Benzopyrimidin-4(3H)-one as a PI3K inhibitor

Abstract

A novel PI3K inhibitor of general formula (1) is described together with its manufacturing method and its use in the treatment of diseases associated with PI3K pathway upregulation or activation. JPEG2025519540000090.jpg7785[wherein, R1 to R8 are as defined.]

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority based on U.S. Provisional Application 63 / 350,234 filed on June 8, 2022, the content of which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] Background of the Invention Phosphatidylinositol lipids (PI) and their various phosphorylated subtypes are second messengers involved in diverse cellular vesicle trafficking and signaling processes. Phosphoinositide 3'-kinase (PI3K) is a group of enzymes responsible for phosphorylating the 3'-hydroxyl position of the inositol ring of PI. PI3K is subclassified into three classes according to structure and substrate. Class II PI3Ks (PI3K - C2α, PI3K - C2β, PI3K - C2γ) and class III PI3K (vps34) are monomeric enzymes mainly 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 consisting of one catalytic kinase subunit (p110α, β, γ, δ) and two regulatory subunits that determine binding partners and intracellular localization. Class I PI3Ks are activated by interaction with receptor tyrosine kinases (RTKs), Ras - related GTPases, G - protein - coupled receptors and / or associated adapter proteins, and in the active form, convert phosphatidylinositol 4,5 - bisphosphate (PIP2) to phosphatidylinositol 3,4,5 - trisphosphate (PIP3) (Fruman et al., Cell 2017, 170, 605).

[0003] High local concentrations of PIP3 promote the recruitment and activation of downstream signaling partners, including AKT and mTOR. Activation of the AKT / mTOR pathway is involved in several growth-related roles and pathologies, including glucose control, cell survival, angiogenesis, and proliferation (Porta et al., Front Oncol. 2014, 4, 1), indicating its role as an important upstream regulator of these functions of class I PI3K.

[0004] Class I PI3Ks are further subdivided into four isoforms (α, β, γ, and δ) based on the identity of their catalytic (p110α, p110β, p110γ, or p110δ) and regulatory (p85α or its various splice variants, p85β, p55γ, or p101) subunits, which give rise to different roles in cell physiology (Vanhaesebroeck et al., J Mol Med (Berl). 2016, 94, 5). PI3Kγ and PI3Kδ are expressed mostly in leukocytes and have 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 ubiquitously expressed and share 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 have a specific function in platelet aggregation (Liu et. al., Nat Rev Drug Discov. 2009, 8, 627; Jackson et al., Nat Med. 2005, 11, 507).

[0005] Elevated or constitutive activation of the PI3K pathway is one of the most frequent events in human cancers. The PI3K pathway is hyperactivated through diverse mechanisms, including activating mutations of PI3K isoforms, upregulation of PI3K isoforms, loss or inactivation of the tumor suppressor PTEN, or hyperactivation of tyrosine kinase growth factor receptors or other upstream signaling partners (Yang et al., Mol Cancer 2019, 18, 1). Mutations in the gene encoding PI3Kα or mutations leading to upregulation of PI3Kα have been found to occur in many 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, PIK3CA, the gene encoding the p110α subunit of PI3Kα, is often mutated or amplified in diverse tumor types. Missense mutations occur throughout the entire domain of p110α but cluster at two 'hot spots', the most common being E542K and E545K in the helical domain and H1047R in the kinase domain. Helical domain mutations reduce the inhibition of p110α by p85 or promote the interaction of p110α with insulin receptor substrate 1 (IRS1) 37, while kinase domain mutations increase the interaction of 110α with the lipid membrane, accompanied by upregulation of signaling events (Thorpe et al., Nat Rev Cancer 2015, 15, 7).

[0006] The development of PI3K pathway inhibitors is highly challenging because it is impossible to achieve a dosage sufficient to achieve tumor suppression without adverse events. To date, clinically available 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 as on-target toxicities. Hyperglycemia is the result of the body's inability to produce sufficient insulin or abnormal utilization. The pancreas controls insulin release in response to changes in blood glucose levels, causing either glucose uptake by muscle and fat cells when insulin levels are high or gluconeogenesis by the liver when insulin levels are low. The tissue cell response to insulin requires PI3K signaling via the ubiquitously expressed p110α subunit. As a result, pan-PI3K inhibition of the target disrupts tissue glucose metabolism and leads to insulin resistance (Hopkins et al., Nature 2018, 560, 499). To reduce adverse events, selective PI3K isoform inhibitors have been developed. The severity of adverse events depends on the selected isoform. For example, PI3Kα inhibitors are associated with hyperglycemia and rash due to the role of the p110α subunit in insulin response (Rugo et al., The Breast 2022, 61, 156). Similarly, the use of a selective PI3Kδ inhibitor (idelalisib) in which the p110δ subunit is highly expressed in immune cells causes severe diarrhea and colitis. Inhibition with a dual inhibitor (taselisib), a potent PI3Kδ inhibitor with moderate PI3Kα inhibition, causes gastrointestinal (GI) side effects, but no GI-related adverse events have been reported with a highly selective and potent PI3Kδ inhibitor (umbralisib) (Gadkar et al., CPT Pharmacometrics Syst Pharmacol. 2021, 11, 616). Such improvement in adverse events with highly isoform-selective and potent inhibitors indicates that the strategy of toxicity reduction by developing mutant-selective isoform inhibitors is promising for reducing the severity of toxicity.Furthermore, the selective inhibition of mutant PI3Kα isoforms beyond the wild type has minimal impact on PI3K signaling in healthy cells that carry only wild-type PI3Kα, can suppress cancer signaling, and leads to a reduction in the toxicity associated with non-selective PI3K inhibition (Castel et al., Nat Cancer 2021 2, 587). Summary of the Invention Problems to be Solved by the Invention

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

[0008] Summary of the Invention One aspect of the present invention is of formula (1)

Chemical formula

【In the formula, R1 is H, C1-C4 alkyl, or C3-C7 cycloalkyl; Each R2 is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, R 14 -C≡C-, halogen, CN, CF3, OCF3, CFH2, or CF2H; R3 is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF3, CFH2, or CF2H. When R3 is not H, the carbon atom bonded to R3 is a chiral center and exists as a (R)- and (S)-racemic mixture or (R)- or (S)-enantiomer; R4 is H or C1-C4 alkyl; R6 is H, C1-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, CF3, CFH2, or CF2H; R7 is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, OCH3, CFH2 or CF2H; R8 is H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF3, OCF3, OCH3, CFH2 or CF2H; R5 is -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; or -(NR 10 )-L1-L2-L3-L4-L5-L6-L7-R9 where: Here: Each of L1, L2, L3, L6 and L7 is independently (CHR 11 ), (CHR 11 -O), (CHR 11 -S), (C3-C7 cycloalkyl) or a bond; L4 is C=O, C=S or a bond; L5 is NR 10 , S, O or a bond; R9 is H, C(=O)R 12 , C(=O)NR 12 R 13 , C(=O)OR 12 , C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or when NR 10 is present, R9 and R 10 may combine with the attached nitrogen atom to form a substituted or unsubstituted ring.]] It is a compound or its solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the ring is a 4- to 7-membered substituted or unsubstituted non-aromatic heterocyclic ring containing 0, 1 or 2 heteroatoms (in addition to nitrogen atoms) which can be N, O, S or Si, provided that if the ring size is 4 or 5, the number of additional heteroatoms is 0 or 1, if the ring size is 6-7, the number of additional heteroatoms is 0, 1 or 2, and if the ring is substituted, the substituents include one or more of CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxetane ring or COR a including but not limited to one or more of these, where R a is C1-C4 alkyl, O-C1-C4 alkyl or NR b R c where R b and R c are independently H or C1-C4 alkyl; R 10 and R 11 each is H or C1-C4 alkyl, where C1-C4 alkyl is unsubstituted or substituted; and R 12 and R 13 each is independently H or C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted; or R 12 and R 13can combine with the attached nitrogen atom to form a substituted or unsubstituted ring. In an exemplary embodiment, the ring is a 4- to 7-membered substituted or unsubstituted non-aromatic heterocyclic ring containing 0, 1, or 2 heteroatoms (in addition to the nitrogen atom) which can be N, O, S, or Si, provided that if the ring size is 4 or 5, the number of additional heteroatoms is 0 or 1, and if the ring size is 6-7, the number of additional heteroatoms is 0, 1, or 2, and if the ring is substituted, the substituents include one or more of CH3, F, Cl, CF3, CF2H, CH2F, OCH3, cyclopropyl, CH2CF3, oxetane ring, or COR a including but not limited to one or more of these, where R a is C1-C4 alkyl, O-C1-C4 alkyl, or NR b R c where R b and R c are independently H or C1-C4 alkyl; and each R 14 is independently H, C1-C3 alkyl, or C3-C7 cycloalkyl; or R5 is a non-aromatic N-bonded heterocyclic ring

Chemical formula

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

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

[0011] In an exemplary embodiment, 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 above.

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

[0013] In an exemplary embodiment, R5 is

Chemical formula

[0014] In an exemplary embodiment, R5 is an N-bonded non-aromatic heterocyclic ring [Chemical formula] where the heterocyclic ring is substituted or unsubstituted and optionally contains one or more additional atoms selected from N (where N is substituted or unsubstituted), O, Si (where Si is substituted or unsubstituted) and S (where S is oxidized or unoxidized), and is optionally part of a bridged, fused or spiro ring system.

[0015] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is not part of a bridged, fused or spiro ring system.

[0016] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si, and S, and is part of a bridged, fused, or spiro ring system.

[0017] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, does not contain additional atoms selected from N, O, Si, and S, and is not part of a bridged, fused, or spiro ring system.

[0018] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, does not contain additional atoms selected from N, O, Si, and S, and is part of a bridged, fused, or spiro ring system.

[0019] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is not part of a bridged, fused, or spiro ring system.

[0020] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is part of a bridged, fused, or spiro ring system.

[0021] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is not part of a bridged, fused, or spiro ring system.

[0022] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is part of a bridged, fused, or spiro ring system.

[0023] In an exemplary embodiment, the N-bonded non-aromatic heterocyclic ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is not part of a bridged, fused, or spiro ring system.

[0024] In an exemplary embodiment, the N-linked non-aromatic heterocyclic ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is part of a bridged, fused or spiro ring system.

[0025] In an exemplary embodiment of the compound of formula (1), R1 is H.

[0026] In an exemplary embodiment of the compound of formula (1), each R2 is H.

[0027] In an exemplary embodiment of the compound of formula (1), R3 is CH3.

[0028] In an exemplary embodiment of the compound of formula (1), R4 is H.

[0029] In an exemplary embodiment of the compound of formula (1), R6 is CH3.

[0030] In an exemplary embodiment of the compound of formula (1), R7 is CH3 or F.

[0031] In an exemplary embodiment of the compound of formula (1), R8 is H.

[0032] In an exemplary embodiment of the compound of formula (1), R1, each R2 and R4 are H.

[0033] In an exemplary embodiment, the compound of formula (1) is of formula (2)

Chemical formula

[0034] In an exemplary embodiment, the compound of formula (1) is of formula (3) [Chemical formula] (wherein R2 is as defined in the compound of formula (1); R3 is CH3, CF3, CFH2 or CF2H; R7 is CH3 or F; R 15 is OCH3, OCH2CH3, OCH2CF3, O-cyclopropyl, CH2CF3, CH2CF2H, aryl (wherein aryl can be, for example, a 6-membered aryl ring) or heteroaryl (wherein heteroaryl can be, for example, a 5- or 6-membered heteroaryl ring or a fused 6,5-heteroaryl ring system such as, for example, benzimidazole, indazole, imidazopyridine or triazolopyridine); each R 16 is independently H or C1-C3 alkyl; and the carbon atom marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as the (R)- or (S)-enantiomer.) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or a pharmaceutically acceptable salt thereof.

[0035] In an exemplary embodiment, the compound of formula (1) is of formula (4) [Chemical formula] (wherein R2 is as defined in the compound of formula (1); R3 is CH3, CF3, CFH2 or CF2H; R7 is CH3 or F; R 15is OCH3, OCH2CH3, OCH2CF3, O-cyclopropyl, CH2CF3, CH2CF2H, aryl (wherein the aryl can be, for example, a 6-membered aryl ring), or heteroaryl (wherein the heteroaryl can be, for example, a 5- or 6-membered heteroaryl ring or a fused 6,5-heteroaryl ring system such as, for example, benzimidazole, indazole, imidazopyridine, or triazolopyridine); and the carbon atom marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as a (R)- or (S)-enantiomer. ), or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof.

[0036] In an exemplary embodiment, the compound of formula (1) is of formula (5)

Chemical formula

[0037] One aspect of the present invention is a pharmaceutical composition comprising any of the compounds of the present invention described herein (e.g., any of formulas (1), (2), (3), (4) or (5)), or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0038] In an exemplary embodiment, a pharmaceutical composition comprising any of the compounds of the present invention described herein (e.g., any of formulas (1), (2), (3), (4) or (5)), or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof further comprises one or more anti-cancer agents.

[0039] Another aspect of the present invention is a method of treating a disease in which PI3K activity is involved in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of any of the compounds of the present invention described herein (e.g., any of formulas (1), (2), (3), (4) or (5)), or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0040] In an exemplary embodiment, the disease to be treated is cancer. In a particular embodiment, the disease is cancer carrying a PI3Kα H1047 mutation (e.g., H1047R).

DETAILED DESCRIPTION OF THE INVENTION

[0041] Detailed Description of the Invention As used herein, the term "at risk" refers to a medical condition or series of medical conditions indicated by a patient that may make the patient more likely to develop a particular disease or illness. For example, these conditions can result from influences including, but not limited to, behavioral, emotional, chemical, biochemical or environmental influences.

[0042] As used herein, the term "effective amount" refers to a particular amount of a pharmaceutical composition comprising a therapeutic agent that achieves a clinically beneficial result (i.e., for example, symptom reduction). The toxicity and therapeutic efficacy of such compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD 50 (50% lethal dose of the population) and the ED 50 (50% therapeutically effective dose of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index and can be expressed as the ratio LD 50 / ED 50 . Compounds that exhibit a large therapeutic index are preferred. The data obtained from these cell culture assays and additional animal studies can be used to formulate the dosage range for human use. The dosage of such compounds preferably falls within the circulating concentration range that includes the ED 50 with little or no toxicity. The dosage will vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0043] As used herein, the term "symptom" refers to any subjective or objective evidence of a disease or physical abnormality observed by a patient. For example, subjective evidence can include, but is not limited to, pain, headache, visual abnormalities, nausea and / or vomiting, typically based on the patient's self-report. Alternatively, objective evidence is typically the result of medical tests, including, but not limited to, body temperature, complete blood count, lipid panel, thyroid panel, blood pressure, heart rate, electrocardiogram, tissue body imaging scans, and other medical test results.

[0044] As used herein, the term "disease" refers to any disorder of the normal state of a living animal or part thereof that interferes with or modifies the performance of a biological function. Typically manifested by characteristic signs and symptoms, a disease is usually a response to i) environmental factors (e.g., nutritional disorders, industrial hazards, or climate); ii) specific infectious agents (e.g., helminths, bacteria, or viruses); iii) congenital deficiencies of an organism (e.g., genetic abnormalities); and / or iv) combinations of these factors.

[0045] The terms "reduce", "inhibit", "decrease", "suppress", "lower", "prevent" and their grammatical synonyms (including "less", "smaller", etc.), when used with reference to the manifestation of any symptom in an untreated subject compared to a treated subject, indicate that the amount and / or intensity of the symptom in the treated subject is lower in any amount than in the untreated subject and is recognized as clinically appropriate by any medical practitioner. In certain embodiments, the amount and / or intensity of the symptom in the treated subject is at least 10% lower, at least 25% lower, at least 50% lower, at least 75% lower and / or at least 90% lower than the amount and / or intensity of the symptom in the untreated subject.

