QUINAZOLINONE DERIVATIVES AND RELATED USES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Application Nos. 63/369,622, filed on July 27, 2022, and 63/489,284, filed on March 9, 2023, which are incorporated by reference herein in their entirety for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (ASET_040_001WO_SeqList_ST26.xml; Size: 3,007 bytes; and Date of Creation: July 25, 2023) are herein incorporated by reference in its entirety. BACKGROUND [0003] Phosphatidylinositol 3-Kinases (PI3Ks) are a group of plasma membrane-associated lipid kinases that upon activation catalyze the transfer of phosphate to the D-3’ position of inositol of phosphoinositol-4,5-phosphate (PIP2) to produce the second messenger phosphoinositol-3,4,5-phosphate (PIP3). PI3Ks are known to control and regulate of a variety of different cellular activities, including transcription, translation, proliferation, survival, chemotaxis, motility, cellular trafficking and metabolism. Genetic alterations such as mutations, amplifications, deletions and translocations in genes encoding PI3K subunits have been implicated in several of different diseases and disorder, including, CLOVES syndrome, PIK3CA-related overgrowth syndrome, as well as a variety of cancers. [0004] More specifically, mutations in the gene PIK3CA, which encodes the p110Į (also referred to as PI3KĮ) catalytic subunit, have been linked to numerous cancers, including bladder cancer, brain cancer, breast cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, lung cancer and prostate cancer. These mutations include oncogenic gain-of-function mutations that occur within mutation hotspots, primarily within the kinase and helicase domains. Accordingly, p110Į has been identified as a potential therapeutic target in the treatment of various cancers and other PI3K-driven diseases. [0005] To this end, multiple inhibitors of PI3Ks have been developed, including alpelisib, buparlisib, taselisib, and inavolisib. However, the efficacy of these existing PI3K inhibitors has been hindered by on-target related toxicities, including hyperglycemia, rash, diarrhea, myelosuppression, and transaminitis. [0006] Accordingly, there is a need in the art for improved PI3K inhibitors, including improved inhibitors of the PI3KĮ catalytic subunit. In particular, there is a need in the art for PI3K inhibitors that specifically target mutated forms of PI3KĮ over wild-type PI3KĮ. SUMMARY [0007] In some aspects, the present disclosure provides a compound of Formula (I): an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, or C ₁ -C ₆ haloalkyl; R ² is H, halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl; R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ - C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is halogen, -OH, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl; or two R ^3a , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl; R ⁴ is –(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, -C(=O)-(C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C6-C10 aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen or cyano; R ⁵ is H, halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxyl; T is -O-*, -NR ^T -*, -C(=O)NR ^T -*, -NR ^T C(=O)-*, -(C1-C6 alkyl)-*, -(C3-C12 cycloalkyl)- *, -(C ₁ -C ₆ alkyl)-O-*, -O-(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-NR ^T -*, -NR ^T -(C ₁ -C ₆ alkyl)-*, -(C ₁ - C6 alkyl)-NR ^T -(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NR ^T -*, -S(=O)2NR ^T -*, or -NR ^T -(C1-C6 haloalkyl)-*, wherein * denotes attachment to A; each R ^T is H or C ₁ -C ₆ alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ - C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is oxo, halogen, -OH, -O(C3-C12 heterocycloalkyl), cyano, -NH2, -N(R ^A1 ) ₂ , -B(OH) ₂ , -NO ₂ , -C(=O)OH, -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)O(C ₃ -C ₁₂ heterocycloalkyl), -C(=O)N(R ^A1 ) ₂ , -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl)2, -S(=O)(=NR ^A1 )R ^A1 , -S(=O)2N(R ^A1 )2, -S(=O)2(C1-C6 alkyl), -S(=O)2(C3-C12 cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)O(C3-C12 heterocycloalkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 ; each R ^A1 independently is H, oxo, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ - C6 alkoxyl, C3-C12 heterocycloalkyl, or C3-C12 cycloalkyl, wherein the -C(=O)(C1-C6 alkyl), C1-C6 alkyl, C3-C12 heterocycloalkyl, or C3-C12 cycloalkyl is optionally substituted with one or more R ^A2 ; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C ₁₂ cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH ₂ ; or each R ^A2 independently is -OH, cyano, C1-C6 alkoxyl, C3-C12 cycloalkyl, or C3-C12 heterocycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ heterocycloalkyl is optionally substituted with one or more halogen or C ₁ -C ₆ alkyl. [0008] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in Schemes 1-4). [0009] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. [0010] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-320). [0011] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0012] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0013] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0014] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3KĮ activity (e.g., in vitro or in vivo). [0015] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein. [0016] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein. [0017] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3KĮ activity (e.g., in vitro or in vivo). [0018] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0019] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [0020] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure. [0021] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein. [0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. [0023] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION [0024] The present disclosure relates to quinazolinone derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which may modulate PI3KĮ activity and are accordingly useful in methods of treatment of the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in which PI3KĮ is implicated, such as cancer. Definitions [0025] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [0026] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options. For example, while various options for variables X, L, and Y are described herein, the disclosure may be interpreted as excluding structures for non-operable compound caused by certain combinations of variables X, L, and Y (e.g., when each of X, L, and Y is -O-). [0027] As used herein, “alkyl”, “C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ alkyl” or “C ₁ -C ₆ alkyl” is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C ₃ , C ₄ , C ₅ or C ₆ branched saturated aliphatic hydrocarbon groups. For example, C ₁ -C ₆ alkyl is intends to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C ₁ -C ₆ for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. [0028] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0029] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C ₂ -C ₆ ” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms. [0030] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0031] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C ₂ -C ₆ ” includes alkynyl groups containing two to six carbon atoms. The term “C ₃ - C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C ₂ - C ₆ alkenylene linker is intended to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkenylene linker groups. [0032] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0033] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl. [0034] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C ₃ -C ₁₂ , C ₃ -C ₁₀ , or C ₃ -C ₈ ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non- aromatic. [0035] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane- 1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H- cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl). [0036] It is understood that when a variable has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is cycloalkyl or heterocycloalkyl, and has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocycloalkyl. [0037] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. [0038] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidised (i.e., N→O and S(O) _p , where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heteroaryl is thiophenyl or benzothiophenyl. In some embodiments, the heteroaryl is thiophenyl. In some embodiments, the heteroaryl benzothiophenyl. [0039] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine. [0040] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl). [0041] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [0042] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. [0043] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. [0044] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O- . [0045] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. [0046] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. [0047] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0048] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy. [0049] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise. [0050] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples. [0051] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [0052] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. [0053] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 ^th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art [0054] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999. [0055] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models. [0056] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. [0057] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human. [0058] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy. [0059] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. [0060] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. [0061] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. [0062] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 ^rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 ^th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure. [0063] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier. [0064] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. [0065] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0066] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. [0067] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. [0068] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. [0069] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. [0070] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat or ameliorate an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. [0071] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50 % of the population) and LD50 (the dose lethal to 50 % of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. [0072] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. [0073] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. [0074] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. [0075] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [0076] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring. [0077] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser. [0078] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays, powders or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. [0079] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. [0080] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved. [0081] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell. [0082] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. [0083] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure. [0084] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. [0085] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt. [0086] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. [0087] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt. [0088] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration. [0089] The dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition. [0090] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 ^th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. [0091] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. [0092] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. [0093] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. [0094] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically. Compounds of the Present Disclosure [0095] In some aspects, the present disclosure provides a compound of Formula (I): ; (I) an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, or C ₁ -C ₆ haloalkyl; R ² is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ - C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is halogen, -OH, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl; or two R ^3a , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl; R ⁴ is –(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, -C(=O)-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, C ₆ -C ₁₀ aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen or cyano; R ⁵ is H, halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxyl; T is -O-*, -NR ^T -*, -C(=O)NR ^T -*, -NR ^T C(=O)-*, -(C1-C6 alkyl)-*, -(C3-C12 cycloalkyl)- *, -(C ₁ -C ₆ alkyl)-O-*, -O-(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-NR ^T -*, -NR ^T -(C ₁ -C ₆ alkyl)-*, -(C ₁ - C6 alkyl)-NR ^T -(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NR ^T -*, -S(=O)2NR ^T -*, or -NR ^T -(C1-C6 haloalkyl)- *, wherein * denotes attachment to A; each R ^T is H or C1-C6 alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is oxo, halogen, -OH, -O(C3-C12 heterocycloalkyl), cyano, -NH2, -N(R ^A1 )2, -B(OH)2, -NO2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)O(C3-C12 heterocycloalkyl), -C(=O)N(R ^A1 ) ₂ , -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ N(R ^A1 ) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), -S(=O) ₂ (C ₃ -C ₁₂ cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)O(C ₃ -C ₁₂ heterocycloalkyl), -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 ; each R ^A1 independently is H, oxo, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C ₆ alkoxyl, C ₃ -C ₁₂ heterocycloalkyl, or C ₃ -C ₁₂ cycloalkyl, wherein the -C(=O)(C ₁ -C ₆ alkyl), C1-C6 alkyl, C3-C12 heterocycloalkyl, or C3-C12 cycloalkyl is optionally substituted with one or more R ^A2 ; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2; or each R ^A2 independently is -OH, cyano, C1-C6 alkoxyl, C3-C12 cycloalkyl, or C3-C12 heterocycloalkyl, wherein the C3-C12 cycloalkyl or C3-C12 heterocycloalkyl is optionally substituted with one or more halogen or C ₁ -C ₆ alkyl. [0096] In some aspects, the present disclosure provides a compound of Formula (I), wherein: R ¹ is H, halogen, C1-C6 alkyl, or C1-C6 alkoxyl; R ² is H, halogen; R ³ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is -OH, cyano, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12- membered heterocycloalkyl; R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; R ⁵ is H, or C1-C6 alkoxyl; T is -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-O-*, -(C ₁ -C ₆ alkyl)-NR ^T -*, wherein * denotes attachment to A; each R ^T is H; A is 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is halogen, cyano, -NH ₂ , -C(=O)OH, -C(=O)O(C ₁ -C ₆ alkyl), - C(=O)N(R ^A1 ) ₂ , -C(=O)(C ₁ -C ₆ alkyl), -S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, or C1-C6 alkoxyl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, or C1-C6 alkoxyl is optionally substituted with one or more R ^A1 ; and each R ^A1 independently is H, halogen, -OH, -NH _2, -C(=O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with - OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more oxo. [0097] In some aspects, the present disclosure provides a compound of Formula (I): ; an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, or C ₁ -C ₆ haloalkyl; R ² is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ - C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is -OH, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ - C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl; R ⁴ is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ - C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C ₁ -C ₆ alkoxyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl; R ⁵ is H, halogen, cyano, or C ₁ -C ₆ alkoxyl; T is -O-*, -NR ^T -*, -C(=O)NR ^T -*, -NR ^T C(=O)-*, -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-NR ^T -*, -NR ^T -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ haloalkyl)-*, -(C ₁ -C ₆ haloalkyl)-O-*, -O-(C ₁ -C ₆ haloalkyl)-*, -(C ₁ -C ₆ haloalkyl)-NR ^T -*, or -NR ^T -(C ₁ -C ₆ haloalkyl)- *, wherein * denotes attachment to A; each R ^T is H or C1-C6 alkyl; A is C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is oxo, halogen, -OH, cyano, -NH ₂ , -C(=O)OH, -C(=O)O(C ₁ - C6 alkyl), -C(=O)N(R ^A1 )2, -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, - alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C ₆ alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 ; and each R ^A1 independently is H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), - S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl is optionally substituted with -OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C ₃ - C ₁₂ cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH ₂ . [0098] In some aspects, the present disclosure provides a compound of Formula (I), wherein: R ¹ is H, halogen, C1-C6 alkyl, or C1-C6 alkoxyl; R ² is H, halogen; R ³ is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C12 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is -OH, cyano, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocycloalkyl; R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkoxyl; R ⁵ is H, or C ₁ -C ₆ alkoxyl; T is -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, -(C1-C6 alkyl)-NR ^T -*, wherein * denotes attachment to A; each R ^T is H; A is 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is halogen, cyano, -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)N(R ^A1 )2, -C(=O)(C1-C6 alkyl), -S(=O)(=NR ^A1 )R ^A1 , -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, or C ₁ -C ₆ alkoxyl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)(C ₁ -C ₆ alkyl), -S(=O) ₂ (C ₁ -C ₆ alkyl), C1-C6 alkyl, or C1-C6 alkoxyl is optionally substituted with one or more R ^A1 ; and each R ^A1 independently is H, halogen, -OH, -NH2, -C(=O)OH, C1-C6 alkyl, C1-C6 alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl is optionally substituted with - OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more oxo. [0099] It is understood that, for a compound of the present disclosure, variables R ¹ , R ² , R ³ , R ^3a , R ⁴ , R ^4a , R ⁵ , T, R ^T , A, R ^A and R ^A1 can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables R ¹ , R ² , R ³ , R ^3a , R ⁴ , R ^4a , R ⁵ , T, R ^T , A, R ^A and R ^A1 can be combined, where applicable, with any group described herein for one or more of the remainder of variables R ¹ , R ² , R ³ , R ^3a , R ⁴ , R ^4a , R ⁵ , T, R ^T , A, R ^A and R ^A1 . Variables R ¹ , R ² , R ³ , R ^3a , R ⁴ , R ^4a , R ⁵ [0100] In some embodiments, R ¹ is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. [0101] In some embodiments, R ¹ is H or halogen. [0102] In some embodiments, R ¹ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. [0103] In some embodiments, R ¹ is H. [0104] In some embodiments, R ¹ is halogen. [0105] In some embodiments, R ¹ is F, Cl, Br, or I. In some embodiments, R ¹ is F, Cl, or Br. In some embodiments, R ¹ is F or Cl. [0106] In some embodiments, R ¹ is F. In some embodiments, R ¹ is Cl. In some embodiments, R ¹ is Br. In some embodiments, R ¹ is I. [0107] In some embodiments, R ¹ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxyl. [0108] In some embodiments, R ¹ is C ₁ -C ₆ alkyl. [0109] In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is ethyl. In some embodiments, R ¹ is propyl. In some embodiments, R ¹ is butyl. In some embodiments, R ¹ is pentyl. In some embodiments, R ¹ is hexyl. In some embodiments, R ¹ is isopropyl. In some embodiments, R ¹ is isobutyl. In some embodiments, R ¹ is isopentyl. In some embodiments, R ¹ is isohexyl. In some embodiments, R ¹ is secbutyl. In some embodiments, R ¹ is secpentyl. In some embodiments, R ¹ is sechexyl. In some embodiments, R ¹ is tertbutyl. [0110] In some embodiments, R ¹ is C1-C6 alkoxyl. [0111] In some embodiments, R ¹ is methoxy. In some embodiments, R ¹ is ethoxy. In some embodiments, R ¹ is propoxy. In some embodiments, R ¹ is butoxy. In some embodiments, R ¹ is pentoxy. In some embodiments, R ¹ is hexoxy. [0112] In some embodiments, R ² is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. [0113] In some embodiments, R ² is H, halogen, or cyano. [0114] In some embodiments, R ² is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. [0115] In some embodiments, R ² is H, or halogen. [0116] In some embodiments, R ² is H. [0117] In some embodiments, R ² is halogen. [0118] In some embodiments, R ² is F, Cl, Br, or I. In some embodiments, R ² is F, Cl, or Br. In some embodiments, R ² is F or Cl. [0119] In some embodiments, R ² is F. In some embodiments, R ² is Cl. In some embodiments, R ² is Br. In some embodiments, R ² is I. [0120] In some embodiments, R ³ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a . [0121] In some embodiments, R ³ is H. [0122] In some embodiments, R ³ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a . [0123] In some embodiments, R ³ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl, is substituted with one or more R ^3a . [0124] In some embodiments, R ³ is C1-C6 alkyl optionally substituted with one or more R ^3a . [0125] In some embodiments, R ³ is C ₁ -C ₆ alkyl substituted with one or more R ^3a . [0126] In some embodiments, R ³ is methyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is ethyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is propyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is butyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is pentyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is hexyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is isopropyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is isobutyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is isopentyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is isohexyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is secbutyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is secpentyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is sechexyl optionally substituted with one or more R ^3a . In some embodiments, R ³ is tertbutyl optionally substituted with one or more R ^3a . [0127] In some embodiments, R ³ is methyl substituted with one or more R ^3a . In some embodiments, R ³ is ethyl substituted with one or more R ^3a . In some embodiments, R ³ is propyl substituted with one or more R ^3a . In some embodiments, R ³ is butyl substituted with one or more R ^3a . In some embodiments, R ³ is pentyl substituted with one or more R ^3a . In some embodiments, R ³ is hexyl substituted with one or more R ^3a . In some embodiments, R ³ is isopropyl substituted with one or more R ^3a . In some embodiments, R ³ is isobutyl substituted with one or more R ^3a . In some embodiments, R ³ is isopentyl substituted with one or more R ^3a . In some embodiments, R ³ is isohexyl substituted with one or more R ^3a . In some embodiments, R ³ is secbutyl substituted with one or more R ^3a . In some embodiments, R ³ is secpentyl substituted with one or more R ^3a . In some embodiments, R ³ is sechexyl substituted with one or more R ^3a . In some embodiments, R ³ is tertbutyl substituted with one or more R ^3a . [0128] In some embodiments, R ³ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl. [0129] In some embodiments, R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₁₂ cycloalkyl. [0130] In some embodiments, R ³ is C ₁ -C ₆ alkyl. [0131] In some embodiments, R ³ is methyl. In some embodiments, R ³ is ethyl. In some embodiments, R ³ is propyl. In some embodiments, R ³ is butyl. In some embodiments, R ³ is pentyl. In some embodiments, R ³ is hexyl. In some embodiments, R ³ is isopropyl. In some embodiments, R ³ is isobutyl. In some embodiments, R ³ is isopentyl. In some embodiments, R ³ is isohexyl. In some embodiments, R ³ is secbutyl. In some embodiments, R ³ is secpentyl. In some embodiments, R ³ is sechexyl. In some embodiments, R ³ is tertbutyl. [0132] In some embodiments, R ³ is C1-C6 haloalkyl. [0133] In some embodiments, R ³ is halomethyl. In some embodiments, R ³ is haloethyl. In some embodiments, R ³ is halopropyl. In some embodiments, R ³ is halobutyl. In some embodiments, R ³ is halopentyl. In some embodiments, R ³ is halohexyl. [0134] In some embodiments, R ³ is C3-C12 cycloalkyl. [0135] In some embodiments, each R ^3a independently is halogen, -OH, cyano, C ₁ -C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl. [0136] In some embodiments, each R ^3a independently is -OH, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl. [0137] In some embodiments, each R ^3a independently is halogen. [0138] In some embodiments, each R ^3a independently is -OH or cyano. [0139] In some embodiments, each R ^3a independently is -OH. [0140] In some embodiments, each R ^3a independently is cyano. [0141] In some embodiments, each R ^3a independently is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl. [0142] In some embodiments, each R ^3a independently is C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl. [0143] In some embodiments, each R ^3a independently is C ₁ -C ₆ alkoxyl. [0144] In some embodiments, each R ^3a independently is C3-C12 cycloalkyl. [0145] In some embodiments, each R ^3a independently is 3- to 12-membered heterocycloalkyl. [0146] In some embodiments, two R ^3a , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl. [0147] In some embodiments, two R ^3a , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl. [0148] In some embodiments, two R ^3a , together with the atoms they are attached, form a C ₃ - C12 cycloalkyl. [0149] In some embodiments, R ⁴ is –(C ₁ -C ₆ alkyl)-(3- to 12-membered heterocycloalkyl), C ₃ - C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a . [0150] In some embodiments, R ⁴ is C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a . [0151] In some embodiments, R ⁴ is –(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl). [0152] In some embodiments, R ⁴ is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the C ₃ -C ₁₂ cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more R ^4a . [0153] In some embodiments, R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a . [0154] In some embodiments, R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is substituted with one or more R ^4a .In some embodiments, R ⁴ is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R ^4a . [0155] In some embodiments, R ⁴ is 3- to 12-membered heterocycloalkyl substituted with one or more R ^4a . [0156] In some embodiments, R ⁴ is a bicyclic 3- to 12-membered heterocycloalkyl. [0157] In some embodiments, R ⁴ is a fused 3- to 12-membered heterocycloalkyl. [0158] In some embodiments, R ⁴ is a spiro 3- to 12-membered heterocycloalkyl. [0159] In some embodiments, R ⁴ is a bridged 3- to 12-membered heterocycloalkyl. [0160] In some embodiments, R ⁴ is morpholinyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is piperidinyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is piperazinyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is azetidinyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 1,4-oxazepanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.4]octanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-7-azaspiro[3.5]nonanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 6-azaspiro[3.4]octanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.5]nonanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.3]heptanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 3-azabicyclo[3.1.0]hexanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 2- azaspiro[3.5]nonanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is hexahydro-1H-furo[3,4-c]pyrrolyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is pyrrolidinyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is octahydropyrrolo[1,2-a]pyrazinyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is tetrahydropyranyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-5-azabicyclo[2.2.1]heptanyl optionally substituted with one or more R ^4a . In some embodiments, R ⁴ is 7-oxa-2-azaspiro[3.5]nonanyl optionally substituted with one or more R ^4a . [0161] In some embodiments, R ⁴ is morpholinyl substituted with one or more R ^4a . In some embodiments, R ⁴ is piperidinyl substituted with one or more R ^4a . In some embodiments, R ⁴ is piperazinyl substituted with one or more R ^4a . In some embodiments, R ⁴ is azetidinyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 1,4-oxazepanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.4]octanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-7-azaspiro[3.5]nonanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 6-azaspiro[3.4]octanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.5]nonanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.3]heptanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 3-azabicyclo[3.1.0]hexanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-azaspiro[3.5]nonanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is