ethyl acetate, the filtrate was washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluting with EA) to give 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine (100 mg, 46%) as a grayish-white solid. LCMS (ESI) + m / z = 268.0 (M+H).

[0349] Step 3: Preparation of 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide A solution of 5-bromo-2-(5-fluoro-2-methylpyridin-3-yl)pyrimidine (110 mg, 0.41 mmol) in DCM (2 mL) was treated with m-CPBA (106 mg, 0.615 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by preparative-TLC (eluting with EA) to give 3-(5-bromopyrimidine-2-yl)-5-fluoro-2-methylpyrimidine 1-oxide (50 mg, 43%) as a grayish-white solid. LCMS (ESI) + m / z = 286.0 (M+H, bromine isotopes).

[0350] Step 4: Preparation of 1-oxide of 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrimidin-2-yl)pyridine A solution of 3-(5-bromopyrimidin-2-yl)-5-fluoro-2-methylpyridin-1-on-1-ol (200 mg, 0.704 mmol) in dioxane (3 mL) was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaboron-2-yl)-1,3,2-dioxaboron-2-yl) (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 the crude product was used directly in the next step without further purification. LCMS (ESI) + )m / z = 332.1 (M+H).

[0351] Step 5: Preparation of (R)-3-(5-(2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide A solution of 5-fluoro-2-methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)pyrimidin-2-yl)pyridine 1-oxide (300 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was treated at room temperature with (R)-3-chloro-2,7-dimethyl-5-(1-((2-(methanesulfonyl)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), 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 x 10 mL). The filtrate was then concentrated under reduced pressure. The residue was dissolved in EtOAc (60 mL), washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative-HPLC to give (R)-3-(5-(2,7-dimethyl-5-(1-((2-(methanesulfonyl)phenyl)amino)ethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrimidin-2-yl)-5-fluoro-2-methylpyridine 1-oxide as a grayish-white solid (11 mg, yield 2%). LCMS (ESI) + m / z = 574.4 (M+H);1 H NMR (400 MHz, DMSO- d 6): 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).

[0352] Example 93: (R)-3-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one Step 1: Preparation of (R)-3-chloro-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one To a stirred solution of (R)-5-(1-aminoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (intermediate 4, 1 g, 4.0 mmol) and 4-fluoro-1-iodo-2-(trifluoromethyl)benzene (1.73 g, 5.98 mmol) in 1,4-dioxane (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 mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by grinding with MeCN (30 mL) to give (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).

[0353] 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-dioxaborhecyclopentan-2-yl)isoquinoline-1(2H)-one Pd(dppf)Cl2 (71 mg, 0.097 mmol) and KOAc (285 mg, 2.91 mmol) were added to a stirred 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-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was then filtered, the filter cake was washed with DCM (2 x 20 mL), and the filtrate was concentrated under reduced pressure to give (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)isoquinoline-1(2H)-one (400 mg, crude yield), which was used directly in the next step without further purification. LCMS (ESI) + m / z = 505.2 (M+H).

[0354] Step 3: Preparation of (R)-3-(2-bromopyrimidin-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one Under a nitrogen atmosphere at room temperature, 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 to a stirred solution of (R)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborheoclav-2-yl)isoquinoline-1(2H)-one (400 mg, 0.79 mmol) in dioxane (10 mL) and H2O (2 mL). The resulting mixture was stirred at 90 °C for 2 hours. The mixture was filtered, and the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative-TLC (eluting with PE:EA = 1:1) to give (R)-3-(2-bromopyrimidin-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (190 mg, 35% yield) as a pale yellow solid. LCMS: (ESI) +m / z = 535.1 (M+H).

[0355] Step 4: Preparation of (R)-3-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one At room temperature, Na₂CO₃ (119 mg, 1.12 mmol) and Pd(PPh₃)₄ (43 mg, 0.037 mmol) were added to a stirred solution of (R)-3-(2-bromopyrimidin-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-dioxaborane-2-yl)pyrazin-2-one (intermediate 14, 140 mg, 0.56 mmol) in H₂O (0.5 mL) and 1,4-dioxane (2 mL). The resulting mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction was then quenched by adding water (5 mL) at 0 °C. The mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by preparative-HPLC to give (R)-3-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyrazin-2-yl)pyrimidin-5-yl)-5-(1-((4-fluoro-2-(trifluoromethyl)phenyl)amino)ethyl)-2,7-dimethylisoquinoline-1(2H)-one (4.3 mg, yield 2%) as a pale 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).

[0356] Examples 20 to 84, 94 to 955, 964, 967, 986, 989, 1022, 1025, 1044 to 1060, 1062, 1068, 1071, and 1072 are listed in Tables 1 and 2 below and were prepared in a manner similar to that described above for Examples 1 to 19 and 85 to 93. Unless otherwise stated, each chiral center illustrated is present as a mixture of (R)- and (S)-racemic mixtures or as (R)- or (S)-enantiomers, respectively. Each compound appearing in Table 1 is identified by both its chemical structure and name, but for the purposes of compound representation, greater weight should be given to the chemical structure.

[0357] Table 1. Examples 20 to 84 and 94 to 1170 Table 2. LCMS and NMR spectra of the examples selected from Table 1 Assays and Compound Testing In vitro cell proliferation: Measurements were performed on T47D cells expressing the mutant PI3Ka (H1047R) and those expressing WT... EC50 value of PI3Ka inhibiting proliferation in SKBR3 cells .