[0046] As used herein, the term "inhibitory compound" refers to any compound that can interact (i.e., for example, attach, bind, etc.) with a binding partner under conditions where the binding partner does not respond to its natural ligand. Inhibitory compounds can include, but are not limited to, small organic molecules, antibodies and proteins / peptides.

[0047] As used herein, the term "bind" refers to the interaction between a medium (or carrier) and a drug. The binding may be reversible or irreversible. Such binding includes, but is not limited to, covalent bonds, ionic bonds, van der Waals forces or friction. A drug binds to a medium (or carrier) when it is impregnated, incorporated, coated, suspended, dissolved, mixed, etc.

[0048] As used herein, the term "drug" or "compound" refers to any pharmacologically active substance that can be administered to achieve a desired effect. A drug or compound can be a non-peptide, protein or peptide, oligonucleotide or nucleotide, polysaccharide or sugar that is synthetic or naturally occurring.

[0049] As used herein, the term "administer" or "administering" refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient. Exemplary methods of administration are by direct means, for example, local tissue administration (i.e., for example, extravascular administration, for example subcutaneous, intramuscular or intraperitoneal), intravenous, oral ingestion, transdermal patch, topical, inhalation, suppository, and the like.

[0050] As used herein, the term "patient" is a human or an animal and does not need to be hospitalized. For example, outpatient and nursing home residents are "patients". A patient can be a human or non-human animal of any age, and thus includes both adults and juveniles (i.e., children). There is no intention that the term "patient" implies the need for medical treatment. Therefore, a patient can be voluntarily subject to experimentation, either in support of a clinical trial or basic science research.

[0051] As used herein, the term "subject" refers to humans (e.g., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or elderly adults)) and / or other primates (e.g., monkeys); non-human mammals, such as cows, pigs, horses, sheep, mice, goats, cats, dogs; and / or birds, such as chickens, ducks and / or geese, but is not limited thereto.

[0052] As used herein, the term "affinity" refers to any attractive force between substances or particles that causes them to form and maintain a chemical combination. For example, an inhibitory compound having a high affinity for a receptor provides greater efficacy in inhibiting the interaction of the receptor with its natural ligand than a low affinity inhibitor.

[0053] As used herein, the term "derived from" refers to the source of a compound or sequence. In some instances, a compound or sequence can be derived from an organism or a particular species. In other instances, a compound or sequence can be derived from a larger complex or sequence.

[0054] As used herein, the term "test compound" refers to any compound or molecule that is considered a candidate for an inhibitory compound.

[0055] As used herein, the term "combination therapy" refers to an administration regimen of two or more different therapeutic active agents over a period of time, where these therapeutic active agents are administered together or separately. In certain embodiments, the combination therapy is an unfixed combination.

[0056] As used herein, the term "unfixed combination" refers to two or more different therapeutic agents that are formulated as separate compositions or dosages and as a result can be administered to a subject in need thereof simultaneously or sequentially at various time-limited intervals.

[0057] As used herein, the term "synergistic" or "synergism" refers to a phenomenon where the combination of two therapeutic agents in a combination therapy is greater in terms of a measured value than the addition of the effects when each agent is administered alone.

[0058] As used herein, the term "in vivo" refers to events that occur within the body of a subject.

[0059] As used herein, the term "in vitro" refers to events that occur outside the body of a subject.

[0060] As used herein, the term "protein" refers to any of a number of 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 typically sulfur. Generally, a protein contains hundreds of amino acids.

[0061] As used herein, the term "peptide" refers to any of various amides derived from two or more amino acids by the combination of the amino group of one acid and the carboxyl group of the other, usually obtained by partial hydrolysis of a protein. Generally, a peptide contains dozens of amino acids.

[0062] As used herein, the term "pharmaceutically acceptable" or "pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.

[0063] As used herein, the term "pharmaceutically acceptable carrier" includes, but is not limited to, water, ethanol, polyols (such as, for example, glycerol, propylene glycol, and liquid polyethylene glycols, etc.), suitable mixtures thereof, vegetable oils, coatings, isotonic and absorption delaying agents, liposomes, commercially available detergents, and any and all solvents or dispersion media. Auxiliary bioactive ingredients can also be incorporated into such carriers.

[0064] As used herein, the term "pharmaceutically acceptable salt" refers to salts that do not adversely affect the biological activity and properties of the compound, and are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, and / or allergic response, etc. Pharmaceutically acceptable salts include those derived from suitable inorganic acids, organic acids, and bases, including 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 certain cases, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group described herein with a base to form salts such as ammonium salts, alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as 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, aluminum, etc. Organic bases from which salts can be produced include, for example, primary, secondary, and tertiary amines.

[0065] As used herein, the term "prodrug" refers to a compound that is converted in vivo to yield the disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive upon administration to a subject, but is converted to an active compound in vivo. In various cases, a prodrug has physicochemical properties (e.g., bioavailability) and / or delivery properties that are improved over the parent compound. A prodrug is typically designed such that the pharmaceutical and / or pharmacokinetic properties associated with the parent compound are enhanced. Prodrug compounds often provide advantages in solubility, tissue compatibility, or delayed release in a subject. A prodrug includes a compound in which a hydroxy, amino, or mercapto group is bonded to some group such that, when the prodrug is administered to a subject, the bond is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively. It is well known that prodrugs are formed, for example, from carboxylic acids in the form of carboxylic acid esters or thioesters.

[0066] As used herein, the term "purified" or "isolated" can refer to a composition (e.g., a peptide composition, etc.) that has been subjected to a process (e.g., fractionation) to remove various other components, and the composition substantially retains its expressed biological activity.

[0067] As used herein, the term "sample" includes, for example, environmental 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., plants). For example, a lung sample can be recovered by bronchoalveolar lavage (BAL) that includes fluid and cells derived from lung tissue. Biological samples can include cells, tissue extracts, body fluids, chromosomes or extrachromosomal elements isolated from cells, genomic DNA (bound to a solid support such as for solution or Southern blot analysis), RNA (bound to a solid support such as for solution or Northern blot analysis), cDNA (bound to a solution or solid support), and the like.

[0068] As used herein, the term "biologically active" refers to any molecule having a structural, regulatory or biochemical function. For example, biological activity can be determined by, for example, the restoration of wild-type growth in cells lacking protein activity. Cells lacking protein activity can be produced by a number of methods (i.e., e.g., point mutations and frameshift mutations). Complementation is achieved by transfecting cells lacking protein activity with an expression vector expressing the protein, its derivative or a portion thereof.

[0069] As used herein, the term "label" or "detectable label" refers to any composition detectable by spectral, photochemical, biochemical, immunochemical, electrical, optical or chemical means. Such labels include biotin for staining with a labeled streptavidin conjugate, magnetic beads (e.g., Dynabeads (登録商標) ), fluorescent dyes (e.g., fluorescein, Texas Red (登録商標) , rhodamine, green fluorescent protein, etc.), radiolabels (e.g., 3 H, 125 I, 35 S, 14 C or 32P), enzymes (e.g., horseradish peroxidase, alkaline phosphatase, and others commonly used in ELISA), and calorimetric labels such as gold colloids 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. Patents 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241 (all incorporated herein by reference in their entirety). The labels contemplated by the present invention can be detected by conventional methods. For example, radioactive labels can be detected by photographic film or scintillation counters, and fluorescent markers can be detected using a light detector that detects emitted light. Enzyme labels are typically detected by preparing an enzyme and a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and calorimetric labels are detected by simply visualizing the colored label.

[0070] As used herein, the term "conjugate" refers to any compound formed by the linkage of two or more moieties.

[0071] As used herein, a "moiety" or "group" is any type of molecular arrangement specified by a formula, chemical name, or structure. Within the context of certain embodiments, a conjugate contains one or more moieties or chemical groups. This means that the formula of the moiety is substituted at a position in order to be linked to and become part of the molecular arrangement of the conjugate. One moiety can be linked by a direct covalent bond, but it is not intended that the linkages of two or more moieties must be direct to each other. A linking group, crosslinking group, or connecting group refers to any molecular arrangement that covalently connects moieties, such as, but not limited to, one or more amide groups. Further, a conjugate may not be substituted, but a conjugate can have various additional substituents that connect to the linking group and / or to the moieties.

[0072] As used herein, "polymer" or "polymeric group" refers to a chemical species or group consisting of repeatedly linked moieties. Within the scope of certain embodiments, the number of repeating moieties is preferably 3 or more or more than 10. The linked moieties may have the same structure or the sub-structures may vary. A "monomeric polymer" or "homopolymer" is a polymer containing the same repeats, 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.

[0073] As used herein, the term "substitution" refers to at least one hydrogen atom of a molecular arrangement replaced by a substituent. The number of substituents present depends on the number of hydrogen atoms available for replacement and includes replacement of more than one hydrogen atom bonded to an atom (e.g., in the case of a carbon or silicon atom that may be available for mono-, di- or tri-substitution or in the case of a nitrogen atom that may be available for mono-, di- or tri-substitution or in the case of an oxygen or sulfur atom that may be available for mono-substitution). In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced (this provides, for example, the substituent -(CH2)-C(=O)-CH3 when two hydrogen atoms of the central carbon atom of -CH2-CH2-CH3 are replaced). When substituted, one or more of the following groups are "substituents". Substituents include halogen (e.g., F, Cl, Br, I), hydroxy (OH), oxo, cyano (CN), 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, OCHFCHF2, OCF2CH2F, OCF2CF3, OCF2CH3, OCF(CH3)2, OCH2CH2CF3, OCF2CH2CF3, OCF2CF2CF3 or OCH2Cl), O-aryl (e.g., O-phenyl), O-heteroaryl, O-heterocyclyl, 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 =CRf 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), heterocyclyl, heterocycloalkyl, and -NR f R g , -NR f C(=O)R g , - NR f C(=O)NR f NR g , -NR f -C(=O)OR f SO2R g , -C(=O)R f , -C(=O)OR f , -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 and -S(=O)OR f (where each R f and R g may be the same or different and are independently hydrogen, alkyl (e.g., CH3), substituted alkyl, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl, substituted heterocyclyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl), but are not limited thereto. Further, the above substituents may be further substituted with one or more of the above substituents such that the substituent constitutes, for example, a substituted alkyl, substituted aryl, substituted arylalkyl, substituted heterocyclyl, or substituted heterocycloalkyl).

[0074] As used herein, the term "unsubstituted" refers to any compound that does not contain additional substituents attached to the compound. An unsubstituted compound refers to the chemical constitution of a compound without additional substituents (e.g., without non-hydrogen substituents). For example, unsubstituted proline is the proline amino acid, even if the amino group of proline can be considered to be disubstituted with alkyl groups.

[0075] As used herein, the term "bond" when referring to an atom having substituents on both sides refers to the absence of such substituents. For example, in the four-atom sequence A-B-C-D, when both B and C are cited as bonds, the resulting two-atom sequence is A-D. When only B is cited as a bond, the resulting three-atom sequence is A-C-D.

[0076] As used herein, the term "alkyl" refers to any straight-chain or branched, acyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term "lower alkyl" has the same meaning as alkyl except that it contains from 1 to 3 carbon atoms. The term "higher alkyl" has the same meaning as alkyl except that it contains from 4 to 10 carbon atoms. Representative saturated straight-chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, etc., while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc. The methyl substituent as used herein can be represented as "CH3" or "Me" or as a terminal bond where specific atoms are not shown.

[0077] As used herein, the term "cycloalkyl" refers to saturated and unsaturated cyclic alkyls. Representative saturated cyclic alkyls are C3-C 14(For example, C3-C7) cycloalkyl, including but not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, etc.; while unsaturated cyclic alkyl includes, but is not limited to, cyclobutenyl, cyclopentenyl and cyclohexenyl, cyclohexadiene, etc. Cyclic alkyl is also referred to herein as "homocycle" or "homocyclic ring".

[0078] As used herein, the term "spiro" or "spirocyclic" refers to a chemical structure having at least two rings sharing one common atom. The rings may be cycloalkyl, heterocyclyl or combinations thereof, and may include one or more aryl or heteroaryl rings. Exemplary embodiments include 1,4-dioxaspiro[4.5]decane, spirocyclic azetidine and spirocyclic pyrrolidine and spirocyclic piperidine, where the other rings are cycloalkyl (e.g., cyclobutane, cyclopentane or cyclohexane) or heterocyclyl (e.g., piperidine, tetrahydropyran, tetrahydrofuran, azetidine or pyrrolidine).

[0079] As used herein, the term "bicyclic compound" includes the "bridged", "fused" and "spiro" compounds described.

[0080] As used herein, the term "bridged" refers to a compound containing two non-adjacent atoms common to two rings. Exemplary embodiments include norbornane, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, 1,4-diazabicyclo[2.2.2]octane, other bridged piperazines and bridged piperidines, but are not limited thereto.

[0081] As used herein, the term "condensed" refers to polycyclic ring systems where any two adjacent rings share exactly two but only two adjacent atoms (ortho-condensed), and where rings are part of a series of continuously ortho-condensed rings where each of two or more rings share exactly two but only two adjacent atoms (ortho- and peri-condensed). Exemplary embodiments include pentalene and dibenzoxepin (ortho-condensed) and pyrene (ortho- and peri-condensed). Ortho-condensed systems have "n" common side chains and "2n" common atoms, while peri-condensed systems have "n" common side chains and less than "2n" common atoms. Other exemplary condensed systems include condensed cyclopropyl rings, condensed aziridines, and condensed azetidines, for example when these rings are condensed to a pyrrolidine ring. Other examples include two condensed pyrrolidine rings (octahydropyrrolo[3,4-c]pyrrole), condensed pyridine rings, such as pyridine rings condensed to cycloalkyl (e.g., cyclopentane) or heterocyclyl (e.g., tetrahydrofuran or tetrahydropyran).

[0082] As used herein, the term "aromatic" or "aryl" refers to any aromatic carbocyclic (i.e., all ring atoms are carbon) substituent such as phenyl (from benzene), tolyl (from toluene), xylyl (from xylene), or polycyclic systems (e.g., naphthyl (from naphthalene) and anthracenyl (from anthracene)), but is not limited thereto.

[0083] As used herein, the term "arylalkyl" or "aralkyl" refers to any alkyl having at least one alkyl hydrogen atom replaced by an aryl moiety, such as benzyl, -(CH2)2phenyl, -(CH2)3phenyl, -CH(phenyl)2, but is not limited thereto.

[0084] As used herein, the term "halogen" refers to any fluoro, chloro, bromo, or iodo moiety.

[0085] As used herein, the term "haloalkyl" refers to any alkyl in which at least one hydrogen atom (including all hydrogen atoms) is replaced by a halogen atom, such as trifluoromethyl, dichloromethyl, difluoromethyl, monofluoromethyl, monobromomethyl, 1,1,1-trifluoroethyl, and the like.

[0086] As used herein, the term "heteroaromatic" or "heteroaryl" refers to any aromatic heterocyclic ring containing 5 to 10 or more members and at least one heteroatom selected from nitrogen, oxygen, or sulfur, including but not limited to both monocyclic and bicyclic ring systems, and containing at least one carbon atom. The heteroaryl ring can be attached as a substituent via a ring heteroatom or a carbon atom. Representative heteroaromatics include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, indole, isoindole, 7-azaindole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindazole, pyridine, quinoline, isoquinoline, oxazole, isoxazole, benzoxazole, pyrazole, imidazole, benzimidazole, thiazole, benzothiazole, isothiazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, cinnoline, phthalazine, quinazoline, 1,8-naphthylpyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-b]pyrazine, pyrido[2,3-b]pyrazine, pteridine, triazolo-pyridine, and the like.