hexahydro-1H-furo[3,4-c]pyrrolyl substituted with one or more R ^4a . In some embodiments, R ⁴ is pyrrolidinyl substituted with one or more R ^4a . In some embodiments, R ⁴ is octahydropyrrolo[1,2-a]pyrazinyl substituted with one or more R ^4a . In some embodiments, R ⁴ is tetrahydropyranyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 2-oxa-5-azabicyclo[2.2.1]heptanyl substituted with one or more R ^4a . In some embodiments, R ⁴ is 7-oxa-2-azaspiro[3.5]nonanyl substituted with one or more R ^4a . [0162] In some embodiments, R ⁴ is C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl. [0163] In some embodiments, R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl. [0164] In some embodiments, R ⁴ is 3- to 12-membered heterocycloalkyl. [0165] In some embodiments, R ⁴ is morpholinyl. In some embodiments, R ⁴ is piperidinyl. In some embodiments, R ⁴ is piperazinyl. In some embodiments, R ⁴ is azetidinyl. In some embodiments, R ⁴ is 1,4-oxazepanyl. In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.4]octanyl. In some embodiments, R ⁴ is 2-oxa-7-azaspiro[3.5]nonanyl. In some embodiments, R ⁴ is 6- azaspiro[3.4]octanyl. In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.5]nonanyl. In some embodiments, R ⁴ is 2-oxa-6-azaspiro[3.3]heptanyl. In some embodiments, R ⁴ is 3- azabicyclo[3.1.0]hexanyl. In some embodiments, R ⁴ is 2-azaspiro[3.5]nonanyl. In some embodiments, R ⁴ is hexahydro-1H-furo[3,4-c]pyrrolyl. In some embodiments, R ⁴ is pyrrolidinyl. In some embodiments, R ⁴ is octahydropyrrolo[1,2-a]pyrazinyl. In some embodiments, R ⁴ is tetrahydropyranyl. In some embodiments, R ⁴ is 2-oxa-5- azabicyclo[2.2.1]heptanyl. In some embodiments, R ⁴ is 7-oxa-2-azaspiro[3.5]nonanyl. [0166] In some embodiments, R ⁴ is 5- to 10-membered heteroaryl. [0167] In some embodiments, R ⁴ is pyridinyl. [0168] In some embodiments, each R ^4a independently is halogen, -C(=O)-(C ₁ -C ₆ alkyl), C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, C ₆ -C ₁₀ aryl, 3- to 12- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen or cyano. [0169] In some embodiments, each R ^4a independently is halogen, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl. [0170] In some embodiments, each R ^4a independently is halogen. [0171] In some embodiments, each R ^4a independently is F, Cl, Br, or I. In some embodiments, each R ^4a independently is F, Cl, or Br. In some embodiments, each R ^4a independently is F or Cl. [0172] In some embodiments, each R ^4a independently is F. In some embodiments, each R ^4a independently is Cl. In some embodiments, each R ^4a independently is Br. In some embodiments, each R ^4a independently is I. [0173] In some embodiments, each R ^4a independently is -C(=O)-(C ₁ -C ₆ alkyl). [0174] In some embodiments, each R ^4a independently is C6-C10 aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen or cyano. [0175] In some embodiments, each R ^4a independently is C ₆ -C ₁₀ aryl optionally substituted with one or more halogen or cyano. [0176] In some embodiments, each R ^4a independently is 3- to 12-membered heterocycloalkyl optionally substituted with one or more halogen or cyano. [0177] In some embodiments, each R ^4a independently is 5- to 10-membered heteroaryl optionally substituted with one or more halogen or cyano. [0178] In some embodiments, each R ^4a independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl. [0179] In some embodiments, each R ^4a independently is C1-C6 alkyl, C1-C6 haloalkyl, or C1- C6 alkoxyl. [0180] In some embodiments, each R ^4a independently is C ₁ -C ₆ alkyl. [0181] In some embodiments, each R ^4a independently is methyl. In some embodiments, each R ^4a independently is ethyl. In some embodiments, each R ^4a independently is propyl. In some embodiments, each R ^4a independently is butyl. In some embodiments, each R ^4a independently is pentyl. In some embodiments, each R ^4a independently is hexyl. In some embodiments, each R ^4a independently is isopropyl. In some embodiments, each R ^4a independently is isobutyl. In some embodiments, each R ^4a independently is isopentyl. In some embodiments, each R ^4a independently is isohexyl. In some embodiments, each R ^4a independently is secbutyl. In some embodiments, each R ^4a independently is secpentyl. In some embodiments, each R ^4a independently is sechexyl. In some embodiments, each R ^4a independently is tertbutyl. [0182] In some embodiments, each R ^4a independently is C ₁ -C ₆ haloalkyl. [0183] In some embodiments, each R ^4a independently is halomethyl. In some embodiments, each R ^4a independently is haloethyl. In some embodiments, each R ^4a independently is halopropyl. In some embodiments, each R ^4a independently is halobutyl. In some embodiments, each R ^4a independently is halopentyl. In some embodiments, each R ^4a independently is halohexyl. [0184] In some embodiments, each R ^4a independently is C1-C6 alkoxyl. [0185] In some embodiments, each R ^4a independently is methoxy. In some embodiments, each R ^4a independently is ethoxy. In some embodiments, each R ^4a independently is propoxy. In some embodiments, each R ^4a independently is butoxy. In some embodiments, each R ^4a independently is pentoxy. In some embodiments, each R ^4a independently is hexoxy. [0186] In some embodiments, R ⁵ is H, halogen, cyano, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxyl. [0187] In some embodiments, R ⁵ is H, halogen, cyano, or C ₁ -C ₆ alkoxyl. [0188] In some embodiments, R ⁵ is H, halogen, or cyano. [0189] In some embodiments, R ⁵ is H. [0190] In some embodiments, R ⁵ is C ₁ -C ₆ alkyl. [0191] In some embodiments, R ⁵ is C1-C6 alkoxyl. [0192] In some embodiments, R ⁵ is methoxy. In some embodiments, R ⁵ is ethoxy. In some embodiments, R ⁵ is propoxy. In some embodiments, R ⁵ is butoxy. In some embodiments, R ⁵ is pentoxy. In some embodiments, R ⁵ is hexoxy. Variables T, R ^T , A, R ^A , R ^A1 , R ^A2 [0193] In some embodiments, T is -O-*, -NR ^T -*, -C(=O)NR ^T -*, -NR ^T C(=O)-*, -(C1-C6 alkyl)-*, -(C3-C12 cycloalkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NR ^T -*, -NR ^T -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-NR ^T -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ haloalkyl)-*, -(C ₁ -C ₆ haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NR ^T -*, -S(=O)2NR ^T -*, or -NR ^T - (C1-C6 haloalkyl)-*, wherein * denotes attachment to A. [0194] In some embodiments, T is -O-*, -NR ^T -*, -C(=O)NR ^T -*, -NR ^T C(=O)-*, -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-O-*, -O-(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-NR ^T -*, -NR ^T -(C ₁ -C ₆ alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NR ^T - *, or -NR ^T - (C ₁ -C ₆ haloalkyl)-*, wherein * denotes attachment to A. [0195] In some embodiments, T is -O-*, -NR ^T -*, -C(=O)NR ^T -*, -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-O-*, -(C1-C6 alkyl)-NR ^T -*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, or -(C1-C6 haloalkyl)-NR ^T -*, wherein * denotes attachment to A. [0196] In some embodiments, T is -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-O-*, or -(C ₁ -C ₆ alkyl)- NR ^T -*, wherein * denotes attachment to A. [0197] In some embodiments, T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [0198] In some embodiments, T is -(C3-C12 cycloalkyl)-*, wherein * denotes attachment to A. [0199] In some embodiments, T is branched -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [0200] In some embodiments, T is -CH(CH3)-*, wherein * denotes attachment to A. [0201] In some embodiments, T is -(C1-C6 alkyl)-O-*, wherein * denotes attachment to A. [0202] In some embodiments, T is -CH(CH ₃ )-O-*, wherein * denotes attachment to A. [0203] In some embodiments, T is -(C ₁ -C ₆ alkyl)-NR ^T -*, wherein * denotes attachment to A. [0204] In some embodiments, T is -(C1-C6 alkyl)-NR ^T -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [0205] In some embodiments, T is -S(=O) ₂ NR ^T -*, wherein * denotes attachment to A. [0206] In some embodiments, T is -CH(CH3)-NR ^T -*, wherein * denotes attachment to A. [0207] In some embodiments, T is -CH(CH ₃ )-NH-*, wherein * denotes attachment to A. [0208] In some embodiments, each R ^T is H or C ₁ -C ₆ alkyl. [0209] In some embodiments, R ^T is H or C1-C6 alkyl. [0210] In some embodiments, R ^T is H. [0211] In some embodiments, R ^T is C ₁ -C ₆ alkyl. [0212] In some embodiments, A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A . [0213] In some embodiments, A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the C ₃ -C ₁₂ cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more R ^A . [0214] In some embodiments, A is 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A . [0215] In some embodiments, A is 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl is substituted with one or more R ^A . [0216] In some embodiments, A is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R ^A . [0217] In some embodiments, A is 3- to 12-membered heterocycloalkyl substituted with one or more R ^A . [0218] In some embodiments, A is 3- to 12-membered heterocycloalkyl. [0219] In some embodiments, A is C6-C10 aryl optionally substituted with one or more R ^A . [0220] In some embodiments, A is C ₆ -C ₁₀ aryl substituted with one or more R ^A . [0221] In some embodiments, A is C6-C10 aryl. [0222] In some embodiments, A is phenyl optionally substituted with one or more R ^A . [0223] In some embodiments, A is phenyl substituted with one or more R ^A . [0224] In some embodiments, A is phenyl. [0225] In some embodiments, A is 5- to 10-membered heteroaryl optionally substituted with one or more R ^A . [0226] In some embodiments, A is 5- to 10-membered heteroaryl substituted with one or more R ^A . [0227] In some embodiments, A is 5- to 10-membered heteroaryl. [0228] In some embodiments, A is 2,3-dihydrobenzo[b]thiophene optionally substituted with one or more R ^A . In some embodiments, A is pyrazolyl optionally substituted with one or more R ^A . In some embodiments, A is pyridinyl optionally substituted with one or more R ^A . In some embodiments, A is [1,2,4]triazolo[4,3-a]pyridinyl optionally substituted with one or more R ^A . In some embodiments, A is thiophenyl optionally substituted with one or more R ^A . [0229] In some embodiments, A is 2,3-dihydrobenzo[b]thiophene substituted with one or more R ^A . In some embodiments, A is pyrazolyl substituted with one or more R ^A . In some embodiments, A is pyridinyl substituted with one or more R ^A . In some embodiments, A is [1,2,4]triazolo[4,3-a]pyridinyl substituted with one or more R ^A . In some embodiments, A is thiophenyl substituted with one or more R ^A . [0230] In some embodiments, A is 2,3-dihydrobenzo[b]thiophene. In some embodiments, A is pyrazolyl. In some embodiments, A is pyridinyl. In some embodiments, A is [1,2,4]triazolo[4,3-a]pyridinyl. In some embodiments, A is thiophenyl. [0231] In some embodiments, each R ^A independently is oxo, halogen, -OH, cyano, -NH ₂ , - C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)N(R ^A1 )2, -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C1-C6 alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ N(R ^A1 ) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), - C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 . [0232] In some embodiments, each R ^A independently is oxo, halogen, -OH, cyano, -NH2, - C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)N(R ^A1 )2, -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C1-C6 alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ N(R ^A1 ) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), - C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is substituted with one or more R ^A1 . [0233] In some embodiments, each R ^A independently is oxo, halogen, -OH, cyano, or -NH ₂ . [0234] In some embodiments, each R ^A independently is oxo. [0235] In some embodiments, each R ^A independently is halogen. [0236] In some embodiments, each R ^A independently is F, Cl, Br, or I. In some embodiments, each R ^A independently is F, Cl, or Br. In some embodiments, each R ^A independently is F or Cl. [0237] In some embodiments, each R ^A independently is F. In some embodiments, each R ^A independently is Cl. In some embodiments, each R ^A independently is Br. In some embodiments, each R ^A independently is I. [0238] In some embodiments, each R ^A independently is -OH. [0239] In some embodiments, each R ^A independently is cyano. [0240] In some embodiments, each R ^A independently is -NH2. [0241] In some embodiments, each R ^A independently is -O(C3-C12 heterocycloalkyl), - N(R ^A1 ) ₂ , -B(OH) ₂ , -NO ₂ , -C(=O)O(C ₃ -C ₁₂ heterocycloalkyl), -S(=O) ₂ (C ₃ -C ₁₂ cycloalkyl), - C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)N(R ^A1 )2, -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)(=NR ^A1 )R ^A1 , -S(=O)2N(R ^A1 )2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), - C(=O)O(C3-C12 heterocycloalkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxyl, 3- to 12- membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 . [0242] In some embodiments, each R ^A independently is -C(=O)OH, -C(=O)O(C ₁ -C ₆ alkyl), - C(=O)N(R ^A1 ) ₂ , -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , - S(=O)(=NR ^A1 )R ^A1 , -S(=O)2N(R ^A1 )2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C ₆ alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 . [0243] In some embodiments, each R ^A independently is -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)N(R ^A1 ) ₂ , -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , - S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ N(R ^A1 ) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ - C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is substituted with one or more R ^A1 . [0244] In some embodiments, each R ^A independently is -C(=O)OH. [0245] In some embodiments, each R ^A independently is -O(C3-C12 heterocycloalkyl). [0246] In some embodiments, each R ^A independently is -N(R ^A1 )2. [0247] In some embodiments, each R ^A independently is -B(OH) ₂ . [0248] In some embodiments, each R ^A independently is -NO2. [0249] In some embodiments, each R ^A independently is -C(=O)O(C3-C12 heterocycloalkyl). [0250] In some embodiments, each R ^A independently is -C(=O)O(C ₃ -C ₁₂ heterocycloalkyl), wherein the heterocycloalkyl is optionally substituted with one or more R ^A1 . [0251] In some embodiments, each R ^A independently is -S(=O)2(C3-C12 cycloalkyl). [0252] In some embodiments, each R ^A independently is -S(=O) ₂ (C ₁ -C ₆ alkyl). [0253] In some embodiments, each R ^A independently is -S(=O)2(C1-C6 alkyl), wherein the alkyl is optionally substituted with one or more R ^A1 . [0254] In some embodiments, each R ^A independently is -S(=O) ₂ (C ₁ -C ₆ alkyl), wherein the alkyl is substituted with one or more R ^A1 . [0255] In some embodiments, each R ^A independently is -S(=O)2(methyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is - S(=O) ₂ (ethyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(propyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (butyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (pentyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(hexyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(isopropyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(isobutyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (isopentyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(isohexyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is - S(=O) ₂ (secbutyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (secpentyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(sechexyl) optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (tertbutyl) optionally substituted with one or more R ^A1 . [0256] In some embodiments, each R ^A independently is -S(=O)2(methyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (ethyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (propyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(butyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is - S(=O) ₂ (pentyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(hexyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(isopropyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (isobutyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(isopentyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O)2(isohexyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (secbutyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is - S(=O)2(secpentyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (sechexyl) substituted with one or more R ^A1 . In some embodiments, each R ^A independently is -S(=O) ₂ (tertbutyl) substituted with one or more R ^A1 . [0257] In some embodiments, each R ^A independently is -S(=O)2(methyl). In some embodiments, each R ^A independently is -S(=O) ₂ (ethyl). In some embodiments, each R ^A independently is -S(=O) ₂ (propyl). In some embodiments, each R ^A independently is - S(=O)2(butyl). In some embodiments, each R ^A independently is -S(=O)2(pentyl). In some embodiments, each R ^A independently is -S(=O) ₂ (hexyl). In some embodiments, each R ^A independently is -S(=O) ₂ (isopropyl). In some embodiments, each R ^A independently is - S(=O)2(isobutyl). In some embodiments, each R ^A independently is -S(=O)2(isopentyl). In some embodiments, each R ^A independently is -S(=O)2(isohexyl). In some embodiments, each R ^A independently is -S(=O)2(secbutyl). In some embodiments, each R ^A independently is - S(=O)2(secpentyl). In some embodiments, each R ^A independently is -S(=O)2(sechexyl). In some embodiments, each R ^A independently is -S(=O) ₂ (tertbutyl). [0258] In some embodiments, each R ^A independently is C1-C6 alkyl optionally substituted with one or more R ^A1 . [0259] In some embodiments, each R ^A independently is C ₁ -C ₆ alkyl substituted with one or more R ^A1 . [0260] In some embodiments, each R ^A independently is C1-C6 alkyl. [0261] In some embodiments, each R ^A independently is methyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is ethyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is propyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is butyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is pentyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is hexyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is isopropyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is isobutyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is isopentyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is isohexyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is secbutyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is secpentyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is sechexyl optionally substituted with one or more R ^A1 . In some embodiments, each R ^A independently is tertbutyl optionally substituted with one or more R ^A1 . [0262] In some embodiments, each R ^A independently is methyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is ethyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is propyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is butyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is pentyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is hexyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is isopropyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is isobutyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is isopentyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is isohexyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is secbutyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is secpentyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is sechexyl substituted with one or more R ^A1 . In some embodiments, each R ^A independently is tertbutyl substituted with one or more R ^A1 . [0263] In some embodiments, each R ^A independently is methyl. In some embodiments, each R ^A independently is ethyl. In some embodiments, each R ^A independently is propyl. In some embodiments, each R ^A independently is butyl. In some embodiments, each R ^A independently is pentyl. In some embodiments, each R ^A independently is hexyl. In some embodiments, each R ^A independently is isopropyl. In some embodiments, each R ^A independently is isobutyl. In some embodiments, each R ^A independently is isopentyl. In some embodiments, each R ^A independently is isohexyl. In some embodiments, each R ^A independently is secbutyl. In some embodiments, each R ^A independently is secpentyl. In some embodiments, each R ^A independently is sechexyl. In some embodiments, each R ^A independently is tertbutyl. [0264] In some embodiments, each R ^A1 independently is H, oxo, halogen, -OH, -NH2, - C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ heterocycloalkyl, or C ₃ -C ₁₂ cycloalkyl, wherein the -C(=O)(C1-C6 alkyl), C1-C6 alkyl, C3-C12 heterocycloalkyl, or C3-C12 cycloalkyl is optionally substituted with -OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0265] In some embodiments, each R ^A1 independently is H, oxo, halogen, -OH, -NH ₂ , - C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C12 heterocycloalkyl, or C3-C12 cycloalkyl, wherein the -C(=O)(C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₃ -C ₁₂ heterocycloalkyl, or C ₃ -C ₁₂ cycloalkyl is optionally substituted with -OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl is optionally substituted with one or more R ^A2 . [0266] In some embodiments, each R ^A1 independently is H, halogen, -OH, -NH ₂ , -C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl is optionally substituted with - OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0267] In some embodiments, each R ^A1 independently is H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl is optionally substituted with - OH. [0268] In some embodiments, two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0269] In some embodiments, each R ^A1 independently is H, oxo, halogen, -OH, or -NH ₂ . [0270] In some embodiments, each R ^A1 independently is H, halogen, -OH, or -NH ₂ . [0271] In some embodiments, each R ^A1 independently is H. [0272] In some embodiments, each R ^A1 independently is oxo. [0273] In some embodiments, each R ^A1 independently is halogen. [0274] In some embodiments, each R ^A1 independently is F, Cl, Br, or I. In some embodiments, each R ^A1 independently is F, Cl, or Br. In some embodiments, each R ^A1 independently is F or Cl. [0275] In some embodiments, each R ^A1 independently is F. In some embodiments, each R ^A1 independently is Cl. In some embodiments, each R ^A1 independently is Br. In some embodiments, each R ^A1 independently is I. [0276] In some embodiments, each R ^A1 independently is -OH. [0277] In some embodiments, each R ^A1 independently is -NH2. [0278] In some embodiments, each R ^A1 independently is -C(=O)OH, -C(=O)(C ₁ -C ₆ alkyl), - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C12 heterocycloalkyl, or C3-C12 cycloalkyl, wherein the -C(=O)(C1-C6 alkyl), C1- C ₆ alkyl, C ₃ -C ₁₂ heterocycloalkyl, or C ₃ -C ₁₂ cycloalkyl is optionally substituted with one or more R ^A2 . [0279] In some embodiments, each R ^A1 independently is -C(=O)OH, -C(=O)(C1-C6 alkyl), - S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ heterocycloalkyl, or C ₃ -C ₁₂ cycloalkyl, wherein the -C(=O)(C ₁ -C ₆ alkyl), C ₁ - C6 alkyl, C3-C12 heterocycloalkyl, or C3-C12 cycloalkyl is optionally substituted with -OH. [0280] In some embodiments, each R ^A1 independently is -C(=O)OH, -C(=O)(C ₁ -C ₆ alkyl), - S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH. [0281] In some embodiments, each R ^A1 independently is -C(=O)OH, -C(=O)(C1-C6 alkyl), - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl. [0282] In some embodiments, each R ^A1 independently is -C(=O)OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C3-C12 heterocycloalkyl, or C3-C12 cycloalkyl. [0283] In some embodiments, each R ^A1 independently is -C(=O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or C ₃ -C ₁₂ cycloalkyl. [0284] In some embodiments, each R ^A1 independently is C1-C6 haloalkyl. [0285] In some embodiments, each R ^A1 independently is C ₃ -C ₁₂ heterocycloalkyl. [0286] In some embodiments, each R ^A1 independently is C ₃ -C ₁₂ heterocycloalkyl optionally substituted with one or more R ^A2 . [0287] In some embodiments, each R ^A1 independently is -C(=O)(C ₁ -C ₆ alkyl). [0288] In some embodiments, each R ^A1 independently is -C(=O)(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^A2 . [0289] In some embodiments, each R ^A1 independently is C1-C6 alkyl. [0290] In some embodiments, each R ^A1 independently is C ₁ -C ₆ alkyl optionally substituted with one or more R ^A2 . [0291] In some embodiments, each R ^A1 independently is C3-C12 cycloalkyl optionally substituted with one or more R ^A2 . [0292] In some embodiments, each R ^A1 independently is C3-C12 cycloalkyl optionally substituted with -OH. [0293] In some embodiments, each R ^A1 independently is C ₃ -C ₁₂ cycloalkyl substituted with - OH. [0294] In some embodiments, each R ^A1 independently is C3-C12 cycloalkyl. [0295] In some embodiments, each R ^A2 independently is -OH, cyano, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ cycloalkyl, or C ₃ -C ₁₂ heterocycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ heterocycloalkyl is optionally substituted with one or more halogen or C1-C6 alkyl. [0296] In some embodiments, each R ^A2 independently is -OH. [0297] In some embodiments, each R ^A2 independently is cyano. [0298] In some embodiments, each R ^A2 independently is C1-C6 alkoxyl. [0299] In some embodiments, each R ^A2 independently is C ₃ -C ₁₂ cycloalkyl. [0300] In some embodiments, each R ^A2 independently is C ₃ -C ₁₂ cycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl. [0301] In some embodiments, each R ^A2 independently is C3-C12 heterocycloalkyl. [0302] In some embodiments, each R ^A2 independently is C3-C12 heterocycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl.. [0303] In some embodiments, the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), or (I-i): (I-e)

or a pharmaceutically acceptable salt or stereoisomer thereof. [0304] In some embodiments, the compound is of Formula (I-j): (I-j) or a pharmaceutically acceptable salt or stereoisomer thereof. [0305] In some embodiments, the compound is of Formula (I-k): (I-k) or a pharmaceutically acceptable salt or stereoisomer thereof. [0306] In some embodiments, the compound is of Formula (I-l), or Formula (I-m): ; ; (I-m) or a pharmaceutically acceptable salt or stereoisomer thereof. [0307] In some embodiments, the compound is of Formula (I-n): (I-n) or a pharmaceutically acceptable salt or stereoisomer thereof. [0308] In some embodiments, the compound is of Formula (I-o): or a pharmaceutically acceptable salt or stereoisomer thereof. [0309] In some embodiments, the compound is a compound described in Table 1 or Table 2, or a prodrug or pharmaceutically acceptable salt thereof. [0310] In some embodiments, the compound is a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. [0311] In some embodiments, the compound is a prodrug of a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. [0312] In some embodiments, the compound is a compound described in Table 1 or Table 2. [0313] In some embodiments, the compound is a compound described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof. [0314] In some embodiments, the compound is a compound described in Table 1, or a pharmaceutically acceptable salt thereof. [0315] In some embodiments, the compound is a prodrug of a compound described in Table 1, or a pharmaceutically acceptable salt thereof. [0316] In some embodiments, the compound is a compound described in Table 1. [0317] In some embodiments, the compound is a compound described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof. [0318] In some embodiments, the compound is a compound described in Table 2, or a pharmaceutically acceptable salt thereof. [0319] In some embodiments, the compound is a prodrug of a compound described in Table 2, or a pharmaceutically acceptable salt thereof. [0320] In some embodiments, the compound is a compound described in Table 2. Table 1 Compo N _o. 182 183 184 185 Table 2