[0358] Trypsinize T47D or SKBR3 cells, resuspend in media and seed onto ready-to-use assay plates. T47D media consists of RPMI, 10% FBS and insulin (0.2 units / mL). SKBR3 media consists of McCoys 5a and 10% FBS. Cells are seeded at a density of 1,500 cells / well and dispensed at a volume of 50 μL onto 384-well ready-to-use assay plates (Corning, 89089-790). The ready-to-use assay plates have previously been spotted with 10-point dilutions of compounds of interest and controls. Compounds or DMSO are spotted onto the plate at a volume of 40 nL using an Echo655. Cells are grown at 37 °C and 5% CO2 for 72 hours. After 72 hours, the cells are equilibrated at room temperature for 15 minutes. 30 uL of CellTiter-Glo reagent is added to the plate and then shaken at 300 - 500 rpm for 30 minutes at room temperature. The cells are then read on an Envision microplate reader. The percentage of proliferation inhibition is calculated using the following formula: Inhibition % = 100 x (Lum D – Lum 样品 ) / (Lum D –Lum Inh ), where D is taken from cells treated with only 0.1% DMSO; Inh is taken from cells treated with 10 uM alpelisib. The effective concentration (EC50) to achieve 50% proliferation inhibition is calculated by curve fitting using Xlfit (v5.3.1.3), where the equation 201 is used: Y = Minimum + (Maximum - Minimum) / (1 + 10^((LogEC50 - X)*HillSlope)).

[0359] Reagent List reagents supplier Item number Cell Titer Glo 2.0 Assay 500 mL Promega G9243 Corning 384-hole, low flange, black flat bottom, polystyrene, TC-treated microplate, 10 pieces / bag, with cap, aseptic SKU: 3571 Corning 89089-790 PBS Solarbio P1020 0.4% trypan blue solution Fisher T10282 Fetal bovine serum, Australian origin Sigma 82051-458 Gibco RPMI 1640 medium Fisher 11875093 Gibco McCoy's 5A (modified) medium, HEPES Fisher 12330031 DMEM, high sugar, HEPES, phenol red-free Fisher 21063045 Recombinant human insulin, zinc solution Fisher 12585-014 For the EC50 values shown in Table 2, "A" refers to 1 nM < EC50 < 500 nM; "B" refers to 500 nM < EC50 < 2 μM; "C" refers to 2 μM < EC50 < 15 μM; and "D" refers to EC50 > 15 μM.