[0087] As used herein, the term "heteroarylalkyl" means any alkyl having at least one alkyl hydrogen atom replaced by a heteroaryl moiety, such as -CH2pyridinyl, -CH2pyrimidinyl, and the like.

[0088] As used herein, the terms "heterocycle" or "heterocyclyl" or "heterocyclic ring" refer to a non-aromatic ring that is saturated or unsaturated and contains one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, where each of the nitrogen and sulfur heteroatoms may be in an oxidized state, each of the nitrogen and silicon heteroatoms is substituted or unsubstituted, the nitrogen heteroatom may be optionally quaternized, and includes bicyclic rings in which any of the above heterocycles is fused to an aryl or heteroaryl ring. The heterocyclic ring may be attached as a substituent via a ring heteroatom or a carbon atom.In various embodiments, the heterocycle may contain 3 to 14 or more ring atoms (e.g., a 3- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic ring), including, but not limited to, 2H-azirine, azetidine, 2,3-dihydroazete, 1,3-diazetidine, 2H-oxete, thietane, 2H-thiete, azetidin-2-one, morpholine, thiomorpholine, pyrrolidinone, pyrrolidine, 2-pyrroline, 3-pyrroline, pyrazolidine, 2-pyrazoline, 2-imidazoline, imidazolidine, piperidine, piperazine, ethylene oxide (oxirane), ethyleneimine (aziridine), ethylene sulfide (thiirane), oxetane, propylene oxide, 1,3-dioxolane, 1,2-oxathiolane, 1,3-oxathiolane, sulfolane, 2,4-thiazolidinedione, succinimide, 2-oxazolidone, dioxane, hydantoin, valerolactam, tetrahydrofuran, tetrahydropyran, 2H-pyran, 4H-pyran, thiane, 2H-thiopyran, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, pyrrolizidine, 1,4,5,6-tetrahydrocyclopenta[b]pyrrole, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, indoline, isoindoline, decahydroisoquinoline, decahydroquinoline, 1,2,3,4-tetrahydroquinoline, 1,2-dihydroquinoline, 2H-benzo[e][1,3]oxazine, 2H-benzo[b][1,4]oxazine, quinolin-2(1H)-one, isoquinolin-1(2H)-one, quinuclidine, 1-azaadamantane, 2-azaadamantane, 2,3-dihydroazepine, 2,5-dihydroazepine, oxepane, azonane, spiro[cyclobutane-1,3'-indole], 1-oxaspiro[4,5]decane, 1,6-dioxaspiro[3,4]octane, 2-oxa-7-azaspiro[3,5]nonane, 1,4-dioxa-7-azaspiro[4,4]nonane, 1,3-diazaspiro[4,4]non-2-en-4-one, 2,9-diazaspiro[5,5]undecan-1-one, 8-azaspiro[4,5]decane-7,9-dione, 1,4-dithia-7-azaspiro[4,4]nonane, and the like.

[0089] As used herein, the term "heterocycloalkyl" refers to any alkyl having at least one alkyl hydrogen atom replaced by a heterocycle such as -CH2 morpholinyl.

[0090] As used herein, the term "alkylamino" includes, but is not limited to, methylamino, ethylamino, dimethylamino, diethylamino, etc., and refers to at least one alkyl moiety (-N-(alkyl) n bonded via a nitrogen bridge, where n = 1 or 2, for example alkylamino or dialkylamino).

[0091] As used herein, the term "alkyloxy" or "alkoxy" refers to an alkyl moiety (-O-alkyl) bonded via an oxygen bridge, such as methoxy, ethoxy, etc., but not limited thereto.

[0092] As used herein, the term "thioalkyl" refers to any alkyl moiety (-S-alkyl) bonded via a sulfur bridge, such as methylthio, ethylthio, etc., but not limited thereto.

[0093] As used herein, the term "alkenyl" refers to an unbranched or branched hydrocarbon chain having one or more carbon-carbon double bonds therein, and may also be referred to as "unsaturated alkyl". The double bond of the alkenyl group may be non-conjugated or conjugated with other unsaturated groups. Suitable alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-buten)-pentenyl. The alkenyl group may be unsubstituted or substituted with one or two suitable substituents.

[0094] As used herein, the term "alkynyl" refers to an unbranched or branched hydrocarbon chain having one or more carbon-carbon triple bonds therein and may also be referred to as "unsaturated alkyl". The triple bond of the alkynyl group may be non-conjugated or conjugated with other unsaturated groups. Suitable alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. The alkynyl group may be unsubstituted or substituted with one or two suitable substituents.

[0095] As used herein, the term "reactive group" refers to a nucleophile, an electrophile or a radical reactive group, i.e., a group that reacts in the presence of a radical. A nucleophile is a moiety that forms a chemical bond with its reaction partner (electrophile) by donating both bonding electrons. An electrophile accepts these electrons. A nucleophile can participate in nucleophilic substitution, whereby the nucleophile is attracted to a fully or partially positive charge on an element and replaces the group to which it is bonded. Alternatively, a nucleophile can participate in the substitution of a carbonyl group. Carboxylic acids often act as electrophiles by forming succinyl esters and reacting these esters with aminoalkyls to form amides. Other common nucleophilic groups are thiolalkyls, hydroxylalkyls, primary and secondary amines and carbon nucleophiles such as enols and alkyl metal complexes. Other preferred methods of ligating proteins, oligosaccharides and cells using reactive groups are disclosed (Lemieux et al., Trends in Biotechnology 1998, 16, 506, which is hereby incorporated by reference in its entirety). In yet other preferred methods, azide-containing moieties and alkynyl reactive groups are used to form triazoles, providing reactive groups for Staudinger ligation, i.e., "click chemistry". Michael addition of a carbon nucleophile enolate to an electrophilic carbonyl or Schiff base formation between a nucleophilic primary or secondary amine and an aldehyde or ketone can also be utilized. Other methods of bioconjugation are provided (Hang et al. Accounts of Chemical Research 2001, 34, 727 and Kiick et al. Proc Natl Acad Sci US.A. 2002, 99, 19, both of which are hereby incorporated by reference in their entirety).

[0096] As used herein, the term "biocompatibility" refers to any substance that does not cause a substantial adverse response in the host. When introducing a foreign object into a living body, there is always a concern that the object may induce an immune response such as an inflammatory response that negatively affects the host. In the context of the present invention, biocompatibility is evaluated according to the intended application: for example, a bandage is considered biocompatible with the skin, while an implantable medical device is considered biocompatible with the internal tissues of the body. Preferably, biocompatible substances include, but are not limited to, biodegradable and bio-stable substances. A substantial adverse response has not occurred if the implant containing the substance is in close proximity to the implant site within the host animal and the response is better than the tissue response recognized and considered appropriate from the substances provided in ASTM. The ASTM Subcommittee F04.16 on Biocompatibility Testing Methods has developed biocompatibility standards for medical and surgical materials and devices, including E1262-88, F612-20, F719-20e1, F720-17, F748-16, F749-20, F750-20, F756-17; F763-04, F813-20, F895-11, F981-04, 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 hereby incorporated by reference herein. For example, substances used in contact with the bloodstream should be composed of substances that meet blood compatibility standards. One of these tests is for hemolysis, i.e., damage to red blood cells that can result in cell destruction, as described in the standard technique for evaluating the hemolytic properties of F756-17 substances.

[0097] As used herein, "bioactive substance" refers to any of a variety of chemical moieties that bind to biomolecules such as, but not limited to, peptides, proteins, enzymes, receptors, substrates, lipids, antibodies, antigens, and nucleic acids. In certain preferred embodiments, the bioactive substance is a biomolecule, although there is no intent to limit bioactive substances 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, alkaline growth factors (isoelectric point 7 or greater) are retained via favorable electrostatic interactions with polycarboxylates and then released in a controlled and sustained manner.

[0098] "Cancer" is a term used with respect to a physiological state in mammals that is typically characterized by unregulated 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 carcinomas, small cell lung cancer, non-small cell lung cancer (NSCLC), gliomas, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal cancers, renal cell carcinoma, kidney cancer (e.g., advanced renal cell carcinoma), ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, gastric cancer, urothelial cancer (including locally advanced or metastatic urothelial cancer), bladder cancer, hepatocellular carcinoma, breast cancer, and head and neck cancer.

[0099] The term "stereoisomer" refers to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, diastereomers, and atropisomers. In the context of the present invention, the term "enantiomerically pure" is understood to mean that the compound is present with an enantiomeric excess of greater than 95%, preferably greater than 97%, with respect to the absolute configuration of the chiral center.

[0100] The present invention contemplates all such compounds including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomeric isomers, (D)-isomers, (L)-isomers, atropisomers, tautomers and racemic and other mixtures thereof, for example enantiomer- or diastereomer-enriched mixtures, and all of these are within the scope of the present invention. As long as the compounds of the present invention as defined herein may exist in optically active or racemic form due to one or more asymmetric carbon atoms, the present invention includes any such optically active or racemic form within its definition. The synthesis of optically active compounds can be carried out by standard techniques of organic chemistry well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemic compounds. Similarly, the enantiomeric or diastereomeric purity of a compound can be evaluated using standard laboratory techniques.

[0101] The pharmaceutical composition of the present invention can take any suitable form for the desired route of administration. When the composition is administered orally, any suitable orally deliverable dosage form can be used. In the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions, water, glycols, oils, alcohols, etc.; or in the case of powders, pills, capsules and tablets, starches, sugars, kaolin, diluents, lubricants, binders, disintegrants, etc., solid carriers, but not limited thereto. Tablets and capsules represent the most advantageous oral dosage unit forms because of the ease of administration. Injectable compositions or intravenous infusions are also provided in the form of solutions, suspensions and emulsions. For parenteral compositions, the carrier usually includes sterile water and possibly other components to aid dissolution. Injectable solutions can be prepared, and the carrier includes saline, glucose solution or a mixture of saline and glucose solution. Suitable oils include, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids and mixtures of these with other oils. In compositions suitable for transdermal administration, the carrier includes, optionally, a penetration enhancer and / or a suitable wetting agent, and optionally a suitable additive as required, where the additive can facilitate the administration of the composition to the skin and / or facilitate the manufacture of the composition to be delivered. These compositions can be administered in various ways, for example, as a transdermal patch or an ointment. Acid or base addition salts of the compounds of the present invention are more suitable for the preparation of aqueous compositions because they typically have increased water solubility compared to the corresponding neutral form of the compound.

[0102] The pharmaceutical composition of the present invention may contain one or more of bulking agents, diluents, adjuvants, vehicles or other additives to facilitate the preservation and / or administration of the active ingredient contained therein.

[0103] In an exemplary embodiment, the pharmaceutical composition of the present invention may comprise one or more additional therapeutic agents, for example, for increasing efficacy or reducing unwanted side effects. In certain embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents useful for treating or preventing a disease mediated directly or indirectly by PI3K. Examples of such agents include, but are not limited to, agents for treating or preventing cancer, Huntington's disease, cystic fibrosis, liver fibrosis, kidney fibrosis, pulmonary fibrosis, dermal fibrosis, rheumatoid arthritis, diabetes or heart failure.

[0104] In a specific embodiment, the additional therapeutic agent included is an anti-cancer agent. Examples of anti-cancer agents include DNA-damaging cytotoxic drugs, alkylating agents such as cyclophosphamide, dacarbazine and cisplatin; antimetabolites such as methotrexate, mercaptopurine, thioguanine, fluorouracil and cytarabine; plant alkaloids such as vinblastine and paclitaxel; antitumor antibiotics such as doxorubicin, bleomycin and mitomycin; hormones / anti-hormones such as prednisone, tamoxifen and flutamide; other types of anti-cancer agents such as asparaginase, rituximab, trastuzumab, imatinib, retinoic acid and derivatives, colony stimulating factors, amifostine, camptothecin, topotecan, thalidomide analogs such as lenalidomide and proteasome inhibitors such as bortezomib, but are not limited thereto.

[0105] In other embodiments, the present invention provides a method of preventing or treating a disease caused by abnormal cell growth and / or differentiation in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present invention. In certain embodiments, the method of preventing or treating a disease comprises administering to a subject in need of treatment a composition comprising an effective amount of one or more compounds of the present invention and a pharmaceutically acceptable carrier. The composition to be administered may further comprise a therapeutic agent such as an anti-cancer agent.

[0106] The compounds of the present invention are defined herein by their chemical structure and / or chemical name, and are generally described according to IUPAC or CAS nomenclature. Abbreviations well-known to those skilled in the art may be used. If a compound is described both by its chemical structure and chemical name and there is a contradiction in the chemical name, the chemical structure is intended to be the determining factor for identifying the compound.

[0107] The present invention includes compounds labeled with various radioactive or non-radioactive isotopes. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), nitrogen-15 ( 15 N), sulfur-35 ( 35 S), and chlorine-36 ( 36 Cl), but are not limited thereto. In an 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 include at least one deuterium atom or two or more deuterium atoms or three or more deuterium atoms, etc. The compounds of the present invention described herein may also be radioactively labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and carbon-14 ( 14 C). Radioactively labeled compounds are useful as therapeutic or prophylactic agents, provide research reagents such as for assays, and / or provide diagnostic agents for techniques such as in vivo imaging. Synthetic methods for incorporating isotopes into organic compounds are well-known in the art.

[0108] In certain embodiments of the present invention, the compounds of the present invention as defined herein (e.g., any of the compounds of formula (1), (2), (3), (4) or (5)) or pharmaceutically acceptable salts thereof are present as a single enantiomer with an enantiomeric excess (%ee) of ≧95%, e.g., ≧98%, e.g., ≧99%.

[0109] In certain embodiments of the present invention, the pharmaceutical composition comprises a compound of the present invention as defined herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, wherein the compound is present as a single enantiomer with an enantiomeric excess (%ee) of ≧95%, e.g., ≧98%, e.g., ≧99%.

[0110] In exemplary embodiments of the present invention, the disease or disorder treated by the compound of the present invention is selected from congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal-spinal syndrome (CLOVES), mosaic tissue overgrowth syndrome, venous malformation with severe epilepsy and brain malformation or PIK3CA-related overgrowth syndrome (PROS) (Keppler-Noreuil et al., Am J Med Genet A. 2015, 167A, 287; Kurek et al. Am. J. Hum. Genet. 2012, 90, 1108).

[0111] In exemplary embodiments of the present invention, the cancer to be treated is a cancer bearing a PI3K H1047 mutation (e.g., H1047R) (Thorpe et al., Nat Rev Cancer 2015, 15, 7).