[0321] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 1. [0322] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 2. [0323] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein. [0324] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof. [0325] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof. [0326] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof. [0327] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1. [0328] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof. [0329] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof. [0330] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof. [0331] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2. [0332] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognised techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0333] In some embodiments, the isotopic derivative is a deuterium labeled compound. [0334] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein. [0335] In some embodiments, the isotopic derivative is a compound described in Table 3, an isomer thereof, or a pharmaceutically acceptable salt thereof. Table 3 [0336] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from ² H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ²⁹ Si, ³¹ P, and ³⁴ S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with ² H with regard to one or more atoms thereof). In some embodiments, the compound is a ¹⁸ F labeled compound. In some embodiments, the compound is a ¹²³ I labeled compound, a ¹²⁴ I labeled compound, a ¹²⁵ I labeled compound, a ¹²⁹ I labeled compound, a ¹³¹ I labeled compound, a ¹³⁵ I labeled compound, or any combination thereof. In some embodiments, the compound is a ³³ S labeled compound, a ³⁴ S labeled compound, a ³⁵ S labeled compound, a ³⁶ S labeled compound, or any combination thereof. [0337] It is understood that the ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I, ¹³⁵ I, ³² S, ³⁴ S, ³⁵ S, and/or ³⁶ S labeled compound, can be prepared using any of a variety of art-recognised techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I, ¹³⁵ I, ³ S, ³⁴ S, ³⁵ S, and/or ³⁶ S labeled reagent for a non-isotope labeled reagent. [0338] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I, ¹³⁵ I, ³² S, ³⁴ S, ³⁵ S, and ³⁶ S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g,, ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I, ¹³⁵ I, ³ S, ³⁴ S, ³⁵ S, and/or ³⁶ S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. [0339] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group. [0340] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. In some embodiments, the molecular weight is less than 600 and, for example, is 550 daltons or less. [0341] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. [0342] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds. [0343] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and to refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound. [0344] It will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof. [0345] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” [0346] As used herein, the term “chiral centre” refers to a carbon atom bonded to four nonidentical substituents. [0347] As used herein, the term “chiral isomer” means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). [0348] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [0349] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. [0350] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity. [0351] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. [0352] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. [0353] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. [0354] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0355] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that modulate PI3KĮ activity. [0356] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions. [0357] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). [0358] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms. [0359] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. [0360] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H ₂ O. [0361] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound. [0362] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein. [0363] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996. [0364] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that modulate PI3KĮ activity. [0365] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which modulate PI3KĮ activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis. [0366] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. [0367] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen- containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. [0368] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein. [0369] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound. [0370] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987. [0371] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C ₁ -C ₁₀ alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. [0372] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C _1-4 alkylamine such as methylamine, a (C ₁ -C ₄ alkyl) ₂ amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1- C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0373] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C ₁ -C ₄ alkyl)piperazin-1- ylmethyl. [0374] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). [0375] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Methods of Synthesis [0376] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure. [0377] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein. [0378] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein. [0379] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein. [0380] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. [0381] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. [0382] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised. [0383] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. [0384] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. [0385] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. [0386] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. [0387] Once a compound of Formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof. [0388] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art. [0389] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water. [0390] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used. [0391] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. [0392] Moreover, by utilising the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. [0393] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well- known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). [0394] General routes for the preparation of a compound of the application are described in Schemes 1-4 herein. [0395] In some embodiments, an appropriately substituted anthranilic acid (1) may be reacted with a variety amines utilizing a peptide coupling reagent (e.g. HATU) to give amide derivatives (2). Condensation of amide (2) with a phosgene reagent may provide quinazolinones (3). Substitution of halogen (3) with a variety of amines may afford intermediate (4). Palladium-catalyzed acylation of halide (4) affords keto quinazolinone (5) which then may be undergo reductive amination in the presence of a reducing agent such as sodium cyanoborohydride to afford amine (6). Subsequent alkylation of amine (6) under mild base conditions or coupling with an aryl halide under palladium catalyst may give racemic mixture (7) of Formula (I). Reaction Scheme 1 [0396] In some embodiments, racemic mixtures of appropriately substituted quinazolinone (7) may be purified on a chiral column to give arbitrarily assigned pure enantiomers (8) and (9) of Formula (I). Reaction Scheme 2 [0397] In some embodiments, quinazolinone ketone (5) may be condensed with tert- butanesulfinamide in the presence of a Lewis acid (e.g. titanium ethoxide) to afford sulfinimine (10). Reduction of sulfinimine (10) with a reducing agent such as borane-THF may yield chiral sulfinamide (11) which can be hydrolyzed to amine (12) under acidic conditions. Subsequent alkylation under mild basic conditions or coupling with an aryl halide using a palladium catalyst may give chiral compound (8) of Formula (I). Reaction Scheme 3 [0398] In some embodiments, quinazolinone bis halide (5) can be substituted to form thiol ether (13). Thiol ether (13) can then be coupled under palladium-catalyzed conditions to reveal acyl ketone (14). Subsequent reaction with tert-butanesulfinamide in the presence of a Lewis acid (e.g. titanium ethoxide) reveals chiral imine (15). Reduction of sulfinimine (15) with a reducing agent such as borane-THF may yield chiral sulfinamide (16) which can be hydrolyzed to amine (17) under acidic conditions. Subsequent alkylation under mild basic conditions or coupling with an aryl halide using a palladium catalyst may give chiral compound (18). Oxidation of thiolether (18) to sulfoxide (19) followed by substitution with a variety of amines also produces chiral quinazolinones of Formula (I). Reaction Scheme 4 Biological Assays [0399] Compounds designed, selected and/or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. [0400] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. [0401] Various in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. [0402] In some embodiments, the biological assay is described in the Examples herein. [0403] In some embodiments, the biological activity of the compounds may be determined utilizing a p-AKT S473 assay. [0404] In some embodiments, cells (e.g., MCF10A-PI3KĮ-WT, MCF10A- PI3KĮ-H1047R and MCF10A- PI3KĮ-E545K cells) may be grown in DMEM/F12 supplemented with Horse Serum, EGF, Hydrocortisone, Cholera toxin and Insulin. In some embodiments, cells may be dissociated with TryPLE, washed with media and plated in wells plate. In some embodiments, serial dilution of compounds were applied to the cell. In some embodiments, p-AKT S473 may be measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol. In some embodiments, p-AKT S473 levels may be measured using the kit. In some embodiments, the cells (e.g., MCF10A-PI3KĮ-WT, MCF10A- PI3KĮ-H1047R and MCF10A- PI3KĮ-E545K cells) may be lysed. In some embodiments, antibodies may be mixed with detection buffer and may be added to the lysate and may be incubated overnight. In some embodiments, luminescence may be read on a plate reader (e.g., Ensight plate reader). In some embodiments, luminescence may be read at 665 nm. In some embodiments, luminescence may be read at 620 nm wavelengths. In some embodiments, a decrease in p-AKT S473 levels indicate a downregulation of the PI3KĮ pathway. In some embodiments, a decrease in p-AKT S473 levels indicate a downregulation of cell proliferation. Pharmaceutical Compositions [0405] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 2. [0406] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. [0407] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts. [0408] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof. [0409] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-ȕ-cyclodextrin, methyl-ȕ-cyclodextrin, randomly methylated-ȕ-cyclodextrin, ethylated-ȕ-cyclodextrin, triacetyl-ȕ-cyclodextrin, peracetylated-ȕ-cyclodextrin, carboxymethyl-ȕ-cyclodextrin, hydroxyethyl-ȕ-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-ȕ-cyclodextrin, glucosyl-ȕ-cyclodextrin, sulfated ȕ-cyclodextrin (S-ȕ-CD), maltosyl-ȕ-cyclodextrin, ȕ-cyclodextrin sulfobutyl ether, branched-ȕ-cyclodextrin, hydroxypropyl-Ȗ-cyclodextrin, randomly methylated-Ȗ-cyclodextrin, and trimethyl-Ȗ- cyclodextrin, and mixtures thereof. [0410] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. [0411] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof. [0412] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. [0413] The aqueous vehicle may also contain a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof. [0414] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range. [0415] The aqueous vehicle may also contain a buffering agent to stabilise the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and İ-aminocaproic acid, and mixtures thereof. [0416] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof. [0417] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, orange flavoring. [0418] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. [0419] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing). [0420] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. [0421] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a PI3KĮ related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0422] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a PI3KĮ related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0423] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Methods of Use [0424] Phosphatidylinositol 3-Kinases (PI3Ks) are a group of plasma membrane-associated lipid kinases that upon activation catalyze the transfer of phosphate to the D-3’ position of inositol of phosphoinositol-4,5-phosphate (PIP2) to produce phosphoinositol-3,4,5-phosphate (PIP ₃ ). PIP ₃ is a second messenger that binds and recruits a subset of Pleckstrin-homology, FYVE, Phox, or other lipid-binding domains of downstream target to the cell membrane. Signaling proteins (e.g. AKT, PDK1) can then bind to the lipid product of PI3K, localize to cell membrane and activate downstream cellular activity that includes transcription, translation, proliferation, survival, chemotaxis, motility, cellular trafficking and metabolism. PI3Ks include a conserved family of 15 kinases that exhibit distinct substrate specificities, expression patterns and modes of regulation. PI3Ks are divided into three classes (I, II and III) based on their structures and substrate specificities. [0425] Class I PI3Ks encompass PI3Ks containing one of the p110Į, p110ȕ, p110δ and p110Ȗ catalytic subunits, which are encoded by the PIK3CA, PIK3CB, PIK3CD and PIK3CG genes, respectively. These catalytic subunits are constitutively associated with regulatory subunits: p85Į, p55Į, p50Į, p85ȕ, p55Ȗ, p101 or p84. [0426] Genetic alterations such as mutation, amplification, deletion or translocation in genes in PI3K signaling are believed to be implicated in several diseases or disorders e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS) as well as human cancers (e.g. B-cell lymphoma, adrenocortical carcinoma, bladder urothelial carcinoma, breast cancer, cervical adenocarcinoma, cervical squamous-cell carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, colorectal cancer, diffuse glioma, esophageal squamous-cell cancer, esophagogastric adenocarcinoma, esophagogastric cancer, fibrolamellar carcinoma, germ-cell carcinoma, glioblastoma, glioma, head and neck squamous-cell carcinoma, hepatocellular carcinoma, leukemia, melanoma, mesothelioma, miscellaneous neuroepithelial tumor, nerve-sheath tumor, non-small-cell lung cancer, ovarian cancer, pancreatic cancer, pheochromocytoma, prostate cancer, renal clear-cell carcinoma, renal nonclear-cell carcinoma, soft-tissue sarcoma, thymic tumor, thyroid cancer and endometrial cancer). [0427] More specifically, mutations in the gene PIK3CA, which encodes the p110Į (also referred to as PI3KĮ) catalytic subunit, have been linked to numerous cancers, including bladder cancer, brain cancer, breast cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, lung cancer and prostate cancer. Mutations in the PIK3CA gene are notably observed within several “mutation hotspots” that are located within the kinase and helicase domains. These mutations include the E542K mutation, the E545K mutation and the H1047R mutation. Moreover, many of these mutations have been shown to be oncogenic gain- of-function mutations. [0428] Given the connection to various disease, including cancer, PI3Ks, and more specifically, PI3KĮ, have been a target for therapeutic intervention. To this end, multiple inhibitors of PI3Ks have been developed, including alpelisib, buparlisib, taselisib, and inavolisib. These inhibitors are active against one or multiple Class I PI3K isoforms. [0429] A major limitation of those agents in the clinic is their inability to reach the required level for target inhibition without on-target related toxicities. Those inhibitors suffer from on target toxicities such as hyperglycemia and rash (associated with PI3KĮ inhibition); diarrhea, myelosuppression and transaminitis (associated with inhibition of PI3Kδ and PI3KȖ). More specifically, PI3KĮ is known to play a central role in regulating glucose homeostasis. Consequently, pharmacologic inhibition of PI3KĮ often results in severe hyperglycemia and/or hyperinsulinemia. In addition to the toxicities associated with high blood glucose, high circulating insulin levels can reactivate the PI3K pathway in cancer cells and be potentially mitogenic. This creates a feedback regulation loop that minimizes the effect of PI3K inhibitors. In the clinic, hyperglycemia and/or hyperinsulinemia are often managed with co-administration of a glucose lowering agent such at metformin. [0430] Without wishing to be bound by theory, in the context of cancer driven by mutated PI3KĮ, selective inhibition of the mutated form of PI3KĮ over the wild-type form of PI3KĮ in tumor cells of host tissues that control glucose metabolism could potentially overcome the limitation of the current generation of PI3KĮ inhibitors. Such specificity could allow for an improvement in the therapeutic window for drug dosing by limiting toxicities and allow higher doses for more complete on-target inhibition. Given that high circulating insulin levels can reactivate the PI3K pathway in cancer cells and be potentially mitogenic as mentioned above, selective inhibition of mutated PI3KĮ will avoid the creation of the feedback regulation loop that minimizes the effect of PI3K inhibitors. [0431] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0432] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0433] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0434] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0435] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0436] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0437] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0438] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0439] In some embodiments, the disease or disorder is associated with an implicated PI3KĮ activity. In some embodiments, the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. [0440] In some embodiments, the disease or disorder is associated with an implicated PI3KĮ activity. In some embodiments, the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. [0441] In some embodiments, the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome. [0442] In some embodiments, the disease or disorder is PIK3CA-related overgrowth syndrome. [0443] In some embodiments, the disease or disorder is cancer. [0444] In some embodiments, the cancer is characterized by an amplification (i.e. increase) in the expression of the PIK3CA gene and/or an amplification (i.e. increase) in the expression of the PI3KĮ protein. [0445] In some embodiments, the cancer is characterized by a decrease in the expression of the PIK3CA gene and/or decrease in the expression of the PI3KĮ protein. [0446] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene. It is understood that a cancer that is characterized by at least one oncogenic mutation in the PIK3CA gene is a cancer that is typically associated with at least one oncogenic mutation in the PIK3CA gene, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by the at least one oncogenic mutation in the PIK3CA gene. [0447] In some embodiments, the cancer is characterized by at least one oncogenic variant of the PI3KĮ protein. [0448] It is understood that a cancer that is characterized by least one oncogenic variant of the PI3KĮ protein is a cancer that is typically associated with at least one oncogenic variant of the PI3KĮ protein, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by the at least one oncogenic variant of the PI3KĮ protein. [0449] It is understood that an oncogenic variant of PI3KĮ protein is a PI3KĮ protein molecule that comprises at least one oncogenic mutation and that is produced as the result of the expression of a PIK3CA gene that comprises at least one oncogenic mutation. [0450] In some embodiments, the subject has at least one oncogenic mutation in the PIK3CA [0451] In some embodiments, the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of the PI3KĮ protein. [0452] As would be appreciated by the skilled artisan, in the context of a gene (e.g. PIK3CA), an oncogenic mutation can include, but is not limited to a mutation that results in the substitution of one amino acid for another at a specific position within the protein product of the gene, a mutation that results in the substitution of one or more amino acids for one or more amino acids between two specific positions within the protein product of the gene, a mutation that results in an insertion of one or more amino acids between two positions within the protein product of the gene, a mutation that results in the deletion of one more amino acids between two positions within the protein product of the gene, and mutation that results in a fusion of the protein product of the gene, or portion thereof, with another protein, or portion thereof, or any combination thereof. As would be appreciated by the skilled artisan, in the context of a gene, an oncogenic mutation can include, but is not limited to, a missense mutation, a nonsynonymous mutation, an insertion of one or more nucleotides, a deletion of one or more nucleotides, an inversion and a deletion-insertion. As would be appreciated by the skilled artisan, in the context of a gene (e.g. PIK3CA), the gene can have one or more of the aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations. [0453] As would be appreciated by the skilled artisan, in the context of a protein (e.g. the PI3KĮ protein), an oncogenic mutation can include, but is not limited to, the substitution of one amino acid for another at a specific position within the protein, the substitution of one or more amino acids for one or more amino acids between two specific positions within the protein, an insertion of one or more amino acids between two positions within the protein, a deletion of one more amino acids between two positions within the protein, and a fusion of the protein, or portion thereof, with another protein, or portion thereof, or any combination thereof. As would be appreciated by the skilled artisan, in the context of a protein (e.g. the PI3KĮ protein), the protein can have one or more of the aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations. [0454] In some embodiments, an oncogenic mutation of the PI3KĮ protein can be any one of E542K, E545K and H1047R (numbering corresponding to SEQ ID NO: 1). [0455] A wild-type PI3KĮ protein sequence of the present disclosure may comprise, consist essentially of, or consist of the amino acid sequence of: 1 MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF 51 KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK 101 VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA 151 VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP 201 NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY 251 ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD 301 CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD 351 IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA 401 RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH 451 GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV 501 SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF 551 LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME 601 LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV 651 RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK 701 HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG 751 FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII 801 FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV 851 VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS 901 CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE 951 RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN 1001 LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG 1051 WTTKMDWIFH TIKQHALN (SEQ ID NO: 1) [0456] In some embodiments, the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer. [0457] In some embodiments, the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, acute myeloid leukemia, brain lower grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectum adenocarcinoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, testicular germ cell tumors, thyroid carcinoma, thymoma, uterine carcinosarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal cancer or gastric cancer. Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary cancer, esophageal cancer, anal cancer, salivary, cancer, vulvar cancer, cervical cancer, Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML), Adrenal gland tumors, Anal cancer, Bile duct cancer, Bladder cancer, Bone cancer, Bowel cancer, Brain tumors, Breast cancer, Cancer of unknown primary (CUP), Cancer spread to bone, Cancer spread to brain, Cancer spread to liver, Cancer spread to lung, Carcinoid, Cervical cancer, Children's cancers, Chronic lymphocytic leukemia (CLL), Chrome myeloid leukemia (CML), Colorectal cancer, Ear cancer, Endometrial cancer, Eye cancer, Follicular dendritic cell sarcoma, Gallbladder cancer, Gastric cancer, Gastro esophageal junction cancers, Germ cell tumors, Gestational trophoblastic disease (GIT), Hairy cell leukemia, Head and neck cancer, Hodgkin lymphoma, Kaposi’s sarcoma, Kidney cancer, Laryngeal cancer, Leukemia, Gastric linitis plastica, Liver cancer, Lung cancer, Lymphoma, Malignant schwannoma, Mediastinal germ cell tumors, Melanoma skin cancer, Men's cancer, Merkel cell skin cancer, Mesothelioma, Molar pregnancy, Mouth and oropharyngeal cancer, Myeloma, Nasal and paranasal sinus cancer, Nasopharyngeal cancer, Neuroblastoma, Neuroendocrine tumors, Non-Hodgkin lymphoma (NHL), Esophageal cancer, Ovarian cancer, Pancreatic cancer, Penile cancer, Persistent trophoblastic disease and choriocarcinoma, Pheochromocytoma, Prostate cancer, Pseudomyxoma peritonei, Rectal cancer. Retinoblastoma, Salivary gland cancer, Secondary' cancer, Signet cell cancer, Skin cancer, Small bowel cancer, Soft tissue sarcoma, Stomach cancer, T cell childhood non Hodgkin lymphoma (NHL), Testicular cancer, Thymus gland cancer, Thyroid cancer, Tongue cancer, Tonsil cancer, Tumors of the adrenal gland, Uterine cancer. Vaginal cancer, Vulval cancer, Wilms' tumor, Womb cancer and Gynaecological cancer. Examples of cancer also include, but are not limited to, Hematologic malignancies, Lymphoma, Cutaneous T-cell lymphoma, Peripheral T-cell lymphoma, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, Multiple myeloma, Chrome lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, Myelodysplastic syndromes, Myelofibrosis, Biliary tract cancer, Hepatocellular cancer, Colorectal cancer, Breast cancer, Lung cancer, Non-small cell lung cancer, Ovarian cancer, Thyroid Carcinoma, Renal Cell Carcinoma, Pancreatic cancer, Bladder cancer, skin cancer, malignant melanoma, merkel cell carcinoma, Uveal Melanoma or Glioblastoma multiforme. [0458] In some embodiments, the cancer is B-cell lymphoma, adrenocortical carcinoma, bladder urothelial carcinoma, breast cancer, cervical adenocarcinoma, cervical squamous-cell carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, colorectal cancer, diffuse glioma, esophageal squamous-cell cancer, esophagogastric adenocarcinoma, esophagogastric cancer, fibrolamellar carcinoma, germ-cell carcinoma, glioblastoma, glioma, head and neck squamous- cell carcinoma, hepatocellular carcinoma, leukemia, melanoma, mesothelioma, miscellaneous neuroepithelial tumor, nerve-sheath tumor, non-small-cell lung cancer, ovarian cancer, pancreatic cancer, pheochromocytoma, prostate cancer, renal clear-cell carcinoma, renal nonclear-cell carcinoma, soft-tissue sarcoma, thymic tumor, thyroid cancer or endometrial cancer. [0459] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0460] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0461] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0462] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0463] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3KĮ activity (e.g., in vitro or in vivo). [0464] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3KĮ activity (e.g., in vitro or in vivo). [0465] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein. [0466] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein. [0467] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject in need thereof. [0468] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof. [0469] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3KĮ activity (e.g., in vitro or in vivo). [0470] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0471] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [0472] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof. [0473] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof. [0474] The present disclosure provides compounds that function as modulators of PI3KĮ activity. [0475] In some embodiments, the compounds of the present disclosure are inhibitors of the PI3KĮ protein. In some embodiments, the compounds of the present disclosure specifically inhibit mutated PI3KĮ protein as compared to wild-type PI3KĮ protein. [0476] In some embodiments, the compounds of the present disclosure bind to the PI3KĮ protein in an allosteric pocket that is in proximity to the 1047 mutational hotspot. [0477] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/ disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge. [0478] The present disclosure also provides a method of treating a disease or disorder in which PI3KĮ activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. Routes of Administration [0479] Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a sole therapy or can be administered in addition with one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. [0480] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering the compound of Formula (I) with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [0481] In the instances where the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the disclosure need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compound of the disclosure may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. The initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician. [0482] The particular choice of other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the disclosure there is provided a combination for use in the treatment of a disease in which PI3KĮ activity is implicated comprising a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent. [0483] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable, in association with a pharmaceutically acceptable diluent or carrier. [0484] In addition to its use in therapeutic medicine, compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of modulators of PI3KĮ activity in laboratory animals such as dogs, rabbits, monkeys, mini-pigs, rats and mice, as part of the search for new therapeutic agents. [0485] In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant disclosure, any of the alternate embodiments of macromolecules of the present disclosure described herein also apply. [0486] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action). [0487] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES [0488] For exemplary purpose, both neutral compounds and salts of the compounds of Formula (I) are synthesized and tested in the examples. It is understood that the neutral compounds of Formula (I) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt). Further, it is understood that the salts (e.g., formate salt) of the compounds of Formula (I) may be converted to the corresponding neutral compounds using routine techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)). [0489] Abbreviations: DMSO Dimethylsulfoxide E ^{S / ESI} _{electrospray ionisation} HPLC high-performance liquid chromatography I ^PA _{Isopropylalcohol} LC liquid chromatography M ^S _{mass spectrometry} NMR nuclear magnetic resonance SFC supercritical fluid chromatography TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TFA trifluoroacetic acid TLC thin layer chromatography Preparation of Common Intermediates Preparation of Intermediate-A: 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (Int-A) [0490] Step 1. Synthesis of 2-amino-3-bromo-N,5-dimethylbenzamide [0491] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (50.0 g, 217 mmol) and methanamine hydrochloride (29.4 g, 435 mmol) in N,N-dimethylformamide (500 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethylammonium hexafluorophosphate (99.2 g, 261 mmol) and diisopropylethylamine (112 g, 869 mmol). The mixture was stirred at 25 °C for 2 hr. The mixture was poured into water (1.5 L) and then filtered. The resulting precipitate was collected and concentrated in vacuo to give 2-amino-3- bromo-N,5-dimethylbenzamide (52.0 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 6.96 (s, 1H), 6.85 (s, 1H), 2.47 (s, 3H), 1.82 (s, 3H). [0492] Step 2. Synthesis of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one [0493] To a solution of 2-amino-3-bromo-N,5-dimethyl-benzamide (52.0 g, 214 mmol) in 1,4- dioxane (520 mL) was slowly added thiophosgene (51.7 g, 449 mmol). The mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 105 °C for 1 hr. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=20/1 to 3/1) to give 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (45.0 g, 139 mmol, 65%) as a yellow solid. m/z ES+ [M+H] ⁺ 289.0. Preparation of Intermediate-B1: 8-acetyl-3,6-dimethyl-2-morpholino-quinazolin-4-one (Int-B1) and Intermediate-B2: 8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin- 4(3H)-one (Int-B2) [0494] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [0495] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (3.5 g, 12.2 mmol) in dichloromethane (35 mL) was added morpholine (5.3 g, 60.9 mmol). The mixture was stirred at 40 °C for 12 h. The mixture was concentrated in vacuo. The residue was dissolved in petroleum ether/ethyl acetate (10/1, 100 mL) and then filtered. The solid was collected and concentrated in vacuo to give 8-bromo-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (3 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 3.46 (s, 3H), 3.26 - 3.23 (m, 4H), 3.05 (br. s, 4H), 2.38 (s, 3H). [0496] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-morpholino-quinazolin-4-one [0497] To a solution of 8-bromo-3,6-dimethyl-2-morpholino-quinazolin-4-one (6.2 g, 18.3 mmol) in toluene (60 mL) was added palladium(II)bis(triphenylphosphine) dichloride (1.29 g, 1.83 mmol) and tributyl(1-ethoxyvinyl)stannane (19.9 g, 55 mmol). The mixture was stirred at 130 °C for 12 hr under nitrogen. Then, hydrochloric acid (1 M, 28.2 mL) was added into the mixture and the mixture was stirred at 25 °C for 30 min. Then sat. sodium bicarbonate solution (30 mL) was added to adjust pH = 8. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-acetyl-3,6- dimethyl-2-morpholino-quinazolin-4-one (3 g, 7.96 mmol, 43%) as a white solid. m/z ES+ [M+H] ⁺ 302.2. [0498] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)- one [0499] To a solution of 8-acetyl-3,6-dimethyl-2-morpholino-quinazolin-4-one (2.5 g, 8.3 mmol) in methanol (2 mL) was added ammonium acetate (12.8 g, 166 mmol) and sodium cyanoborohydride (521 mg, 8.3 mmol). The mixture was stirred at 60 °C for 1 hr. The residue was directly purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-(1- aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (1 g, 3.31 mmol, 40%) as a white solid. m/z ES+ [M+H] ⁺ 303.1. Preparation of Intermediate C: 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one (Int-C) [0500] Step 1. Synthesis of 2-amino-3-bromo-N-ethyl-5-methyl-benzamide [0501] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (8 g, 34.7 mmol), ethanamine (2.35 g, 52.1 mmol) in N,N-dimethylformamide (80 mL) was added diisopropylethylamine (6.74 g, 52.1 mmol) and [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (19.8 g, 52.1 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give 2-amino-3-bromo-N-ethyl-5- methyl-benzamide (7.2 g, 28.0 mmol, 100%) as a white oil. m/z ES + [M+H] ⁺ 257.0. [0502] Step 2. Synthesis of 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one [0503] To a solution of 2-amino-3-bromo-N-ethyl-5-methyl-benzamide (8 g, 31.1 mmol) in 1,4-dioxane (80 mL) was added thiocarbonyl dichloride (7.51 g, 65.3 mmol). The mixture was stirred at 25 °C for 0.5 hr and then at 105 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one (7 g, crude) as a white solid. m/z ES + [M+H] ⁺ 301.0. Preparation of Intermediate-D: 8-bromo-2-chloro-3-methylquinazolin-4(3H)-one (Int-D) [0504] Step 1. Synthesis of 2-amino-3-bromo-N-methylbenzamide [0505] To a solution of 2-amino-3-bromobenzoic acid (15 g, 69.4 mmol) in N,N- dimethylformamide (150 mL) was added 2-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (39.6 g, 104 mmol), diisopropylethylamine (44.9 g, 347 mmol) and methanamine (18.8 g, 278 mmol, hydrochloride). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- amino-3-bromo-N-methylbenzamide (13.0 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 228.3. [0506] Step 2. Synthesis of 8-bromo-2-chloro-3-methylquinazolin-4(3H)-one [0507] To a solution of 2-amino-3-bromo-N-methylbenzamide (10.0 g, 43.7 mmol) in 1,4- dioxane (100 mL) was added thiocarbonyl dichloride (10.5 g, 91.7 mmol). The mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 105 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 1/1) to give 8-bromo-2-chloro- 3-methylquinazolin-4(3H)-one (7.00 g, 25.6 mmol, 59%) as a white solid. m/z ES+ [M+H] ⁺ 275.2. Preparation of Intermediate E: 8-bromo-2-chloro-3-ethylquinazolin-4(3H)-one (Int-E) [0508] Step 1. 2-Synthesis of amino-3-bromo-N-ethylbenzamide [0509] To a solution of 2-amino-3-bromo-benzoic acid (10 g, 46.3 mmol,) and ethanamine (6.26 g, 139 mmol, 9.09 mL) in N,N-dimethylformamide (100 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (26.4 g, 69.4 mmol) and diisopropylethylamine (12 g, 92.6 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was poured in water (200 mL) and then filtered to give 2-amino-3-bromo-N-ethylbenzamide (9 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.57 - 7.45 (m, 2H), 6.52 (t, J = 7.6 Hz, 1H), 6.45 (s, 2H), 3.28 - 3.20 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). [0510] Step 2. Synthesis of 8-bromo-2-chloro-3-ethylquinazolin-4(3H)-one [0511] To a solution of 2-amino-3-bromo-N-ethyl-benzamide (9 g, 37 mmol) in 1,4-dioxane (100 mL) was added thiophosgene (10.6 g, 92.6 mmol). The mixture was stirred at 25 °C for 1 h. Then the mixture was stirred at 105 °C for 1 h. The mixture was concentrated in vacuo to give 8-bromo-2-chloro-3-ethylquinazolin-4(3H)-one (11 g, crude) as a yellow solid. m/z ES + [M+H] ⁺ 288.9. Preparation of intermediate F: 8-(1-aminoethyl)-3,6-dimethyl-2-(piperidin-1- yl)quinazolin-4(3H)-one (Int-F) [0512] Step 1. Synthesis of 8-bromo-3-ethyl-2-morpholinoquinazolin-4(3H)-one [0513] To a solution of 8-bromo-2-chloro-3-ethyl-quinazolin-4-one (5 g, 17.4 mmol) in 1,2- dichloroethane (50 mL) was added morpholine (7.57 g, 86.9 mmol). The mixture was stirred at 40 °C for 12 h. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in petroleum ether/ethyl acetate=10/1 (100 mL), then filter and the solid was concentrated in vacuo to give 8-bromo-3-ethyl-2-morpholinoquinazolin-4(3H)-one (5.5 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.07 - 8.00 (m, 2H), 7.31 - 7.21 (m, 2H), 7.17 (d, J = 7.2 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.81 - 3.75 (m, 4H), 3.27 - 3.20 (m, 4H), 2.30 (s, 1H), 1.24 (t, J = 6.9 Hz, 3H). [0514] Step 2. Synthesis of 8-acetyl-3-ethyl-2-morpholinoquinazolin-4(3H)-one [0515] To a solution of 8-bromo-3-ethyl-2-morpholino-quinazolin-4-one (5 g, 14.8 mmol) and 1-vinyloxybutane (4.44 g, 44.4 mmol) in n-butanol (50 mL) was added palladium acetate (332 mg, 1.48 mmol), diisopropylethylamine (5.73 g, 44.4 mmol) and [2-(2- diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (796 mg, 1.48 mmol). The mixture was stirred at 95 °C for 12 hr. Then hydrochloric acid (1 M, 73.9 mL) was added in the mixture and stirred at 25 °C for 30 min. Sodium bicarbonate (sat. aq, 30 mL) was added to the mixture until pH = 8. Then the mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/1) to give 8-acetyl-3-ethyl-2-morpholinoquinazolin-4(3H)-one (3.56 g, 11.8 mmol, 80%) as a yellow oil. m/z ES + [M+H] ⁺ 302.1. [0516] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin- 4(3H)-one [0517] To a solution of 8-acetyl-3-ethyl-2-morpholino-quinazolin-4-one (3.56 g, 11.8 mmol) in methanol (30 mL) was added ammonium acetate (18.2 g, 236 mmol) and sodium cyanoborohydride (742 mg, 11.8 mmol). The mixture was stirred at 60 °C for 1 hr. The mixture was quenched by water (3 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)- 3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (2.5 g, 8.27 mmol, 70%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (s, 2H), 8.02 (dd, J = 1.6, 8.0 Hz, 1H), 7.86 (dd, J = 1.2, 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 5.02 (q, J = 6.8 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.85 - 3.75 (m, 4H), 3.30 - 3.18 (m, 4H), 1.54 (d, J = 6.8 Hz, 3H), 1.25 (t, J = 6.8 Hz, 3H). Preparation of Intermediate-G: 8-bromo-2,4-dichloro-6-methyl-quinazoline (Int-G) [0518] Step 1. Synthesis of 8-bromo-6-methylquinazoline-2,4-diol [0519] A mixture of 2-amino-3-bromo-5-methyl-benzoic acid (30 g, 130 mmol) and urea (50.9 g, 847 mmol) was stirred at 200 °C for 2 hr. On completion, the mixture was cooled to 25 °C and diluted with water (1 L). The solid product was filtered and washed with methanol (1 L). The crude product was triturated with methanol (500 mL) at 25 °C for 60 min and filtered. Then the filtered cake was concentrated in vacuo to give 8-bromo-6-methyl-quinazoline-2,4- diol (33 g, crude) as a yellow solid. m/z ES + [M+H] ⁺ 256. [0520] Step 2. Synthesis of 8-bromo-2,4-dichloro-6-methylquinazoline [0521] To a solution of 8-bromo-6-methyl-quinazoline-2,4-diol (33 g, 129 mmol) in phosphorus oxychloride (200 mL) was added N,N-dimethylformamide (950 mg, 13.00 mmol). The mixture was stirred at 120 °C for 48 hr. On completion, the reaction mixture was poured into ice-water (1 L) slowly. The resulting solid was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with water (1 L) at 25 °C for 60 min and then filtered. Then the filtrate was concentrated in vacuo to give 8-bromo-2,4-dichloro- 6-methyl-quinazoline (37 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (d, J = 1.2 Hz, 1H), 8.01 (s, 1H), 2.54 (s, 3H); m/z ES + [M+H] ⁺ 292.7. Preparation of Intermediate-H: 1-[4-hydroxy-6-methyl-2-(1-piperidyl)quinazolin-8- yl]ethanone (Int-H) [0522] Step 1. Synthesis of 8-bromo-2-chloro-6-methylquinazolin-4-ol [0523] A solution of 8-bromo-2,4-dichloro-6-methyl-quinazoline (24 g, 82.2 mmol) in anhydrous tetrahydrofuran (80 mL) and saturated sodium bicarbonate solution (400 mL) was stirred at 100 °C for 16 hr. On completion, the reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (1 L x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-2-chloro-6-methyl- quinazolin-4-ol (19 g, 69.4 mmol, 70%) as a white solid. m/z ES + [M+H] ⁺ 292.7. [0524] Step 2. Synthesis of 8-bromo-6-methyl-2-(1-piperidyl)quinazolin-4-ol [0525] A solution of 8-bromo-2-chloro-6-methyl-quinazolin-4-ol (7 g, 25.5 mmol), piperidine (4.36 g, 51.1 mmol) and diisopropylethylamine (6.62 g, 51.1 mmol) in 1-methylpyrrolidin-2- one (50 mL) was stirred at 100 °C for 16 hr. On completion, the reaction mixture was diluted with water (100 mL) at 25 °C and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-6-methyl-2-(1- piperidyl)quinazolin-4-ol (8.5 g, crude) as a yellow solid. m/z ES + [M+H] ⁺ 324.2. [0526] Step 3. Synthesis of 1-[4-hydroxy-6-methyl-2-(1-piperidyl)quinazolin-8-yl]ethanon e [0527] To a solution of 8-bromo-6-methyl-2-(1-piperidyl)quinazolin-4-ol (8 g, 24.8 mmol) and dichloropalladium triphenylphosphane (1.74 g, 2.48 mmol) in toluene (100 mL) was added tributyl(1-ethoxyvinyl)stannane (22.4 g, 62.0 mmol). The mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was adjusted the pH to 4~5 with hydrochloric acid (1 M). The mixture was stirred at 25 °C for 0.5 hr, then adjusted to pH 8~9 with saturated sodium bicarbonate solution. Then the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 0/1) to give 1-[4- hydroxy-6-methyl-2-(1-piperidyl)quinazolin-8-yl]ethanone (4.6 g, 16.1 mmol, 65%) as a yellow solid. m/z ES + [M+H] ⁺ 286.2. Preparation of Intermediate-I: 8-(1-aminoethyl)-3,6-dimethyl-2-(piperidin-1- yl)quinazolin-4(3H)-one (Int-I) [0528] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one [0529] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (1 g, 3.48 mmol) in dichloromethane (10 mL) was added piperidine (1.48 g, 17.4 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was dissolved in petroleum ether/ethyl acetate=10/1 (100 mL) and then filtered. The filtered cake was collected and concentrated in vacuo to give 8-bromo-3,6-dimethyl-2- (piperidin-1-yl)quinazolin-4(3H)-one (1 g, crude) as a yellow solid. m/z ES + [M+H] ⁺ 338.0. [0530] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one [0531] To a solution of 8-bromo-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (0.5 g, 1.49 mmol) in toluene (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.61 g, 4.46 mmol) and dichloropalladium triphenylphosphane (104 mg, 148 μmol). The mixture was stirred at 110 °C for 12 h under nitrogen atmosphere. After cooled to room temperature, the solution was added formic acid (10 mL) and stirred for another 0.5 hr. On completion, the mixture was poured into water (50 mL) and adjusted the pH to 7~8 with saturated sodium bicarbonate. The mixture was then extracted with ethyl acetate (50 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (0.33 g, 1.10 mmol, 74%) as a white solid. m/z ES + [M+H] ⁺ 300.0. [0532] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin- 4(3H)-one [0533] To a solution of 8-acetyl-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (0.33 g, 1.10 mmol) in methanol (5 mL) was added ammonium acetate (1.70 g, 22.1 mmol) and sodium cyanoborohydride (69.3 mg, 1.10 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the mixture was quenched by water (1 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4 (3H)-one (0.3 g, 866 μmol, 79%) as a white solid. m/z ES + [M+H] ⁺ 301.2. Preparation of Intermediate-J: 2-bromo-4-(1-piperidyl)aniline (Int-J) [0534] Step 1. Synthesis of 1-(3-bromo-4-nitro-phenyl)piperidine [0535] To a solution of 2-bromo-4-fluoro-1-nitro-benzene (11 g, 50.0 mmol) in N,N- dimethylformamide (100 mL) was added potassium carbonate (20.7 g, 150 mmol) and piperidine (5.11 g, 60.0 mmol). The mixture was stirred at 75 °C for 8 hr. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 10/1) to give 1-(3-bromo-4-nitro-phenyl)piperidine (14 g, 49.1 mmol, 98%) as a yellow solid. m/z ES+ [M+H] ⁺ 285.0. [0536] Step 2. Synthesis of 2-bromo-4-(1-piperidyl)aniline [0537] To a solution of 1-(3-bromo-4-nitro-phenyl)piperidine (5 g, 17.5 mmol) in acetic acid (50 mL) was added zinc powder (5.73 g, 87.7 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3) The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=100/1 to 6/1) to afford 2-bromo-4-(1-piperidyl)aniline (3.7 g, 14.5 mmol, 83%) as a brown oil. m/z ES+ [M+H] ⁺ 255.0. Preparation of Intermediate-K: (R)-8-(1-aminoethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (Int-K) [0538] Step 1. Synthesis of (R)-N-(1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [0539] A mixture of 8-acetyl-3,6-dimethyl-2-morpholino-quinazolin-4-one (21 g, 69.7 mmol) in anhydrous tetrahydrofuran (200 mL) was added (R)-2-methylpropane-2-sulfinamide (42.2 g, 348 mmol) and tetraethoxytitanium (79.5 g, 348 mmol). The mixture was stirred at 75 °C for 12 h. The mixture was poured into water (50 mL) and then filtered. The filtered cake was collected and concentrated in vacuo to give a residue. The residue was purified by reversed- phase HPLC (I.D.200mm*H400mm Phenomenex Luna C1815 μm; 100 A 1 L/min acetonitrile /water 45-45%, 45 min) and repurified by column chromatography (SiO2, petroleum ether/ethyl acetate=5/1 to 1/1) to give (R)-N-(1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (11.1 g, 22.7 mmol, 33%) as a yellow oil. m/z ES+ [M+H] ⁺ 405.0. [0540] Step 2. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [0541] To a solution of (R)-N-(1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazo lin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (20 g, 49.4 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane-methyl sulfide complex (10 M, 24.7 mL) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 h. The mixture was carefully quenched by methanol (200 mL) at 0 °C and then stirred at 25 °C for 0.5 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroqui nazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (12 g, 28.3 mmol, 57%) as a yellow oil. m/z ES+ [M+H] ⁺ 407.1. [0542] Step 3. Synthesis of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin- 4(3H)-one [0543] To a solution of (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (11.5 g, 28.3 mmol) in 1,4- dioxane (100 mL) was added hydrogen chloride/1,4-dioxane (4 M, 50 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give (R)-8-(1-aminoethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one (8 g, 23 mmol, 81%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.57 (s, 2H), 7.85 (s, 1H), 7.78 (s, 1H), 5.10 – 5.00 (m, 1H), 3.79 - 3.75 (m, 4H), 3.49 (s, 3H), 3.27 - 3.23 (m, 4H), 2.42 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H). Preparation of intermediate L: 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)- one (Int-L) [0544] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one [0545] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (5 g, 17.4 mmol) in acetonitrile (50 mL) was added sodium methyl mercaptide (1.83 g, 26.1 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (100 mL) and then filtered. The filtered cake was collected and dried in vacuo to give 8-bromo-3,6-dimethyl-2- (methylthio)quinazolin-4(3H)-one (4.7 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 7.95 (d, J = 1.2 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 3.60 (s, 3H), 2.73 (s, 3H), 2.43 (s, 3H). [0546] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one [0547] To a solution of 8-bromo-3,6-dimethyl-2-methylsulfanyl-quinazolin-4-one (3.4 g, 11.4 mmol) in n-butanol (35 mL) was added 1-vinyloxybutane (5.69 g, 56.8 mmol), palladium acetate (255 mg, 1.14 mmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (612 mg, 1.14 mmol) and diisopropylethylamine (4.41 g, 34.1 mmol). The mixture was stirred at 95 °C for 12 hr. Then hydrogen chloride (1 M, 56.8 mL) was added in the mixture and stirred at 25 °C for 30 min. Saturated solution of sodium bicarbonate was added to the mixture until pH ~8. Then the mixture was poured in water (100 mL) then extracted with ethyl acetate (100 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (2.5 g, 9.05 mmol, 80%) as a white solid. m/z ES+ [M+H] ⁺ 263.1. Preparation of Intermediate M: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl- quinazolin-4-one (Int-M) and Intermediate N: 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfinyl- 4-oxo-quinazolin-8-yl)ethyl]amino]benzoic acid (Int-N) [0548] Step 1. Synthesis of (R)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [0549] To a mixture of 8-acetyl-3,6-dimethyl-2-methylsulfanyl-quinazolin-4-one (40 g, 152 mmol) in 2-methyl tetrahydrofuran (400 mL) was added (R)-2-methylpropane-2-sulfinamide (55.4 g, 457 mmol) and tetraethoxytitanium (104 g, 457 mmol), the mixture was stirred at 85 °C for 8 hr. On completion, the mixture was treated with water (1 L) and diluted with ethyl acetate (1.2 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide (120 g, crude) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.58 (s, 1H), 2.88 (s, 3H), 2.60 (s, 3H), 2.56 (s, 3H), 2.46 (s, 3H), 1.32 (s, 9H); m/z ES+ [M+H] ⁺ 366.2. [0550] Step 2. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [0551] To a mixture of sodium borohydride (12.4 g, 328 mmol) in anhydrous tetrahydrofuran (100 mL) was added (R)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquina zolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (60 g, 164 mmol) in anhydrous tetrahydrofuran (500 mL) dropwise. The mixture was stirred at -50 °C for 3 hr, then the mixture was slowly warmed to 15 °C and stirred for 16 hr. On completion, the mixture was quenched by saturated ammonium chloride solution (800 mL). Then the mixture was extracted with ethyl acetate (400 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (Phenomenex luna C18 (250 x 70 mm, 10 um); mobile phase: [water(ammonium bicarbonate)-acetonitrile]; B%: 40%-72%, 23 min) to give (R)-N-((R)-1- (3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-y l)ethyl)-2-methylpropane-2- sulfinamide (50 g, 135 mmol, 41%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.50 (s, 1H), 5.18 (quin, J = 6.4 Hz, 1H), 4.34 (d, J = 5.6 Hz, 1H), 3.61 (s, 3H), 2.70 (s, 3H), 2.46 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.22 (s, 9H); m/z ES+ [M+H] ⁺ 368.3. [0552] Step 3. Synthesis of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl- quinazolin-4-one [0553] To a solution of (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (43 g, 117 mmol) in 1,4- dioxane (24 mL) and water (500 mL) was added hydrochloric acid /1,4-dioxane (4 M, 172 mL). The mixture was stirred at 25 °C for 2 hr. On completion, the solution was adjusted pH to 8 with saturated sodium bicarbonate solution. The mixture was filtered and concentrated to give 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl-quinazol in-4-one (37 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 2H), 4.81 (q, J = 6.4 Hz, 1H), 3.51 (s, 3H), 2.64 (s, 3H), 2.42 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H). [0554] Step 4. Synthesis of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]benzoic acid [0555] To a mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl-quinazol in-4- one (15 g, 56.9 mmol) in dimethyl acetamide (150 mL) was added 2-iodobenzoic acid (70.6 g, 284 mmol), triethylamine (28.8 g, 284 mmol) and copper (5.43 g, 85.4 mmol), the mixture was stirred at 110 °C for 4 hr under nitrogen. On completion, the mixture was diluted with water (300 mL) and filtered to give a mixture, the mixture was extracted with ethyl acetate (300 mL x 2), the combined organic layers were washed with brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=1/0 to 7:1) to give 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]benzoic acid (4.6 g, 9.96 mmol, 17%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 8.02 - 7.98 (m, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.23 - 7.18 (m, 1H), 6.59 (t, J = 7.2 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 3.67 - 3.64 (m, 3H), 2.72 - 2.67 (m, 3H), 2.39 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 384.2. [0556] Step 5. Synthesis of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfinyl-4-oxo-quinazolin-8 - yl)ethyl]amino]benzoic acid [0557] To a mixture of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]benzoic acid (4.3 g, 11.2 mmol) in tetrahydrofuran (43 mL) and water (14 mL) was added oxone (10.3 g, 16.8 mmol) portionwise. The mixture was stirred at 0 °C for 3 hr. On completion, the mixture was quenched by saturated sodium sulfite solution (100 mL) and extracted with ethyl acetate (200 mL x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[[(1R)- 1-(3,6-dimethyl-2-methylsulfinyl-4-oxo-quinazolin-8-yl)ethyl ]amino]benzoic acid (4.27 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.34 - 8.08 (m, 1H), 8.03 - 7.97 (m, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.23 - 7.14 (m, 1H), 6.63 - 6.53 (m, 1H), 6.36 (dd, J = 8.4, 16.8 Hz, 1H), 5.53 (quin, J = 6.4 Hz, 1H), 3.99 (s, 3H), 3.19 (d, J = 8.4 Hz, 3H), 2.45 (s, 3H), 1.66 (dd, J = 6.8, 10.8 Hz, 3H); m/z ES+ [M+H] ⁺ 400.1. Preparation of Intermediate O: 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (Int-O) and Intermediate P: (R)-3,6-dimethyl-2-(methylsulfonyl)-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (Int-P) [0558] Step 1. Synthesis of 3,6-dimethyl-2-methylsulfanyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]quinazolin-4-one [0559] To a mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl-quinazol in-4- one (13 g, 49.3 mmol) in diisopropylethylamine (96.4 g, 746 mmol) was added 1-fluoro-2- methylsulfonyl-benzene (16.3 g, 93.8 mmol), the mixture was stirred at 100 °C for 60 hr. On completion, the mixture was diluted with ethyl acetate (300 mL) and washed by water (50 mL x 5). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=1/0 to 3:2) to give 3,6-dimethyl-2- methylsulfanyl-8-[(1R)-1-(2-methylsulfonylanilino)ethyl]quin azolin-4-one (15 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 417.9. [0560] Step 2. Synthesis of 3,6-Dimethyl-2-methylsulfanyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]quinazolin-4-one &(R)-3,6-dimethyl-2-(methylsulfonyl)-8-(1- ((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one [0561] To a mixture of 3,6-dimethyl-2-methylsulfanyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]quinazolin-4-one (14 g, 33.5 mmol) in tetrahydrofuran (140 mL) and water (50 mL) was added oxone (30.9 g, 50.3 mmol) portionwise at 0 °C. Then the mixture was stirred at 0 °C for 3 h. On completion, the mixture was quenched by saturated sodium sulfite solution (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=1/0 to 0/1) to give 3,6-dimethyl-2-methylsulfinyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]quinazolin-4-one (7 g, 14.6 mmol, 44%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (s, 1H), 7.43 (dd, J = 1.2, 8.0 Hz, 1H), 6.98 - 6.85 (m, 1H), 6.48 (dd, J = 3.6, 6.4 Hz, 1H), 6.44 - 6.36 (m, 1H), 6.15 (dd, J = 8.4, 16.0 Hz, 1H), 5.18 (quin, J = 6.4 Hz, 1H), 3.80 (q, J = 7.2 Hz, 1H), 3.64 (d, J = 3.2 Hz, 3H), 2.85 (d, J = 11.2 Hz, 3H), 2.80 (d, J = 3.2 Hz, 3H), 2.13 (s, 3H), 1.33 (dd, J = 6.8, 8.8 Hz, 3H); m/z ES+ [M+H] ⁺ 434.1. And (R)- 3,6-dimethyl-2-(methylsulfonyl)-8-(1-((2-(methylsulfonyl)phe nyl)amino)ethyl)quinazolin- 4(3H)-one (2 g, 4.45 mmol, 13%) as a white solid. NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.78 (dd, J = 1.5, 8.0 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.26 - 7.23 (m, 1H), 6.82 - 6.74 (m, 2H), 6.37 (d, J = 8.3 Hz, 1H), 5.33 (quin, J = 6.6 Hz, 1H), 3.97 (s, 3H), 3.58 (s, 3H), 3.13 (s, 3H), 2.46 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 450.1. [0562] Preparation of Intermediate-3: 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one – (Int-1) and Intermediate 2: 8-acetyl-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one – (Int-2), Intermediate-3: 8-(2-aminopropan-2-yl)-3,6-dimethyl-2-morpholinoquinazolin- 4(3H)-one (Int-3), Intermediate-9: 2-amino-3-bromo-N,5-dimethylbenzamide (Int-9) and Intermdiate-518-bromo-3,6-dimethyl-2-morpholinoquinazolin-4( 3H)-one (Int-51) [0564] Step 1. Synthesis of 2-amino-3-bromo-N,5-dimethylbenzamide [0565] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (50.0 g, 217 mmol) and methanamine;hydrochloride (29.4 g, 435 mmol) in N,N-dimethylformamide (500 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethylammonium;hexafluorophosphate (99.2 g, 261 mmol) and diisopropylethylamine (112 g, 869 mmol). The mixture was stirred at 25 °C for 2 hr. The mixture was poured in water (1500 mL) and then filtered and the solid was collected and concentrated in vacuo to give 2-amino-3-bromo-N,5-dimethylbenzamide (52.0 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 6.96 (s, 1H), 6.85 (s, 1H), 2.47 (s, 3H), 1.82 (s, 3H). [0566] Step 2. Synthesis of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one [0567] To a solution of 2-amino-3-bromo-N,5-dimethyl-benzamide (52.0 g, 214 mmol) in dioxane (520 mL) was added thiophosgene (51.7 g, 449 mmol). The mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 105 °C for 1 hr. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 3/1) to give 8-bromo-2-chloro-3,6- dimethylquinazolin-4(3H)-one (45.0 g, 139 mmol, 65%) as a yellow solid. m/z ES+ [M+H] ⁺ 289.0. [0568] Step 3. Synthesis of 8-bromo-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [0569] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (5 g, 17.4 mmol) in dichloromethane (100 mL) was added morpholine (7.57 g, 86.9 mmol), then the reaction mixture was stirred at 40 °C for 12 hr. The reaction mixture was filtered and the filtrate was diluted with water (60 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-3,6-dimethyl-2-morpholino-quinazolin-4-one (5 g, crude) as an off-white solid. m/z ES+ [M+H]+ 338.0. [0570] Step 4. Synthesis of 8-acetyl-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [0571] To a solution of 8-bromo-3,6-dimethyl-2-morpholino-quinazolin-4-one (3 g, 8.87 mmol) and 1-vinyloxybutane (4.44 g, 44.3 mmol) in n-butyl alcohol (15 mL) was added palladium acetate (99.6 mg, 443 μmol), diisopropylethylamine (3.44 g, 26.6 mmol) and [2- (2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (477 mg, 887 μmol). The mixture was stirred at 95 °C for 12 hr. Then hydrochloric acid (1 M, 44.4 mL) was added to the mixture and stirred at 25 °C for 30 min. The mixture was added saturated sodium bicarbonate solution to pH = 8-9, then most solid was appeared and then filtered. The residue was purified by prep-HPLC (column: Waters Xbridge C18150 x 50mm, 10um; mobile phase: [water(sodium bicarbonate)- acetonitrile]; B%: 20%-50%, 10 min) to give 8-acetyl- 3,6-dimethyl-2-morpholino-quinazolin-4-one (1.1 g, 3.39 mmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 3.93 - 3.84 (m, 4H), 3.61 (s, 3H), 3.30 - 3.22 (m, 4H), 2.86 (s, 3H), 2.47 (s, 3H); m/z ES+ [M+H] ⁺ 302.1. [0572] Step 5. Synthesis of 8-(2-hydroxypropan-2-yl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one [0573] To a solution of 8-acetyl-3,6-dimethyl-2-morpholino-quinazolin-4-one (600 mg, 1.99 mmol) in anhydrous tetrahydrofuran (30 mL) at -10 °C was added magnesium methyl bromide (3 M, 1.33 mL), then the reaction mixture was stirred at -10 °C - 25 °C for 3 hr. The reaction mixture was quenched by saturated ammonium chloride solution (50 mL) at 0 °C, and then diluted with water (30 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (60 mL x 2), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=40/1 to 0/1) to give 8-(1-hydroxy-1-methyl-ethyl)-3,6-dimethyl-2-morpholino- quinazolin-4-one (430 mg, 1.08 mmol, 54%) as a yellow solid. NMR (400 MHz, CDCl3) δ 7.92 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.41 (s, 1H), 3.91 - 3.85 (m, 4H), 3.60 (s, 3H), 3.26 - 3.17 (m, 4H), 2.46 - 2.42 (m, 3H), 1.68 (s, 6H); m/z ES+ [M+H]+ 318.2. [0574] Step 6. Synthesis of 8-(2-Azidopropan-2-yl)-3,6-dimethyl-2-morpholinoquinazolin- 4(3H)-one [0575] To a solution of 8-(1-hydroxy-1-methyl-ethyl)-3,6-dimethyl-2-morpholino- quinazolin-4-one (300 mg, 945 μmol) in toluene (3 mL) was added trimethylsilane azide (2.63 g, 22.81 mmol) and boron trifluoride diethyl etherate (3.45 g, 24.3 mmol) under nitrogen atmosphere. The mixture was stirred at 30 °C for 12 hr. After cooling, the reaction was quenched with saturated sodium bicarbonate (15 mL), and the mixture was stirred for 10 min at 25 °C. Then diluted with water (15 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=40/1 to 0/1) to give 8-(1-azido-1-methyl-ethyl)-3,6-dimethyl-2-morpholino- quinazolin-4-one (240 mg, 512 μmol, 54%) as a yellow solid. m/z ES+ [M+H]+ 343.2. [0576] Step 7. Synthesis of 8-(2-aminopropan-2-yl)-3,6-dimethyl-2-morpholinoquinazolin- 4(3H)-one [0577] To a solution of 8-(1-azido-1-methyl-ethyl)-3,6-dimethyl-2-morpholino-quinazo lin- 4-one (320 mg, 934 μmol) in acetic acid (6 mL) was added zinc powder (366 mg, 5.61 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was filtered and then filter cake quenched by addition hydrochloric acid (1 N, 100 mL) at 25 °C. Then the filtrate was collected and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonia water ) to give 8-(1-amino-1-methyl- ethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (150 mg, 450 μmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.69 (d, J = 1.2 Hz, 1H), 3.97 - 3.87 (m, 4H), 3.64 (s, 3H), 3.37 - 3.34 (m, 4H), 2.50 (s, 3H), 1.90 (s, 6H). [0578] [0579] Preparation of Intermediate-4: 8-(1-aminoethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (Int-4) [0581] Step 1. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)- one [0582] To a solution of 8-acetyl-3,6-dimethyl-2-morpholino-quinazolin-4-one (2.5 g, 8.3 mmol) in methanol (2 mL) was added ammonium acetate (12.8 g, 166 mmol) and sodium cyanoborohydride (521 mg, 8.3 mmol). The mixture was stirred at 60 °C for 1 hr. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (1 g, 3.31 mmol, 40%) as a white solid. m/z ES+ [M+H] ⁺ 303.1. [0583] [0584] Preparation of Intermediate 5: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl- quinazolin-4-one (Int-5) and Intermediate 13: 2-(((1R)-1-(3,6-dimethyl-2-(methylsulfinyl)-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzoic acid (Int-13) [0586] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one [0587] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (5 g, 17.4 mmol) in acetonitrile (50 mL) was added sodium thiomethoxide (1.83 g, 26.1 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was poured into water (100 mL) and then filtered. The filtered cake was collected and concentrated in vacuo to give 8-bromo-3,6-dimethyl-2- (methylthio)quinazolin-4(3H)-one (4.7 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.2 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 3.60 (s, 3H), 2.73 (s, 3H), 2.43 (s, 3H). [0588] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one [0589] To a solution of 8-bromo-3,6-dimethyl-2-methylsulfanyl-quinazolin-4-one (3.4 g, 11.4 mmol) in n-butanol (35 mL) was added 1-vinyloxybutane (5.69 g, 56.8 mmol), palladium acetate (255 mg, 1.14 mmol), [2-(2-diphenylphosphanylphenoxy)phenyl]- diphenyl-phosphane (612 mg, 1.14 mmol) and diisopropylethylamine (4.41 g, 34.1 mmol). The mixture was stirred at 95 °C for 12 hr. Then hydrogenchloride (1 M, 56.8 mL) was added in the mixture and stirred at 25 °C for 30 min. saturated sodium bicarbonate solution was added to the mixture until pH = 8. Then the mixture was poured in water (100 mL), then extracted with ethyl acetate (100 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-acetyl-3,6-dimethyl-2- (methylthio)quinazolin-4(3H)-one (2.5 g, 9.05 mmol, 80%) as a white solid. m/z ES+ [M+H] ⁺ 263.1. [0590] Step 3. Synthesis of (R)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [0591] To a mixture of 8-acetyl-3,6-dimethyl-2-methylsulfanyl-quinazolin-4-one (40 g, 152 mmol) in 2-methyl tetrahydrofuran (400 mL) was added (R)-2-methylpropane-2-sulfinamide (55.4 g, 457 mmol) and tetraethoxytitanium (104 g, 457 mmol), the mixture was stirred at 85 °C for 8 hr. On completion, the mixture was added to water (1 L) and diluted with ethyl acetate (1.2 L), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-N-(1-(3,6-dimethyl-2- (methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (120 g, crude) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.58 (s, 1H), 2.88 (s, 3H), 2.60 (s, 3H), 2.56 (s, 3H), 2.46 (s, 3H), 1.32 (s, 9H); m/z ES+ [M+H] ⁺ 366.2. [0592] Step 4. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [0593] To a mixture of sodium borohydride (12.4 g, 328 mmol) in anhydrous tetrahydrofuran (100 mL) was added (R)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (60 g, 164 mmol) in anhydrous tetrahydrofuran (500 mL) dropwise. The mixture was stirred at -50 °C for 3 hr, then the mixture was slowly warmed to 15 °C and stirred for 16 hr. On completion, the mixture was quenched by saturated ammonium chloride solution (800 mL). Then the mixture was extracted with ethyl acetate (400 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (Phenomenex luna C18 (250*70mm,10 um);mobile phase: [water(ammonium bicarbonate)-acetonitrile];B%: 40%- 72%,23min) to give (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroq uinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (50 g, 135 mmol, 41%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.50 (s, 1H), 5.18 (quin, J = 6.4 Hz, 1H), 4.34 (d, J = 5.6 Hz, 1H), 3.61 (s, 3H), 2.70 (s, 3H), 2.46 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.22 (s, 9H); m/z ES+ [M+H] ⁺ 368.3. [0594] Step 5. Synthesis of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl- quinazolin-4-one [0595] To a solution of (R)-N-((R)-1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (43 g, 117 mmol) in dioxane (24 mL) and water (500 mL) was added hydrochloric acid / dioxane (4 M, 172 mL). The mixture was stirred at 25 °C for 2 hr. On completion, the solution was adjusted to pH = 8 with saturated sodium bicarbonate solution. The mixture was filtered and concentrated to give 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl-quinazol in-4-one (37 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 2H), 4.81 (q, J = 6.4 Hz, 1H), 3.51 (s, 3H), 2.64 (s, 3H), 2.42 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H). [0596] Step 6. Synthesis of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]benzoic acid [0597] To a mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl-quinazol in-4- one (15 g, 56.9 mmol) in dimethyl acetamide (150 mL) was added 2-iodobenzoic acid (70.6 g, 284 mmol), triethylamine (28.8 g, 284 mmol) and copper (5.43 g, 85.4 mmol), the mixture was stirred at 110 °C for 4 hr under nitrogen. On completion, the mixture was diluted with water (300 mL) and filtered to give a mixture, the mixture was extracted with ethyl acetate (300 mL x 2) and the combined organic layers were washed with brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=100/1 to 7:1) to give 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo- quinazolin-8-yl)ethyl]amino]benzoic acid (4.6 g, 9.96 mmol, 17%) as a brown solid. NMR (400 MHz, CDCl ₃ ) δ 8.02 - 7.98 (m, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.23 - 7.18 (m, 1H), 6.59 (t, J = 7.2 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 3.67 - 3.64 (m, 3H), 2.72 - 2.67 (m, 3H), 2.39 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 384.2. [0598] Step 7. Synthesis of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfinyl-4-oxo-quinazolin-8 - yl)ethyl]amino]benzoic acid [0599] To a mixture of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]benzoic acid (4.3 g, 11.2 mmol) in tetrahydrofuran (43 mL) and water (14 mL) was added oxone (10.3 g, 16.8 mmol) portionwise. The mixture was stirred at 0 °C for 3 hr. On completion, the mixture was quenched by saturated sodium sulfite solution (100 mL) and extracted with ethyl acetate (200 mL x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[[(1R)- 1-(3,6-dimethyl-2-methylsulfinyl-4-oxo-quinazolin-8-yl)ethyl ]amino]benzoic acid (4.27 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 - 8.08 (m, 1H), 8.03 - 7.97 (m, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.23 - 7.14 (m, 1H), 6.63 - 6.53 (m, 1H), 6.36 (dd, J = 8.4, 16.8 Hz, 1H), 5.53 (quin, J = 6.4 Hz, 1H), 3.99 (s, 3H), 3.19 (d, J = 8.4 Hz, 3H), 2.45 (s, 3H), 1.66 (dd, J = 6.8, 10.8 Hz, 3H); m/z ES+ [M+H] ⁺ 400.1. [0600] Preparation of Intermdiate 6: (R)-8-(1-aminoethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (Int-6) [0601] [0602] Step 1. Synthesis of (R)-N-(1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [0603] A mixture of 8-acetyl-3,6-dimethyl-2-morpholino-quinazolin-4-one (21 g, 69.7 mmol) in anhydrous tetrahydrofuran (200 mL) was added (R)-2-methylpropane-2- sulfinamide (42.2 g, 348 mmol) and tetraethoxytitanium (79.5 g, 348 mmol). The mixture was stirred at 75 °C for 12 hr. The mixture was poured into water (50 mL) and then filtered. The filtered cake was collected and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (I.D.200mm*H400mm Phenomenex Luna C1815μm; 100 A 1000ml/min acetonitrile /water 45-45% 45min;% min) and repurified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5/1 to 1/1) to give (R)-N-(1- (3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl) ethylidene)-2-methylpropane- 2-sulfinamide (11.1 g, 22.7 mmol, 33%) as a yellow oil. m/z ES+ [M+H] ⁺ 405.0. [0604] Step 2. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [0605] To a solution of (R)-N-(1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazo lin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (20 g, 49.4 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane dimethyl sulfide complex (10 M, 24.7 mL) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hr. The mixture was carefully quenched by methanol (200 mL) at 0 °C and then stirred at 25 °C for 0.5 hr. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (12 g, 28.3 mmol, 57%) as a yellow oil. m/z ES+ [M+H] ⁺ 407.1. [0606] Step 3. Synthesis of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin- 4(3H)-one [0607] To a solution of (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (11.5 g, 28.3 mmol) in dioxane (100 mL) was added hydrogen chloride/dioxane (4 M, 50 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give (R)-8-(1-aminoethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one (8 g, 23 mmol, 81%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 7.85 (s, 1H), 7.78 (s, 1H), 5.10 - 5.00 (m, 1H), 3.79 - 3.75 (m, 4H), 3.49 (s, 3H), 3.27 - 3.23 (m, 4H), 2.42 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H). [0608] Preparation of Intermediate 7: 8-(1-bromoethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (Int-7) and Intermediate 20: 8-(1-hydroxyethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one (Int-20) [0609] [0610] Step 1. Synthesis of 8-(1-hydroxyethyl)-3,6-dimethyl-2-morpholino-quinazolin-4- one [0611] To a solution of 8-acetyl-3,6-dimethyl-2-morpholino-quinazolin-4-one (2.6 g, 8.63 mmol) in methanol (35 mL) was added sodium borohydride (653 mg, 17.3 mmol). The mixture was stirred at 0 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150 x 40mm, 15um; mobile phase: [water (formic acid)-acetonitrile]; B%: 27%-57%, 10 min) to give 8-(1-hydroxyethyl)-3,6-dimethyl-2- morpholino-quinazolin-4-one (2.1 g, 6.30 mmol, 91%) as a white solid. m/z ES+ [M+H] ⁺ 304.2. [0612] Step 2. Synthesis of 8-(1-bromoethyl)-3, 6-dimethyl-2-morpholino-quinazolin-4-one [0613] To a solution of 8-(1-hydroxyethyl)-3, 6-dimethyl-2-morpholino-quinazolin-4-one (100 mg, 330 μmol) in dichloromethane (3 mL) was added phosphorus tribromide (268 mg, 989 μmol) under 0 °C. The mixture was stirred at 20 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 8-(1-bromoethyl)-3, 6-dimethyl-2- morpholino-quinazolin-4-one (120 mg, crude) as a yellow oil. [0614] [0615] Preparation of Intermediate 8: (R)-8-(1-aminoethyl)-3-cyclopropyl-6-methyl-2- morpholinoquinazolin-4(3H)-one (Int-8) [0616] [0617] Step 1. Synthesis of 2-amino-3-bromo-N-cyclopropyl-5-methyl-benzamide [0618] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (5.00 g, 21.7 mmol) and cyclopropanamine (2.48 g, 43.5 mmol) in N,N-dimethylformamide (50 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (9.92 g, 26.1 mmol) and diisopropylethylamine (11.2 g, 86.9 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the residue was triturated with water (500 mL) and filtered, the filter cake was collected to give 2-amino-3- bromo-N-cyclopropyl-5-methyl-benzamide (5.00 g, crude) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 3.6 Hz, 1H), 7.37 (d, J = 1.2 Hz, 1H), 7.29 (s, 1H), 6.20 (s, 2H), 2.81 (m, 1H), 2.17 (s, 3H), 0.71 - 0.65 (m, 2H), 0.58 - 0.53 (m, 2H); m/z ES+ [M+H] ⁺ 213.9. [0619] Step 2. Synthesis of 8-bromo-2-chloro-3-cyclopropyl-6-methyl-quinazolin-4-one [0620] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-methyl-benzamide (4.00 g, 14.9 mmol) in dioxane (40 mL) was added thiocarbonyl dichloride (3.42 g, 29.7 mmol, 2.28 mL) and stirred at 25 °C for 1 hr. Then mixture was stirred at 105 °C for 1 hr. On completion, the mixture was concentrated to give 8-bromo-2-chloro-3-cyclopropyl-6-methyl-quinazolin-4- one (5.00 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 3.14 - 3.04 (m, 1H), 2.50 (s, 3H), 1.32 - 1.25 (m, 2H), 1.06 - 0.99 (m, 2H); m/z ES+ [M+H] ⁺ 314.7. [0621] Step 3. Synthesis of 8-bromo-3-cyclopropyl-6-methyl-2-morpholino-quinazolin-4- one [0622] A solution of 8-bromo-2-chloro-3-cyclopropyl-6-methyl-quinazolin-4-one (5.00 g, 16.0 mmol) and morpholine (2.78 g, 31.9 mmol, 2.81 mL) in dichloromethane (50 mL) was stirred at 40 °C for 12 hr. On completion, the mixture was concentrated to give a residue. The residue purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give 8-bromo-3-cyclopropyl-6-methyl-2-morpholino-quinazolin-4-one (1.80 g, 4.60 mmol, 29%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 3.78 - 3.72 (m, 4H), 3.49 - 3.45 (m, 4H), 3.22 - 3.12 (m, 1H), 2.35 (s, 3H), 1.21 - 1.11 (m, 2H), 0.79 - 0.70 (m, 2H); m/z ES+ [M+H]+ 365.7. [0623] Step 4. Synthesis of 8-acetyl-3-cyclopropyl-6-methyl-2-morpholino-quinazolin-4- one [0624] To a solution of 8-bromo-3-cyclopropyl-6-methyl-2-morpholino-quinazolin-4-one (2.60 g, 6.00 mmol, 84% purity) and 1-vinyloxybutane (3.00 g, 30.0 mmol) in n-butyl alcohol (26 mL) was added diacetoxypalladium (134 mg, 599 μmol), diisopropylethylamine (2.32 g, 18.0 mmol, 3.13 mL), and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (323 mg, 600 μmol). The mixture was stirred at 95 °C for 12 hr. Then hydrochloric acid (1 M, 29.9 mL) was added into the mixture and stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1 and dichloromethane: methanol = 10:1) to give 8-acetyl-3-cyclopropyl-6-methyl-2-morpholino-quinazolin-4-on e (1.30 g, 3.26 mmol, 54%) as a red solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 3.79 - 3.73 (m, 4H), 3.45 - 3.40 (m, 4H), 3.22 - 3.14 (m, 1H), 2.74 (s, 3H), 2.38 (s, 3H), 1.18 (q, J = 6.8 Hz, 2H), 0.80 - 0.73 (m, 2H); m/z ES+ [M+H]+ 328.1. [0625] Step 5. Synthesis of (NZ,R)-N-[1-(3-cyclopropyl-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide [0626] To a solution of 8-acetyl-3-cyclopropyl-6-methyl-2-morpholino-quinazolin-4-on e (2.30 g, 7.03 mmol) and (R)-2-methylpropane-2-sulfinamide (4.26 g, 35.2 mmol) in anhydrous tetrahydrofuran (23 mL) was added titanium tetraethoxy (8.01 g, 35.1 mmol). The mixture was stirred at 85 °C for 12 hr. On completion, the residue was triturated with water (40 mL) and filtered. The filtrate concentrated to give a residue. The residue purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1 and dichloromethane: methanol = 10:1) to give (NZ,R)-N-[1-(3-cyclopropyl-6-methyl-2- morpholino-4-oxo-quinazolin-8-yl)ethylidene]-2-methyl-propan e-2-sulfinamide (3.20 g, crude) as a red solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.47 (s, 1H), 3.73 (s, 4H), 3.37 (d, J = 4.0 Hz, 4H), 3.15 (d, J = 4.0 Hz, 1H), 2.75 (s, 3H), 2.38 (s, 3H), 1.20 (s, 9H), 1.17 - 1.15 (m, 2H), 0.80 - 0.73 (m, 2H); m/z ES+ [M+H]+ 353.6. [0627] Step 6. Synthesis of (R)-N-[(1R)-1-(3-cyclopropyl-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide [0628] A solution of sodium borohydride (510 mg, 13.5 mmol) in anhydrous tetrahydrofuran (10 mL) at 25 °C under nitrogen atmosphere. Then cooled to -40 °C, a solution of (NZ,R)-N- [1-(3-cyclopropyl-6-methyl-2-morpholino-4-oxo-quinazolin-8-y l)ethylidene]-2-methyl- propane-2-sulfinamide (2.90 g, 6.74 mmol) in anhydrous tetrahydrofuran (20 mL) was added into the mixture and stirred at -40 °C for 3 hr. Then the mixture was stirred at 25 °C for 12 hr. On completion, the mixture was quenched by saturated ammonium chloride solution (100 mL). Then extracted with ethyl acetate (50 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um;mobile phase: [water(ammonium bicarbonate)-acetonitrile];B%: 20%- 50%,20min) to give (R)-N-[(1R)-1-(3-cyclopropyl-6-methyl-2-morpholino-4-oxo-qui nazolin- 8-yl)ethyl]-2-methyl-propane-2-sulfinamide (700 mg, 1.55 mmol, 23%) as a white solid. NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.41 (s, 1H), 5.13 (m, J = 6.8 Hz, 1H), 4.31 (d, J = 6.0 Hz, 1H), 3.94 - 3.80 (m, 4H), 3.48 - 3.36 (m, 4H), 3.09 - 2.97 (m, 1H), 2.41 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.32 - 1.22 (m, 2H), 1.19 (s, 9H), 1.04 - 0.94 (m, 1H), 0.88 - 0.79 (m, 1H); m/z ES+ [M+H]+ 433.4. [0629] Step 7. Synthesis of (R)-8-(1-aminoethyl)-3-cyclopropyl-6-methyl-2- morpholinoquinazolin-4(3H)-one [0630] A solution of (R)-N-[(1R)-1-(3-cyclopropyl-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (670 mg, 1.55 mmol) in hydrochloric acid /dioxane (4 M, 6.70 mL) .The mixture was stirred at 25 °C for 10 min. On completion, the mixture was adjusted to pH = 7~8 with saturated sodium bicarbonate solution. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3).The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-3-cyclopropyl-6-methyl-2- morpholinoquinazolin-4(3H)-one (500 mg, 1.29 mmol, 84%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 4.67 (q, J = 6.8 Hz, 1H), 3.90 - 3.86 (m, 4H), 3.48 - 3.43 (m, 4H), 3.08 - 2.98 (m, 1H), 2.42 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H), 1.31 - 1.28 (m, 2H), 0.95 - 0.87 (m, 2H); m/z ES+ [M+H]+ 329.1. [0631] [0632] Preparation of Intermediate 10: (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(4- methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (Int-10) and Intermediate 11: (R)-8- (1-((4-fluoro-2-(piperidin-4-yl)phenyl)amino)ethyl)-3,6-dime thyl-2-(4-methyltetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one (Int-11) [0633] [0634] Step 1. Synthesis of 4-methyltetrahydro-2H-pyran-4-carbonyl chloride [0635] To a solution of 4-methyltetrahydropyran-4-carboxylic acid (20.0 g, 139 mmol), N,N-dimethylformamide (1.01 g, 13.8 mmol) in dichloromethane (200 mL) was added oxalyl dichloride (52.8 g, 416 mmol) dropwise at 0 °C. The mixture was then stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give 4-methyltetrahydropyran- 4-carbonyl chloride (22.6 g, crude) as a yellow solid. [0636] Step 2. Synthesis of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-4- methyltetrahydro-2H-pyran-4-carboxamide [0637] To a solution of 2-amino-3-bromo-N,5-dimethyl-benzamide (16.9 g, 69.4 mmol), triethylamine (28.1 g, 277 mmol) in dichloromethane (200 mL) was added a solution of 4- methyltetrahydropyran-4-carbonyl chloride (22.6 g, 138 mmol) in dichloromethane (30 mL) dropwise at 0 °C, the mixture was stirred at 25 °C for 12 hr. On completion, the mixture was concentrated in vacuo. The crude product was triturated with ethyl acetate (500 mL x 3) for 20 min to give N-[2-bromo-4-methyl-6-(methylcarbamoyl)phenyl]-4-methyl- tetrahydropyran-4-carboxamide (20.0 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO- d6) δ 9.40 (s, 1H), 8.19 (br. d, J = 4.0 Hz, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 3.72 - 3.61 (m, 2H), 3.56 - 3.45 (m, 2H), 2.67 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 2.10 (br. d, J = 13.6 Hz, 2H), 1.48 - 1.36 (m, 2H), 1.23 (br. s, 3H). [0638] Step 3. Synthesis of 8-bromo-3,6-dimethyl-2-(4-methyltetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0639] To a mixture of N-[2-bromo-4-methyl-6-(methylcarbamoyl)phenyl]-4-methyl- tetrahydropyran-4-carboxamide (20.0 g, 54.2 mmol) in N,N-dimethylacetamide (200 mL) was added dichlorozinc (22.2 g, 162 mmol) and [dimethyl-(trimethylsilylamino)silyl]methane (26.2 g, 162 mmol, 34.1 mL), then the mixture was stirred at 140 °C for 72 hr. On completion, the mixture was poured into water (300 mL), and much precipitate was formed. The precipitate was collected via filtration, which was further dissolved in dichloromethane (50 mL) and stirred for 10 min. The mixture was filtered and the filtrate was concentrated in vauo to give 8-bromo-3,6-dimethyl-2-(4-methyltetrahydropyran-4-yl)quinazo lin-4-one (14.0 g, 39.8 mmol, 73%) as a white solid. m/z ES+ [M+1] ⁺ 351.2. [0640] Step 4. Synthesis of 8-acetyl-3,6-dimethyl-2-(4-methyltetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0641] To a solution of 8-bromo-3,6-dimethyl-2-(4-methyltetrahydropyran-4-yl)quinazo lin- 4-one (14.0 g, 39.9 mmol) in 1,4-dioxane (140 mL) was added dichloropalladium;triphenylphosphane (1.96 g, 2.79 mmol) and tributyl(1- ethoxyvinyl)stannane (43.2 g, 120 mmol). The mixture was stirred at 90 °C for 12 hr under nitrogen. On completion, the reaction mixture was quenched by saturated potassium fluoride solution (100 mL), and then diluted with water (100 mL) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (140 mL) and aqueous hydrochloric acid (2 M, 60 mL) was added. The mixture was stirred at 15 °C for 0.5 hr. The mixture was adjusted to pH = 8 with potassium carbonate and then extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with mixed solvent (petroleum ether/ethyl acetate =10/1, 100 mL) to give 8-acetyl-3,6-dimethyl-2-(4-methyltetrahydropyran-4-yl)quinaz olin-4-one (9.00 g, 28.63 mmol, 72%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (br. s, 1H), 7.82 (br. s, 1H), 3.78 (br. s, 4H), 3.74 (s, 3H), 2.81 (br. s, 3H), 2.50 (br. s, 3H), 2.48 - 2.33 (m, 2H), 1.91 (br. d, J = 13.2 Hz, 2H), 1.59 (br. s, 3H); m/z ES+ [M+H] ⁺ 315.2. [0642] Step 5. Synthesis of (R)-N-(1-(3,6-dimethyl-2-(4-methyltetrahydro-2H-pyran-4-yl)- 4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane -2-sulfinamide [0643] To a solution of 8-acetyl-3,6-dimethyl-2-(4-methyltetrahydropyran-4-yl)quinaz olin- 4-one (9.00 g, 28.6 mmol) and (R)-2-methylpropane-2-sulfinamide (10.4 g, 85.9 mmol) in anhydrous tetrahydrofuran (100 mL) was added tetraethoxytitanium (32.7 g, 143 mmol), the mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was poured into water (300 mL) at 25 °C, and then filtered through celite. The filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with a mixture solvent (petroleum ether/ethyl acetate =10/1, 50 mL) to give (R)-N-(1-(3,6-dimethyl-2-(4-methyltetrahydro-2H-pyran-4-yl)- 4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide (13 g, crude) as a brown solid. m/z ES+ [M+H] ⁺ 418.3 [0644] Step 6. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-2-(4-methyltetrahydro-2H-pyran-4- yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane- 2-sulfinamide [0645] To a solution of (R)-N-(1-(3,6-dimethyl-2-(4-methyltetrahydro-2H-pyran-4-yl)- 4- oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2 -sulfinamide (12.0 g, 28.7 mmol) in anhydrous tetrahydrofuran (120 mL) was added borane-dimethyl sulfide complex (10 M in tetrahydrofuran, 8.62 mL) dropwise at -78 °C. Then the mixture was stirred at -20 °C for 1 hr. On completion, the mixture was carefully quenched by methanol (50 mL) at -20 °C and further stirred at 15 °C for 1 hr. Then the mixture was evaporated to dryness. The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250*80mm*10um;mobile phase: [water(ammonium hydroxide)-acetonitrile];gradient:22%- 52% B over 20 min) to give (R)-N-((R)-1-(3,6-dimethyl-2-(4-methyltetrahydro-2H-pyran-4- yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane- 2-sulfinamide (6.5 g, 15.14 mmol, 53%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 5.12 (br. d, J = 6.4 Hz, 1H), 4.38 (br. s, 1H), 3.87 - 3.76 (m, 4H), 3.71 (s, 3H), 2.56 - 2.41 (m, 5H), 1.99 - 1.86 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H), 1.58 (s, 3H), 1.22 (s, 9H); m/z ES+ [M+H] ⁺ 420.3 [0646] Step 7. Synthesis of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(4-methyltetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [0647] To a solution of (R)-N-((R)-1-(3,6-dimethyl-2-(4-methyltetrahydro-2H-pyran-4- yl)-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide (1.00 g, 2.38 mmol) in dioxane (10 mL) was added hydrochloric acid/dioxane (4 M, 10 mL), the mixture was stirred at 20 °C for 1 hr. On completion, the mixture was adjusted to pH = 8 with aqueous ammonium hydroxide. Then it was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(4- methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (0.70 g, crude) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.6 Hz, 2H), 4.81 - 4.71 (m, 1H), 3.78 - 3.63 (m, 4H), 3.61 (s, 3H), 2.43 (s, 3H), 2.39 - 2.30 (m, 2H), 2.11 - 1.86 (m, 2H), 1.86 - 1.77 (m, 2H), 1.49 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 316.2 [0648] Step 8. Synthesis of (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2-(4-methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [0649] To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(4-methyltetrahydro-2H-p yran- 4-yl)quinazolin-4(3H)-one (600 mg, 1.90 mmol) and (2-bromo-4-fluoro-phenyl)boronic acid (4.16 g, 19.0 mmol) in dichloromethane (10 mL) was added triethylamine (1.92 g, 19.0 mmol) and copper acetate (691 mg, 3.80 mmol), the mixture was stirred at 25 °C for 24 hr under oxygen atomosphere (15 psi). On completion, the mixture was quenched with water (1 mL) and then filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% ammonium hydroxide -acetonitrile) to give (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2-(4-methyltetrahydro- 2H-pyran-4-yl)quinazolin-4(3H)-one (200 mg, 410 μmol, 22%) as a white solid. m/z ES+ [M+H] ⁺ 488.1/490.1 [0650] [0651] Step 9. Synthesis of tert-butyl (R)-4-(2-((1-(3,6-dimethyl-2-(4-methyltetrahydro-2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5- fluorophenyl)piperidine-1- carboxylate [0652] A mixture of (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2-(4- methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (200 mg, 409 μmol), tert-butyl 4- bromopiperidine-1-carboxylate (141 mg, 532 μmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)- 2-pyridyl]phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (4.59 mg, 4.10 μmol), 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;dichloronickel (0.8 mg, 2.05 μmol), bis(trimethylsilyl)silyl-trimethyl-silane (102 mg, 409 μmol) and sodium carbonate (86.8 mg, 819 μmol) in 1,2-dimethoxyethane (8 mL) was degassed and purged with nitrogen, and then the mixture was stirred at 25 °C for 16 hr irradiated with a 455 nm blue LED. On completion, the mixture was filtered and evaporated to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (R)-4-(2-((1-(3,6-dimethyl-2-(4-methyltetrahydro- 2H-pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl) [0653] ethyl)amino)-5-fluorophenyl)piperidine-1-carboxylate (200 mg, 310 μmol, 76%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.53 (s, 1H), 6.87 - 6.77 (m, 1H), 6.68 - 6.55 (m, 1H), 6.33 - 6.14 (m, 1H), 5.43 - 5.29 (m, 1H), 4.44 - 4.01 (m, 4H), 3.86 - 3.78 (m, 4H), 3.75 (s, 3H), 2.97 - 2.80 (m, 2H), 2.72 - 2.48 (m, 4H), 2.42 (s, 3H), 2.00 - 1.83 (m, 4H), 1.51 (s, 9H), 1.46 (s, 6H); m/z ES+ [M+H] ⁺ 593.5. [0654] Step 10. Synthesis of (R)-8-(1-((4-fluoro-2-(piperidin-4-yl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(4-methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H )-one [0655] To a solution of tert-butyl (R)-4-(2-((1-(3,6-dimethyl-2-(4-methyltetrahydro-2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5- fluorophenyl)piperidine-1- carboxylate (25.0 mg, 42.2 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (384 mg, 3.37 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was evaporated to give (R)-8-(1-((4-fluoro-2-(piperidin-4-yl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(4-methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H )-one (20.