[0360] Table 3. Cell Proliferation Data Example # Average T-47D EC50 Average SKBR3 EC50 1 B C 2 B D 3 B D 4 D D 5 A C 6 B C 7 A C 8 A C 9 B D 10 - - 11 B C 12 A A 13 A B 14 A C 15 A B 16 A B 17 A C 18 B C 19 C C 20 C D 21 D D 22 A C 23 B C 24 B C 25 B C 26 B C 27 A C 28 C C 29 B C 30 A B 31 A B 32 A B 33 A D 34 A C 35 A C 36 A C 37 B C 38 C C 39 B C 40 B C 41 B C 42 B D 43 B C 44 B C 45 A C 46 B C 47 A C 48 A B 49 A B 50 A C 51 A C 52 A C 53 A C 54 A C 55 A C 56 C C 57 C C 58 A C 59 B C 60 B C 61 B C 62 A C 63 D C 64 C C 65 A B 66 A B 67 A C 68 A B 69 - - 70 A C 71 A B 72 A C 73 C D 74 C C 75 B C 76 B C 77 B D 78 C C 79 A C 80 B C 81 A C 82 A B 83 B C 84 B C 85 A C 86 A B 87 A B 88 A B 89 A B 90 A B 91 A B 92 A C 93 A B 94 A B 95 A C 96 A C 97 C D 98 A D 99 C D 100 C D 101 C C 102 C D 103 D D 104 D D 105 C D 106 D D 107 B D 108 D D 109 B C 110 B C 111 A C 112 A B 113 A B 114 B C 115 B D 116 A C 117 C D 118 B D 119 A C 120 B D 121 A C 122 C C 123 B D 124 B D 125 B D 126 A C 127 A C 128 A C 129 A C 130 C D 131 C D 132 B C 133 B D 134 D D 135 D D 136 A B 137 A B 138 A B 139 A A 140 A B 141 A B 142 A B 143 A B 144 A C 145 A C 146 B D 147 A C 148 A C 149 C C 150 A B 151 A B 152 C C 153 B C 154 A B 155 A C 156 A C 157 A C 158 B C 159 A B 160 A C 161 A C 162 A C 163 A C 164 A A 165 A B 166 A C 167 A B 168 A C 169 C C 170 A A 171 B C 172 B C 173 B C 174 A C 175 B C 176 A C 177 A C 178 A B 179 A B 180 A B 181 A C 182 B D 183 A C 184 A B 185 A B 186 A B 187 A B 188 A B 189 A A 190 A A 191 A C 192 C C 193 A B 194 A B 195 B D 196 A C 197 A B 198 A B 199 A A 200 A B 201 A B 202 B C 203 A C 204 B B 205 B B 206 B B 207 B B 208 B B 209 A C 210 A B 211 A B 212 A B 213 A B 214 A B 215 A A 216 A B 217 A C 218 A B 219 A B 220 A C 221 B C 222 A B 223 A B 224 A B 225 A B 226 A B 227 A B 228 A B 229 B B 230 A B 231 A B 232 A B 233 A B 234 A B 235 A B 236 A B 237 A B 238 A B 239 A B 240 A B 241 A C 242 B C 243 A C 244 A B 245 A C 246 A C 247 C D 248 A B 249 A B 250 A B 251 A B 252 A C 253 A A 254 A B 255 A B 256 A B 257 C D 258 A B 259 A B 260 A B 261 A B 262 B C 263 A B 264 A A 265 A B 266 D D 267 A A 268 A B 269 A B 270 A C 271 A C 272 A A 273 B C 274 B C 275 A C 276 A C 277 B D 278 A B 279 A C 280 A C 281 B C 282 C C 283 A B 284 A B 285 A B 286 A C 287 C D 288 A C 289 D D 290 A B 291 A C 292 A B 293 A B 294 A B 295 A A 296 D D 297 A B 298 A C 299 A A 300 A B 301 A C 302 A B 303 A C 304 A C 305 A C 306 A B 307 A A 308 A C 309 A C 310 A C 311 A B 312 A C 313 A C 314 A C 315 A C 316 A B 317 A C 318 A B 319 A C 320 A C 321 A C 322 A B 323 A C 324 A C 325 A C 326 A B 327 A B 328 A B 329 A B 330 A B 331 A B 332 A B 333 A B 334 A C 335 A C 336 A C 337 A C 338 A C 339 B D 340 A B 341 A B 342 A B 343 A C 344 A B 345 B C 346 A C 347 B C 348 A C 349 B D 350 A B 351 B D 352 A C 353 A B 354 A B 355 A C 356 A A 357 A A 358 A A 359 A C 360 A C 361 A C 362 A C 363 C C 364 A C 365 A B 366 A B 367 A C 368 A C 369 A C 370 A C 371 A C 372 A D 373 A D 374 B C 375 A C 376 D D 377 B C 378 A C 379 A C 380 A C 381 A B 382 A B 383 A B 384 A B 385 A A 386 A B 387 A B 388 A A 389 A B 390 A C 391 A C 392 A C 393 A A 394 A A 395 A A 396 A A 397 A C 398 A C 399 A C 400 A C 401 A B 402 A B 403 A B 404 A C 405 A C 406 A C 407 A B 408 B C 409 A C 410 B C 411 A C 412 A C 413 A A 414 A A 415 A B 416 A C 417 A C 418 A A 419 A A 420 A A 421 A B 422 A A 423 A A 424 A B 425 A B 426 A C 427 A B 428 A B 429 A B 430 A B 431 A C 432 A B 433 A B 434 A A 435 A B 436 A B 437 A A 438 A B 439 A C 440 A B 441 A B 442 A C 443 A C 444 A C 445 B C 446 B D 447 A C 448 A C 449 A B 450 A B 451 A A 452 A B 453 A B 454 A A 455 A B 456 A A 457 A B 458 A B 459 A B 460 A B 461 A A 462 A C 463 A B 464 A C 465 A C 466 A C 467 A A 468 A B 469 A B 470 A B 471 C D 472 A C 473 A C 474 A C 475 B C 476 B C 477 A B 478 A A 479 A A 480 A C 481 A B 482 A B 483 A B 484 A C 485 A A 486 A B 487 A A 488 A B 489 A C 490 A D 491 A C 492 A B 493 A B 494 A C 495 A B 496 A B 497 A C 498 A B 499 A B 500 A C 501 C C 502 C D 503 A B 504 C D 505 A C 506 A B 507 A A 508 A B 509 B D 510 B D 511 A B 512 C D 513 A B 514 B C 515 A B 516 A B 517 A B 518 A A 519 A B 520 B D 521 A D 522 B C 523 A C 524 A C 525 C D 526 B D 527 C C 528 A C 529 A B 530 A C 531 A C 532 B D 533 B C 534 C D 535 A C 536 D D 537 C C 538 A B 539 A D 540 B C 541 A C 542 A C 543 A C 544 A C 545 B D 546 C D 547 C C 548 A C 549 A B 550 A C 551 A B 552 B C 553 A B 554 A B 555 A B 556 A C 557 D D 558 A C 559 A C 560 A C 561 A B 562 B C 563 A C 564 B C 565 C C 566 B D 567 B D 568 A C 569 A C 570 A C 571 A C 572 A B 573 B D 574 B D 575 B C 576 A C 577 A C 578 C D 579 A A 580 C D 581 A C 582 A B 583 C D 584 C D 585 A C 586 C C 587 A C 588 A C 589 A C 590 B C 591 A C 592 B C 593 B C 594 A B 595 B C 596 B C 597 A B 598 C C 599 B C 600 C C 601 A C 602 A C 603 A B 604 A C 605 A C 606 A B 607 A C 608 C D 609 B D 610 A B 611 A C 612 B C 613 B C 614 A C 615 A C 616 B C 617 B D 618 C C 619 B C 620 B C 621 C C 622 A C 623 A D 624 B C 625 B C 626 A C 627 C C 628 A C 629 A C 630 D D 631 C C 632 A C 633 B C 634 A C 635 A C 636 A B 637 B C 638 A C 639 B C 640 A C 641 B C 642 A C 643 A C 644 A C 645 A B 646 A A 647 C C 648 A C 649 A C 650 A C 651 A B 652 B D 653 B C 654 A B 655 A B 656 C C 657 A B 658 B C 659 C C 660 A C 661 B C 662 A C 663 A C 664 A C 665 A C 666 B C 667 A C 668 A C 669 A C 670 A C 671 A C 672 A C 673 A B 674 A B 675 A B 676 A B 677 B C 678 A C 679 A C 680 A B 681 B C 682 B C 683 A B 684 B C 685 A C 686 A C 687 A B 688 A B 689 A B 690 A C 691 A B 692 A B 693 A B 694 A B 695 A B 696 A A 697 A B 698 A C 699 A C 700 A B 701 A C 702 A C 703 A C 704 A C 705 A C 706 A B 707 A B 708 A B 709 B C 710 B C 711 A C 712 A C 713 A C 714 A C 715 A B 716 A C 717 A C 718 A C 719 A B 720 A C 721 A B 722 A C 723 A B 724 A B 725 A B 726 B C 727 A B 728 A C 729 A C 730 A B 731 A C 732 A C 733 A C 734 A C 735 A B 736 A B 737 B C 738 A B 739 A B 740 A C 741 A C 742 A C 743 A C 744 B C 745 B C 746 A C 747 A B 748 A C 749 A B 750 A B 751 A C 752 B C 753 C C 754 C D 755 C C 756 A C 757 A B 758 A C 759 B C 760 A C 761 A B 762 B C 763 B C 764 A B 765 A B 766 B B 767 A B 768 A C 769 A A 770 A B 771 A A 772 A B 773 A B 774 A C 775 B B 776 A C 777 A C 778 A C 779 A B 780 A C 781 A B 782 C C 783 A C 784 A C 785 A C 786 A C 787 A C 788 B C 789 A C 790 A B 791 C D 792 A C 793 A C 794 C C 795 B C 796 B C 797 A C 798 A C 799 A B 800 A B 801 A C 802 A B 803 A C 804 A C 805 A C 806 A B 807 A D 808 A C 809 A C 810 A A 811 A B 812 A B 813 A B 814 A B 815 A C 816 A B 817 C C 818 A B 819 A B 820 A C 821 A C 822 A B 823 B C 824 C C 825 A C 826 A B 827 A C 828 A C 829 A B 830 A A 831 A C 832 A C 833 B C 834 A C 835 A C 836 A C 837 A B 838 A A 839 B D 840 B C 841 A C 842 A B 843 A C 844 A C 845 A B 846 A C 847 A C 848 A C 849 A C 850 A C 851 A C 852 A C 853 A B 854 A C 855 A B 856 A C 857 A C 858 A B 859 A A 860 A A 861 A C 862 A C 863 A B 864 A B 865 A C 866 A B 867 A B 868 A C 869 A C 870 A A 871 A C 872 A C 873 A B 874 A B 875 A C 876 A C 877 B B 878 A C 879 A B 880 C D 881 A B 882 A C 883 A C 884 A C 885 A B 886 A B 887 A A 888 A A 889 A B 890 B C 891 C D 892 A B 893 A B 894 A D 895 A B 896 A B 897 A B 898 A B 899 A C 900 D C 901 D D 902 A B 903 A B 904 A C 905 A C 906 A C 907 A C 908 A B 909 A B 910 A B 911 B D 912 B C 913 A C 914 A B 915 A B 916 A B 917 A C 918 B C 919 C D 920 A B 921 A C 922 A C 923 A C 924 A B 925 A C 926 A B 927 A C 928 A B 929 A C 930 B C 931 A C 932 A C 933 A C 934 A C 935 A C 936 A C 937 A C 938 A C 939 A A 940 A C 941 A D 942 A B 943 A A 944 A A 945 A B 946 B D 947 A C 948 A C 949 A C 950 A C 951 A C 952 A B 953 A A 954 B C 955 A C 1044 A C 1045 B D 1046 A C 1047 A C 1048 A C 1049 A C 1050 A C In vitro cellular pKAT: Determine the IC50 values for the inhibition of AKT phosphorylation (pAKT) in T47D cells expressing the mutant PI3Ka (H1047R) mutation and SKBR3 cells expressing WT PI3Ka.