[0112] The compound of Formula I of the present invention is generally prepared by a synthetic route identified in the following scheme:

Chemical formula

[0113] Starting from aminobenzoic acid 1, which is generally known or commercially available (e.g., from BLD Pharmatech Ltd.), intermediate quinazoline-2,4-dione 2 can be produced under cyclization conditions. In an exemplary embodiment when R6 = H, cyclization occurs by treatment with urea at elevated temperature. In an exemplary embodiment when R6 = alkyl, cyclization occurs via a two-step procedure consisting of first amide coupling with the corresponding alkylamine and HATU, followed by treatment with triphosgene. Chlorination of 2 affords an intermediate of general structure 3. In an exemplary embodiment, chlorination occurs by refluxing 2 in POCl3, followed by neutralization with an aqueous base (NaOH when R6 = H or NaHCO3 when R6 = alkyl). The intermediate of general structure 4 is S NIt was produced by Ar substitution. In an exemplary embodiment, in a suitable solvent (such as, but not limited to, ACN, NMP or DMF) at room temperature or, in some embodiments, at high temperature (up to 140 °C), with a suitable base (such as, but not limited to, DIEA, K2CO3 or NaH) added, treatment with an amine, amine hydrochloride, alcohol or thiol of 3 (depending on whether R5 is desired to be an N-bond, O-bond or S-bond respectively) gave an intermediate of general structure 4. The intermediate of general structure 5 was produced by carbonylation. In an exemplary embodiment, the bromine substituent of 4 was treated at high temperature with tributyl(1-ethoxyvinyl)tin and a catalytic palladium species (such as, but not limited to, Pd(PPh3)4 or PdCl2(PPh3)2), followed by hydrolysis with aqueous HCl to replace the acetyl group to produce ketone 5. Intermediate 5 when R3 = H can also be produced by formylation of 4 via various known methods (such as palladium-catalyzed carbonylation in the presence of H2 (Klaus, et al., Angew. Chem. Int. Ed. 2006, 45, 154) or cyanation followed by DIBAL reduction). Intermediate 5 can serve as a platform for the expansion to various R3 substitutions (such as trifluoromethyl, difluoromethyl, fluoromethyl, alkyl, etc.) via various known techniques (including, but not limited to, Prakash, et al., J. Am. Chem. Soc. 1989, 111, 393; Zhao, et al., Org. Lett. 2011, 13, 5342; Reichel, et al., Angew. Chem. Int. Ed. 2020, 59, 12268, etc.). The alcohol intermediate of general structure 6 can be prepared by reduction of 5. In an exemplary embodiment, the reduction was carried out by treating 5 with NaBH4 in MeOH. The conversion from 6 to arylamines of general structures 8 and 9 can be achieved via substitution reactions. In an exemplary embodiment, 6 was converted to 9 via Mitsunobu conditions involving PPh3, DBAD and intermediate 7 when R4 = H.In other exemplary embodiments, substitution of intermediate 7 of 6 under Mitsunobu conditions gave sulfonamide intermediate 8 when R4 = 2-nitrophenylsulfonyl or 2,4-dinitrophenylsulfonyl. In other exemplary embodiments, 6 was first converted to the methanesulfonate via treatment with Ms2O or MsCl and an amine base (e.g., but not limited to, Et3N or DIEA), followed by treatment with amine 7 to give benzylamine 9. The sulfonamide of general structure 8 can be converted to secondary amine 9 via known desulfonylation protocols. In an exemplary embodiment, treatment of 8 with potassium thiophenolate and K2CO3 gave intermediate 9. Intermediate 9 where R5 = thioalkyl or thio(hetero)aryl can be further elaborated to the corresponding sulfinyl or sulfonyl compound via known oxidation methods (e.g., but not limited to, treatment with mCPBA or potassium peroxymonosulfate). The ester intermediate 9 can be converted to the corresponding carboxylic acid of general structure 10 via known deesterification protocols. In certain exemplary embodiments when R1 = CH3, deesterification was achieved via treatment with a metal hydroxide (e.g., but not limited to, LiOH or NaOH) to give the product of general structure 10. In other exemplary embodiments, intermediate 9 when R1 = tert-butyl was deesterified by treatment with a suitable acid (e.g., but not limited to, TFA or HCl in 1,4-dioxane or water) to give 10. Separation of racemic 10 via known chiral HPLC chromatography techniques (e.g., DAICEL Chiralpak column) gave enantiomerically enriched compounds of general structures 11 and 12.

[0114] The following compounds (racemic or enantiomerically resolved forms) represent various embodiments of the present invention. The list of substituents in parentheses for a given compound indicates the individual compounds containing one of each of these substituents.

Chemical formula

Chemical formula

[0115] The following compounds represent various embodiments of the present invention in which only R5 in the structure is changed and all other atoms are fixed. The carbon atom marked with * in the following general structure is a chiral center and exists as a (R)- and (S)-racemic mixture or as a (R)- or (S)-enantiomer. The list of substituents in parentheses for a given compound indicates the individual compounds containing one of each of these substituents. When present, each R h and R i is independently selected from H, CH3, c-Pr, c-Bu, CF3 and OH; and each R j is independently selected from CF3, CH2CF3, CH2CF2H, OCH3, OCF3, OCH2CF 3、 Oc-Pr, aryl, heteroaryl, COCH3 and CO2CH3.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0116] The following compounds represent various embodiments of the present invention in which only R5 in the structure is changed and all other atoms are fixed. The carbon atom marked with * in the following general structure is a chiral center and exists as a (R)- and (S)-racemic mixture or as a (R)- or (S)-enantiomer. The list of substituents in parentheses for a given compound indicates the individual compounds containing one of each of these substituents.

Chemical formula

[0117] The following compounds represent various embodiments of the present invention in which only R5 in the structure is changed and all other atoms are fixed. The carbon atom marked with * in the following general structure is a chiral center and exists as a (R)- and (S)-racemic mixture or as a (R)- or (S)-enantiomer. The list of substituents in parentheses for a compound indicates the individual compounds containing one of each of these substituents. The variable group "A" is selected from O, S, S(O), and S(O)2. [Chemical formula] [In the formula, R5 is [Chemical formula] [Chemical formula] as follows.].

[0118] Experiment All commercially available solvents and reagents were used as received. All 11H NMR spectra were recorded using a Bruker Avance III HD 300 MHz or a Bruker Avance III HD 400 MHz. MS samples were analyzed using a SHIMADZU LCMS-2020 mass spectrometer operating in positive and negative ion modes with electrospray ionization. Samples were introduced into the mass spectrometer using chromatography. All final products had a purity of ≥90% unless otherwise specified in the experimental details. HPLC purity was measured using a SHIMADZU Acquity HPLC system.

[0119] The following are the abbreviations used for well-known chemical solvents, reagents, parameters, and techniques in the experimental section: 1 H-NMR: Proton nuclear magnetic resonance spectroscopy ACN: Acetonitrile AcOH: Acetic acid c-Bu: Cyclobutyl c-Pr: Cyclopropyl DBAD: Di-tert-butyl azodicarboxylate DCM: Dichloromethane DIBAL: Diisobutylaluminum hydride DIEA: N,N-Diisopropylethylamine DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide ee: Enantiomeric excess Et3N: Triethylamine EtOAc: Ethyl acetate EtOH: Ethanol FA: Formic acid h: Hour HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl: Hydrochloric acid HPLC: High performance liquid chromatography IPA: Isopropanol K2CO3: Potassium carbonate LiOH: Lithium hydroxide mCPBA: meta-Chloroperoxybenzoic acid Me: Methyl MeOH: Methanol mg: Milligram min: Minute mL: Milliliter MsCl: Methanesulfonyl chloride Ms2O: Methanesulfonic anhydride NaBH4: Sodium borohydride NaH: Sodium hydride NaOH: Sodium hydroxide NaHCO3: Sodium bicarbonate Na2SO4: Sodium sulfate NMP: N-Methylpyrrolidone Oxetane: A four-membered ring containing three carbon ring atoms and one oxygen ring atom. Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride PE: Petroleum ether POCl3: Phosphorus oxychloride PPh3: Triphenylphosphine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin layer chromatography

Example

[0120] Intermediate 1: 8-Bromo-2-chloro-3,6-dimethylquinazolin-4-one

Chem.

[0121] Project 2: Preparation of 8-bromo-3,6-dimethyl-1H-quinazoline-2,4-dione A solution of a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (19.2 g, 79 mmol), triphosgene (23.4 g, 79 mmol) and DIEA (13.8 mL, 79 mmol) in DCM (250 mL) was stirred under a nitrogen atmosphere at 50 °C overnight. The mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a PE solution of 0 - 50% EtOAc to obtain the title compound 8-bromo-3,6-dimethyl-1H-quinazoline-2,4-dione (18 g, 85% yield) as a solid. MS: (ES + ) m / z = 269.0 [M+H] + .

[0122] Project 3: Preparation of 8-bromo-2-chloro-3,6-dimethylquinazolin-4-one A solution of a mixture of 8-bromo-3,6-dimethyl-1H-quinazoline-2,4-dione (2.9 g, 10.78 mmol) and DIEA (7.51 mL, 43.11 mmol) in POCl3 (13.2 mL, 141.4 mmol) was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, quenched with water (100 mL), and then neutralized to pH = 7 with NaHCO3. The resulting solution was extracted with DCM (3 × 30 mL), and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a PE solution of 0 - 50% EtOAc to give 8-bromo-2-chloro-3,6-dimethylquinazolin-4-one (800 mg, 26% yield) as a solid. 1 H NMR (chloroform-d, 300 MHz): δ 7.90 (dd, J=2.0, 0.9 Hz, 1H), 7.85 - 7.79 (m, 1H), 3.73 (s, 3H), 2.43 (s, 3H), MS: (ES + ) m / z = 287.0 [M+H] + .

[0123] Intermediate 2: tert-Butyl 2-(2-nitrobenzenesulfonamido)benzoate

Chemical formula

[0124] Intermediate 3: Methyl 2-(2,4-dinitrobenzenesulfonamido)benzoate

Chemical Structure

[0125] Intermediates 4, 5, 6 and 7

Chem.

[0126] Example 1: 2-((1-(2-(4,4-Dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0127] Example 2: 2-((1-(2-(4,4-Dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2).

Chem.

[0128] Project 2: Preparation of 8-acetyl-2-(4,4-dimethyl-1,4-azasilan-1-yl)-3,6-dimethylquinazolin-4-one To a solution of 8-bromo-2-(4,4-dimethyl-1,4-azasilan-1-yl)-3,6-dimethylquinazolin-4-one (800 mg, 2.1 mmol) and tributyl(1-ethoxyvinyl)tin (836 mg, 2.3 mmol) in dioxane (10 mL) was added Pd(PPh3)4 (266 mg, 0.23 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature. 1M HCl (2 mL) was added to the above mixture. The resulting mixture was stirred at 50 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 1:1) to give 8-acetyl-2-(4,4-dimethyl-1,4-azasilan-1-yl)-3,6-dimethylquinazolin-4-one (600 mg, 83% yield) as a light yellow solid. MS: (ES + ) m / z = 344.2 [M+H] + .

[0129] Project 3: Preparation of 2-(4,4-dimethyl-1,4-azasilan-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one A solution of 8-acetyl-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-dimethylquinazolin-4-one (600 mg, 1.74 mmol) and NaBH4 (264 mg, 6.98 mmol) in MeOH (5 mL) was stirred at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 1:1) to give 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one (400 mg, 66% yield) as a white solid. MS: (ES + ) m / z = 346.6 [M+H] + .

[0130] Project 4: Preparation of tert-butyl 2-((N-(1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-nitrophenyl)sulfonamido)benzoate A solution of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one (400 mg, 1.15 mmol), PPh3 (759 mg, 2.89 mmol) and tert-butyl 2-(2-nitrobenzenesulfonamido)benzoate (Intermediate 2) (657 mg, 1.73 mmol) in THF (5 mL) was cooled to 0 °C, and then a solution of DBAD (800 mg, 3.47 mmol) in THF (5 mL) was added dropwise. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere, then quenched with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC eluting with DCM:MeOH = 20:1 to give tert-butyl 2-((N-(1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-nitrophenyl)sulfonamido)benzoate (500 mg, 61% yield) as a solid. MS: (ES +) m / z = 706.3 [M+H] + .

[0131] Project 5: Preparation of tert-butyl 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate A solution of a mixture of tert-butyl 2-((N-(1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-nitrophenyl)sulfonamido)benzoate (300 mg, 0.42 mmol), K2CO3 (174 mg, 1.3 mmol) and potassium thiophenolate (252 mg, 1.7 mmol) in DMF (10 mL) was stirred at 60 °C for 3 hours. The solution was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure and purified by preparative TLC using PE:EtOAc = 2:1 to give tert-butyl 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (180 mg, 81% yield) as a solid. MS: (ES + ) m / z = 521.2 [M+H] + .

[0132] Project 6: Preparation of 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid tert-Butyl 2-((1-(2-(4,4-dimethyl-1,4-azasila-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (180 mg, 0.35 mmol) and HCl (4 M in 1,4-dioxane, 5 mL) solution were stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and purified by preparative TLC eluting with DCM:MeOH = 10:1 to afford 2-((1-(2-(4,4-dimethyl-1,4-azasila-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (100 mg, 62% yield) as a solid. MS: (ES + ) m / z = 465.3 [M+H] + .

[0133] Project 7: Example 1 Preparation of 2-((1-(2-(4,4-dimethyl-1,4-azasila-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1; and Example 2 Preparation of 2-((1-(2-(4,4-dimethyl-1,4-azasila-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 A racemic mixture of 2-((1-(2-(4,4-dimethyl-1,4-azasila-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (100 mg, 0.22 mmol) was resolved by chiral preparative HPLC (column: Chiralpak IF, 2×25 cm, 5 μm; mobile phase: hexane (0.1% FA):EtOH = 95:5; flow rate: 20 mL / min) to afford the title compound Example 1: 2-((1-(2-(4,4-dimethyl-1,4-azasila-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1 (34.6 mg, 39% yield, >99% ee)( 11H NMR (DMSO-d6, 300 MHz): δ 12.63 (s, 1H), 8.43 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.21 - 7.09 (m, 1H), 6.52 - 6.36 (m, 2H), 5.46 - 5.31 (m, 1H), 3.54 - 3.39 (m, 7H), 2.30 (s, 3H), 1.53 (d, J = 6.6 Hz, 3H), 1.02 - 0.79 (m, 4H), 0.12 (s, 6H), MS: (ES - ) m / z = 463.2 [M-H] - ) and Example 2: 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (21 mg, 23% yield, >99% ee)( 1 1H NMR (DMSO-d6, 300 MHz): δ 12.60 (s, 1H), 8.43 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.20 - 7.09 (m, 1H), 6.51 - 6.37 (m, 2H), 5.46 - 5.31 (m, 1H), 3.53 - 3.40 (m, 7H), 2.30 (s, 3H), 1.53 (d, J = 6.6 Hz, 3H), 1.00 - 0.81 (m, 4H), 0.12 (s, 6H), MS: (ES - ) m / z = 463.2 [M-H] - ) was obtained.

[0134] Example 3: 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0135] Example 4: 2-((1-(2-(3,3-Dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2). [Chemical formula] Project 1: Production of 8-bromo-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4-one A solution of a mixture of 8-bromo-2-chloro-3,6-dimethylquinazolin-4-one (intermediate 1) (700 mg, 2.43 mmol), 3,3-dimethylpiperidine hydrochloride (437 mg, 2.92 mmol) and DIEA (629 mg, 4.87 mmol) in ACN (7 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc = 2:1 to give 8-bromo-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4-one (700 mg, 79% yield). MS: (ES + ) m / z = 364.1 [M+H] + .

[0136] Project 2: Production of 8-acetyl-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4-one This step was carried out in a manner similar to that of Example 1, Step 2, using PdCl2(PPh3)2 as a catalyst instead of Pd(PPh3)4 to give 8-acetyl-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4-one (600 mg, 95% yield). MS: (ES + ) m / z = 328.1 [M+H] + .

[0137] Project 3:Production of 2-(3,3-Dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one This step was carried out in a manner similar to that in Example 1, Step 3 to obtain 2-(3,3-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one (350 mg, 86% yield). MS: (ES + ) m / z = 330.1 [M+H] + .

[0138] Project 4: Production of Methyl 2-((1-(2-(3,3-Dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate A solution of a mixture of 2-(3,3-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one (600 mg, 1.82 mmol), methyl 2-(2,4-dinitrobenzenesulfonamido)benzoate (Intermediate 3) (1.04 g, 2.73 mmol) and PPh3 (717 mg, 2.73 mmol) in THF (6 mL) was cooled to 0 °C, and then DBAD (629 mg, 2.73 mmol) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. The 2,4-dinitrobenzenesulfonyl group was removed simultaneously during the reaction. The reaction was diluted with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE:EtOAc = 5:2 to obtain methyl 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (600 mg, 71% yield). MS: (ES + ) m / z = 463.3 [M+H] + .