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 493.2. [0656] [0657] Preparation of Intermediate 12: 2-amino-3-bromo-N-cyclopropyl-5-fluorobenzamide (Int-12) and Intermediate 15: 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H - pyran-3-yl)quinazolin-4(3H)-one (Int-15) [0658] [0659] Step 1. Synthesis of 2-amino-3-bromo-N-cyclopropyl-5-fluorobenzamide [0660] To a solution of 2-amino-3-bromo-5-fluoro-benzoic acid (20.0 g, 85.4 mmol) and cyclopropanamine (4.88 g, 85.4 mmol) in N,N-dimethylformamide (200 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (51.9 g, 136 mmol) and diisopropylethylamine (55.2 g, 427 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water (600 mL) and extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with brine (600 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/1) to give 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (20.1 g, 68.4 mmol, 80%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.32 (dd, J = 2.8, 7.6 Hz, 1H), 6.99 (dd, J = 2.8, 8.8 Hz, 1H), 6.16 (br. s, 1H), 5.87 (br. s, 2H), 2.85 (dt, J = 3.2, 7.2 Hz, 1H), 0.96 - 0.79 (m, 2H), 0.69 - 0.55 (m, 2H); m/z ES+ [M+H] ⁺ 274.8. [0661] Step 2. Synthesis of N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydro-2H-pyran-3-carboxamide [0662] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (5.00 g, 18.3 mmol) in pyridine (65 mL) was added 2,4,6-tributyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6- trioxide (39.6 g, 54.9 mmol, 50% purity) and tetrahydropyran-3-carboxylic acid (2.38 g, 18.3 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water (100 mL) and then filtered. The filtered cake was collected and concentrated under reduced pressure to give N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro- phenyl]tetrahydropyran-3-carboxamide (5.50 g, 14.0 mmol, 76%) as a white solid. m/z ES+ [M+H] ⁺ 385.0. [0663] Step 3. Synthesis of 8-bromo-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-3- yl)quinazolin-4(3H)-one [0664] To a solution of N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro- phenyl]tetrahydropyran-3-carboxamide (5.00 g, 13.0 mmol) in acetonitrile (54 mL) was added dichlorozinc (5.31 g, 38.9 mmol) and [dimethyl-(trimethylsilylamino)silyl]methane (5.24 g, 32.5 mmol). The mixture was stirred at 80 °C for 1 hr. The reaction mixture was diluted with water (100 mL) and then filtered. The filtered cake was collected and concentrated under reduced pressure to give 8-bromo-3-cyclopropyl-6-fluoro-2- tetrahydropyran-3-yl-quinazolin-4-one (4.70 g, 11.1 mmol, 86%) as a white solid. m/z ES+ [M+H] ⁺ 367.0. [0665] Step 4. Synthesis of 3-8-acetyl-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-3- yl)quinazolin-4(3H)-one [0666] To a solution of 8-bromo-3-cyclopropyl-6-fluoro-2-tetrahydropyran-3-yl-quinaz olin- 4-one (4.70 g, 12.8 mmol) in toluene (47 mL) was added dichloropalladium triphenylphosphane (898 mg, 1.28 mmol) and tributyl(1-ethoxyvinyl)stannane (13.9 g, 38.4 mmol, 13.0 mL). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. The reaction mixture was adjusted to pH 7~8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (250 mL × 3). The combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was dissolved in dichloromethane (10 mL) and formic acid (10 mL) was stirred at 25 °C for 0.5 hr. The reaction mixture was adjusted to pH= 9 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-acetyl-3-cyclopropyl-6- fluoro-2-tetrahydropyran-3-yl-quinazolin-4-one (2 g, 5.57 mmol, 44%) as a brown solid. m/z ES+ [M+H] ⁺ 331.1. [0667] Step 5. Synthesis of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylp ropane-2-sulfinamide [0668] To a solution of 8-acetyl-3-cyclopropyl-6-fluoro-2-tetrahydropyran-3-yl-quina zolin- 4-one (2.00 g, 6.05 mmol) and (R)-2-methylpropane-2-sulfinamide (2.94 g, 24.2 mmol) in anhydrous tetrahydrofuran (25 mL) was added tetraethoxytitanium (5.52 g, 24.2 mmol, 5.02 mL). The mixture was stirred at 75 °C for 12 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2- (tetrahydro-2H-pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyli dene)-2-methylpropane-2- sulfinamide (2.5 g, 5.31 mmol, 88%) as a yellow solid. m/z ES+ [M+H] ⁺ 434.2. [0669] Step 6. Synthesis of (R)-N-((1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H - pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide [0670] To a solution of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-pyra n-3- yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2 -sulfinamide (2.30 g, 5.31 mmol) in anhydrous tetrahydrofuran (23 mL) was added borane-dimethyl sulfide complex (10 M, 2.12 mL) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at - 78 °C for 0.5 hr. Then the mixture was slowly warmed to 0 °C and stirred at 0 °C for 0.5 hr under nitrogen atmosphere. The mixture was carefully quenched by methanol (50 mL) dropwise at -10 °C and then stirred at 25 °C for 0.5 hr. Then the mixture was concentrated in vacuo to give a residue. The crude product was purified by prep-HPLC (column: Kromasil Eternity XT 250x80mmx10um;mobile phase: [water (ammonia hydroxide v/v)- acetonitrile];gradient:35%-65% B over 20 min) to give (R)-N-((1R)-1-(3-cyclopropyl-6- fluoro-4-oxo-2-(tetrahydro-2H-pyran-3-yl)-3,4-dihydroquinazo lin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (1.30 g, 2.98 mmol, 56%) as a yellow solid. m/z ES+ [M+H] ⁺ 436.3. [0671] Step 7. Synthesis of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H - pyran-3-yl)quinazolin-4(3H)-one [0672] To a solution of (R)-N-((1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H - pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide (1.30 g, 2.98 mmol) in dichloromethane (6 mL) was added hydrochloric acid/dioxane (4 M, 13.0 mL). The mixture was stirred at 20 °C for 0.5 hr. The reaction mixture was then filtered. The filtered cake was diluted with water (10 mL) and neutralized to pH = 9 with ammonium hydroxide, which was further extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2- (tetrahydro-2H-pyran-3-yl)quinazolin-4(3H)-one (600 mg, 1.81 mmol, 61%) as a yellow solid. m/z ES+ [M+H] ⁺ 332.1. [0673] [0674] Preparation of Intermediate 14: (R)-8-(1-aminoethyl)-6-methyl-3-(methyl-d3)-2- morpholinoquinazolin-4(3H)-one (Int-14) [0675] [0676] Step 1. Synthesis of 2-amino-3-bromo-5-methyl-N-(methyl-d3)benzamide [0677] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (5.22 g, 22.7 mmol), diisopropylethylamine (14.7 g, 113 mmol) in N,N-dimethylformamide (16 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (12.94 g, 34.02 mmol). The mixture was stirred at 15 °C for 0.5 hr. Then trideuteriomethanamine; hydrochloride (4.80 g, 68.1 mmol) was added and the mixture was stirred at 15 °C for 12 hr. On completion, the mixture was diluted with water (500 mL) and filtered. The filtered cake was washed with petroleum ether (100 mL) and then dried in vacuo to give 2-amino-3-bromo-5-methyl-N-(trideuteriomethyl)benzamide (4.80 g, 19.5 mmol, 86%) as a light-yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.08 (s, 1H), 6.05 (br. s, 1H), 5.83 (br. s, 2H), 2.22 (s, 3H); m/z ES+ [M+H] ⁺ 248.1. [0678] Step 2. Synthesis of 8-bromo-2-chloro-6-methyl-3-(methyl-d ₃ )quinazolin-4(3H)-one [0679] To a solution of 2-amino-3-bromo-5-methyl-N-(trideuteriomethyl)benzamide (5.30 g, 21.53 mmol) in dioxane (55 mL) was added thiocarbonyl dichloride (5.20 g, 45.22 mmol) portionwise at 25 °C under nitrogen atmosphere, and the mixture was stirred at 25 °C for 0.5 hr. Then the mixture was stirred at 105 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was triturated with solvent (petroleum ether/ethyl acetate=1/1, 30 mL) to give 8-bromo-2-chloro-6-methyl-3- (trideuteriomethyl)quinazolin-4-one (5.80 g, 18.4 mmol, 85%) as a pink solid. ¹ H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.85 (s, 1H), 2.46 (s, 3H); m/z ES+ [M+H] ⁺ 292.0. [0680] Step 3. Synthesis of 8-bromo-6-methyl-3-(methyl-d ₃ )-2-morpholinoquinazolin- 4(3H)-one [0681] A mixture of 8-bromo-2-chloro-6-methyl-3-(trideuteriomethyl)quinazolin-4- one (5.80 g, 18.36 mmol), morpholine (5.22 g, 59.88 mmol) in dichloromethane (60 mL) was stirred at 40 °C for 2 hr. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was triturated with a solution of solvent (petroleum ether/ethyl acetate=3/1, 15 mL) to give 8-bromo-6-methyl-2-morpholino-3- (trideuteriomethyl)quinazolin-4-one (6.50 g, 17.14 mmol, 86%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.79 (s, 1H), 3.89 (t, J = 4.4 Hz, 4H) 3.34 (t, J = 4.4 Hz, 4H) 2.43 (s, 3H); m/z ES+ [M+H] ⁺ 341.1. [0682] Step 4. Synthesis of 8-acetyl-6-methyl-3-(methyl-d ₃ )-2-morpholinoquinazolin- 4(3H)-one [0683] To a solution of 8-bromo-6-methyl-2-morpholino-3-(trideuteriomethyl)quinazoli n-4- one (6.50 g, 17.14 mmol) and 1-vinyloxybutane (5.72 g, 57.15 mmol) in n-butanol (35 mL) was added diacetoxypalladium (214 mg, 952 μmol), diisopropylethylamine (7.39 g, 57.2 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (1.03 g, 1.90 mmol). The mixture was stirred at 95 °C for 2 hr under nitrogen atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give 8-(1-butoxyvinyl)- 6-methyl-2-morpholino-3-(trideuteriomethyl)quinazolin-4-one (6.80 g, crude) as a black oil. The crude product was dispersed in n-butanol (30 mL) and then hydrochloric acid (1 M, 56.6 mL) was added. The mixture was stirred at 15 °C for 0.5 hr. The mixture was adjusted to pH = 8~9 with saturated sodium bicarbonate solution and much precipitate was formed. The precipitate was filtered, washed with water 60 mL and petroleum ether 60 mL, then the filter cake was concentrated in vacuo to give 8-acetyl-6-methyl-2-morpholino-3- (trideuteriomethyl)quinazolin-4-one (5.50 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.15 (br. s, 1H), 7.86 (br. s, 1H), 3.95 – 3.85 (m, 4H), 3.30 – 3.20 (m, 4H), 2.85 (br. s, 3H). 2.46 (br. s, 3H); m/z ES+ [M+H] ⁺ 305.1 [0684] Step 5. Synthesis of (R)-2-methyl-N-(1-(6-methyl-3-(methyl-d ₃ )-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethylidene)propane-2-sulfinam ide [0685] To a solution of 8-acetyl-6-methyl-2-morpholino-3-(trideuteriomethyl)quinazol in-4- one (5.50 g, 18.1 mmol), (R)-2-methylpropane-2-sulfinamide (6.57 g, 54.2 mmol) in tetrahydrofuran (50 mL) was added tetraethoxytitanium (12.4 g, 54.2 mmol). The mixture was stirred at 80 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was poured into water (300 mL) at 25 °C and then filtered. The filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give (R)-2-methyl-N-(1-(6-methyl-3-(methyl-d ₃ )-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)propane-2-sulfinamide (6.50 g, 15.63 mmol, 86%) as a white solid. m/z ES+ [M+H] ⁺ 408.3. [0686] Step 6. Synthesis of (R)-2-methyl-N-((R)-1-(6-methyl-3-(methyl-d ₃ )-2-morpholino- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)propane-2-sulfinamide [0687] To a solution of (R)-2-methyl-N-(1-(6-methyl-3-(methyl-d3)-2-morpholino-4-oxo - 3,4-dihydroquinazolin-8-yl)ethylidene)propane-2-sulfinamide (4.60 g, 11.30 mmol) in tetrahydrofuran (40 mL) was added borane-dimethylsulfide complex (10 M in tetrahydrofuran, 5.64 mL) dropwise at -78 °C. After addition, the mixture was warmed to - 10 °C and stirred at -10 °C for 2.5 hr under nitrogen atmosphere. On completion, the mixture was quenched by methanol (15 mL) dropwise at -30 °C and then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um);mobile phase: [water(ammonium bicarbonate)- acetonitrile];gradient:25%-50% B over 25 min) to give (R)-2-methyl-N-((R)-1-(6-methyl-3- (methyl-d3)-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)et hyl)propane-2-sulfinamide (3.60 g, 8.79 mmol, 78%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (d, J = 1.2 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 4.97 - 4.84 (m, 2H), 3.95 – 3.85 (m, 4H), 3.28 - 3.19 (m, 4H), 2.43 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H), 1.23 (s, 9H); m/z ES+ [M+H] ⁺ 410.3. [0688] Step 7. Synthesis of (R)-8-(1-aminoethyl)-6-methyl-3-(methyl-d ₃ )-2- morpholinoquinazolin-4(3H)-one [0689] To a solution of (R)-2-methyl-N-((R)-1-(6-methyl-3-(methyl-d3)-2-morpholino-4 - oxo-3,4-dihydroquinazolin-8-yl)ethyl)propane-2-sulfinamide (300 mg, 732 μmol) in dioxane (5 mL) was added hydrochloric acid/dioxane (4 M, 750 ^L), the mixture was stirred at 15 °C for 1 hr. On completion, the mixture was quenched with water (1 mL) and then adjusted to pH = 8~9 by saturated sodium bicarbonate solution and then extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (R)-8-(1-aminoethyl)-6- methyl-3-(methyl-d ₃ )-2-morpholinoquinazolin-4(3H)-one (150 mg, 491 μmol, 67%) as a yellow oil; m/z ES+ [M+H] ⁺ 306.2. [0690] Preparation of Intermediate 16: 1-(6-bromo-2,3-difluorophenyl)-4-((tert- butyldimethylsilyl)oxy)piperidine (Int-16) [0691] [0692] Step 1. Synthesis of 1-(2,3-difluoro-6-nitrophenyl)piperidin-4-ol [0693] To a solution of 1,2,3-trifluoro-4-nitro-benzene (5.00 g, 28.2 mmol) and piperidin-4- ol (2.57 g, 25.4 mmol) in acetonitrile (30 mL) was added diisopropylethylamine (10.9 g, 84.7 mmol). The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was diluted with brine (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 1-(2,3-difluoro-6-nitro-phenyl)piperidin-4-ol (4.60 g, 17.8 mmol, 64%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (ddd, J = 2.0, 5.6, 9.2 Hz, 1H), 6.94 - 6.84 (m, 1H), 3.89 (tt, J = 4.0, 8.8 Hz, 1H), 3.35 - 3.22 (m, 2H), 3.08 (t, J = 11.2 Hz, 2H), 2.03 - 1.94 (m, 2H), 1.76 - 1.64 (m, 2H). [0694] Step 2. Synthesis of 1-(6-amino-2,3-difluorophenyl)piperidin-4-ol [0695] To a solution of 1-(2,3-difluoro-6-nitro-phenyl)piperidin-4-ol (1.00 g, 3.87 mmol) in ethanol (10 mL) and water (3 mL) was added ammonium chloride (1.04 g, 19.3 mmol) and iron powder (1.08 g, 19.3 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was filtered. The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/3) to give 1-(6- amino-2,3-difluoro-phenyl)piperidin-4-ol (840 mg, 3.64 mmol, 94%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 6.87 - 6.72 (m, 1H), 6.43 (ddd, J = 2.0, 4.8, 8.8 Hz, 1H), 5.28 - 3.97 (m, 2H), 3.94 - 3.65 (m, 1H), 3.28 - 2.90 (m, 4H), 2.05 – 1.95 (m, 2H), 1.75 – 1.60 (m, 2H); m/z ES+ [M+H] ⁺ 229.2. [0696] Step 3. Synthesis of 1-(6-bromo-2,3-difluorophenyl)piperidin-4-ol [0697] To a stirred solution of concentrated sulfuric acid (378 mg, 3.86 mmol) in water (5 mL) was added 1-(6-amino-2,3-difluoro-phenyl)piperidin-4-ol (800 mg, 3.51 mmol) slowly at 0 °C. Then sodium nitrite (266 mg, 3.86 mmol) was added portionwise at 0 °C. The mixture was stirred at 25 °C for 1.5 hr. Then a suspension of sodium bromide (1.44 g, 14.0 mmol) and cuprous bromide (502 mg, 3.51 mmol) in water (5 mL) was added into the mixture and the mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 3/1) to give 1-(6-bromo-2,3-difluoro- phenyl)piperidin-4-ol (730 mg, 2.10 mmol, 60%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 - 7.29 (m, 1H), 6.86 - 6.78 (m, 1H), 3.97 - 3.83 (m, 1H), 3.40 – 3.24 (m, 2H), 3.19 - 3.09 (m, 2H), 2.06 - 1.99 (m, 2H), 1.82 - 1.71 (m, 2H); m/z ES+ [M+H] ⁺ 292.1/294.1. [0698] Step 4. Synthesis of 1-(6-bromo-2,3-difluorophenyl)-4-((tert- butyldimethylsilyl)oxy)piperidine [0699] To a solution of 1-(6-bromo-2,3-difluoro-phenyl)piperidin-4-ol (730 mg, 2.50 mmol) in N,N-dimethylformamide (10 mL) was added tert-butylchlorodimethylsilane (564 mg, 3.75 mmol) and imidazole (425 mg, 6.25 mmol), the mixture was stirred at 25 °C for 2 hr. On completion, the mixture was quenched with ammonium chloride solution (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 10/1) to give [1-(6-bromo-2,3-difluoro-phenyl)-4-piperidyl]oxy-tert-butyl- dimethyl-silane (850 mg, 1.78 mmol, 71%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 - 7.20 (m, 1H), 6.80 - 6.73 (m, 1H), 3.94 - 3.78 (m, 1H), 3.39 - 3.25 (m, 2H), 3.14 - 3.00 (m, 2H), 1.94 - 1.82 (m, 2H), 1.80 - 1.67 (m, 2H), 0.93 (s, 9H), 0.09 (s, 6H); m/z ES+ [M+H] ⁺ 406.2/408.2. [0700] [0701] Preparation of Intermediate 17: 1-(4-(2-bromo-5-fluorophenyl)piperazin-1-yl)propan- 1-one (Int-17) [0702] [0703] Step 1. Synthesis of tert-butyl 4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate [0704] To a solution of tert-butyl piperazine-1-carboxylate (3.00 g, 16.11 mmol) and 2,4- difluoro-1-nitro-benzene (2.56 g, 16.1 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (6.68 g, 48.3 mmol). The mixture was stirred at 80 °C for 3 hr. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate =3/1) to give tert-butyl 4-(5-fluoro-2-nitro-phenyl)piperazine-1- carboxylate (4.00 g, 12.30 mmol, 76%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 7.99 - 7.86 (m, 1H), 6.81 - 6.69 (m, 2H), 3.67 - 3.54 (m, 4H), 3.04 (br. s, 4H), 1.49 (s, 9H); m/z ES+ [M+H] ⁺ 326.2. [0705] Step 2. Synthesis of 1-(5-fluoro-2-nitrophenyl)piperazine [0706] To a solution of tert-butyl 4-(5-fluoro-2-nitro-phenyl)piperazine-1-carboxylate (4.00 g, 12.3 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (15.4 g, 135 mmol), the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was quenched with 1 mL water and then adjusted to pH 7~8 with saturated sodium bicarbonate solution. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-(5-fluoro-2-nitro-phenyl)piperazine (2.7 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 226.1. [0707] Step 3. Synthesis of 1-(4-(5-fluoro-2-nitrophenyl)piperazin-1-yl)propan-1-one [0708] To a solution of 1-(5-fluoro-2-nitro-phenyl)piperazine (2.70 g, 12.0 mmol), N,N- diethylethanamine (2.43 g, 24.0 mmol) in anhydrous tetrahydrofuran (30 mL) was added propanoyl chloride (2.22 g, 24.0 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate =3/1) to give 1-[4-(5-fluoro-2-nitro-phenyl)piperazin-1-yl]propan-1-one (1.00 g, 3.52 mmol, 29%) as a yellow solid. m/z ES+ [M+H] ⁺ 282.1. [0709] Step 4. Synthesis of 1-(4-(2-amino-5-fluorophenyl)piperazin-1-yl)propan-1-one [0710] To a solution of 1-[4-(5-fluoro-2-nitro-phenyl)piperazin-1-yl]propan-1-one (1.00 g, 3.56 mmol) in ethanol (5 mL) and water (5 mL) was added iron powder (596 mg, 10.7 mmol) and ammonium chloride (1.90 g, 35.6 mmol), the mixture was stirred at 80 °C for 12 hr. On completion, the mixture was quenched with water (30 mL) and then filtered. The filtrate was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate =3/1) to give 1-[4-(2-amino-5-fluoro-phenyl)piperazin-1- yl]propan-1-one (700 mg, 2.79 mmol, 78%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 6.73 - 6.64 (m, 3H), 3.77 (br. s, 2H), 3.61 (br. s, 2H), 2.88 (br. d, J = 3.6 Hz, 4H), 2.40 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H); m/z ES+ [M+H] ⁺ 252.2. [0711] Step 5. Synthesis of 1-(4-(2-bromo-5-fluorophenyl)piperazin-1-yl)propan-1-one [0712] To a solution of 1-[4-(2-amino-5-fluoro-phenyl)piperazin-1-yl]propan-1-one (300 mg, 1.19 mmol), concentrated sulfuric acid (131 mg, 1.31 mmol), cuprous bromide (171 mg, 1.19 mmol), sodium bromide (491 mg, 4.78 mmol) in water (4 mL) was added a solution of sodium nitrite (90.6 mg, 1.31 mmol) in water (2 mL) at 70 °C under nitrogen, the mixture was stirred at 70 °C for 3 hr. On completion, the mixture was quenched with aqueous ammonium hydroxide (40 mL), then diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate =5/1) to give 1-[4-(2-bromo- 5-fluoro-phenyl)piperazin-1-yl]propan-1-one (150 mg, 476 μmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (br. t, J = 7.2 Hz, 1H), 6.82 - 6.57 (m, 2H), 3.89 - 3.58 (m, 4H), 3.01 (br. s, 4H), 2.40 (q, J = 7.6 Hz, 2H), 1.19 (br. t, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 315.1/317.1. [0713] [0714] Preparation of Intermediate 18: 1-(4-(2-bromo-5-fluorophenyl)piperazin-1-yl)-2- ((tert-butyldimethylsilyl)oxy)ethan-1-one (Int-18) [0715] [0716] Step 1. Synthesis of 1-(4-(5-fluoro-2-nitrophenyl)piperazin-1-yl)-2-hydroxyethan- 1- one [0717] To a solution of 2-hydroxy-1-piperazin-1-yl-ethanone (2.00 g, 13.8 mmol) in N,N- dimethylformamide (20 mL) was added potassium carbonate (1.92 g, 13.8 mmol) and 2,4- difluoro-1-nitro-benzene (2.21 g, 13.8 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 1-[4-(5-fluoro-2-nitro-phenyl)piperazin-1-yl]-2- hydroxy-ethanone (1.40 g, 4.89 mmol, 35%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 - 7.93 (m, 1H), 6.90 - 6.76 (m, 2H), 4.23 (s, 2H), 3.93 - 3.85 (m, 2H), 3.56 - 3.45 (m, 2H), 3.17 - 3.07 (m, 4H); m/z ES+ [M+H] ⁺ 284.1. [0718] Step 2. Synthesis of 1-(4-(2-amino-5-fluorophenyl)piperazin-1-yl)-2-hydroxyethan- 1-one [0719] To a solution of 1-[4-(5-fluoro-2-nitro-phenyl)piperazin-1-yl]-2-hydroxy-etha none (1.40 g, 4.94 mmol) in ethanol (14 mL) was added saturated ammonium chloride solution (8 M, 6.18 mL) and iron powder (1.38 g, 24.7 mmol), the mixture was stirred at 60 °C for 3 hr. On completion, the reaction mixture was filtered and washed with ethyl acetate (30 mL x 3). Then the organic phase of the filtrate was separated, washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/1 to 0/1) to give 1-[4-(2-amino-5-fluoro-phenyl)piperazin-1-yl]-2- hydroxy-ethanone (600 mg, 2.37 mmol, 48%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 6.74 - 6.67 (m, 3H), 4.24 (s, 2H), 3.97 - 3.79 (m, 2H), 3.72 - 3.58 (m, 1H), 3.50 - 3.40 (m, 2H), 3.00 - 2.85 (m, 4H). [0720] [0721] Step 3. Synthesis of 1-(4-(2-bromo-5-fluorophenyl)piperazin-1-yl)-2-hydroxyethan- 1-one [0722] 1-[4-(2-amino-5-fluoro-phenyl)piperazin-1-yl]-2-hydroxy-etha none (500 mg, 1.97 mmol) was added slowly into a solution of concentrated sulfuric acid (213 mg, 2.17 mmol) in water (5 mL) at 0 °C. Then a solution of sodium nitrite (149 mg, 2.17 mmol) in water (2.5 mL) was slowly dropped into the above mixture while controlling the temperature at 0~10 °C. After completion, the reaction mixture was raised to 25 °C and stirred at 25 °C for 1.5 hr to form a diazonium salt. Then a suspension of sodium bromide (812 mg, 7.90 mmol) and cuprous bromide (283 mg, 1.97 mmol) in water (2.5 mL) was added and the mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and washed with ethyl acetate (30 mL x 3). The organic phase in the filtrate was separated, washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[4-(2-bromo-5-fluoro-phenyl)piperazin-1-yl]- 2-hydroxy-ethanone (600 mg, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 6.0, 8.4 Hz, 1H), 6.84 - 6.68 (m, 2H), 4.24 (s, 2H), 3.93 - 3.84 (m, 2H), 3.64 (br. s, 1H), 3.53 - 3.45 (m, 2H), 3.15 – 3.00 (m, 4H). [0723] Step 4. Synthesis of 1-(4-(2-bromo-5-fluorophenyl)piperazin-1-yl)-2-((tert- butyldimethylsilyl)oxy)ethan-1-one [0724] To a solution of 1-[4-(2-bromo-5-fluoro-phenyl)piperazin-1-yl]-2-hydroxy-etha none (550 mg, 1.73 mmol) and imidazole (354 mg, 5.20 mmol) in dichloromethane (5.5 mL) was added tert-butylchlorodimethylsilane (392 mg, 2.60 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 hr. On completion, the reaction mixture was diluted with water 30 mL and extracted with dichloromethane (15 mLx 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 4/1) to give 1-[4-(2-bromo-5-fluoro- phenyl)piperazin-1-yl]-2-[tert-butyl(dimethyl)silyl]oxy-etha none (700 mg, 1.60 mmol, 92%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (dd, J = 6.0, 8.8 Hz, 1H), 6.81 - 6.67 (m, 2H), 4.35 (s, 2H), 3.80 (br. s, 4H), 3.04 (br. s, 4H), 0.94 (s, 9H), 0.15 (s, 6H). m/z ES+ [M+H] ⁺ 433.1. [0725] [0726] Preparation of Intermediate 21: 1-(2-amino-5-fluorophenyl)piperidin-4-ol (Int-21) and Intermediate 52: [1-(2-bromo-5-fluoro-phenyl)-4-piperidyl]oxy-tert-butyl-dime thyl silane (Int-52) [0727] [0728] Step 1. Synthesis of 1-(5-fluoro-2-nitro-phenyl)piperidin-4-ol [0729] A suspension of piperidin-4-ol (20 g, 197 mmol), 2,4-difluoro-1-nitro-benzene (31.4 g, 197 mmol) and potassium carbonate (54.6 g, 395 mmol) in N,N-dimethylformamide (200 mL) was stirred at 80 °C for 1 hr. The mixture was diluted with water 600 mL and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 5/1) to give 1-(5-fluoro-2-nitro- phenyl)piperidin-4-ol (30 g, 124 mmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 6.0, 9.2 Hz, 1H), 6.78 (dd, J = 2.8, 10.8 Hz, 1H), 6.68 – 6.65 (m, 1H), 3.96 – 3.91 (m, 1H), 3.41 - 3.22 (m, 2H), 3.03 - 2.88 (m, 2H), 2.13 - 1.98 (m, 2H), 1.85 - 1.68 (m, 2H). [0730] Step 2. Synthesis of 1-(2-amino-5-fluoro-phenyl)piperidin-4-ol [0731] To a solution of 1-(5-fluoro-2-nitro-phenyl)piperidin-4-ol (15.0 g, 62.4 mmol) in ethanol (150 mL) was added ammonium chloride (8 M, 78 mL) and iron powder (17.4 g, 312 mmol), the mixture was stirred at 60 °C for 2 hr. The mixture was filtered and washed with ethyl acetate (30 mL x 3), then the filtrate was used potassium carbonate to adjust pH = 8. The organic phase was separated, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 1/1) to give 1-(2- amino-5-fluoro-phenyl)piperidin-4-ol (10 g, 47.5 mmol, 76%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 6.73 (d, J = 10.4 Hz, 1H), 6.65 (d, J = 6.4 Hz, 2H), 4.09 - 3.56 (m, 3H), 3.20 - 3.04 (m, 2H), 2.68 (t, J = 10.0 Hz, 2H), 2.07 - 2.02 (m, 2H), 1.72 (d, J = 9.2 Hz, 2H). [0732] Step 3. Synthesis of 1-(2-bromo-5-fluoro-phenyl)piperidin-4-ol [0733] Concentrated sulfuric acid (3.67 g, 36.6 mmol) was dropped slowly into water (46 mL) at 0 ° C. 1-(2-amino-5-fluoro-phenyl)piperidin-4-ol (7 g, 33.2 mmol) was added slowly into the system and stirred. sodium nitrite (2.53 g, 36.6 mmol) was added into water (12 mL), stirred until clarification, and then slowly dropped into the raw material system while controlling the temperature to 0 to 10 ° C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 1.5 hr to form a diazonium salt system. Then a solution of sodium bromide (13.7 g, 133 mmol) and cuprous bromide (4.78 g, 33.2 mmol) in water (12 mL) were added, the mixture was stirred at 80 °C for 1.5 hr under nitrogen atmosphere. The mixture was quenched with ammonium hydroxide (40 mL), diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 4/1) to give 1-(2-bromo-5-fluoro-phenyl)piperidin-4-ol (6.3 g, 22.9 mmol, 69%) as a yellow oil. m/z ES+ [M+H] ⁺ 274.0. [0734] Step 4. Synthesis of [1-(2-bromo-5-fluoro-phenyl)-4-piperidyl]oxy-tert-butyl- dimethyl-silane [0735] To a mixture of 1-(2-bromo-5-fluoro-phenyl)piperidin-4-ol (6.3 g, 22.9 mmol) in N,N-dimethylformamide (63 mL) was added tert-butyl-chloro-dimethylsilane (5.20 g, 34.4 mmol) and 1H-imidazole (3.91 g, 57.4 mmol). Then the mixture was stirred at 25 °C for 1 hr. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (500 mL), the organic phase was separated, washed with brine 500 mL (250 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/0 to 1:1) to give [1-(2-bromo-5-fluoro-phenyl)-4-piperidyl]oxy-tert-butyl- dimethyl-silane (7 g, 18.0 mmol, 78%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (dd, J = 6.4, 8.8 Hz, 1H), 6.86 - 6.74 (m, 1H), 6.62 (dt, J = 2.8, 8.0 Hz, 1H), 3.90 (td, J = 3.6, 6.8 Hz, 1H), 3.21 (t, J = 7.2 Hz, 2H), 2.95 - 2.77 (m, 2H), 2.00 - 1.87 (m, 2H), 1.82 - 1.65 (m, 2H), 0.92 (s, 9H), 0.09 (s, 6H); m/z ES+ [M+H] ⁺ 390.0. [0736] [0737] Preparation of Intermediate 30: 8-bromo-3,6-dimethyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one (Int-30); Intermediate 22: 8-acetyl-3,6-dimethyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one (Int-22); and Intermediate 19: 8-(1-aminoethyl)-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (Int-19) [0738] [0739] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one [0740] To a mixture of 2-amino-3-bromo-N,5-dimethyl-benzamide (10 g, 41.14 mmol) in ethanol (150 mL) was added tetrahydropyran-4-carbaldehyde (6.10 g, 53.5 mmol) and iodine (11.5 g, 45.3 mmol), then the mixture was stirred at 80 °C for 18 hr. Then iodine (5.22 g, 20.6 mmol) was added and stirred at 100 °C for 4 hr. The mixture was poured in water (2 L) while a lot of yellow solid was generated. The collected yellow solid was concentrated in vacuo to give 8-bromo-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (10.6 g, 31.4 mmol, 76%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.94 (s, 1H), 7.87 (s, 1H), 3.98 (d, J = 12.0 Hz, 2H), 3.60 (s, 3H), 3.54 - 3.48 (m, 2H), 3.32 - 3.23 (m, 1H), 2.42 (s, 3H), 1.97 - 1.80 (m, 4H). [0741] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-on e [0742] To a solution of 8-bromo-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (10.3 g, 30.5 mmol) in n-butyl alcohol (100 mL) was added 1-vinyloxybutane (9.18 g, 91.63 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane (1.64 g, 3.05 mmol), diisopropylethylamine (11.8 g, 91.6 mmol) and palladium (II) acetate (343 mg, 1.53 mmol), then the mixture was stirred at 100 °C for 4 hr under nitrogen. The reaction mixture was concentrated under reduced pressure and dissolved in n-butyl alcohol (100 mL) and formic acid (8.76 g, 182 mmol) was added, then the mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was poured into water (500 mL), extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/2) to give 8-acetyl-3,6-dimethyl-2- tetrahydropyran-4-yl-quinazolin-4-one (9.7 g, 26.5 mmol, 72%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.85 (s, 1H), 4.13 (d, J = 12.0 Hz, 2H), 3.69 (s, 3H), 3.57 (t, J = 12.0 Hz, 2H), 3.12 (t, J = 12.0 Hz, 1H), 2.89 (s, 3H), 2.48 (s, 3H), 2.20 - 2.00 (m, 2H), 1.90 - 1.85 (m, 2H). [0743] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one [0744] To a solution of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-on e (2.00 g, 6.66 mmol) in methanol (20 mL) was added sodium cyanoboranuide (837 mg, 13.3 mmol) and azanium acetate (10.3 g, 133 mmol), then the mixture was stirred at 60 °C for 5 hr. The mixture was was concentrated under reduced pressure to give a residue. The residue by reversed-phase HPLC (0.1% ammonium hydroxide) to give 8-(1-aminoethyl)-3,6-dimethyl- 2-tetrahydropyran-4-yl-quinazolin-4-one (1.4 g, 4.47 mmol, 67%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.70 (s, 1H), 4.75 - 4.70 (m, 1H), 4.00 - 3.95 (m, 2H), 3.60 (s, 3H), 3.54 - 3.46 (m, 2H), 3.27 - 3.24 (m, 1H), 2.42 (s, 3H), 1.89 - 1.79 (m, 4H), 1.35 (d, J = 8.0 Hz, 3H). [0745] [0746] Preparation of Intermediate 23: 8-(2-aminopropan-2-yl)-3,6-dimethyl-2-(tetrahydro- 2H-pyran-4-yl)quinazolin-4(3H)-one (Int-23) [0747] [0748] Step 1. Synthesis of 8-(2-hydroxypropan-2-yl)-3,6-dimethyl-2-(tetrahydro-2H-pyran - 4-yl)quinazolin-4(3H)-one [0749] To a solution of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-on e (1 g, 3.33 mmol) in anhydrous tetrahydrofuran (15mL) was added methyllithium (1.6 M, 2.7 mL) at -20 °C under nitrogen atmosphere. The mixture was stirred from -20 °C to 0 °C for 1 hr. The mixture was quenched with saturated ammonium chloride (13 mL) at 0 °C. The mixture was extracted with ethyl acetate (10 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-(1-hydroxy-1-methyl-ethyl)-3,6-dimethyl-2-tetrahydropyran- 4-yl-quinazolin-4- one (550 mg, 1.68 mmol, 50%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.88 - 7.76 (m, 2H), 5.89 (s, 1H), 3.96 (dd, J = 3.2, 11.2 Hz, 2H), 3.61 (s, 3H), 3.55 - 3.44 (m, 2H), 2.42 (s, 3H), 1.92 - 1.72 (m, 5H), 1.67 (s, 6H); m/z ES+ [M+H] ⁺ 317.2. [0750] Step 2. Synthesis of 8-(2-azidopropan-2-yl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 - yl)quinazolin-4(3H)-one [0751] To a solution of 8-(1-hydroxy-1-methyl-ethyl)-3,6-dimethyl-2-tetrahydropyran- 4-yl- quinazolin-4-one (550 mg, 1.74 mmol) in toluene (10 mL) was added trimethylsilane azide (1.07 g, 9.29 mmol) and boron trifluoride diethyl etherate (1.05 g, 7.43 mmol) under nitrogen atmosphere at 25 °C. The mixture was stirred at 25 °C for 12 hr. The reaction was quenched with saturated sodium bicarbonate solution (15 mL), and the mixture was stirred for 10 min at 25 °C. Then the mixture was extracted with ethyl acetate (25 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-(1-azido-1-methyl-ethyl)-3,6-dimethyl-2-tetrahydropyran-4- yl-quinazolin-4-one (300 mg, 743 μmol, 43%) as a yellow solid. m/z ES+ [M+H]+ 342.2. [0752] Step 3. Synthesis of 8-(2-aminopropan-2-yl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 - yl)quinazolin-4(3H)-one [0753] To a solution of 8-(1-azido-1-methyl-ethyl)-3,6-dimethyl-2-tetrahydropyran-4- yl- quinazolin-4-one (300 mg, 878 μmol) in acetic acid (7 mL) was added zinc powder (450 mg, 6.88 mmol). The mixture was stirred at 25 °C for 1.5 hr. The reaction mixture was filtered and filter cake quenched by addition hydrochloric acid (1N, 7 mL) at 25 °C. The filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% hydrochloric acid condition) to give 8-(1-amino-1-methyl- ethyl)-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (300 mg, 852 μmol, 97%) as a white solid. m/z ES+ [M+H] ⁺ 316.2. [0754] [0755] Preparation of Intermediate 24: (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one (Int-24) [0756] [0757] Step 1. Synthesis of (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide [0758] To a solution of 8-acetyl-3, 6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (4.2 g, 13.9 mmol) and (R)-2-methylpropane-2-sulfinamide (8.47 g, 69.9 mmol) in 2- methyltetrahydrofuran (60 mL) was added titanium tetraethoxy (15.9 g, 69.9 mmol). And then the mixture was stirred at 85 °C for 16 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide, petroleum ether/Ethyl acetate=15/1 to 1:1) to give (R,Z)-N-(1-(3,6-dimethyl- 4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-y l)ethylidene)-2- methylpropane-2-sulfinamide (6.5 g, 16.1 mmol, 72%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 - 7.91 (m, 1H), 7.62 - 7.44 (m, 1H), 3.97 - 3.91 (m, 2H), 3.68 - 3.59 (m, 3H), 3.54 - 3.41 (m, 2H), 3.28 (s, 1H), 2.46 (s, 3H), 1.86 - 1.74 (m, 4H), 1.08 (s, 9H); m/z ES+ [M+H] ⁺ 404.2. [0759] Step 2. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl )- 3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinam ide [0760] To a mixture of sodium borohydride (188 mg, 4.96 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred at -55 °C, then a solution of (NZ,R)-N-[1-(3,6-dimethyl- 4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethylidene]-2-m ethyl-propane-2-sulfinamide (1 g, 2.48 mmol) in anhydrous tetrahydrofuran (10 mL) was added, then the mixture was stirred at -55 °C ~ 15 °C for 12 hr. The mixture was quenched by water (50 mL) and saturated ammonium chloride solution (50 mL) at 0 °C, then the mixture was extracted with ethyl acetate (30 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18250 x 50mm, 10um; mobile phase: [water(ammonium bicarbonate)-acetonitrile]; B%: 32%-52%, 8 min) to give (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-qui nazolin-8-yl)ethyl]-2-methyl- propane-2-sulfinamide (300 mg, 740 μmol, 30%) as a white solid. m/z ES+ [M+H] ⁺ 406.2. [0761] Step 3. Synthesis of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0762] To a solution of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (150 mg, 339 μmol, hydrochloric acid) in dichloromethane (2 mL) was add hydrochloric acid/dioxane (4 M, 424 ^L). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water (FA)-ACN]; B%: 3%-33%, 8 min) to give 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydro-pyran-4-yl-q uinazolin-4-one (0.1 g, 98%) as a white solid. m/z ES+ [M+H] ⁺ 302.2. [0763] [0764] Preparation of Intermediate 25: 8-(1-bromoethyl)-3,6-dimethyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one (Int-25) [0765] [0766] Step 1. Synthesis of 8-(1-hydroxyethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0767] To a mixture of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-on e (1.00 g, 3.33 mmol) in methanol (10 mL) was added sodium borohydride (252 mg, 6.66 mmol) slowly, the mixture was stirred at 0 °C for 1 hr under nitrogen atmosphere. On completion. The mixture was quenched by water (30 mL) and saturated ammonium chloride solution (15 mL) at 0 °C. Then the mixture was extracted with ethyl acetate (20 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 0/1) to give 8-(1-hydroxyethyl)-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (1.00 g, 3.31 mmol, 99%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77 (s, 1H), 7.73 (s, 1H), 5.57 - 5.46 (m, 1H), 3.96 (d, J = 12.0 Hz, 2H), 3.60 (s, 3H), 3.56 - 3.47 (m, 2H), 2.43 (s, 3H), 1.88 - 1.80 (m, 4H), 1.42 - 1.35 (m, 3H); m/z ES+ [M+H]+ 303.0. [0768] Step 2. Synthesis of 8-(1-bromoethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0769] To a mixture of 8-(1-hydroxyethyl)-3,6-dimethyl-2-tetrahydropyran-4-yl-quina zolin- 4-one (400 mg, 1.32 mmol) in dichloromethane (8 mL) was phosphorus tribromide (1.07 g, 3.97 mmol) at 0 °C, then the mixture was stirred at 0 °C for 1 hr under nitrogen atmosphere. On completion. The mixture was filtered and concentrated to give 8-(1-bromoethyl)-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (400 mg, crude) as a white solid. [0770] [0771] Preparation of Intermediate 26: (R)-8-(1-aminoethyl)-6-bromo-3-methyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (Int-26) and Intermediate 27: 2-amino-5- bromo-3-iodobenzoic acid (Int-27) [0772] [0773] Step 1. Synthesis of 2-amino-5-bromo-3-iodobenzoic acid [0774] To a solution of 2-amino-5-bromo-benzoic acid (25.0 g, 116 mmol) in N, N- dimethylformamide (300 mL) was added N-iodosuccinimide (46.8 g, 208 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the mixture was poured in water (1000 mL) then extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (500 mL), the organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 4/1) to give 2-amino- 5-bromo-3-iodo-benzoic acid (9 g, 22.9 mmol, 20%) as a black solid. m/z ES+ [M+H] ⁺ 341.9. [0775] Step 2. Synthesis of 2-amino-5-bromo-3-iodo-N-methylbenzamide [0776] To a solution of 2-amino-5-bromo-3-iodo-benzoic acid (9 g, 26.3 mmol) in N,N- dimethylformamide (90 mL) was added diisopropylethylamine (13.6 g, 105 mmol), methanamine; hydrochloride (3.55 g, 52.6 mmol) and [dimethylamino(triazolo[4,5-b]pyridin- 3-yloxy)methylene]-dimethyl-ammonium;hxafluor-ophosphate(12. 0 g, 31.6 mmol). On completion, the mixture was stirred at 25 °C for 2 hr. The mixture is poured into water (500 mL), where solids are precipitated and filtered to obtain the solid by spin drying to give 2- amino-5-bromo-3-iodo-N-methyl-benzamide (7.7 g, 19.1 mmol, 73%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J = 2.0 Hz, 1H), 7.43 (s, 1H), 6.22 (s, 1H), 6.09 (s, 2H), 2.96 (s, 3H). m/z ES+ [M+H] ⁺ 354.9. [0777] Step 3. Synthesis of 6-bromo-8-iodo-3-methyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0778] To a solution of 2-amino-5-bromo-3-iodo-N-methyl-benzamide (7.20 g, 20.3 mmol) and tetrahydropyran-4-carbaldehyde (2.78 g, 24.3 mmol) in ethanol (72 mL) was added iodine (9.06 g, 35.7 mmol). The mixture was stirred at 80 °C for 16 hr. Then the mixture was added another iodide (5.15 g, 20.3 mmol) and stirred at 80 °C for 24 hr. On completion, the mixture was poured in anhydrous sodium sulfite (50 mL), where solids are precipitated and filtered to obtain the solid by spin drying. The crude product was triturated with petroleum ether/ethyl acetate (2/1, 20 mL) at 25 °C for 30 min to give 6-bromo-8-iodo-3-methyl-2- tetrahydropyran-4-yl-quinazolin-4-one (5.8 g, 11.1 mmol, 55%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 4.01 - 3.95 (m, 2H), 3.60 (s, 3H), 3.56 - 3.45 (m, 2H), 2.00 - 1.80(m, 5 H); m/z ES+ [M+H] ⁺ 448.9. [0779] Step 4. Synthesis of 8-acetyl-6-bromo-3-methyl-2-tetrahydropyran-4-yl-quinazolin- 4-one [0780] A mixture of 6-bromo-8-iodo-3-methyl-2-tetrahydropyran-4-yl-quinazolin-4- one (2 g, 4.45 mmol), tributyl (1-ethoxyvinyl)stannane (2.41 g, 6.68 mmol), dichloropalladium; triphenylphosphane (313 mg, 445 μmol) in toluene (20 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition potassium fluoride solution (100 mL) at 25 °C, the mixture was stirred at 25 °C for 2 hr, then diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to a residue which dissolved in hydrogen chloride (1 M, 24.0 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the solution was adjusted to pH = 8 with saturated sodium bicarbonate solution. The mixture was poured in water (100 mL) then extracted with petroleum ether (100 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-acetyl-6-bromo-3-methyl-2-tetrahydropyran-4-yl-quinazolin- 4-one (750 mg, 1.79 mmol, 29%) as a yellow solid. m/z ES+ [M+H] ⁺ 365.0. [0781] Step 5. Synthesis of (R,E)-N-(1-(6-bromo-3-methyl-4-oxo-2-(tetrahydro-2H-pyran-4- yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2 -sulfinamide [0782] To a solution of 8-acetyl-6-bromo-3-methyl-2-tetrahydropyran-4-yl-quinazolin- 4-one (750 mg, 2.05 mmol) and (R)-2-methylpropane-2-sulfinamide (747 mg, 6.16 mmol) in 2- methyltetrahydrofuran (8 mL) was added titanium acid ethyl ester (1.41 g, 6.16 mmol). The mixture was stirred at 85 °C for 3 hr. On completion, the mixture was poured in water (50 mL) then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), the organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give (NE,R)-N-[1-(6-bromo-3-methyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethylidene]-2-methyl-pr opane-2-sulfinamide (300 mg, 576 μmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 4.18 - 4.07 (m, 4H), 3.60 - 3.50 (m, 3H), 2.91 - 2.87 (m, 3H), 2.55 (s, 1H), 2.12 - 1.99 (m, 4H), 1.34 (s, 9H); m/z ES+ [M+H] ⁺ 468.1. [0783] Step 6. Synthesis of (R)-N-((R)-1-(6-bromo-3-methyl-4-oxo-2-(tetrahydro-2H-pyran- 4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-su lfinamide [0784] To a solution of (NE,R)-N-[1-(6-bromo-3-methyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (0.2 g, 427 μmol) in anhydrous tetrahydrofuran (2 mL) was added borane-methyl sulfide complex (10 M, 213 ^L) at -78 °C under nitrogen atmosphere. The mixture was stirred at -25 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was quenched by methanol (20 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex C18150 x 25mm,10um;mobile phase: [water(ammonium bicarbonate)-acetonitrile]; B%: 35%-65%,14 min) to give (R)-N-[(1R)-1-(6-bromo-3-methyl- 4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]-2-methyl -propane-2-sulfinamide (0.15 g, 312 μmol, 73%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 4.96 - 4.80 (m, 2H), 4.18 - 4.13 (m, 2H), 3.67 (s, 3H), 3.05 - 3.10 (m, 1H), 2.17 - 2.07 (m, 2H), 1.89 (d, J = 12.0 Hz, 3H), 1.65 (d, J = 6.4 Hz, 3H), 1.23 (s, 9H); m/z ES+ [M+H] ⁺ 470.1. [0785] Step 7. Synthesis of (R)-8-(1-aminoethyl)-6-bromo-3-methyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [0786] To a solution of (R)-N-[(1R)-1-(6-bromo-3-methyl-4-oxo-2-tetrahydropyran-4-yl - quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (0.15 g, 319 μmol) in hydrogen chloride/dioxane (1.5 mL). The mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated under reduced pressure to give a residue. On completion, the crude product was purified by reversed-phase HPLC (0.1% FA condition) to give (R)-8-(1-aminoethyl)-6- bromo-3-methyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)- one (59.0 mg, 150 μmol, 47%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 4.86 (q, J = 6.8 Hz, 1H), 4.19 - 4.10 (m, 2H), 3.69 (s, 3H), 3.61 - 3.50 (m, 2H), 2.19 - 1.99 (m, 2H), 1.89 (d, J = 13.2 Hz, 2H), 1.70 (d, J = 6.8 Hz, 3H). m/z ES+ [M+H] ⁺ 366.1. [0787] [0788] Preparation of Intermediate 33: 2-amino-3-bromo-5-fluoro-N-methylbenzamide (Int- 33) and Intermediate 28: (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2-(tetrahydro-2H-pyra n-4- yl)quinazolin-4(3H)-one (Int-28) [0789] [0790] Step 1. Synthesis of 2-amino-3-bromo-5-fluoro-N-methylbenzamide [0791] To a solution of 2-amino-3-bromo-5-fluoro-benzoic acid (10 g, 42.73 mmol) and methanamine;hydrochloride (5.77 g, 85.5 mmol) in N,N-dimethylformamide (50 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethylammonium;hexafluorophosphate (19.5 g, 51.3 mmol) and diisopropylethylamine (16.6 g, 128 mmol). The mixture was stirred at 25 °C for 12 hr. The mixture was poured in water (800 mL) and then filter and the solid was collected and concentrated invacuo to give 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (6.5 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.35 - 7.28 (m, 1 H), 7.08 - 7.00 (m, 1 H), 6.15 (s, 1 H), 6.03 - 5.44 (m, 2 H), 2.97 (d, J = 4.8 Hz, 3 H); m/z ES+ [M+H] ⁺ 247.0. [0792] Step 2. Synthesis of 8-bromo-6-fluoro-3-methyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0793] To a solution of 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (6.35 g, 25.7 mmol) and tetrahydropyran-4-carbaldehyde (3.52 g, 30.8 mmol) in ethanol (70 mL) was added iodine (7.18 g, 28.3 mmol). The mixture was stirred at 80 °C for 17 hr. The reaction mixture was quenched with saturated sodium sulfite solution (30 mL) and extracted with ethyl acetate (80 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 1/1) to give 8-bromo- 6-fluoro-3-methyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3 H)-one (3 g, 7.73 mmol, 30%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.92 - 7.72 (m, 2 H), 4.25 - 4.13 (m, 2 H) 3.68 (s, 3 H), 3.65 - 3.53 (m, 2 H), 3.16 - 3.03 (m, 1 H), 2.32 - 2.13 (m, 2 H), 1.88 (d, J = 13.6 Hz, 2 H). [0794] Step 3. Synthesis of 8-acetyl-6-fluoro-3-methyl-2-tetrahydropyran-4-yl-quinazolin -4- one [0795] A mixture of 8-bromo-6-fluoro-3-methyl-2-tetrahydropyran-4-yl-quinazolin- 4-one (2.9 g, 8.50 mmol), 1-vinyloxybutane (2.55 g, 25.5 mmol) in n-butyl alcohol (30 mL) was added [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (458 mg, 850 μmol), diacetoxypall-adium [0796] (229 mg, 1.02 mmol) and diisopropylethylamine (3.30 g, 25.5 mmol). Then the mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere. Then hydrogen chloride (1 M, 7.77 mL) was added to the solution and stirred at 25 °C for 10 min. The reaction mixture was added saturated sodium bicarbonate solution until pH = 6 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-acetyl-6-fluoro-3-methyl-2-tetrahydropyran-4-yl- quinazolin-4-one (1 g, 1.70 mmol, 22%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 - 8.00 (m, 1H), 7.81 - 7.74 (m, 1H), 4.20 - 4.07 (m, 2H), 3.70 (s, 3H), 3.65 - 3.50 (m, 2H), 3.17 - 3.07 (m, 1H), 2.90 (s, 3H), 2.19 - 2.02 (m, 2H), 1.88 (d, J = 13.2 Hz, 2H); m/z ES+ [M+H] ⁺ 305.1. [0797] Step 4. Synthesis of (R,Z)-N-(1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro-2H-pyran-4 - yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2 -sulfinamide [0798] To a solution of 8-acetyl-6-fluoro-3-methyl-2-tetrahydropyran-4-yl-quinazolin -4-one (900 mg, 2.96 mmol) in anhydrous tetrahydrofuran (9 mL) was added tetraethoxytitanium (3.37 g, 14.79 mmol) and (R)-2-methylpropane-2-sulfinamide (1.08 g, 8.87 mmol). The mixture was stirred at 75 °C for 12 hr. The reaction mixture was quenched by water (100 mL) at 25 °C, and then filtered and concentrated under reduced pressure to give a residue. The residue was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give (NZ,R)- N-[1-(6-fluoro-3-methyl-4-oxo-2-tetrahydropyran-4-yl-quinazo lin-8-yl)ethylidene]-2-methyl- propane-2-sulfinamide (1.1 g, 2.64 mmol, 89%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.04 - 7.88 (m, 1 H), 7.63 - 7.30 (m, 1 H), 4.14 (d, J = 11.2 Hz, 2 H), 3.74 - 3.66 (m, 3 H), 3.62 - 3.50 (m, 2 H), 3.18 - 3.03 (m, 1 H), 2.99- 2.90 (m, 2 H), 2.58 (s, 1 H), 2.16 - 2.00 (m, 2 H), 1.85 (d, J = 13.2 Hz, 2 H), 1.35 (s, 6 H), 1.23 (s, 3 H); m/z ES+ [M+H] ⁺ 408.2. [0799] Step 5. Synthesis of (R)-N-((R)-1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro-2H-pyran - 4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-su lfinamide [0800] To a solution of (NZ,R)-N-[1-(6-fluoro-3-methyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (1 g, 2.45 mmol) in anhydrous tetrahydrofuran (10 mL) was added borane-methyl sulfide complex (10 M, 1.23 mL). The mixture was stirred at -50 °C for 2 hr. The mixture was quenched by methanol (10 mL) at -10 °C slowly, the mixture was stirred at 25 °C for 0.5 hr. Then the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (6 mL× 3). The combined organic layers were washed with brine (6 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge 150 × 25mm, 5um; mobile phase: [water (ammonia hydroxide v/v)-acetonitrile]; B%: 33%-63%,9 min) to give (R)-N-[(1R)-1-(6-fluoro-3- methyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]-2 -methyl-propane-2-sulfinamide (460 mg, 973 μmol, 40%) as a yellow solid. m/z ES+ [M+H] ⁺ 410.2. [0801] Step 6. Synthesis of (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [0802] To a solution of (R)-N-[(1R)-1-(6-fluoro-3-methyl-4-oxo-2-tetrahydropyran-4-y l- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (400 mg, 977 μmol) in dioxane (4 mL) was added hydrogen chloride/dioxane (4M, 4 mL). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (5-60% ammonium hydroxide) to give (R)- 8-(1-aminoethyl)-6-fluoro-3-methyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-on (204 mg, 668 μmol, 68%) as a white solid. m/z ES+ [M+H] ⁺ 306.2. [0803] [0804] Preparation of Intermediate 29: (R)-8-(1-aminoethyl)-3-cyclopropyl-6-fluoro-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (Int-29) and Intermediate 31: 8-acetyl-3- cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-4-yl)quinazolin- 4(3H)-one (Int-31) [0805] [0806] Step 1. Synthesis of N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydro-2H-pyran-4-carboxamide [0807] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (10.0 g, 36.6 mmol) and tetrahydropyran-4-carboxylic acid (5.72 g, 43.9 mmol) in pyridine (100 mL) was added trin-propyl cyclic phosphate anhydride (69.9 g, 109 mmol), the mixture was stirred at 25 °C for 12 hr. The reaction solution was added to water (150 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure to give N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro-phenyl]tetrahyd ropyran-4- carboxamide (12 g, 31.1 mmol, 85%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 - 7.71 (m, 1H), 7.41 (s, 1H), 7.17 - 7.08 (m, 1H), 6.55 - 6.45 (m, 1H), 4.16 - 4.02 (m, 2H), 3.55 - 3.40 (m, 2H), 2.87 - 2.75 (m, 1H), 2.67 - 2.55 (m, 1H), 1.91 (d, J = 1.2 Hz, 4H), 0.85 (d, J = 6.4 Hz, 2H), 0.59 (s, 2H); m/z ES+ [M+H] ⁺ 385.0. [0808] Step 2. Synthesis of 8-bromo-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0809] To a solution of N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro- phenyl]tetrahydropyran-4-carboxamide (5.50 g, 14.2 mmol) in acetonitrile (55 mL) was added zinc chloride (5.84 g, 42.8 mmol) and [dimethyl-(trimethylsilylamino)silyl]methane (5.76 g, 35.6 mmol), the mixture was stirred at 80 °C for 2 hr. The mixture was poured into water (100 mL), then filtered and the filter cake was concentrated under reduced pressure to give 8-bromo-3-cyclopropyl-6-fluoro-2-tetrahydropyran-4-yl-quinaz olin-4-one (5 g, 13.6 mmol, 95%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J = 2.8, 8.4 Hz, 1H), 7.77 (dd, J = 2.8, 8.4 Hz, 1H), 4.04 - 3.91 (m, 2H), 3.80 - 3.68 (m, 1H), 3.55 -3.41 (m, 2H), 3.15 - 3.03 (m, 1H), 1.95 - 1.82 (m, 4H), 1.29 - 1.20 (m, 2H), 0.92 - 0.84 (m, 2H); m/z ES+ [M+H] ⁺ 367.0. [0810] Step 3. Synthesis of 8-acetyl-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0811] A mixture of 8-bromo-3-cyclopropyl-6-fluoro-2-tetrahydropyran-4-yl-quinaz olin-4- one (4 g, 10.8 mmol), tributyl(1-ethoxyvinyl)stannane (11.8 g, 32.6 mmol), Bis(triphenylphosphine)palladium(II) dichloride (764 mg, 1.09 mmol) in toluene (40 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 120 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched by addition potassium fluoride (30 mL) at 25 °C, and then extracted with ethyl acetate 30 mL, then added hydrochloric acid (2 M, 21.8 mL), the mixture was stirred at 25 °C for 2 hr. The mxiture was added saturated potassium carbonate to pH = 8, and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=3/1, 40 mL) at 25 °C for 15 min to give 8-acetyl-3- cyclopropyl-6-fluoro-2-tetrahydropyran-4-yl-quinazolin-4-one (2 g, 6.05 mmol, 56%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 3.2, 7.6 Hz, 1H), 7.77 (dd, J = 3.2, 8.8 Hz, 1H), 4.14 (dd, J = 4.0, 11.2 Hz, 2H), 3.80 - 3.70 (m, 1H), 3.62 - 3.50 (m, 2H), 3.05 - 2.96 (m, 1H), 2.91 (s, 3H), 2.16 - 2.04 (m, 2H), 1.85 (d, J = 13.6 Hz, 2H), 1.45 - 1.35 (m, 2H), 0.94 (d, J = 4.0 Hz, 2H); m/z ES+ [M+H] ⁺ 331.1. [0812] Step 4. Synthesis of (R,E)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylp ropane-2-sulfinamide [0813] To a solution of 8-acetyl-3-cyclopropyl-6-fluoro-2-tetrahydropyran-4-yl-quina zolin- 4-one (2.00 g, 6.05 mmol), (R)-2-methylpropane-2-sulfinamide (2.94 g, 24.2 mmol) and tetraethoxytitanium (6.90 g, 30.2 mmol) in anhydrous tetrahydrofuran (20 mL), the mixture was stirred at 75 °C for 12 hr. The reaction mixture was quenched with water (30 mL), filtered and the filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were and concentrated under reduced pressure to give (R,E)-N-(1-(3-cyclopropyl-6- fluoro-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazo lin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (2.0 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 434.2. [0814] Step 5. Synthesis of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide [0815] To a solution of (NE,R)-N-[1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyran- 4-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (1.00 g, 2.31 mmol) in anhydrous tetrahydrofuran (10 mL) was added borane-methyl sulfide complex (10 M, 2.31 mL) at -50 °C under nitrogen, the mixture was stirred at -20 °C for 2 hr. The mixture was added methanol (20 mL) dropwised at -30 °C the mixture was stirred at 25 °C for 0.5 hr. Then the mixture was concentrated in vacuo to give a residue. The residue was purified by pre-HPLC (column: Kromasil Eternity XT 250 x 80mm,10um;mobile phase: [water (ammonia hydroxide v/v)-acetonitrile];gradient:24%-54% B over 20 mins) to give (R)-N- [(1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyran-4-yl -quinazolin-8-yl)ethyl]-2- methyl-propane-2-sulfinamide (800 mg, 1.83 mmol, 79%) as a white solid. m/z ES+ [M+H] ⁺ 436.2. [0816] Step 6. Synthesis of (R)-8-(1-aminoethyl)-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H - pyran-4-yl)quinazolin-4(3H)-one [0817] To a solution of (R)-N-[(1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyra n-4- yl-quinazolin-8-yl) [0818] ethyl]-2-methyl-propane-2-sulfinamide (400 mg, 918 μmol) in dichloromethane (10 mL) was added hydrochloric acid/dioxane (4 M, 4 mL), the mixture was stirred at 25 °C for 0.5 hr. The mixture was adjusted to pH = 8 by ammonium hydroxide, then diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H -pyran-4-yl)quinazolin-4(3H)- one (300 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 332.2. [0819] [0820] Preparation of Intermediate 32: 3-cyclopropyl-6-fluoro-8-(1-hydroxyethyl)-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (Int-32) [0821] [0822] Step 1. Synthesis of 3-cyclopropyl-6-fluoro-8-(1-hydroxyethyl)-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [0823] To a mixture of 8-acetyl-3-cyclopropyl-6-fluoro-2-tetrahydropyran-4-yl-quina zolin- 4-one (5.00 g, 15.1 mmol) in methanol (50 mL) was added sodium borohydride (1.15 g, 30.2 mmol) portionwise at 0 °C, the reaction mixture was stirred at 0 °C for 1 hr. On completion, the reaction mixture was quenched by water (80 mL) dropwise at 0 °C and then extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-cyclopropyl-6-fluoro-8-(1-hydroxyethyl)-2-tetrahydropyran- 4-yl-quinazolin- 4-one (4.50 g, crude) as a brown solid. m/z ES+ [M+H] ⁺ 333.4. [0824] [0825] Preparation of Intermediate 34: (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2-(4- methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (Int-34)