[0361] Trypsinize T47D or SKBR3 cells, resuspend in medium and seed onto ready-to-use assay plates. T47D medium consists of RPMI, 10% FBS and insulin (0.2 units / mL). SKBR3 medium consists of McCoy’s 5a and 10% FBS. Cells are seeded at a density of 5000 cells / well and dispensed at a volume of 12.5 μL onto 384-well ready-to-use assay plates (Perkin Elmer, 6008238)). The ready-to-use assay plates have previously been spotted with 10-point dilutions of compounds of interest and controls. Use an Echo655 to spot compounds or DMSO onto the plate at a volume of 12.5 nL. Cells are grown at 37 °C and 5% CO2 for 6 hours. After 6 hours, add 4 μL of lysis buffer reagent to the plate and then centrifuge at 1000 rpm for 1 minute. Then incubate the plate at room temperature for 30 minutes. After 30 minutes, add 4 μL of antibody mixture to the plate, which consists of Eu cryptate, d2 cryptate and detection buffer. Centrifuge the plate at 1000 rpm and then incubate overnight at room temperature. Read the plate on an Envision microplate reader using the HTRF protocol. Calculate the percentage of AKT phosphorylation inhibition using the following formula: % Inhibition = 100 x (pAKT HC – pAKT Sample) / (pAKT HC – pAKT LC)), where pAKT HC is taken from cells treated with only 0.1% DMSO; pAKT LC is taken from cells treated with 10 μM alpelisib. The IC50 (concentration to achieve 50% pAKT inhibition) is calculated by curve fitting using Xlfit (v5.3.1.3), where Equation 201 is used: Y = Minimum + (Maximum - Minimum) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0362] Reagent table reagents supplier Item number Gibco RPMI 1640 medium, phenol red-free Fisher 11835030 Gibco RPMI 1640 medium Fisher 11875093 McCoy's 5A (modified) medium, HEPES Fisher 12330031 DMEM, high sugar, HEPES, phenol red-free Fisher 21063045 Gibco trypsin-EDTA (0.5%), phenol red-free Fisher 15400054 PBS Solarbio P1020 0.4% trypan blue solution Fisher T10282 Fetal bovine serum, Australian origin Sigma 82051-458 ProxiPlate-384 Plus, white, TC treated, 160 pieces / box Perkin Elmer 6008238 pAKT (Ser473) HTRF Cisbio 64AKSPEH For the IC50 values shown in Table 3, “A” refers to 1 nM < IC50 < 500 nM; “B” refers to 500 nM < IC50 < 2 μM; “C” refers to 2 μM < IC50 < 15 μM; and “D” refers to IC50 > 15 μM.