[0139] Project 5:Example 3 Preparation of 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1; and Example 4 Preparation of 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 2 A solution of methyl 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (540 mg, 1.16 mmol) in THF (6 mL) was treated at room temperature with a solution of LiOH (1.40 g, 58.35 mmol) in water (6 mL). The resulting mixture was stirred at 90 °C for 2 days under a nitrogen atmosphere. The mixture was acidified to pH = 3 with 6M aqueous HCl, and the resulting mixture was extracted with DCM (5 × 50 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: 60 - 100% aqueous ACN for 20 minutes). The racemic product was separated by chiral preparative HPLC (column: Chiralpak IF, 2 × 25 cm, 5 μm; mobile phase: hexane (0.1% FA):EtOH = 95:5; flow rate: 20 mL / min) to give the title compound Example 3: 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1 (57 mg, 11% yield, >99% ee)( 11H NMR (methanol-d4, 300 MHz): δ 7.87 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 7.16 - 7.02 (m, 1H), 6.55 - 6.39 (m, 2H), 5.61 - 5.43 (m, 1H), 3.61 (s, 3H), 3.27 - 3.10 (m, 2H), 2.96 (s, 2H), 2.34 (s, 3H), 1.94 - 1.76 (m, 2H), 1.60 (d, J = 6.7 Hz, 3H), 1.54 - 1.43 (m, 2H), 1.08 (s, 3H), 1.07 (s, 3H), MS: (ES + ) m / z = 449.2 [M+H] + ) and Example 4: 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (65 mg, 12% yield, 98% ee)( 1 1H NMR (methanol-d4, 300 MHz): δ 7.87 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 7.18 - 7.00 (m, 1H), 6.55 - 6.39 (m, 2H), 5.57 - 5.44 (m, 1H), 3.61 (s, 3H), 3.27 - 3.11 (m, 2H), 2.96 (s, 2H), 2.34 (s, 3H), 1.94 - 1.76 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H), 1.54 - 1.41 (m, 2H), 1.08 (s, 3H), 1.07 (s, 3H), MS: (ES + ) m / z = 449.2 [M+H] + ) was obtained.

[0140] Example 5: 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1; and

[0141] Example 6: 2-((1-(3,6-Dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 [Chemical formula] Project 1: Preparation of 8-Bromo-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one Using a method similar to that in Step 1 of Example 1, with 2-azaspiro[3.5]nonane as the amine, 8-bromo-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one (1.35 g, 52% yield) was obtained as a solid. MS: (ES + ) m / z = 376.1 [M+H] + .

[0142] Project 2: Preparation of 8-Acetyl-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one This step was carried out in a method similar to that in Step 2 of Example 1 to obtain 8-acetyl-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one (1 g, 82% yield) as a solid. MS: (ES + ) m / z = 340.2 [M+H] + .

[0143] Project 3: Preparation of 8-(1-Hydroxyethyl)-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one This step was carried out in a method similar to that in Step 3 of Example 1 to obtain 8-(1-hydroxyethyl)-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one (450 mg, 44% yield) as a solid. MS: (ES + ) m / z = 342.1 [M+H] + .

[0144] Project 4: Production of tert-butyl 2-((N-(1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-nitrophenyl)sulfonamido)benzoate It was carried out in a manner similar to Step 4 of Example 1 to obtain tert-butyl 2-((N-(1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-nitrophenyl)sulfonamido)benzoate (625 mg, 76% yield) as a solid. MS: (ES + ) m / z = 702.3 [M+H] + .

[0145] Project 5: Production of tert-butyl 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate It was carried out in a manner similar to Step 5 of Example 1 to obtain tert-butyl 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (200 mg, 53% yield) as a solid. MS: (ES + ) m / z = 517.3 [M+H] + .

[0146] Project 6: Production of 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid It was carried out in a manner similar to Step 6 of Example 1 to obtain 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (110 mg, 62% yield) as a solid. MS: (ES+ ) m / z = 461.2 [M+H] + .

[0147] Project 7: Example 5 Preparation of 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1; and Example 6 Preparation of 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 2 A racemic mixture of 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (110 mg, 0.24 mmol) was purified by chiral preparative HPLC (column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase: hexane (0.1% FA):EtOH = 93:7; flow rate: 20 mL / min). The relevant fractions were concentrated to give the title compound Example 5: 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1 (8.0 mg, 8% yield, >99% ee)( 1 H NMR (DMSO-d6, 300 MHz): δ 8.44 (s, 1H), 7.85 - 7.74 (m, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 7.23 - 7.10 (m, 1H), 6.56 - 6.41 (m, 2H), 5.46 - 5.28 (m, 1H), 3.94 (s, 4H), 3.40 (s, 3H), 2.28 (s, 3H), 1.79 - 1.60 (m, 4H), 1.54 (d, J=6.6 Hz, 3H), 1.50 - 1.19 (m, 6H), MS: (ES + ) m / z = 461.2 [M+H] +) and Example 6: (2-((1-(3,6-Dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (10.2 mg, 10% yield, >99% ee)( 1 H NMR (DMSO-d6, 300 MHz): δ 8.43 (s, 1H), 8.00 - 7.73 (m, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 7.32 - 7.05 (m, 1H), 6.66 - 6.34 (m, 2H), 5.55 - 5.23 (m, 1H), 3.95 (s, 4H), 3.40 (s, 3H), 2.29 (s, 3H), 1.81 - 1.60 (m, 4H), 1.55 (d, J = 6.5 Hz, 3H), 1.50 - 1.13 (m, 6H), MS: (ES + ) m / z = 461.1 [M+H] + ) was obtained.

[0148] Example 7: 2-((1-(2-(5-Methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1; and

[0149] Example 8: 2-((1-(2-(5-Methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2

Chemical Structure

[0150] Project 2: Preparation of 8-acetyl-2-(5-methoxy-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one This step was carried out in a manner similar to Example 1, Step 2, using PdCl2(PPh3)2 as a catalyst instead of Pd(PPh3)4 to give 8-acetyl-2-(5-methoxy-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one (560 mg, 62% yield) as a solid. MS: (ES + ) m / z = 364.2 [M+H] + .

[0151] Project 3: Preparation of 8-(1-hydroxyethyl)-2-(5-methoxy-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one A mixture of 8-acetyl-2-(5-methoxy-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one (500 mg, 1.38 mmol) and MeOH (5 mL) was cooled to 0 °C and treated with NaBH4 (260 mg, 6.88 mmol). The mixture was heated to 80 °C and stirred overnight. The resulting mixture was cooled to room temperature, diluted with water (30 mL), and then extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (C18 silica gel; 10% - 80% aqueous MeOH for 40 min) to give 8-(1-hydroxyethyl)-2-(5-methoxy-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one (200 mg, 40% yield) as a solid. MS: (ES + ) m / z = 366.2 [M+H] + .

[0152] Project 4: Preparation of methyl 2-((1-(2-(5-methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate To a 40 mL vial were added 8-(1-hydroxyethyl)-2-(5-methoxy-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one (200 mg, 0.547 mmol), THF (5 mL), methyl anthranilate (124 mg, 0.82 mmol) and PPh3 (359 mg, 1.37 mmol). A solution of DBAD (315 mg, 1.37 mmol) in THF (5 mL) was added to the mixture at 0 °C, and the mixture was stirred at room temperature overnight under N2. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA = 3:1) to give the crude product. The crude product was purified by reverse-phase flash under the following conditions to give methyl 2-((1-(2-(5-methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (40 mg, 15% yield) as a white solid. MS: (ES + ) m / z = 499.2 [M+H] + .

[0153] Project 5: Example 11 Preparation of 2-((1-(2-(5-methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1; and Example 12 Preparation of 2-((1-(2-(5-methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 A solution of a mixture of methyl 2-((1-(2-(5-methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (60 mg, 0.12 mmol) and LiOH hydrate (101 mg, 2.40 mmol) in THF (1 mL) and water (1 mL) was stirred at room temperature overnight. The mixture was acidified to pH = 6 with 1M aqueous HCl and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: 5 - 100% aqueous ACN for 40 minutes) to obtain the racemic product, which was further purified by chiral preparative HPLC (column: Chiralpak IF, 2 × 25 cm, 5 μm; mobile phase: hexane (0.1% FA):EtOH = 9:1; flow rate: 20 mL / min) to give the title compound Example 7: 2-((1-(2-(5-methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1 (5.8 mg, 10% yield, 98% ee)( 1 H NMR (methanol-d4, 300 MHz): δ 7.87 (dd, J = 8.0, 1.7 Hz, 1H), 7.76 (dd, J = 2.1, 1.0 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.06 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.3, 2.4 Hz, 1H), 6.52 - 6.39 (m, 2H), 5.50 (q, J = 6.6 Hz, 1H), 5.03 (td, J = 19.0, 18.6, 14.7 Hz, 4H), 3.80 (s, 3H), 3.70 (s, 3H), 2.32 (s, 3H), 1.61 (d, J = 6.7 Hz, 3H), MS: (ES + ) m / z = 485.2 [M+H] +) and Example 8: 2-((1-(2-(5-Methoxyisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 2 (6.8 mg, 11% yield, 99% ee)( 1 H NMR (methanol-d4, 300 MHz): δ 7.87 (dd, J=8.0, 1.7 Hz, 1H), 7.76 (dd, J=2.1, 1.0 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.05 (ddd, J=8.7, 7.1, 1.7 Hz, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.87 (dd, J=8.3, 2.4 Hz, 1H), 6.52 - 6.39 (m, 2H), 5.50 (q, J=6.6 Hz, 1H), 5.04 (td, J=19.0, 18.6, 14.7 Hz, 4H), 3.79 (s, 3H), 3.69 (s, 3H), 2.32 (s, 3H), 1.61 (d, J=6.7 Hz, 3H), MS: (ES + ) m / z = 485.2 [M+H] + ) was obtained.

[0154] Example 9: 2-((1-(2-(5-Chloroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1; and

[0155] Example 10: 2-((1-(2-(5-Chloroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 2

Chemical formula

[0156] Project 2: Production of 8-acetyl-2-(5-chloro-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one This step was carried out in a method similar to that of Step 2 of Example 1 to obtain 8-acetyl-2-(5-chloro-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one (2 g, 78% yield) as a solid. MS: (ES + ) m / z = 368.1 [M+H] + .

[0157] Project 3: Production of 2-(5-chloro-1,3-dihydroisoindol-2-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one It was carried out in a method similar to that of Step 3 of Example 1 to obtain 2-(5-chloro-1,3-dihydroisoindol-2-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one (483 mg, 24% yield) as a solid. MS: (ES + ) m / z = 370.1 [M+H] + .

[0158] Project 4: Production of methyl 2-((1-(2-(5-chloroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate Example 1 was carried out in a method similar to Step 4 to obtain methyl 2 - ((1 - (2 - (5 - chloroisoindolin - 2 - yl) - 3,6 - dimethyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoate (181 mg, 44% yield) as an oil. MS: (ES + ) m / z = 503.1 [M+H] + .

[0159] Project 5: Example 9 Preparation of 2 - ((1 - (2 - (5 - chloroisoindolin - 2 - yl) - 3,6 - dimethyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid, Enantiomer 1; and Example 10 Preparation of 2 - ((1 - (2 - (5 - chloroisoindolin - 2 - yl) - 3,6 - dimethyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid, Enantiomer 2 Example 1 was carried out in a method similar to Step 5 to prepare racemic 2 - ((1 - (2 - (5 - chloroisoindolin - 2 - yl) - 3,6 - dimethyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid, which was then separated by chiral preparative HPLC (column: Chiralpak IF, 2×25 cm, 5 μm; mobile phase: hexane (0.1% FA): IPA = 9:1; flow rate: 20 mL / min) to give the title compound Example 9: 2 - ((1 - (2 - (5 - chloroisoindolin - 2 - yl) - 3,6 - dimethyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid, Enantiomer 1 (17 mg, 11% yield, >99% ee)( 11H NMR (methanol-d4, 300 MHz): δ 7.86 (dd, J = 7.9, 1.7 Hz, 1H), 7.76 (dd, J = 2.0, 1.0 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.39 - 7.23 (m, 3H), 7.03 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 6.50 - 6.35 (m, 2H), 5.47 (q, J = 6.7 Hz, 1H), 5.14 - 4.91 (m, 4H), 3.67 (s, 3H), 2.32 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H), MS: (ES + ) m / z = 489.2 [M+H] + ) and Example 10: 2-((1-(2-(5-chloroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (14 mg, 9% yield, 99% ee)( 1 1H NMR (methanol-d4, 300 MHz): δ 7.86 (dd, J = 7.9, 1.7 Hz, 1H), 7.76 (dd, J = 2.0, 1.0 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.40 - 7.21 (m, 3H), 7.04 (ddd, J = 8.6, 7.1, 1.6 Hz, 1H), 6.51 - 6.34 (m, 2H), 5.48 (q, J = 6.6 Hz, 1H), 5.11 - 4.91 (m, 4H), 3.68 (s, 3H), 2.32 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H), MS: (ES + ) m / z = 489.2 [M+H] + ) was obtained.

[0160] Example 11: 2-((1-(2-isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1; and

[0161] Example 12: 2-((1-(2-Isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 [Chemical formula] Project 1: Production of 8-Bromo-2-isobutoxy-3,6-dimethylquinazolin-4(3H)-one A solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4-one (Intermediate 1) (170 mg, 0.59 mmol) in DMF (6 mL) was treated with NaH (36 mg, 0.89 mmol) by stirring at room temperature for 30 minutes, and then isobutanol (53 mg, 0.71 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then quenched with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with PE:EtOAc = 10:1 to give the title product 8-bromo-2-isobutoxy-3,6-dimethylquinazolin-4(3H)-one as a solid (160 mg, 83% yield). MS: (ES + ) m / z = 325.0 [M+H] + .

[0162] Project 2: Production of 8-Acetyl-3,6-dimethyl-2-(2-methylpropoxy)quinazolin-4-one Prepared in a manner similar to Step 2 of Example 1 to give the title product 8-acetyl-3,6-dimethyl-2-(2-methylpropoxy)quinazolin-4-one as a solid (120 mg, 71% yield). MS: (ES + ) m / z = 289.1 [M+H] + .

[0163] Project 3: Production of 8-(1-Hydroxyethyl)-3,6-dimethyl-2-(2-methylpropoxy)quinazolin-4-one Example 1. Prepared in a manner similar to Step 3 to obtain the title product 8-(1-hydroxyethyl)-3,6-dimethyl-2-(2-methylpropoxy)quinazolin-4-one as a solid (120 mg, 99% yield). MS: (ES + ) m / z = 291.1 [M+H] + .

[0164] Project 4: Preparation of Methyl 2-((1-(2-isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate A solution of a mixture of 8-(1-hydroxyethyl)-3,6-dimethyl-2-(2-methylpropoxy)quinazolin-4-one (110 mg, 0.38 mmol) and Et3N (230 mg, 2.27 mmol) in DCM (6 mL) was cooled to 0 °C, then Ms2O (427 mg, 1.52 mmol) was added, and the mixture was stirred for 1 h while warming to room temperature. Methyl anthranilate (54 mg, 0.36 mmol) was added, and the reaction mixture was warmed to 50 °C and stirred overnight. The reaction was quenched by the addition of water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography eluting with DCM:MeOH = 10:1 to obtain the title product methyl 2-((1-(2-isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate as a solid (128 mg, 80% yield). MS: (ES + ) m / z = 424.2 [M+H] + .