[0363] Table 4. Cellular pAKT data Example # Average T-47D IC50 Average SKBR3 IC50 1 A C 2 C D 3 C D 4 D D 5 A C 6 A C 7 A C 8 A B 9 A D 10 - - 11 A C 12 A A 13 A B 14 A C 15 A B 16 A A 17 A B 18 A C 19 C D 20 - - 21 - - 22 A C 23 A C 24 A C 25 A C 26 A C 27 A B 28 D D 29 A C 30 A A 31 A C 32 A B 33 A D 34 A C 35 A B 36 A C 37 C C 38 C D 39 B C 40 A C 41 A C 42 B D 43 A C 44 A C 45 A C 46 A C 47 A C 48 A A 49 A A 50 A C 51 A C 52 A B 53 A C 54 A C 55 A B 56 D D 57 D D 58 A B 59 B C 60 B C 61 B C 62 A B 63 D D 64 D D 65 A B 66 A B 67 A C 68 A C 69 - - 70 A C 71 A A 72 A B 73 B D 74 C D 75 A C 76 A C 77 A C 78 B D 79 A C 80 A C 81 A C 82 A C 83 B C 84 B D 85 A B 86 A A 87 A A 88 A B 89 A B 90 A A 91 A A 92 A B 93 A A 94 A A 95 A B 96 A B 97 C D 98 A C 99 C D 100 C D 101 C D 102 C D 103 C D 104 C D 105 C D 106 C D 107 B D 108 C D 109 B C 110 B C 111 A C 112 A B 113 A B 114 A C 115 B C 116 A B 117 C D 118 B C 119 A C 120 B D 121 A C 122 B D 123 B D 124 B D 125 B D 126 A C 127 A C 128 A C 129 A C 130 C D 131 C D 132 B C 133 B C 134 C D 135 D D 136 A A 137 A A 138 A A 139 A A 140 A A 141 A A 142 A A 143 A A 144 A A 145 A B 146 A C 147 A A 148 A B 149 C D 150 A A 151 A B 152 B C 153 B C 154 A A 155 A B 156 A B 157 A B 158 A C 159 A A 160 A B 161 A B 162 A B 163 A B 164 A A 165 A C 166 A C 167 A A 168 A C 169 C D 170 A A 171 B C 172 B C 173 B C 174 A B 175 A C 176 A B 177 A A 178 A B 179 A B 180 A B 181 A C 182 B D 183 B C 184 A A 185 A A 186 A A 187 A A 188 A A 189 A A 190 A A 191 A C 192 C D 193 A A 194 A B 195 B C 196 A B 197 A B 198 A A 199 A A 200 A B 201 A B 202 A C 203 A B 204 B B 205 B B 206 B B 207 A B 208 A B 209 A C 210 A B 211 A B 212 A B 213 A A 214 A A 215 A A 216 A A 217 A B 218 B B 219 A A 220 A B 221 B D 222 A B 223 A A 224 A A 225 A B 226 A B 227 A B 228 A B 229 A B 230 A B 231 A A 232 A B 233 A B 234 A B 235 A B 236 A A 237 A A 238 A B 239 A A 240 A A 241 A C 242 A C 243 A B 244 A A 245 A B 246 A B 247 B C 248 A C 249 A A 250 A A 251 A A 252 A C 253 A A 254 A B 255 A A 256 A A 257 B D 258 A A 259 A A 260 A A 261 A A 262 A C 263 A B 264 A A 265 A A 266 D D 267 A A 268 A B 269 A A 270 A C 271 A C 272 A A 273 A C 274 A C 275 A C 276 A C 277 A C 278 A A 279 A A 280 A C 281 A C 282 B C 283 A B 284 A B 285 A A 286 A C 287 D D 288 A B 289 D D 290 A A 291 A A 292 A A 293 A A 294 A A 295 A A 296 D D 297 A B 298 A C 299 A A 300 A A 301 A B 302 A B 303 A B 304 A C 305 C D 306 A A 307 A A 308 A C 309 A B 310 A B 311 A B 312 A B 313 A B 314 A B 315 A B 316 A A 317 A A 318 A A 319 A A 320 A A 321 A A 322 A A 323 A B 324 A B 325 A C 326 A A 327 A A 328 A A 329 A A 330 A A 331 A A 332 A A 333 A A 334 A B 335 A C 336 A B 337 A C 338 A B 339 A D 340 A A 341 A B 342 A B 343 A B 344 A B 345 A D 346 B C 347 A D 348 A C 349 B D 350 A A 351 B D 352 A B 353 A A 354 A A 355 A B 356 A A 357 A A 358 A A 359 A B 360 A C 361 A A 362 A C 363 B D 364 A C 365 A A 366 A A 367 A B 368 A C 369 A B 370 A B 371 A B 372 A B 373 A B 374 A C 375 A C 376 D D 377 A C 378 A C 379 A C 380 A B 381 A A 382 A A 383 A A 384 A A 385 A A 386 A A 387 A A 388 A A 389 A B 390 A B 391 A A 392 A B 393 A A 394 A A 395 A A 396 A A 397 A B 398 A B 399 A B 400 A B 401 A A 402 A A 403 A A 404 A C 405 A A 406 A B 407 A A 408 A C 409 A C 410 A C 411 A C 412 A B 413 A A 414 A A 415 A A 416 A B 417 A C 418 A A 419 A A 420 A A 421 A A 422 A A 423 A A 424 A A 425 A A 426 A A 427 A A 428 A A 429 A A 430 A B 431 A B 432 A A 433 A B 434 A A 435 A A 436 A B 437 A A 438 A A 439 A B 440 A A 441 A A 442 A C 443 A B 444 A B 445 A D 446 A C 447 A C 448 A B 449 A A 450 A A 451 A A 452 A A 453 A A 454 A A 455 A A 456 A B 457 A B 458 A A 459 A A 460 A A 461 A A 462 A B 463 A A 464 A B 465 A C 466 A C 467 A A 468 A B 469 A A 470 A A 471 C D 472 A B 473 A B 474 A C 475 A C 476 A C 477 A A 478 A A 479 A A 480 A B 481 A A 482 A B 483 A A 484 A B 485 A A 486 A B 487 A A 488 A B 489 A B 490 A C 491 A C 492 A A 493 A A 494 A C 495 A A 496 A B 497 A B 498 A A 499 A B 500 A B 501 C D 502 B D 503 A A 504 C D 505 A C 506 A B 507 A A 508 A A 509 A D 510 A D 511 A A 512 B D 513 A C 514 A C 515 A A 516 A A 517 A A 518 A A 519 A A 520 B D 521 A C 522 B C 523 A C 524 A B 525 B D 526 A D 527 B D 528 A A 529 A A 530 A A 531 A C 532 A D 533 A C 534 B D 535 A C 536 D D 537 D D 538 A B 539 A D 540 A C 541 A C 542 A C 543 A C 544 A C 545 B D 546 B D 547 A C 548 A B 549 A A 550 A B 551 A C 552 A C 553 A A 554 A A 555 A A 556 A B 557 D D 558 A B 559 A C 560 A B 561 A A 562 A D 563 A C 564 A C 565 B D 566 B D 567 B D 568 A C 569 A C 570 A B 571 A B 572 A B 573 A C 574 A C 575 A B 576 A B 577 A C 578 B D 579 A A 580 D D 581 A B 582 A A 583 C D 584 B D 585 A C 586 B C 587 A B 588 A C 589 A B 590 A C 591 A B 592 A D 593 A C 594 A A 595 A C 596 A C 597 A B 598 D C 599 A C 600 B D 601 A B 602 A C 603 A B 604 A A 605 A C 606 A A 607 A B 608 B D 609 B D 610 A B 611 A B 612 A C 613 A D 614 A C 615 A B 616 A C 617 A D 618 D D 619 A C 620 A C 621 B C 622 A B 623 A B 624 A C 625 A C 626 A B 627 B C 628 A B 629 A C 630 B D 631 C C 632 A C 633 A C 634 A C 635 A C 636 A C 637 A C 638 A C 639 A C 640 A B 641 A C 642 A C 643 A C 644 A C 645 A A 646 A A 647 D D 648 A B 649 A C 650 A B 651 A B 652 B C 653 A C 654 A B 655 A B 656 D D 657 A B 658 A C 659 D D 660 A C 661 A C 662 A C 663 A C 664 A B 665 A B 666 A C 667 A B 668 A B 669 A C 670 A C 671 A C 672 A B 673 A B 674 A A 675 A B 676 A A 677 B D 678 A C 679 A C 680 A B 681 A C 682 A D 683 A B 684 A C 685 A B 686 A C 687 A B 688 A B 689 A B 690 A B 691 A B 692 A A 693 A A 694 A C 695 A A 696 A A 697 A B 698 A C 699 A C 700 A C 701 A C 702 A C 703 A B 704 A B 705 A B 706 A B 707 C C 708 A B 709 A D 710 A D 711 A B 712 A B 713 A B 714 A A 715 A A 716 A B 717 A B 718 A B 719 A B 720 A B 721 A C 722 A C 723 A B 724 A B 725 A B 726 A D 727 A C 728 A C 729 A C 730 A B 731 A C 732 A B 733 A A 734 A B 735 A C 736 A C 737 A D 738 A A 739 A A 740 A B 741 A B 742 A C 743 A B 744 A C 745 A C 746 A B 747 A B 748 A B 749 A A 750 A B 751 A B 752 B D 753 C D 754 C D 755 C D 756 A B 757 A A 758 A C 759 A D 760 A C 761 A B 762 A C 763 A C 764 A B 765 A B 766 A C 767 A B 768 A C 769 A A 770 A A 771 A A 772 A B 773 A B 774 A C 775 D D 776 A C 777 A B 778 A B 779 A A 780 A B 781 A A 782 C D 783 A A 784 A B 785 A C 786 A B 787 A B 788 A C 789 A C 790 A B 791 B D 792 A B 793 A B 794 C D 795 A C 796 A C 797 A B 798 A B 799 A A 800 A B 801 A B 802 A A 803 A B 804 A C 805 A C 806 A A 807 A C 808 A C 809 A C 810 A A 811 A B 812 A A 813 A B 814 A A 815 A A 816 A A 817 C D 818 A B 819 A A 820 A C 821 A B 822 A A 823 B D 824 B D 825 A A 826 A B 827 A B 828 A B 829 A B 830 A A 831 A B 832 A A 833 B C 834 A B 835 A B 836 A B 837 A A 838 A A 839 B D 840 B D 841 A A 842 A A 843 A C 844 A C 845 A A 846 A B 847 A C 848 A B 849 A B 850 A C 851 A B 852 A B 853 A B 854 A B 855 A B 856 A B 857 A C 858 A B 859 A A 860 A A 861 A B 862 A C 863 A A 864 A A 865 A B 866 A A 867 A A 868 A B 869 A A 870 A A 871 A B 872 A C 873 A A 874 A B 875 A B 876 A B 877 A B 878 A B 879 A A 880 B D 881 A A 882 A A 883 A A 884 A B 885 A A 886 A A 887 A A 888 A A 889 A A 890 A C 891 B D 892 A A 893 A A 894 A B 895 A B 896 A B 897 A B 898 A A 899 A B 900 D D 901 D D 902 A A 903 A A 904 A B 905 A C 906 A B 907 A B 908 A B 909 A A 910 A A 911 A A 912 A B 913 A B 914 A A 915 A A 916 A A 917 A B 918 A C 919 B D 920 A B 921 A B 922 A B 923 A B 924 A A 925 A C 926 A A 927 A B 928 A A 929 A B 930 A C 931 A C 932 A A 933 A B 934 A B 935 A A 936 A B 937 A C 938 A B 939 A A 940 A B 941 A B 942 A A 943 A A 944 A A 945 A A 946 A C 947 A B 948 A A 949 A C 950 A B 951 A A 952 A A 953 D D 954 A C 955 A C 967 A A 986 A C 989 A B 1044 A B 1045 A D 1046 A D 1047 A C 1048 A B 1049 A C 1050 A B 1051 A A 1052 A C 1053 A A 1054 A B 1055 A A 1056 A B 1057 A A 1058 A B 1059 A A References Ali, K., Bilancio, A., Thomas, M., Pearce, W., Gilfillan, A. 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Claims