[0165] Project 5: Example 11: Preparation of 2-((1-(2-isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1; and Example 12: Preparation of 2-((1-(2-isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 The racemic product 2-((1-(2-isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid was prepared in a method similar to that of Example 1, Step 5, and then separated by chiral preparative HPLC (column: Chiralpak IF, 2×25 cm, 5 μm; mobile phase: hexane (0.1% FA): IPA = 98:2; flow rate: 20 mL / min) to obtain Example 11: 2-((1-(2-isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1 (3.5 mg, 19% yield, >99% ee)( 1 H NMR (methanol-d4, 300 MHz): δ 7.88 (dd, J=7.9 Hz, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.48 (t, J=7.5 Hz, 1H), 6.43 (d, J=8.4 Hz, 1H), 5.45 (q, J=13.5 Hz, 1H), 4.37 (dd, J=6.6 Hz, 2H), 3.54 (s, 3H), 2.34 (s, 3H), 2.30 - 2.15 (m, 1H), 1.60 (d, J=6.6 Hz, 3H), 1.08 (d, J=1.2 Hz, 6H), MS (ES + ) m / z = 410.2 [M+H] + ) and Example 12: 2-((1-(2-isobutoxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 2 (4.5 mg, 25% yield, 95% ee)( 11H NMR (methanol-d4, 300 MHz): δ 7.88 (dd, J = 7.9 Hz, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.48 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.45 (q, J = 13.5 Hz, 1H), 4.37 (dd, J = 6.6 Hz, 2H), 3.54 (s, 3H), 2.34 (s, 3H), 2.30 - 2.15 (m, 1H), 1.60 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 1.2 Hz, 6H), MS (ES + ) m / z = 410.2 [M+H] + ) was obtained.

[0166] Example 13: 5-Chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1; and

[0167] Example 14: 5-Chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2

Chemical Structure

[0168] Project 2: Preparation of 8-acetyl-2-(5-fluoro-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one It was carried out in a method similar to that of Step 2 of Example 1 to obtain the title compound 8-acetyl-2-(5-fluoro-1,3-dihydroisoindol-2-yl)-3,6-dimethylquinazolin-4-one (300 mg, 40% yield) as a solid. MS: (ES + ) m / z = 352.1 [M+H] + .

[0169] Project 3: Preparation of 2-(5-fluoro-1,3-dihydroisoindol-2-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one It was carried out in a method similar to that of Step 3 of Example 1 to obtain 2-(5-fluoro-1,3-dihydroisoindol-2-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4-one (284 mg, 91% yield) as an oil. MS: (ES + ) m / z = 354.2 [M+H] + .

[0170] Project 4: Preparation of methyl 5-chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate It was carried out in a method similar to that of Step 4 of Example 7 to obtain methyl 5-chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (334 mg, 65% yield) as an oil. MS: (ES + ) m / z = 521.1 [M+H] + .

[0171] Project 5:Example 13: 5-Chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1; and Example 14: 5-Chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 2 Preparation The racemic product 5-chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid was prepared in a manner similar to Example 1, Step 5, and then separated by chiral preparative HPLC (column: Lux 5μm Cellulose-4, 2.12×25 cm, 5μm; mobile phase: hexane (0.1% FA): EtOH = 80:20; flow rate: 20 mL / min) to obtain the title compound Example 13: 5-chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1 (32.6 mg, 10% yield, >99% ee) as a solid ( 1 H NMR (methanol-d4, 300 MHz): δ 7.84 - 7.65 (m, 2H), 7.44 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 8.3, 4.9 Hz, 1H), 7.13 - 6.82 (m, 3H), 6.40 (d, J = 9.1 Hz, 1H), 5.43 (q, J = 6.6 Hz, 1H), 5.07 - 4.87 (m, 4H), 3.65 (s, 3H), 2.31 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H), MS: (ES + ) m / z = 507.2 [M+H] + ) and Example 14: 5-chloro-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 2 (51 mg, 15% yield, 99% ee)( 11H NMR (methanol-d4, 300 MHz): δ 7.84 - 7.65 (m, 2H), 7.44 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 8.4, 4.9 Hz, 1H), 7.13 - 6.92 (m, 3H), 6.40 (d, J = 9.1 Hz, 1H), 5.43 (q, J = 6.6 Hz, 1H), 5.14 - 4.89 (m, 4H), 3.65 (s, 3H), 2.31 (s, 3H), 1.58 (d, J = 6.7 Hz, 3H), MS: (ES + ) m / z = 507.2 [M+H] + ) was obtained.

[0172] Example 15: 5-Cyano-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1; and

[0173] Example 16: 5-Cyano-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2

Chemical Structure

[0174] Project 2: Production of 5-cyano-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomers 1 and 2 To a stirred solution of methyl 5-cyano-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (130 mg, 0.27 mmol) in THF (5 mL) and water (5 mL) was added LiOH hydrate (447 mg, 10.7 mmol). The reaction mixture was warmed to 50 °C, stirred for 12 h, then diluted with water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: 10 - 100% aqueous ACN for 30 min) to isolate the racemic product 5-cyano-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (90 mg, 71% yield) as a solid, which was then separated by chiral preparative HPLC (column: Chiralpak IE, 2 × 25 cm, 5 μm; mobile phase: hexane (0.1% FA):EtOH = 80:20; flow rate: 20 mL / min) to give Example 15: 5-cyano-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1 (36.4 mg, 29% yield, >99% ee) as a solid ( 11H NMR (methanol-d4, 300 MHz): δ 8.18 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 2.0, 0.9 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 8.9, 2.1 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H), 5.53 (q, J = 6.7 Hz, 1H), 3.58 (s, 3H), 3.32 - 3.23 (m, 4H), 2.37 (s, 3H), 1.66 (d, J = 6.7 Hz, 3H), 1.63 - 1.53 (m, 4H), 1.06 (s, 6H), MS: (ES + ) m / z = 474.2 [M+H] + ) and Example 16: 5-Cyano-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 2 (34.3 mg, 26% yield, 99% ee)( 1 1H NMR (methanol-d4, 300 MHz): δ 8.18 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 2.1, 0.9 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 8.9, 2.1 Hz, 1H), 6.62 (d, J = 9.0 Hz, 1H), 5.53 (q, J = 6.7 Hz, 1H), 3.58 (s, 3H), 3.33 - 3.23 (m, 4H), 2.37 (s, 3H), 1.66 (d, J = 6.7 Hz, 3H), 1.63 - 1.54 (m, 4H), 1.06 (s, 6H) MS: (ES + ) m / z = 474.2 [M+H] + ) was obtained.

[0175] Example 17: 2-((1-(2-(5-Cyanoisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, Enantiomer 1; and

[0176] Example 18: 2-((1-(2-(5-Cyanoisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 [Chemical formula] Project 1: Production of methyl 2-((1-(2-(5-cyanoisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate To a solution of methyl 2-((1-(2-(5-chloroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (550 mg, 1.09 mmol) and tBuXphos Pd G3 (174 mg, 0.22 mmol) in H2O (2 mL) and DMF (4 mL), t-BuXphos (93 mg, 0.22 mmol) and Zn(CN)2 (154 mg, 1.3 mmol) were added. The resulting mixture was stirred at 70 °C for 12 hours under a N2 atmosphere. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to obtain methyl 2-((1-(2-(5-cyanoisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (350 mg, 65% yield) as a solid. MS: (ES + ) m / z = 494.3 [M+H] + .

[0177] Project 2: Production of 2-((1-(2-(5-cyanoisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomers 1 and 2 The title compound was produced using a method similar to that described in Example 7, Step 5, to give Example 17: 2-((1-(2-(5-cyanoisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1 (6.4 mg, 3% yield, 99% ee)( 1 H NMR (methanol-d4, 300 MHz): δ 7.91 - 7.82 (m, 1H), 7.82 - 7.72 (m, 2H), 7.72 - 7.64 (m, 1H), 7.60 - 7.45 (m, 2H), 7.14 - 7.02 (m, 1H), 6.53 - 6.39 (m, 2H), 5.55 - 5.42 (m, 1H), 5.22 - 5.00 (m, 4H), 3.71 (s, 3H), 2.34 (s, 3H), 1.62 (d, J = 6.7 Hz, 3H), MS: (ES + ) m / z = 480.1 [M+H] + ) and Example 18: 2-((1-(2-(5-cyanoisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (6.3 mg, 3% yield, >95% ee)( 1 H NMR (methanol-d4, 300 MHz): δ 7.91 - 7.82 (m, 1H), 7.82 - 7.72 (m, 2H), 7.72 - 7.64 (m, 1H), 7.60 - 7.45 (m, 2H), 7.14 - 7.04 (m, 1H), 6.54 - 6.40 (m, 2H), 5.55 - 5.42 (m, 1H), 5.22 - 5.01 (m, 4H), 3.71 (s, 3H), 2.35 (s, 3H), 1.62 (d, J = 6.7 Hz, 3H), MS: (ES + ) m / z = 480.1 [M+H] + ) were obtained.

[0178] Example 19: 2-((1-(2-(5-carbamoylisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid.

Chemical formula

Chemical formula

[0179] Example 20: 2-((1-(7-Fluoro-3,6-dimethyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0180] Example 21: 2-((1-(7-Fluoro-3,6-dimethyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2)

Chemical formula

[0181] Project 2: Preparation of 6-amino-2-fluoro-N,3-dimethylbenzamide To a 1000 mL round-bottom flask, 6-amino-3-bromo-2-fluoro-N-methylbenzamide (19.3 g, 19.5 mmol), dioxane (360 mL), H2O (40 mL), methylboronic acid (8 g, 33.4 mmol), K3PO4 (49.8 g, 58.7 mmol) and Pd(dppf)Cl2 (2.86 g, 0.98 mmol) were added. The mixture was stirred at 110 °C for 2 hours under a N2 atmosphere. The reaction was quenched with water (400 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 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 = 1:1) to obtain 6-amino-2-fluoro-N,3-dimethylbenzamide (8.40 g, 59% yield) as a white solid. MS: (ES + ) m / z = 183.1 [M+H] + .

[0182] Project 3: Preparation of 2-amino-3-bromo-4-fluoro-N,5-dimethylbenzamide To a 500 mL round-bottom flask, 2-amino-4-fluoro-N,5-dimethylbenzamide (8.4 g, 46.1 mmol), MeCN (100 mL) and NBS (8.21 g, 46.1 mmol) were added. The mixture was stirred at 75 °C for 4 h. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 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 = 1:1) to afford 2-amino-3-bromo-4-fluoro-N,5-dimethylbenzamide (14.6 g, >95% crude yield) as a pale yellow solid. MS: (ES + ) m / z = 263.0 [M+H] + .

[0183] Project 4: Preparation of 2-((1-(7-fluoro-3,6-dimethyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomers 1 and 2) The title compound was prepared from 2-amino-3-bromo-4-fluoro-N,5-dimethylbenzamide using a method similar to that described in Examples 7 and 8 via a method similar to that described for Intermediate 1 (Steps 2 and 3) using 8-bromo-2-chloro-7-fluoro-3,6-dimethylquinazolin-4(3H)-one obtained from 2-amino-3-bromo-4-fluoro-N,5-dimethylbenzamide. Example 20: 2-((1-(7-fluoro-3,6-dimethyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1) (15.6 mg, 7% yield, >99% ee)( 11H NMR (400 MHz, methanol-d4) δ 7.89 - 7.82 (m, 2H), 7.21 - 7.17 (m, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.52 - 6.44 (m, 1H), 5.68 (d, J=7.3 Hz, 1H), 3.58 (s, 3H), 3.52 - 3.43 (m, 4H), 3.25 - 3.15 (m, 2H), 3.00 - 2.94 (m, 4H), 2.33 (d, J=2.4 Hz, 3H), 1.76 (d, J=6.9 Hz, 3H), MS: (ES + ) m / z = 522.4 [M+H] + ) and Example 21: 2-((1-(7-Fluoro-3,6-dimethyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2) (18.9 mg, 9% yield, 98.4% ee)( 1 1H NMR (400 MHz, methanol-d4) δ 7.89 - 7.82 (m, 2H), 7.21 - 7.17 (m, 1H), 6.83 d, J=8.5 Hz, 1H), 6.52 - 6.44 (m, 1H), 5.68 (m, 1H), 3.58 (s, 3H), 3.52 - 3.44 (m, 4H), 3.25 - 3.15 (m, 2H), 3.00 - 2.94 (m, 4H), 2.33 (d, J=2.1 Hz, 3H), 1.76 (d, J=6.9 Hz, 3H), MS: (ES + ) m / z = 522.4 [M+H] + ) was obtained.

[0184] Example 22: 2-((1-(6-Chloro-2-(4,4-dimethylpiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0185] Example 23: 2-((1-(6-Chloro-2-(4,4-dimethylpiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2)

Chemical formula

[0186] Example 24: 2-((1-(6-Chloro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (enantiomer 1); and

[0187] Example 25: 2-((1-(6-Chloro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (enantiomer 2)

Chem.

[0188] Example 26: 2-((1-(6-chloro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0189] Example 27: 2-((1-(6-Chloro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2) [Chemical formula] The title compound was prepared using Intermediate 5 by a method similar to that described in Examples 7 and 8 to give Example 26: 2-((1-(6-Chloro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1) (31.4 mg, 18% yield, 99% ee) as a white solid( 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.25 - 7.20 (m, 1H), 6.52 - 6.48 (m, 1H), 6.44 - 6.40 (m, 1H), 5.38 - 5.25 (m, 1H), 3.48 (s, 3H), 3.30 - 3.20 (m, 6H), 2.90 - 2.85 (m, 4H), 1.59 (d, J = 6.5 Hz, 3H), MS: (ES + ) m / z = 524.1 [M+H] + ) and Example 27: 2-((1-(6-Chloro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (36.6 mg, 21% yield, 99% ee) as a white solid( 11H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.25 - 7.20 (m, 1H), 6.52 - 6.48 (m, 1H), 6.44 - 6.40 (m, 1H), 5.38 - 5.25 (m, 1H), 3.48 (s, 3H), 3.30 - 3.18 (m, 6H), 2.90 - 2.85 (m, 4H), 1.59 (d, J = 6.5 Hz, 3H), MS: (ES + ) m / z = 524.1 [M+H] + ) was obtained as

[0190] Example 28: 2-((1-(2-(4,4-Dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-fluorobenzoic acid

Chemical formula

[0191] Example 29: 2-((1-(2-(4,4-Dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (enantiomer 1); and

[0192] Example 30: 2-((1-(2-(4,4-Dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (enantiomer 2)

Chemical formula

[0193] Example 31: 2-((1-(2-((4-chloro-3-(trifluoromethoxy)benzyl)thio)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, (enantiomer 1); and

[0194] Example 32: 2-((1-(2-((4-chloro-3-(trifluoromethoxy)benzyl)thio)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, (enantiomer 2)

Chemical formula

[0195] Project 2: Production of 8-acetyl-3,6-dimethyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one A solution of 8-bromo-3,6-dimethyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (10 g, 35.1 mmol) in dioxane (100 mL) was treated with tributyl(1-ethoxyethenyl)stannane (25.4 g, 70.1 mmol) for 3 minutes at room temperature under an argon atmosphere, and then Pd(PPh3)4 (8.1 g, 7 mmol) was added portionwise at room temperature. The resulting mixture was stirred overnight at 100 °C under an argon atmosphere. Aqueous 1N HCl (100 mL) was added dropwise to the above mixture over 1 minute at room temperature. The resulting mixture was stirred at 50 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. Thereby, 8-acetyl-3,6-dimethyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2 g, 23% yield) was obtained as a pale yellow solid. MS: (ES + ) m / z = 249.2 [M+H] + .