1. A compound of formula (1) Or its solvates, enantiomers, diastereomers, tautomers, polymorphs, or isotopically labeled compounds, or pharmaceutically acceptable salts thereof. in: R1 is selected from ； Each A is independently a 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 groups, (CH2) 0-5 -Aryl, (CH2) 0-5 -Heteroaryl, (CH2) 0-5 -Heterocyclic group, (CH2) 0-5 -NR a -(CH2) 0-5 -Heteroaryl or (CH2) 0-5 -NR a -(CH2) 1-5 -N-heterocyclic group, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are substituted or unsubstituted, or alternatively, A and A together with the attached -P(=O)- portion may form a substituted or unsubstituted heterocyclic ring; 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 -Aryl, (CH2) 0-5 -Heteroaryl, (CH2) 0-5 -Heterocyclic group, (CH2) 0-5 -C(O)-(CH2) 1-5 -O-C1-C4 alkyl group, (CH2) 1-5 -NR a -(CH2) 0-5 -Heteroaryl or (CH2) 1-5 -NR a -(CH2) 2-5 -N-heterocyclic group, OC 1-5 -alkyl, OC 0-5 -cycloalkyl, OC 0-5 - Heterocyclic group, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are substituted or unsubstituted, or alternatively, B and B together with the attached -[O or NH]-P(=O)-O- portion can form a substituted or unsubstituted heterocyclic ring, or alternatively, A and B together with the attached -P(=O)-O- portion can form a substituted or unsubstituted heterocyclic ring; Each R a Independently, it can be H, C1-C4 alkyl, C3-C7 cycloalkyl, C(O)C1-C3 alkyl, or (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, wherein the alkyl and cycloalkyl groups are substituted or unsubstituted, or alternatively, for -S(=O)(A)(=NR) a ) or for -S(=O)(A)(NR a ), R a A, together with the atoms it is attached to, can form substituted or unsubstituted heterocyclic rings; R2 is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF3, CFH2 or CF2H, and wherein R2 is not H, the carbon atom attached to R2 is a chiral center and exists as a racemic mixture of (R)- and (S)- or as an enantiomer of (R)- or (S)-. R3 is H or a C1-C4 alkyl group; 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 group, 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, and X3 is independently N, CH, or a substituted C; X4 is CH or a 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 , in: Each of L1, L2, L3, L6, and L7 is independently (CHR) 11 (CHR) 11 -O), (CHR) 11 -S), (C3-C7 cycloalkyl), (CH2) 1-4 OR key; L4 represents 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, heterocyclic, aryl, or heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted; or alternatively, when NR is present 10 At that time, R9 and R 10 Together with the nitrogen atom to which it is attached, it can form substituted or unsubstituted rings; R 10 and R 11 Each of them is independently H or a C1-C4 alkyl group (such as CH3, CH2CH3 or CH(CH3)2), wherein the C1-C4 alkyl group is unsubstituted or substituted; R 12 and R 13 Each of these is independently H, C1-C6 alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each of the C1-C6 alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted; or alternatively, R 12 and R 13 Together with the nitrogen atom to which it is attached, it can form substituted or unsubstituted rings; L8 is (CHR) 15 (CHR) 15 -O), (CHR) 15 -S), (CHR) 15 -NR 16 ), C=O, C=S or bond; L9 is a C3-C7 cycloalkyl group (optionally part of a bridged ring, fused ring, or spirocyclic system), C(R 15 )=C(R 15 ), C≡C or key; L 10 Independently for (CHR) 15 ), O, S, (NCR) 15 ), N (C=O) or bond; L 11 For (CHR) 15 ), C=O, C=S or bond; L 12 The C3-C7 cycloalkyl, heterocyclic, aryl, heteroaryl or bond is H, (C3-C7 cycloalkyl), heterocyclic, aryl or heteroaryl, each of which is unsubstituted or substituted, and the C3-C7 cycloalkyl and / or heterocyclic is optionally part of a bridged ring, fused ring or spirocyclic system. R 14 For H, CR 15 R 16 R 17 OR 17 SR 17 NR 16 R 17 The group comprises C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted. R 15 and R 16 Each of them is independently H or a C1-C3 alkyl group; and Each R 17 Independently, it is H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is unsubstituted or substituted; or alternatively, R 16 and R 17 Together with the nitrogen atom it is attached to, it can form substituted or unsubstituted rings. The premise is that R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 At that time, L8, L9, L 10 L 11 L 12 and R 14 At least one of them is a carbon-containing part and R5 is directly connected to the (isoquinolone) core structure through a carbon atom; Or R5 is a non-aromatic N-linked heterocyclic ring. The heterocyclic ring is substituted or unsubstituted, optionally contains one or more additional ring atoms selected from N, O, Si and S, and optionally is part of a bridged ring, fused ring or spirocyclic system.

2. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R5 is -(NR) 10 )-L1-L2-L3-L4-L5-L6-L7-R9, where L1 to L7, R9 and R 10 As defined.

3. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein R5 is -O-L1-L2-L3-L4-L5-L6-L7-R9, wherein L1 to L7 and R9 are as defined.

4. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein 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, wherein L1 to L7 and R9 are as defined.

5. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 L8 to L 12 and R 14 As defined.

6. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R5 is a non-aromatic N-linked heterocyclic ring. The heterocyclic base ring is substituted or unsubstituted, optionally contains one or more additional ring atoms selected from N, O, Si and S, and optionally is part of a bridged ring, fused ring or spiro ring system.

7. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R1 is selected from... Where A and B are as defined in claim 1.

8. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R1 is selected from... Among them, A, B and R a As defined in claim 1.

9. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R1 is selected from... Wherein B is as defined in claim 1.

10. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X4 is CH or CF.

11. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein R2 is CH3 or CH2F.

12. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein R3 is H.

13. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X1 is N, and X2 and X3 are independently CH or substituted C.

14. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X2 is N, and X1 and X3 are independently CH or substituted C.

15. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X3 is N, and X1 and X3 are independently CH or substituted C.

16. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X1 and X3 are N, and X2 is CH or a substituted C.

17. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X1 and X2 are N, and X3 is CH or a substituted C.

18. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X2 and X3 are N, and X1 is CH or a substituted C.

19. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X1, X2 and X3 are N.

20. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein X1, X2 and X3 are independently CH or substituted C.

21. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein R2 is CH3 or CH2F, R3 is H and X4 is N.

22. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein R2 is CH3 or CH2F, R3 is H and X4 is CH or CF.

23. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R2 is CH3 or CH2F, R3 is H, and R5 is -L8-L9-L. 10 -L 11 -L 12 -R 14 .

24. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein R2 is CH3 or CH2F, R3 is H and R5 is -O-L1-L2-L3-L4-L5-L6-L7-R9.

25. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 1, wherein R2 is CH3 or CH2F, R3 is H and R5 is -S-L1-L2-L3-L4-L5-L6-L7-R9.

26. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R2 is CH3 or CH2F, R3 is H, and R5 is -(NR) 10 )-L1-L2-L3-L4-L5-L6-L7-R9.

27. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein X4 is CH, R2 is CH3 or CH2F, R3 is H, and R5 is -L8-L9-L 10 -L 11 -L 12 -R 14 .

28. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound of formula (1) is a compound of formula (2). Or a solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof. in: X1, X2, X3, R1, and R5 are defined in the compounds as shown in formula (1), and Carbons marked with * are chiral centers and exist as a mixture of (R)- and (S)- racemic compounds or as (R)- or (S)- enantiomers.

29. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound, or pharmaceutically acceptable salt thereof, according to claim 28, wherein each of X1, X2 and X3 is independently CH or CF.

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

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

32. The pharmaceutical composition according to claim 31, wherein the one or more anticancer agents are selected from cyclophosphamide, dacarbazine, cisplatin, methotrexate, mercaptopurine, thioguanine, fluorouracil, cytarabine, vinblastine, paclitaxel, doxorubicin, bleomycin, mitomycin, prednisone, tamoxifen, flutamide, asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, amifostine, camptothecin, topotecan, thalidomide, lenalidomide, CDK inhibitors, and proteasome inhibitors.

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

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

35. The method of claim 33, wherein the disease is congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome (CLOVES), chimeric tissue overgrowth syndrome, venous malformation, and brain malformation associated with severe epilepsy or PIK3CA-associated overgrowth syndrome (PROS).

36. The method of claim 33, wherein the disease is cancer carrying the PI3Kα H1047R mutation.

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