[0196] Project 3: Preparation of 8-acetyl-2-((4-chloro-3-(trifluoromethoxy)benzyl)thio)-3,6-dimethylquinazolin-4(3H)-one A solution of 8-acetyl-3,6-dimethyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2 g, 8.1 mmol) in THF (100 mL) was treated with 4-(bromomethyl)-1-chloro-2-(trifluoromethoxy)benzene (2.45 g, 8.5 mmol) for 1 minute at room temperature under an argon atmosphere, and then Cs2CO3 (5.27 g, 16.1 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C for 2 hours under an argon atmosphere. The resulting mixture was filtered to remove solids and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH2Cl2) to obtain 8-acetyl-2-((4-chloro-3-(trifluoromethoxy)benzyl)thio)-3,6-dimethylquinazolin-4(3H)-one (0.85 g, 23% yield) as a pale yellow solid. MS: (ES + ) m / z = 457.1 [M+H] + .

[0197] Project 4: 2-((1-(2-((4-Chloro-3-(trifluoromethoxy)benzyl)thio)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, production of enantiomers 1 and 2

Chem.

[0198] Example 33: 5-Fluoro-2-((1-(6-fluoro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0199] Example 34: 5-Fluoro-2-((1-(6-fluoro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2)

Chem.

[0200] Example 35: 2-((1-(6-Fluoro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0201] Example 36: 2-((1-(6-Fluoro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2) [Chemical formula] Project 1: Preparation of methyl 2-((1-(6-fluoro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate To a 250 mL round-bottom flask were added 6-fluoro-8-(1-hydroxyethyl)-3-methyl-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinazolin-4(3H)-one (50 mg, 0.13 mmol) (prepared by a method similar to that described in Example 7) and CH2Cl2 (2 mL). To this mixture, PBr3 (87 mg, 0.32 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (50 mL). The mixture was basified to pH 7 by the addition of saturated aqueous NaHCO3. The resulting mixture was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ACN (10 mL). Methyl anthranilate (489 mg, 0.32 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 2:1) to obtain methyl 2-((1-(6-fluoro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (75 mg, >95% crude yield) as a pale yellow solid. MS: (ES + ) m / z = 522.3 [M+H] + .

[0202] Project 2: Preparation of 2-((1-(6-Fluoro-3-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomers 1 and 2

Chemical formula

[0203] Example 37: 2-((1-(3-Methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-6-(trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0204] Example 38: 2-((1-(3-Methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-6-(trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2)

Chemical formula

[0205] Example 39: 2-((1-(2-(isobutylthio)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0206] Example 40: 2-((1-(2-(Isobutylthio)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2). [Chemical formula] The title compound was prepared using a method similar to that described in Examples 31 and 32 to give Example 39: 2-((1-(2-(Isobutylthio)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1 (6.3 mg, 5% yield, 99% ee) as a white solid ( 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.84 - 7.74 (m, 2H), 7.51 (s, 1H), 7.15 - 7.11 (m, 1H), 6.51 - 6.47 (m, 1H), 6.31 (d, J = 8.5 Hz, 1H), 5.50 (d, J = 7.2 Hz, 1H), 3.55 (s, 3H), 3.24 (d, J = 6.7 Hz, 2H), 2.33 (s, 3H), 2.13 - 2.06 (m, 1H), 1.54 (d, J = 6.6 Hz, 3H), 1.07 - 1.01 (m, 6H), LCMS (ESI) m / z = 426.0 (M + H)) and Example 40: 2-((1-(2-(Isobutylthio)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (3.8 mg, 2% yield, 99% ee) as a white solid ( 11H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.82 - 7.79 (m, 1H), 7.77 - 7.75 (m, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.14 - 7.09 (m, 1H), 6.53 - 6.44 (m, 1H), 6.30 (d, J = 8.4 Hz, 1H), 5.50 (d, J = 6.9 Hz, 1H), 3.55 (s, 3H), 3.24 (d, J = 6.7 Hz, 2H), 2.33 (s, 3H), 2.15 - 2.04 (m, 1H), 1.54 (d, J = 6.7 Hz, 3H), 1.07 - 1.01 (m, 6H), LCMS (ESI) m / z = 426.0 (M + H)) was obtained.

[0207] Example 41: 2 - ((1 - (2 - ((4 - Chlorophenyl)amino)-3,6 - dimethyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0208] Example 42: 2 - ((1 - (2 - ((4 - Chlorophenyl)amino)-3,6 - dimethyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid (enantiomer 2)

Chemical Structure

[0209] Project 2: Preparation of 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one To a solution of a mixture of 8-bromo-3,6-dimethyl-2-sulfanylidene-1H-quinazolin-4-one (9.0 g, 31.5 mmol) and NaOH (2.52 g, 63.1 mmol) in DMF (90 mL) under stirring, dimethyl sulfate (5.9 g, 47.3 mmol) was added portionwise at room temperature under an argon atmosphere. The resulting mixture was stirred under an argon atmosphere at room temperature for 2 h. The mixture was cooled to 0 °C. The reaction was quenched with ice water (50 mL) at 0 °C. The resulting solid was washed 5 times with water (each 10 mL) and then dried under reduced pressure. Thereby, 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (8.0 g, 85% yield) was obtained 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).

[0210] Project 3: Preparation of 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one To a solution of a mixture of 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (7.1 g, 23.7 mmol) and tributyl(1-ethoxyethenyl)stannane (10.3 g, 28.5 mmol) in 1,4-dioxane (100 mL) under stirring, tetrakis(triphenylphosphine)palladium (2.7 g, 2.4 mmol) was added portionwise at room temperature under an argon atmosphere. The resulting mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature. 1N aqueous HCl solution (14.4 mL) was added portionwise to the mixture over 5 minutes at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with ice water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 1:0 for 30 minutes and then increased to PE:EA = 5:1), and 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (4.0 g, 64% yield) was obtained 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).

[0211] Project 4: Preparation of 8-(1-hydroxyethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one A solution of 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (2.9 g, 11.1 mmol) in MeOH (20 mL) was treated with NaBH4 (836 mg, 22 mmol) for 5 minutes at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure and then quenched with ice water (50 mL) at 0 °C. The resulting mixture was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 1:0 and increasing to PE:EA = 5:1 over 30 minutes) to give 8-(1-hydroxyethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (2.3 g, 79% yield) as a white solid. LCMS (ESI) m / z = 265.2 (M+H).

[0212] Project 5: Preparation of methyl 2-((1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate A solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (2.5 g, 9.4 mmol) in DCM (30 mL) was treated with PBr3 (25.6 g, 94.5 mmol) for 5 minutes at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with ice water (100 mL). The resulting mixture was extracted with CH2Cl2 (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was suspended in MeCN (30 mL) and K2CO3 (2.6 g, 18.9 mmol), and methyl anthranilate (4.3 g, 28.3 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. Then, the reaction was cooled to room temperature and quenched with ice water (50 mL). The resulting mixture was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 1:0 and increasing to PE:EA = 5:1 over 30 minutes) to give methyl 2-((1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (2.5 g, 67% yield) as a white solid. LCMS (ESI) m / z = 397.9 (M+H).

[0213] Project 6: Preparation of methyl 2-((1-(3,6-dimethyl-2-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate A solution of methyl 2-((1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (1.5 g, 3.7 mmol) in DMF (15 mL) was treated with m-CPBA (1.9 g, 11.3 mmol) for 5 minutes at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 solution (50 mL) at 0 °C. The resulting mixture was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EA = 1:0 and increasing to PE:EA = 5:1 over 30 minutes) to give methyl 2-((1-(3,6-dimethyl-2-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (911 mg, 56% yield) as an off-white solid. LCMS (ESI) m / z = 430.0 (M+H).

[0214] Project 7: Preparation of methyl 2-((1-(2-((4-chlorophenyl)amino)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate A solution of a mixture of methyl 2-((1-(3,6-dimethyl-2-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (120 mg, 0.3 mmol) and 4-chloroaniline (107 mg, 0.8 mmol) in THF (4.0 mL) was added dropwise with a THF solution of LiHMDS (2 M, 1.2 mL) at 0 °C under an argon atmosphere. The resulting mixture was then warmed to room temperature and stirred for 30 minutes. The reaction was quenched with ice water (20 mL). The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA = 1:0 and increased to PE:EA = 1:1 over 30 minutes) to obtain methyl 2-((1-(2-((4-chlorophenyl)amino)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (125 mg, 94% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.14 (d, J = 6.3 Hz, 1H), 7.79 (d, J = 9.0 Hz, 3H), 7.70 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 8.9 Hz, 3H), 7.22 - 7.11 (m, 1H), 6.57 - 6.46 (m, 1H), 6.29 (d, J = 8.6 Hz, 1H), 5.32 - 5.22 (m, 1H), 3.83 (s, 3H), 3.63 (s, 3H), 2.29 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H).

[0215] Project 8: Preparation of 2-((1-(2-((4-chlorophenyl)amino)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomers 1 and 2)

Chemical Structure

[0216] Example 43: 2-((1-(2-((4-chlorobenzyl)amino)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0217] Example 44: 2-((1-(2-((4-Chlorobenzyl)amino)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2) [Chemical formula] The title compound was prepared using a method similar to that described in Examples 41 and 42 to give Example 43: 2-((1-(2-((4-Chlorobenzyl)amino)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1 (32 mg, 39% yield, 95% ee) as a white solid( 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.85 - 7.78 (m, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 2.2 Hz, 1H), 7.06 - 6.97 (m, 1H), 6.48 - 6.40 (m, 1H), 6.11 (d, J = 8.5 Hz, 1H), 5.19 (d, J = 6.4 Hz, 1H), 4.74 - 4.64(m, 1H), 4.60 - 4.51 (m, 1H), 3.50 (s, 3H), 2.22 (s, 3H), 1.25 (d, J = 6.6 Hz, 3H). LCMS (ESI) m / z = 476.9 / 479.0 (M + H)) and Example 44: 2-((1-(2-((4-Chlorobenzyl)amino)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (30 mg, 36% yield, 95% ee) as a white solid( 11H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.85 - 7.78 (m, 1H), 7.77 - 7.71 (m, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 - 7.29 (m, 2H), 7.26 (d, J = 2.2 Hz, 1H), 7.07 - 6.99 (m, 1H), 6.48 - 6.40 (m, 1H), 6.12 (d, J = 8.5 Hz, 1H), 5.19 (d, J = 6.4 Hz, 1H), 4.74 - 4.64 (m, 1H), 4.60 - 4.50 (m, 1H), 3.50 (s, 3H), 2.22 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H). Obtained as LCMS (ESI) m / z = 477.0 / 479.0 (M + H).

[0218] Example 45: 2 - ((1 - (3,6 - dimethyl - 4 - oxo - 2 - (((R) - 2 - phenylpropyl)amino) - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid (enantiomer 1); and

[0219] Example 46: 2 - ((1 - (3,6 - dimethyl - 4 - oxo - 2 - (((R) - 2 - phenylpropyl)amino) - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid (enantiomer 2)

Chemical Structure

[0220] Example 47: 2-((1-(3,6-dimethyl-4-oxo-2-(((S)-2-phenylpropyl)amino)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 1); and

[0221] Example 48: 2-((1-(3,6-Dimethyl-4-oxo-2-(((S)-2-phenylpropyl)amino)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2)

Chem.

[0222] Example 49: 2 - ((1 - (3 - cyclopropyl - 2 - (4,4 - dimethylpiperidin - 1 - yl) - 6 - methyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid (enantiomer 1) and

[0223] Example 50: 2 - ((1 - (3 - cyclopropyl - 2 - (4,4 - dimethylpiperidin - 1 - yl) - 6 - methyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid (enantiomer 2) [Chemical formula] The title compound was prepared using Intermediate 7 by a method similar to that described in Examples 7 and 8 to give Example 49: 2 - ((1 - (3 - cyclopropyl - 2 - (4,4 - dimethylpiperidin - 1 - yl) - 6 - methyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethyl)amino)benzoic acid, enantiomer 1 (20 mg, 99% ee) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.38 (s, 1H), 7.80 - 7.73 (m, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.22 - 7.13 (m, 1H), 6.53 - 6.44 (m, 2H), 5.35 (m, 1H), 3.52 - 3.36 (m, 4H), 3.22 - 3.13 (m, 1H), 2.28 (s, 3H), 1.58 - 1.41 (m, 7H), 1.20 - 1.10 (m, 2H), 1.00 (s, 6H), 0.81 - 0.73 (m, 1H), 0.73 - 0.62 (m, 1H), LCMS (ESI) m / z = 475.3 (M + H)) and Example 50: 2 - ((1 - (3 - cyclopropyl - 2 - (4,4 - dimethylpiperidin - 1 - yl) - 6 - methyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl) ethyl) amino) benzoic acid, enantiomer 2 (19 mg, 99% ee) as a white solid( 1 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.38 (s, 1H), 7.80 - 7.73 (m, 1H), 7.66 - 7.60 (m, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.22 - 7.13 (m, 1H), 6.53 - 6.44 (m, 2H), 5.35 (s, 1H), 3.48 - 3.41 (m, 4H), 3.22 - 3.13 (m, 1H), 2.28 (s, 3H), 1.56 - 1.42 (m, 7H), 1.19 - 1.13 (m, 2H), 1.00 (s, 6H), 0.75 (s, 1H), 0.67 (d, J = 7.9 Hz, 1H), LCMS (ESI) m / z = 475.2 (M + H)) was obtained.

[0224] Example 51: 2 - ((1 - (2 - (4,4 - dimethylpiperidin - 1 - yl) - 3 - (fluoromethyl) - 6 - methyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl) ethyl) amino) benzoic acid (enantiomer 1); and

[0225] Example 52: 2-((1-(2-(4,4-Dimethylpiperidin-1-yl)-3-(fluoromethyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomer 2)

Chem.

[0226] Project 2: Production of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3-(fluoromethyl)-6-methylquinazolin-4-one A solution of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-3H-quinazolin-4-one (1.2 g, 3.4 mmol) in DMF (15 mL) was treated with NaH (411 mg, 17.1 mmol, 60% in oil) for 10 min at 0 °C under a nitrogen atmosphere, and then bromofluoromethane (1.9 g, 17.1 mmol) was added dropwise. The resulting mixture was stirred at 60 °C for 4 h. The reaction was cooled to room temperature and quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, aqueous MeCN solution, 40% - 100% gradient for 20 min). This gave 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3-(fluoromethyl)-6-methylquinazolin-4-one (1.0 g, 76% yield) as a yellow solid. LCMS (ESI) m / z = 382.1 / 384.3 (M+H).

[0227] Project 3: Preparation of 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(fluoromethyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (enantiomers 1 and 2) [Chemical formula] The title compound was prepared using a method similar to that described in Examples 7 and 8 to give Example 51: 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(fluoromethyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 1 (11 mg, 99% ee) as a white solid( 11H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.46 (s, 1H), 7.80 - 7.75 (m, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.18 - 7.12 (m, 1H), 6.51 - 6.40 (m, 2H), 6.33 (m, 1H), 6.20 (m, 1H), 5.43 (m, 1H), 3.9 - 3.83 (m, 4H), 2.31 (s, 3H), 1.57 (d, J = 6.6 Hz, 3H), 1.45 - 1.36 (m, 4H), 1.00 (s, 6H), LCMS (ESI) m / z = 467.2(M+H); and Example 52: 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(fluoromethyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid, enantiomer 2 (9 mg, 99% ee) as a white solid ( 1 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.46 (s, 1H), 7.80 - 7.75 (m, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.18 - 7.12 (m, 1H), 6.51 - 6.40 (m, 2H), 6.33 (m, 1H), 6.20 (m, 1H), 5.43 (m, 1H), 3.9 - 3.83 (m, 4H), 2.31 (s, 3H), 1.57 (d, J = 6.6 Hz, 3H), 1.45 - 1.36 (m, 4H), 1.00 (s, 6H); LCMS (ESI) m / z = 467.2 (M+H)) was obtained as.

[0228] Assay and Compound Testing In vitro cell proliferation: EC for growth inhibition in T47D cells expressing the mutant PI3Ka (H1047R) mutation and SKBR3 cells expressing WT PI3Ka 50 Value determination T47D or SKBR3 cells were trypsinized, resuspended in culture medium, and seeded into assay ready plates. The T47D culture medium consisted of RPMI, 10% FBS, and insulin (0.2 units / mL). The SKBR3 culture medium consisted of McCoys 5a and 10% FBS. Cells were seeded at a density of 1,500 cells / well, and 50 μL was dispensed into 384-well assay plates (Corning, 89089-790). The assay plates were pre-stamped with 10-point dilutions of the compound of interest and controls. The plates were stamped with 40 nL of the compound or DMSO using an Echo655. Cells were grown for 72 hours at 37 °C and 5% CO2. After 72 hours, the cells were equilibrated at room temperature for 15 minutes. 30 μL of CellTiter-Glo reagent was added to the plates, which were then shaken at 300 - 500 rpm for 30 minutes at room temperature. The cells were then read on an Envision plate reader. The percentage of growth inhibition was calculated using the following formula: % inhibition = 100 × (Lum D -Lum サンプル ) / (Lum D -Lum Inh ) (where D is obtained from cells treated with 0.1% DMSO only; Inh is obtained from cells treated with 10 μM alpelisib). The effective concentration (EC 50 ) to achieve 50% inhibition of growth was calculated by fitting a curve to equation 201 in Xlfit (v5.3.1.3): Y = bottom + (top - bottom) / (1 + 10^((LogEC 50 -X) × Hill slope)).

Table 1

[0229] In vitro cell pAKT: IC for inhibition of AKT (pAKT) phosphorylation in T47D cells expressing the mutant PI3Ka (H1047R) mutation and SKBR3 cells expressing WT PI3Ka 50 Value determination T47D or SKBR3 cells were trypsinized, resuspended in culture medium, and seeded onto assay plates. The T47D culture medium consisted of RPMI, 10% FBS, and insulin (0.2 units / mL). The SKBR3 culture medium consisted of McCoy's 5a and 10% FBS. Cells were seeded at a density of 5000 cells / well, and 12.5 μL was dispensed into a 384-well assay plate (Perkin Elmer, 6008238). The assay plate was pre-stamped with 10-point dilutions of the compound of interest and controls. Using an Echo655, 12.5 nL of the compound or DMSO was stamped onto the plate. The cells were grown for 6 hours at 37 °C and 5% CO2. After 6 hours, 4 μL of lysis buffer reagent was added to the plate, and then it was centrifuged at 1000 rpm for 1 minute. The plate was then incubated at room temperature for 30 minutes. After 30 minutes, 4 μL of an antibody mix containing Eu cryptate, d2 cryptate, and detection buffer was added to the plate. The plate was centrifuged at 1000 rpm for 1 minute and then incubated overnight at room temperature. The plate was read using an Envision plate reader with the HTRF protocol. The percentage of AKT phosphorylation inhibition was calculated using the following formula: % inhibition = 100 × (pAKT HC - pAKT sample) / (pAKT HC - pAKT LC)) (where pAKT HC is obtained from cells treated with 0.1% DMSO only; pAKT LC is obtained from cells treated with 10 μM alpelisib). IC 50 (the concentration achieving 50% inhibition of pAKT) was calculated by fitting a curve to Equation 201 in Xlfit (v5.3.1.3): Y = bottom + (top - bottom) / (1 + 10^((LogIC 50 - X) × Hill slope)).

Table 2

[0230] For the EC 50 values shown in Table 1, "A" refers to 1 nM < EC 50 < 500 nM; "B" refers to 500 nM < EC 50<2 μM is good; "C" is 2 μM < EC 50 <15 μM is good; and "D" is EC 50 > 15 μM means.

Table 3

Table 4

[0231] The IC shown in Table 2 50 value, "A" is 1 nM < IC 50 <1 μM is good; "B" is 1 μM < IC 50 <5 μM is good; "C" is 5 μM < IC 50 <15 μM is good; and "D" is IC 50 > 15 μM means.

Table 5

Table 6

[0232] CD1 mice were administered a single IV or PO dose, and plasma was then sampled continuously at 0.0833 h (IV only), 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose. The working solution of the desired serial concentrations was obtained by diluting the analyte stock solution with 50% aqueous acetonitrile. 10 μL of the working solution (0.5 ng / mL, 1 ng / mL, 2 ng / mL, 5 ng / mL, 10 ng / mL, 50 ng / mL, 100 ng / mL, 500 ng / mL, 1000 ng / mL) was added to 10 μL of blank female CD1 mouse plasma to obtain calibration standards of 0.5 - 1000 ng / mL (0.5 ng / mL, 1 ng / mL, 2 ng / mL, 5 ng / mL, 10 ng / mL, 50 ng / mL, 100 ng / mL, 500 ng / mL, 1000 ng / mL) with a total volume of 20 μL. Five quality control samples of 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL, and 800 ng / mL for plasma were prepared independently from those used for the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standards. 20 μL of the standard, 20 μL of the QC sample, and 20 μL of the unknown sample (10 μL blank solution added to 10 μL plasma) were added to 200 μL of acetonitrile containing the IS mixture to precipitate the respective proteins. The samples were then vortexed for 30 s. After centrifugation at 4°C and 4000 rpm for 15 min, the supernatant was diluted 1:2 (V / V, 1:2) with water. Then, 5 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis. The results are shown in Table 3.

Table 7

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Claims

1. Formula (1) 【Chemical 1】 〔Wherein: R １ is H, C １ -C ４ alkyl or C ３ -C ７ cycloalkyl; Each R ２ is independently H, C １ -C ４ alkyl, C ３ -C ７ cycloalkyl, R １４ -C≡C-, halogen, CN, CF ３ , OCF ３ , CFH ２ or CF ２ H; R ３ is H, C １ -C ４ alkyl, C ３ -C ７ cycloalkyl, CF ３ , CFH ２ or CF ２ H, and when R ３ is not H, the carbon atom bonded to R ３ is a chiral center and exists as a (R)- and (S)-racemic mixture or as a (R)- or (S)-enantiomer; R ４ is H or C １ -C ４ is alkyl; R ６ is H, C １ -C ４ alkyl, C ３ -C ７ cycloalkyl, heteroaryl, CF ３ , CFH ２ or CF ２ H; R ７ is H, C １ -C ４ alkyl, C ３ -C ７ cycloalkyl, halogen, CN, CF ３ , OCF ３ , OCH ３ , CFH ２ or CF ２ H; R ８ is H, C １ -C ４ alkyl, C ３ -C ７ cycloalkyl, halogen, CN, CF ３ , OCF ３ , OCH ３ , CFH ２ or CF ２ H; R ５ is -O-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ ; -S-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ ; -S(O)-L １ -L ２ -L ３ -L ５ -L ６ -L ７ -R ９ ; -S(O) ２ -L １ -L ２ -L ３ -L ５ -L ６ -L ７ -R ９ ; or -(NR １０ )-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ and wherein: L １ 、 L ２ 、 L ３ 、 L ６ and L ７ each of which is independently (CHR １１ ), (CHR １１ -O), (CHR １１ -S), (C ３ -C ７ cycloalkyl) or a bond; L ４ is C=O, C=S or a bond; L ５ is NR １０ , S, O or a bond; R ９ is H, C(=O)R １２ 、C(=O)NR １２ R １３ 、C(=O)OR １２ 、C １ -C ６ alkyl, C １ -C ６ fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of C １ -C ６ alkyl, C １ -C ６ fluoroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted or when NR １０ is present, R ９ and R １０ may combine with the nitrogen atom to which they are attached to form a 4- to 7-membered non-aromatic heterocyclic ring, where the ring may further contain heteroatoms and is substituted or unsubstituted; R １０ and R １１ each of which is H or C １ -C ４ alkyl, where C １ -C ４ alkyl is unsubstituted or substituted; and R １２ and R １３ each independently is H or C １ -C ６ alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where the C １ -C ６ alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl each is unsubstituted or substituted or alternatively, R １２ and R １３ may combine with the nitrogen atom to which they are attached to form a 4- to 7-membered non-aromatic heterocyclic ring, where the ring may further contain heteroatoms and is substituted or unsubstituted; Each R １４ is independently H, C １ -C ３ -alkyl or C ３ -C ７ -cycloalkyl; or R ５ is is a non-aromatic N-bonded heterocyclic ring 【Chemical 2】 and wherein the heterocyclic ring is substituted or unsubstituted and optionally contains one or more additional atoms selected from N (wherein N is substituted or unsubstituted), O, Si (wherein Si is substituted or unsubstituted), and S (wherein S is oxidized or unoxidized), and is optionally part of a bridged, fused, or spiro ring system.〕 A compound of or a solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

2. R ５ is -(NR １０ )-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ and wherein L １ to L ７ , R ９ and R １０ are as defined, a compound according to claim 1 or a solvate, enantiomer, diastereoisomer, tautomer, polymorph or isotopically-labelled compound thereof or a pharmaceutically acceptable salt.

3. R ５ is -O-L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ and wherein L １ to L ７ and R ９ are as defined, a compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labelled compound thereof or a pharmaceutically acceptable salt.

4. R ５ is - S - L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ９ ; -S(O)-L １ -L ２ -L ３ -L ５ -L ６ -L ７ -R ９ ; or -S(O) ２ -L １ -L ２ -L ３ -L ５ -L ６ -L ７ -R ９ wherein, L １ to L ７ and R ９ are as defined, a compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound thereof or a pharmaceutically acceptable salt.

5. R ５ is an N-bonded non-aromatic heterocyclic ring [Chemical Formula 3] and wherein the heterocyclic ring is substituted or unsubstituted and optionally contains one or more additional atoms selected from N (wherein N is substituted or unsubstituted), O, Si (wherein Si is substituted or unsubstituted), and S (wherein S is oxidized or unoxidized), and is optionally part of a bridged, fused, or spiro ring system, a compound of Claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

6. A compound of Claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted and optionally contains one or more additional heteroatoms selected from N, O, Si, and S and is not part of a bridged, fused, or spiro ring system.

7. A compound of Claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted and optionally contains one or more additional heteroatoms selected from N, O, Si, and S and is part of a bridged, fused, or spiro ring system.

8. A compound of Claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph, or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted, does not contain additional heteroatoms, and is not part of a bridged, fused, or spiro ring system.

9. The compound of claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted, contains no further heteroatoms, and is part of a bridged, fused or spiro ring system.

10. The compound of claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is not part of a bridged, fused or spiro ring system.

11. The compound of claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is part of a bridged, fused or spiro ring system.

12. The compound of claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is not part of a bridged, fused or spiro ring system.

13. The compound of claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is part of a bridged, fused or spiro ring system.

14. The compound of claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted, contains at least one further nitrogen ring atom, and is not part of a bridged, fused or spiro ring system.

15. The compound of claim 5 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is substituted or unsubstituted, contains at least one further nitrogen ring atom, and is part of a bridged, fused or spiro ring system.

16. The compound of formula (1) is [Chemical Formula 4] [Chemical Formula 5] The compound of claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, selected from

17. R ５ is 【Chemical Formula 6】 【Chemical Formula 7】 【Chemical 8】 【Chemical Formula 9】 【Chemical 10】 【Chemical 11】 【Chemical 12】 【Chemical 13】 【Chemical 14】 selected from, wherein: A is O, S, S(O) or S(O) ２ and; Each R ｈ and R ｉ are independently selected from H, CH ３ , c-Pr, c-Bu, CF ３ and OH; Each R ｊ is independently CF ３ , CH ２ CF ３ , CH ２ CF ２ H, OCH ３ , OCH ２ CF ３、 OCF ３ , Oc-Pr, aryl, heteroaryl, COCH ３ and CO ２ CH ３ is selected from; and Each R ｋ and R ｍ are independently H, C １ -C ３ alkyl and acetyl (COCH ３ ), a compound according to any of claims 1 to 15 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound thereof or a pharmaceutically acceptable salt.

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

19. Each R ２ The compound or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof according to claim 1, wherein each R is H.

20. R ３ is CH ３ The compound according to claim 1, or a solvate, enantiomer, diastereoisomer, tautomer, polymorph or isotopically-labelled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R is CH

21. R ４ The compound of claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, wherein R is H.

22. R ６ is CH ３ The compound of claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R is CH.

23. R ７ is CH ３ or F, a compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labelled compound thereof or a pharmaceutically acceptable salt thereof.

24. R ８ The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is H.

25. R １ 、 each R ２ and R ４ is H, a compound according to claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound thereof or a pharmaceutically acceptable salt.

26. The compound of formula (1) is of formula (2) 【Chemical Formula 15】 (wherein R ３ is CH ３ , CF ３ , CFH ２ or CF ２ H; R ５ is as defined by the compound of formula (1); R ７ is CH ３ or F; and the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or (R)- or (S)-enantiomer.) The compound of claim 1, or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof.

27. The compound of formula (1) is of formula (3) 【Chemical 16】 (wherein R ２ is as defined for the compound of formula (1); R ３ is CH ３ CF ３ CFH ２ or CF ２ H; R ７ is CH ３ or F; R １５ is OCH ３ OCH ２ CH ３ OCH ２ CF ３ O - cyclopropyl, CH ２ CF ３ CH ２ CF ２ H, aryl or heteroaryl; each R １６ is independently H or C １ -C ３ alkyl; and the carbon marked with * is a chiral center and exists as a (R)-and (S)-racemic mixture or as a (R)-or (S)-enantiomer, the compound of claim 1.) a compound or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof of the compound of claim 1.) the compound of claim 1.

28. The compound of formula (1) is of formula (4) 【Chemical 17】 (wherein R ２ is as defined for the compound of formula (1); R ３ is CH ３ , CF ３ CFH ２ or CF ２ H; R ７ is CH ３ or F; R １５ is OCH ３ OCH ２ CH ３ OCH ２ CF ３ O-cyclopropyl, CH ２ CF ３ CH ２ CF ２ H, aryl or heteroaryl; and the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as a (R)- or (S)-enantiomer.) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof of the compound of claim 1.

29. The compound of formula (1) is of formula (5) 【Chemical 18】 (wherein R ２ is as defined for the compound of formula (1); R ３ is CH ３ CF ３ CFH ２ or CF ２ H; R ７ is CH ３ or F; R １５ is OCH ３ OCH ２ CH ３ OCH ２ CF ３ cyclopropyl, CH ２ CF ３ CH ２ CF ２ H, aryl or heteroaryl; and the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as a (R)- or (S)-enantiomer.) The compound or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof according to claim 1.

30. The compound of formula (1) is 【Chemical Formula 19】 【Chemical 20】 【Chemical 21】 The compound of claim 1 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof, selected from

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

32. The pharmaceutical composition of claim 31, further comprising one or more anti-cancer agents.

33. The pharmaceutical composition of claim 32, wherein the one or more anti-cancer 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 and proteasome inhibitors.

34. A method of treating a disease in which PI3K activity is involved in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 30 or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically labeled compound or pharmaceutically acceptable salt thereof.

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

36. The method of claim 34, wherein the disease is selected from congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal-spinal syndrome (CLOVES), mosaic tissue overgrowth syndrome, venous malformation and brain malformation with severe epilepsy or PIK3CA-related overgrowth syndrome.

37. The method of claim 34, wherein the disease is cancer carrying the PI3Kα H1047R mutation.

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