[0826] [0827] Step 1. Synthesis of N-(2-bromo-4-fluoro-6-(methylcarbamoyl)phenyl)-4- methyltetrahydro-2H-pyran-4-carboxamide [0828] To a solution of N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (7.30 g, 26.0 mmol), 1-methylimidazole (4.27 g, 52.0 mmol) and 4- methyltetrahydropyran-4-carboxylic acid (3.00 g, 20.8 mmol) in acetonitrile (50 mL) was added 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (4.28 g, 17.3 mmol), the mixture was stirred at 60 °C for 5 hr. The reaction solution was slowly poured into water (100 mL) and then filtered. The filtered cake was concentrated under reduced pressure to give N-[2-bromo- 4-fluoro-6-(methylcarbamoyl)phenyl]-4-methyl-tetrahydropyran -4-carboxamide (4.00 g, 10.7 mmol) as a white solid. m/z ES+ [M+H] ⁺ 376.1. [0829] Step 2. Synthesis of 8-bromo-6-fluoro-3-methyl-2-(4-methyltetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0830] To a solution of N-[2-bromo-4-fluoro-6-(methylcarbamoyl)phenyl]-4-methyl- tetrahydropyran-4-carboxamide (3.60 g, 9.65 mmol) and dichlorozinc (3.94 g, 28.9 mmol) in dimethyl acetamide (37 mL) was added [dimethyl-(trimethylsilylamino)silyl]methane (3.89 g, 24.1 mmol), the mixture was stirred at 140 °C for 2 hr. The reaction mixture was slowly poured into water (200 mL) and some solid was precipitated. The mixture was filtered and the solid was collected, concentrated under reduced pressure to give 8-bromo-6-fluoro-3- methyl-2-(4-methyltetrahydropyran-4-yl)quinazolin-4-one (3.5 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (dd, J = 2.8, 8.4 Hz, 1H), 7.82 (dd, J = 2.8, 8.4 Hz, 1H), 3.68 (t, J = 5.2 Hz, 4H), 3.61 (s, 3H), 2.45 - 2.37 (m, 2H), 1.85 - 1.75 (m, 2H), 1.50 (s, 3H). [0831] Step 3. Synthesis of 8-acetyl-6-fluoro-3-methyl-2-(4-methyltetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [0832] A mixture of 8-bromo-6-fluoro-3-methyl-2-(4-methyltetrahydropyran-4- yl)quinazolin-4-one (2.50 g, 7.04 mmol), tributyl(1-ethoxyvinyl)stannane (7.63 g, 21.1 mmol) and dichloropalladium triphenylphosphan (247 mg, 351 μmol) in toluene (25 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 120 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched by addition potassium fluoride (50 mL) at 25 °C, and then extracted with ethyl acetate (50 mL). The organic layer was then added hydrochloric acid (2 M, 30 mL) and stirred at 25 °C for 2 hr. The mxiture was basified with potassium carbonate until pH = 8, and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether/ethyl acetate (30 mL, 3/1) at 25 °C for 15 min to give 8-acetyl-6-fluoro-3- methyl-2-(4-methyltetrahydropyran-4-yl)quinazolin-4-one (1 g, 3.14 mmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (dd, J = 2.8, 7.6 Hz, 1H), 7.73 (dd, J = 2.8, 8.4 Hz, 1H), 3.79 (br. t, J = 5.2 Hz, 4H), 3.75 (s, 3H), 2.82 (s, 3H), 2.50 - 2.38 (m, 2H), 1.92 (td, J = 4.4, 13.6 Hz, 2H), 1.60 (s, 3H). [0833] Step 4. Synthesis of (R)-N-(1-(6-fluoro-3-methyl-2-(4-methyltetrahydro-2H-pyran-4 - yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpro pane-2-sulfinamide [0834] To a solution of 8-acetyl-6-fluoro-3-methyl-2-(4-methyltetrahydropyran-4- yl)quinazolin-4-one (1.00 g, 3.14 mmol) and (R)-2-methylpropane-2-sulfinamide (1.52 g, 12.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added tetraethoxytitanium (3.58 g, 15.7 mmol), the mixture was stirred at 75 °C for 12 hr. The reaction mixture was quenched with water (30 mL) and then filtered. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were concentrated under reduced pressure to give (R)-N-(1- (6-fluoro-3-methyl-2-(4-methyltetrahydro-2H-pyran-4-yl)-4-ox o-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.2 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 422.1. [0835] Step 5. Synthesis of (R)-N-((R)-1-(6-fluoro-3-methyl-2-(4-methyltetrahydro-2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methyl propane-2-sulfinamide [0836] To a solution of (R)-N-(1-(6-fluoro-3-methyl-2-(4-methyltetrahydro-2H-pyran-4 -yl)- 4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane -2-sulfinamide (600 mg, 1.42 mmol) in anhydrous tetrahydrofuran (6 mL) was added borane-dimethyl sulfide complex (10 M in tetrahydrofuran, 1.42 mL) dropwise at -50 °C under nitrogen. After addition completed, the mixture was then warmed to -10 °C and stirred at -10 °C for 1 hr. The mixture was carefully quenched by methanol (20 mL) dropwise at -30 °C, then stirred at 25 °C for 0.5 hr and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250x50x10um;mobile phase: [hexane- ethanol];gradient:1%-35% B over 15 min) to give (R)-N-((R)-1-(6-fluoro-3-methyl-2-(4- methyltetrahydro-2H-pyran-4-yl)-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)-2-methylpropane- 2-sulfinamide (550 mg, 1.22 mmol, 43%, obtained from two batches) as a yellow oil. m/z ES+ [M+H] ⁺ 424.3. [0837] Step 6. Synthesis of (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2-(4-methyltetrahydro - 2H-pyran-4-yl)quinazolin-4(3H)-one [0838] To a solution of (R)-N-((R)-1-(6-fluoro-3-methyl-2-(4-methyltetrahydro-2H-pyr an-4- yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane- 2-sulfinamide (550 mg, 1.30 mmol) in dichloromethane (6 mL) was added hydrochloric acid/dioxane (4 M, 1 mL), the mixture was stirred at 25 °C for 0.5 hr. The mixture was adjusted to pH = 8 by ammonium hydroxide, then diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2-(4- methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (300 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 320.2. [0839] [0840] Preparation of Intermediate 35: 8-(1-aminoethyl)-3,6,7-trimethyl-2- morpholinoquinazolin-4(3H)-one (Int-35) [0841] [0842] Step 1. Synthesis of 2-amino-3-bromo-4,5-dimethyl-benzoic acid [0843] To a solution of 2-amino-4,5-dimethyl-benzoic acid (4.50 g, 27.2 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (6.30 g, 35.4 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mLx 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate= 8:1, 45 mL) at 25 ^o C for 0.5 hr to give 2-amino- 3-bromo-4,5-dimethyl-benzoic acid (3.80 g, 14.9 mmol, 54%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 2.33 (s, 3H), 2.20 (s, 3H). m/z ES+ [M+H] ⁺ 244.0. [0844] Step 2. Synthesis of 2-amino-3-bromo-N,4,5-trimethyl-benzamide [0845] To a solution of 2-amino-3-bromo-4,5-dimethyl-benzoic acid (3.30 g, 13.5 mmol) and methanamine; hydrochloride (1.83 g, 27.0 mmol) in N,N-dimethylformamide (50 mL) was added diisopropylethylamine (5.24 g, 40.5 mmol) and [dimethylamino(triazolo[4,5- b]pyridin-3-yloxy)methyl-ene]-dimethyl-ammonium;hexafluoroph osphate (6.17 g, 16.2 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, add the reaction droplets to the water 100 mL at 0 °C, the solution was filtered and the cake was concentrated under reduced pressure to give 2-amino-3-bromo-N,4,5-trimethyl-benzamide (2.75 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.28 (d,J = 4.0 Hz, 1H), 7.35 (s, 1H), 6.44 - 6.31 (m, 2H), 2.30 (s, 3H), 2.21 (s, 3H); m/z ES+ [M+H] ⁺ 257.0. [0846] Step 3. Synthesis of 8-bromo-2-chloro-3,6,7-trimethyl-quinazolin-4-one [0847] To a solution of 2-amino-3-bromo-N,4,5-trimethyl-benzamide (2.75 g, 10.7 mmol) in dioxane (30 mL) was added thiocarbonyl dichloride (3.69 g, 32.0 mmol), the mixture was stirred at 25 °C for 1 hr. The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro-3,6,7- trimethyl-quinazolin-4-one (3.00 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 301.0. [0848] Step 4. Synthesis of 8-bromo-3,6,7-trimethyl-2-morpholino-quinazolin-4-one [0849] To a solution of 8-bromo-2-chloro-3,6,7-trimethyl-quinazolin-4-one (3.20 g, 10.6 mmol) in dichloromethane (30 mL) was added morpholine (4.62 g, 53.0 mmol) and diisopropylethylamine (6.86 g, 53.0 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-bromo-3,6,7-trimethyl-2-morpholino- quinazolin-4-one (3.00 g, 7.25 mmol, 68%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (s, 1H), 3.83 - 3.73 (m, 4H), 3.47 (s, 3H), 3.30 - 3.22 (m, 4H), 2.49 (s, 3H), 2.41 (s, 3H). m/z ES+ [M+H] ⁺ 352.1. [0850] Step 5. Synthesis of 8-acetyl-3,6,7-trimethyl-2-morpholino-quinazolin-4-one [0851] To a solution of 8-bromo-3,6,7-trimethyl-2-morpholino-quinazolin-4-one (2.50 g, 7.10 mmol) in toluene (25 mL) was added dichloropalladium triphenylphosphane (498 mg, 709 μmol) and tributyl(1-ethoxyvinyl)stannane (7.69 g, 21.2 mmol). The mixture was stirred at 130 °C for 12 hr under nitrogen atmosphere atmosphere. Then hydrochloric acid (1 M, 12.7 mL) was added in the mixture and stirred at 25 °C for 0.5 hr. On completion, the reaction was adjusted to pH = 7~8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-acetyl-3,6,7-trimethyl-2-morpholino- quinazolin-4-one (1.70 g, 4.64 mmol, 65%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 3.83 - 3.72 (m, 4H), 3.50 (s, 3H), 3.20 - 3.08 (m, 4H), 2.55 (s, 3H), 2.30 (s, 3H), 2.18 (s, 3H). m/z ES+ [M+H] ⁺ 316.2. [0852] Step 6. Synthesis of 8-[(Z)-N-hydroxy-C-methyl-carbonimidoyl]-3,6,7-trimethyl-2- morpholino-quinazolin-4-one [0853] To a solution of 8-acetyl-3,6,7-trimethyl-2-morpholino-quinazolin-4-one (1.20 g, 3.81 mmol) in methanol (25 mL) was added hydroxylamine hydrochloride (740 mg, 10.6 mmol), sodium acetate (1.03 g, 12.5 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-[(Z)-N-hydroxy-C-methyl-carbonimidoyl]-3,6,7- trimethyl-2-morpholino-quinazolin-4-one (1.00 g, 2.88 mmol, 75%) as a yellow solid. m/z ES+ [M+H] ⁺ 331.2. [0854] Step 7. Synthesis of 8-ethanimidoyl-3,6,7-trimethyl-2-morpholino-quinazolin-4-one [0855] To a solution of 8-[(Z)-N-hydroxy-C-methyl-carbonimidoyl]-3,6,7-trimethyl-2- morpholino-quinazolin-4-one (1.00 g, 3.03 mmol) in methanol (30 mL) and ammonium hydroxide (3 mL) was added Raney Nickel (249 mg, 291 μmol) under nitrogen atmosphere. Then it was degassed and purged with hydrogen atmosphere (3x) at 25 °C and the mixture was stirred at 25 °C for 12 hr under hydrogen atmosphere at 50 psi. On completion, the reaction mixture was filtered, washed with methanol (30 mL x 3) and concentrated under reduced pressure to give 8-ethanimidoyl-3,6,7-trimethyl-2-morpholino-quinazolin-4-one (900 mg, crude) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 3.87 - 3.81 (m, 4H), 3.56 (s, 3H), 3.23 - 3.20 (m, 4H), 2.42 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H); m/z ES+ [M+H] ⁺ 315.2. [0856] Step 8. Synthesis of 8-(1-aminoethyl)-3,6,7-trimethyl-2-morpholino-quinazolin-4- one [0857] To a solution of 8-ethanimidoyl-3,6,7-trimethyl-2-morpholino-quinazolin-4-one (520 mg, 1.65 mmol) in methanol (5 mL) was added sodium cyanoborohydride (519 mg, 8.27 mmol) and acetic acid (198 mg, 3.31 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 2%-32%, 10min) to give 8-(1-aminoethyl)-3,6,7-trimethyl-2-morpholino-quinazolin-4-o ne (200 mg, 587 μmol, 35%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 5.03 (d, J = 5.6 Hz, 1H), 4.05 - 3.76 (m, 4H), 3.60 (s, 3H), 3.38 - 3.10 (m, 4H), 2.40 (d, J = 9.2 Hz, 6H), 1.75 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 317.2. [0858] Preparation of Intermediate 49: 2-amino-3-bromo-6-fluoro-N,5-dimethylbenzamide (Int-49) and Intermediate 36: (R)-8-(1-aminoethyl)-5-fluoro-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (Int-36) [0859] [0860] Step 1. Synthesis of N-(2-bromo-5-fluoro-4-methyl-phenyl)-2-hydroxyimino- acetamide [0861] To a solution of 2-bromo-5-fluoro-4-methyl-aniline (10 g, 49.0 mmol) in water (270 mL) was added hydroxylamine;hydrochloride (12.3 g, 176 mmol), 2,2,2-trichloroethane-1,1- diol (9.73 g, 58.8 mmol) and hydrochloric acid (2 M, 12.1 mL) and anhydrous sodium sulfate (55.7 g, 392 mmol). The mixture was stirred at 70 °C for 12 hr. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-(2-bromo-5- fluoro-4-methyl- phenyl)-2-hydroxyimino-acetamide (6 g, crude) as a white solid; m/z ES+ [M+H] ⁺ 275.0. [0862] Step 2. Synthesis of 7-bromo-4-fluoro-5-methyl-indoline-2,3-dione [0863] To a solution of N-(2-bromo-5-fluoro-4-methyl-phenyl)-2-hydroxyimino-acetamid e (6.00 g, 21.8 mmol) in sulfuric acid (30 mL). The mixture was stirred at 80 °C for 0.5 hr. The reaction mixture was added to ice water (300 mL) and neutralized to pH = 9 with saturated sodium bicarbonate solution then extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=3/1, 20 mL) at 25 °C for 30 min to give 7-bromo-4-fluoro-5-methyl-indoline-2,3-dione (5 g, 19.4 mmol, 88% ) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.56 (d, J = 6.4 Hz, 1H), 2.26 (d, J = 1.6 Hz, 3H); m/z ES+ [M+H] ⁺ 257.9. [0864] Step 3. Synthesis of 2-amino-3-bromo-6-fluoro-5-methyl-benzoic acid [0865] To a solution of 7-bromo-4-fluoro-5-methyl-indoline-2,3-dione (5 g, 19.4 mmol) in sodium hydroxide (2 M, 48.4 mL) was added hydrogen peroxide (14.3 g, 147 mmol, 35% purity). The mixture was stirred at 25 °C for 12 hr. the mixture was adjusted to pH = 2 by hydrogen chloride (4N), then the mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-3-bromo-6-fluoro-5-methyl-benzoic acid (4.5 g, 17.2 mmol, 89%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J = 7.6 Hz, 1H), 6.63 - 5.96 (m, 2H), 2.18 (d, J = 2.4 Hz, 3H); m/z ES+ [M+H] ⁺ 248.0. [0866] Step 4. Synthesis of 2-amino-3-bromo-6-fluoro-N,5-dimethyl-benzamide [0867] To a solution of 2-amino-3-bromo-6-fluoro-5-methyl-benzoic acid (4.5 g, 18.1 mmol) and methylamine hydrochloride (1.84 g, 27.2 mmol) in N,N-dimethylformamide (45 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethylammoniumhexafluorophosphate (10.4 g, 27.2 mmol) and diisopropylethylamine (9.38 g, 72.6 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (10 mL) at 25 °C for 10 min to give 2-amino-3-bromo-6-fluoro- N,5-dimethyl-benzamide (4 g, 15.3 mmol, 84%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 1H), 6.70 - 6.46 (m, 1H), 6.19 (s, 2H), 3.00 (d, J = 4.4 Hz, 3H), 2.14 (s, 3H); m/z ES+ [M+H] ⁺ 261.0. [0868] Step 5. Synthesis of 8-bromo-2-chloro-5-fluoro-3,6-dimethyl-quinazolin-4-one [0869] To a solution of 2-amino-3-bromo-6-fluoro-N,5-dimethyl-benzamide (4 g, 15.3 mmol) in dioxane (40 mL) was added thiocarbonyl dichloride (3.70 g, 32.2 mmol) dropwised at 25 °C. The mixture was stirred at 25 °C for 1 hr, then stirred at 105 °C for 0.5 hr under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro-5-fluoro-3,6-dimethyl-qu-inazolin-4-one (4 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 304.9. [0870] Step 6. Synthesis of 8-bromo-5-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one [0871] To a solution of 8-bromo-2-chloro-5-fluoro-3,6-dimethyl-quinazolin-4-one (4 g, 13.1 mmol) in dichloromethane (40 mL) was added morpholine (3.42 g, 39.3 mmol). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=1/1, 20 mL) at 25 °C for 30 min, then filtered and the cake was diluted with dichloromethane (200 mL) and washed with hydrogen chloride (1N, 200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-5-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one (2.5 g, 6.95 mmol, 53%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (d, J = 7.2 Hz, 1H), 3.92 - 3.85 (m, 4H), 3.54 (s, 3H), 3.39 - 3.33 (m, 4H), 2.32 (d, J = 2.4 Hz, 3H); m/z ES+ [M+H] ⁺ 356.0. [0872] Step 7. Synthesis of 8-acetyl-5-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one [0873] To a solution of 8-bromo-5-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one (2.2 g, 6.18 mmol) in toluene (22 mL) was added dichloropalladium triphenylphosphane (433 mg, 618 μmol) and tributyl(1-ethoxyvinyl)stannane (6.69 g, 18.5 mmol). The mixture was stirred at 130 °C for 12 hr under nitrogen atmosphere. Then the reaction mixture added hydrogen chloride (1 M, 61.8 mL) at 25 °C and stirred at 25 °C for 0.5 hr. The reaction was neutralized to pH = 9 with saturated sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give 8-acetyl- 5-fluoro-3,6-dimethyl-2-morpholino- quinazolin-4-one (1.2 g, 3.01 mmol, 48%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 7.6 Hz, 1H), 3.92 - 3.86 (m, 4H), 3.58 (s, 3H), 3.33 - 3.24 (m, 4H), 2.83 (s, 3H), 2.35 (d, J = 2.4 Hz, 3H); m/z ES+ [M+H] ⁺ 320.1. [0874] Step 8. Synthesis of (NE,R)-N-[1-(5-fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide [0875] To a solution of 8-acetyl-5-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one (1.1 g, 3.44 mmol) and (R)-2-methylpropane-2-sulfinamide (2.09 g, 17.2 mmol) in anhydrous tetrahydrofuran (16.5 mL) was added tetraethoxytitanium (3.93 g, 17.2 mmol). The mixture was stirred at 75 °C for 12 hr. The reaction mixture was diluted with anhydrous tetrahydrofuran (30 mL) and poured into water (100 mL), filtered and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give (NE,R)-N-[1-(5-fluoro-3,6-dimethyl-2-morpholino-4-oxo-quinaz olin-8- yl)ethylidene]-2-methyl-propane-2-sulfinamide (800 mg, 1.70 mmol, 49%) as a white solid. m/z ES+ [M+H] ⁺ 423.2. [0876] Step 9. Synthesis of (R)-N-[(1R)-1-(5-fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide [0877] To a mixture of (NE,R)-N-[1-(5-fluoro-3,6-dimethyl-2-morpholino-4-oxo-quinaz olin- 8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (800 mg, 1.89 mmol) in anhydrous tetrahydrofuran (16 mL) under nitrogen atmosphere at -78 °C, was added borane dimethyl sulfide (10 M, 947 ^L) slowly, the mixture was stirred at -78 °C for 2 hr. The mixture was quenched by water (50 mL) at -10 °C. The mixture was stirred at 25 °C for 0.5 hr. Then the mixture was poured in water (100 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was concentrated in vacuo to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water (ammonia hydroxide v/v)- acetonitrile];B%: 30%-60%,9 min) to give (R)-N-[(1R)-1-(5- fluoro-3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)ethyl ]-2-methyl-propane-2- sulfinamide (400 mg, 942 μmol, 50% ) as a white solid. m/z ES+ [M+H] ⁺ 425.2. [0878] Step 10. Synthesis of 8-[(1R)-1-aminoethyl]-5-fluoro-3,6-dimethyl-2-morpholino- quinazolin-4-one [0879] To a solution of (R)-N-[(1R)-1-(5- fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (400 mg, 942 μmol) in dioxane (5 mL) was added hydrochloric acid /dioxane (4 M, 5 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC ( 0.1% formic acid condition) to give 8- [(1R)-1-aminoethyl]-5-fluoro-3,6-dimethyl-2-morpholino-quina zolin-4-one (200 mg, 624 μmol, 66%) as a white solid. m/z ES+ [M+H] ⁺ 321.2. [0880] [0881] Preparation of Intermediate 37: (R)-2-((1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (Int-37) [0882] [0883] Step 1. Synthesis of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]-5-fluoro-benzoic acid [0884] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl-quinazol in-4- one (1.00 g, 3.80 mmol) and 5-fluoro-2-iodo-benzoic acid (3.03 g, 11.4 mmol) in dimethyl acetamide (10 mL) was added triethylamine (3.84 g, 38.0 mmol), 4A molecular sieve and copper power (241 mg, 3.80 mmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered, diluted with water (30 mL) and extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4- oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-benzoic acid (650 mg, 1.36 mmol, 36%) as a red solid. m/z ES+ [M+1] ⁺ 402.1. [0885] [0886] Preparation of Intermediate 38: N-((3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)methylene)-2-methylpropane-2-sulfinam ide (Int-38) [0887] [0888] Step 1. Synthesis of 3,6-dimethyl-2-morpholino-8-vinyl-quinazolin-4-one [0889] To a solution of 8-bromo-3,6-dimethyl-2-morpholino-quinazolin-4-one (9 g, 26.6 mmol), potassium; trifluoro(vinyl)boranuide (14.2 g, 106 mmol) in dioxane (225 mL) and water (27 mL) was added potassium phosphate (16.9 g, 79.8 mmol) and methanesulfonato(2- dicyclohexylphosphino-2,4,6-tri-i-propyl-1,1'-biphenyl)(2-am ino-1,1'-biphenyl-2- yl)palladium(II) (2.09 g, 2.66 mmol), then the mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (120 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100:1 to 1:1) to give 3,6-dimethyl-2-morpholino-8-vinyl-quinazolin-4-one (4.43 g, 14.7 mmol, 55%) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.55- 7.44 (m, 1H), 5.86-5.79(m, 1H), 5.28-5.25 (m, 1H), 3.85 - 3.76 (m, 4H), 3.53 (s, 3H), 3.28 - 3.20 (m, 4H), 2.43 (s, 3H); m/z ES+ [M+H] ⁺ 286.1. [0890] Step 2. Synthesis of 3,6-dimethyl-2-morpholino-4-oxo-quinazoline-8-carbaldehyde [0891] To a solution of 3,6-dimethyl-2-morpholino-8-vinyl-quinazolin-4-one (3.8 g, 13.3 mmol) in anhydrous tetrahydrofuran (80 mL) and water (20 mL) was added sodium periodate (11.3 g, 53.2 mmol) and potassium osmate(VI) dihydrate (98.1 mg, 266 μmol), the mixture was stirred at 25 °C for 2 hr under nitrogen atmosphere. On completion, the mixture was quenched with water (500 mL) and extracted with ethyl acetate (300 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 3,6- dimethyl-2-morpholino-4-oxo-quinazoline-8-carbaldehyde (4.56 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.9 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 3.80 - 3.75 (m, 4H), 3.50 (s, 3H), 3.32 - 3.28 (m, 4H), 2.47 - 2.43 (m, 3H); m/z ES+ [M+H] ⁺ 288.1. [0892] Step 3. Synthesis of N-[(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)methylene]-2-methyl-propane-2-sulfinamide [0893] To a solution 3,6-dimethyl-2-morpholino-4-oxo-quinazoline-8-carbaldehyde (4.5 g, 15.6 mmol) and 2-methylpropane-2-sulfinamide (9.49 g, 78.3 mmol) in anhydrous tetrahydrofuran (100 mL) was added Tetraacetyl titanium oxide (17.8 g, 78.3 mmol), the mixtuer was stirred at 80 °C for 16 hr. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (120 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/1) to give N-[(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- methylene]- yl)2-methyl-propane-2-sulfinamide (3.7 g, 9.26 mmol, 59%) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 9.53 (s, 1H), 8.22 - 8.05 (m, 2H), 3.83 - 3.77 (m, 4H), 3.53 (s, 3H), 3.28 - 3.21 (m, 4H), 2.50 (s, 3H), 1.23 (s, 9H); m/z ES+ [M+H] ⁺ 391.2. [0894] Preparation of Intermediate 42: 2-amino-3-bromo-5-fluorobenzamide (Int-42); Intermediate 40: 8-acetyl-6-fluoro-2-morpholinoquinazolin-4(3H)-one (Int-40); and Intermediate 39: (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-fluoro-2-morpholin oquinazolin- 4(3H)-one (Int-39) [0895] [0896] Step 1. Synthesis of 2-amino-3-bromo-5-fluorobenzamide [0897] To a solution of 2-amino-3-bromo-5-fluoro-benzoic acid (10 g, 42.7 mmol), ammonium chloride (9.14 g, 171 mmol) in N,N-dimethylformamide (120 mL) was added [dimethylamino(triazolo[4,5-b]pyridine-3-yloxy)methylene]-di methyl- ammonium;hexafluorophosphate (24.4 g, 64.1 mmol) and diisopropylethylamine (11.1 g, 85.5 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was poured into water (200 mL), then filtered and the filter cake was washed with petroleum ether (200 mL) and concentrated under reduced pressure to give 2-amino-3-bromo-5-fluoro- benzamide (7.5 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (s, 1H), 7.59 - 7.42 (m, 3H), 6.52 (s, 2H). [0898] Step 2. Synthesis of 8-bromo-2-chloro-6-fluoroquinazolin-4(3H)-one [0899] A mixture of 2-amino-3-bromo-5-fluoro-benzamide (7 g, 30.0 mmol), thiocarbonyl dichloride (25 g, 63.1 mmol) in dioxane (252 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 25 - 105 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=4/1, 40 mL) at 25 ^o C for 20 min to give 8-bromo-2-chloro-6-fluoro-3H-quinazolin-4-one (6.7 g, 24.2 mmol, 80%) as a yellow solid. [0900] Step 3. Synthesis of 8-bromo-6-fluoro-2-morpholinoquinazolin-4(3H)-one [0901] A mixture of 8-bromo-2-chloro-6-fluoro-3H-quinazolin-4-one (6.7 g, 24.2 mmol), morpholine (6.31 g, 72.4 mmol) and diisopropylethylamine (12.5 g, 96.6 mmol) in dichloromethane (134 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 40 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (120 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by re-crystallization from solvent (petroleum ether/ethyl acetate= 1/1, 100 mL) at 20 ^o C for 0.5 hr to give 8-bromo-6-fluoro-2-morp-holino-3H- quinazolin-4-one (3.5 g, 10.4 mmol, 43%) as a white solid. m/z ES+ [M+H] ⁺ 328.0. [0902] Step 4. Synthesis of 8-acetyl-6-fluoro-2-morpholinoquinazolin-4(3H)-one [0903] To a solution of 8-bromo-6-fluoro-2-morpholino-3H-quinazolin-4-one (3.5 g, 10.7 mmol) in toluene (70 mL) was added triphenylphosphine palladium dichloride (749 mg, 1.07 mmol) and tributyl (1-eth-oxyvinyl)stannane (11.6 g, 32 mmol), then the reaction mixture was stirred at 125 °C for 12 hr. On completion, the reaction mixture was quenched by saturated potassium fluoride solution 300 mL, and then diluted with water (100 mL), and extracted with ethyl acetate (400 mL x 2). The combined organic layers were washed with brine (400 mL), then adjusted pH=3 by hydrochloric acid (1N) and stirred at 20 °C for 0.5 hr, seperated, the aqueous phase was adjusted pH=8 by saturated sodium bicarbonate solution, extracted with difluoromethane (500 mL x 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-acetyl-6-fluoro-2-morpholino-3H-quinazolin-4-one (1.8 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 292.1 [0904] Step 5. Synthesis of 8-acetyl-3-(difluoromethyl)-6-fluoro-2-morpholinoquinazolin- 4(3H)-one [0905] A mixture of 8-acetyl-6-fluoro-2-morpholino-3H-quinazolin-4-one (400 mg, 1.37 mmol), (2-chloro-2,2-difluoro-acetyl)oxysodium (314 mg, 2.06 mmol) and sodium carbonate (873 mg, 8.24 mmol) in N,N-dimethylformamide (10 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 100 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (20 mL) and brine (20 mL). The organic phase was separated, washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-acetyl-3-(difluoromethyl)-6-fluoro-2-morpholino-quinazolin - 4-one (180 mg, 414 μmol, 30%) as a white solid. m/z ES+ [M+H] ⁺ 342.1 [0906] Step 6. Synthesis of (R,Z)-N-(1-(3-(difluoromethyl)-6-fluoro-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide [0907] A mixture of 8-acetyl-3-(difluoromethyl)-6-fluoro-2-morpholino-quinazolin -4-one (176 mg, 516 μmol), (R)-2-methylpropane-2-sulfinamide (250 mg, 2.06 mmol) and tetraethoxytitanium (588 mg, 2.58 mmol) in tetrahydrofuran (2 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by water (10 mL), then filtered and washed with ethyl acetate (10 mL), the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give (R,Z)-N-(1-(3-(difluoromethyl)-6-fluoro-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide (180 mg, 224 μmol, 44%) as a yellow solid. m/z ES+ [M+H] ⁺ 445.1. [0908] Step 7. Synthesis of (R)-N-[(1R)-1-[3-(difluoromethyl)-6-fluoro-2-morpholino-4- oxo-quinazolin-8-yl]ethyl]-2-methyl-propane-2-sulfinamide [0909] To a mixture of (R,Z)-N-(1-(3-(difluoromethyl)-6-fluoro-2-morpholino-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (300 mg, 675 μmol) in tetrahydrofuran (20 mL) at -70 °C was added borane dimethyl sulfide (10 M, 675 ^L) slowly, then the mixture was stirred at -30 °C for 2 hr. On completion, the reaction mixture was quenched by methanol 10 mL at 0 °C, and then stirred at 0 - 20 °C for 0.5 hr. At last, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water (ammonia hydroxide v/v)- acetonitrile];B%: 52%-82%,9 min) to give (R)-N-[(1R)-1-[3- (difluoromethyl)-6-fluoro-2-morpholino-4-oxo-quinazolin-8-yl ]ethyl]-2-methyl-propane- 2sulfinamide (180 mg, 362 μmol, 53%) as a yellow solid. m/z ES+ [M+H] ⁺ 447.2. [0910] Step 8. Synthesis of (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-fluoro-2- morpholinoquinazolin-4(3H)-one [0911] To a solution of (R)-N-[(1R)-1-[3-(difluoromethyl)-6-fluoro-2-morpholino-4-ox o- quinazolin-8-yl]eth-yl]-2-methyl-propane-2-sulfinamide (50 mg, 112 μmol) in dichloromethane (2 mL) at 0 °C was added hydrochloric acid / dioxane (4 M, 2 mL). The mixture was stirred at 0 - 20 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-fluoro-2-morpholi no- quinazolin-4-one (50 mg, crude, hydrochloride salt) as a yellow solid. m/z ES+ [M+H] ⁺ 343.1. [0912] Preparation of Intermediate 44: 2-amino-3-bromo-5-methylbenzamide (Int-44) and Intermediate41: (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-methyl-2-(tetrahyd ro-2H-pyran- 4-yl)quinazolin-4(3H)-one (Int-41) [0913] Step 1. Synthesis of 2-amino-3-bromo-5-methylbenzamide [0914] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (25 g, 108 mmol) and ammonium chloride (58.1 g, 1.09 mol) in N,N-dimethylformamide (400 mL) was added diisopropylethylamine (140 g, 1.09 mol) and [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (61.9 g, 163 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was poured into water (1 L), then filtered and the filter cake was washed with petroleum ether (1 L) and filtered to give light yellow solid. The light yellow silid was triturated with solvent (petroleum ether/ethyl acetate=10/1, 440 mL) at 25 °C for 20 min to give 2-amino-3-bromo- 5-methyl-benzamide (22.7 g, 99.4 mmol, 91%) as light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.94 - 7.81 (m, 1H), 7.44 - 7.37 (m, 2H), 7.28 (br. s, 1H), 6.40 (s, 2H), 2.17 (s, 3H). [0915] Step 2. Synthesis of 8-bromo-6-methyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin- 4(3H)-one [0916] To a solution of 2-amino-3-bromo-5-methyl-benzamide (7.36 g, 32.1 mmol) and tetrahydropyran-4-carbaldehyde (4.4 g, 38.5 mmol) in ethanol (70 mL) was added iodide (14.3 g, 56.5 mmol) and the mixture was stirred at 80 °C for 16 hr. On completion, the mixture was quenched with sodium sulfite solution (100 mL), remove ethanol concentrated to give a residue. The crude product was triturated with water at 25 °C for 30 min and then filtered to give 8-bromo-6-methyl-2-tetrahydropyran-4-yl-3H-quinazolin-4-one (10 g, 30.9 mmol, 96%) as white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.29 (br. s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.87 (s, 1H), 3.96 (td, J = 3.2, 11.2 Hz, 2H), 3.43 - 3.36 (m, 2H), 2.86 (td, J = 7.6, 15.0 Hz, 1H), 2.41 (s, 3H), 1.88 - 1.81 (m, 4H); m/z ES+ [M+H] ⁺ 323.0. [0917] Step 3. Synthesis of 8-acetyl-6-methyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin- 4(3H)-one [0918] The mixture of 8-bromo-6-methyl-2-tetrahydropyran-4-yl-3H-quinazolin-4-one (10 g, 30.9 mmol), 1-vinyloxybutane (9.30 g, 92.8 mmol), [2-(2- diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (1.67 g, 3.09 mmol), diisopropylethylamine (12.0 g, 92.8 mmol) and diacetoxypalladium (694 mg, 3.09 mmol) in n-butanol (100 mL) was stirred at 90 °C for 16 hr. Then the mixture was added hydrochloric acid (1 M) and stirred at 25 °C for 0.5 hr. On completion, the mixture was filtered and the filter cake was washed with petroleum ether (100 mL) and filtered to give brown solid. The crude product was triturated with solvent (petroleum ether/ethyl acetate=10:1, 110 mL) at 25 °C for 30 min to give 8-acetyl-6-methyl-2-tetrahydropyran-4-yl-3H-quinazolin-4-one (8.5 g, 29.7 mmol, 96%) as brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.05 (dd, J = 0.8, 2.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 3.95 (br dd, J = 2.4, 11.6 Hz, 2H), 3.43 - 3.38 (m, 2H), 2.92 - 2.82 (m, 1H), 2.77 (s, 3H), 2.44 (s, 3H), 1.90 - 1.73 (m, 4H). [0919] Step 4. Synthesis of 8-acetyl-3-(difluoromethyl)-6-methyl-2-(tetrahydro-2H-pyran- 4- yl)quinazolin-4(3H)-one [0920] To a mixture of 8-acetyl-6-methyl-2-tetrahydropyran-4-yl-3H-quinazolin-4-one (2 g, 6.99 mmol) and sodium;2-chloro-2,2-difluoro-acetate (3.19 g, 20.9 mmol) in N,N- dimethylformamide (20 mL) was added potassium carbonate (5.79 g, 41.9 mmol) and stirred at 100 °C for 20 hr. On completion, the reaction mixture was poured into ethyl acetate (20 mL) and water (20 mL), then the mixture was separated. The organic phase was washed with water (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 0/1) to give 8- acetyl-3-(difluoromethyl)-6-methyl-2-tetrahydropyran-4-yl-qu inazolin-4-one (700 mg, 2.08 mmol, 30%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 - 7.88 (m, 3H), 4.10 (br dd, J = 4.0, 11.2 Hz, 2H), 3.60 - 3.50 (m, 2H), 3.38 (br. t, J = 11.2 Hz, 1H), 2.88 (s, 3H), 2.50 (s, 3H), 2.13 (dq, J = 4.0, 12.4 Hz, 2H), 1.89 (br. d, J = 12.4 Hz, 2H); m/z ES+ [M+H] ⁺ 337.2 [0921] Step 5. Synthesis of (R,Z)-N-(1-(3-(difluoromethyl)-6-methyl-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-meth ylpropane-2-sulfinamide [0922] To a mixture of 8-acetyl-3-(difluoromethyl)-6-methyl-2-tetrahydropyran-4-yl- quinazolin-4-one (1.2 g, 3.57 mmol) and (R)-2-methylpropane-2-sulfinamide (1.30 g, 10.7 mmol) in 2-methyltetrahydrofuran (15 mL) was added titanium tetraethoxide (4.07 g, 17.8 mmol) and stirred at 75 °C for 16 hr. On completion, the reaction mixture was diluted with water (10 mL) and filtered to remove the undissolved solid. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give a residue. The residue was purified by column chromatography (Silicon dioxide, petroleum ether/ethyl acetate=1/0 to 3/1) to give (R,Z)-N-(1-(3-(difluoromethyl)-6-methyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyli dene)-2-methylpropane-2- sulfinamide (800 mg, 1.82 mmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.23 - 7.88 (m, 3H), 7.70 (s, 1H), 4.09 - 4.04 (m, 3H), 3.52 (br. t, J = 12.0 Hz, 3H), 3.32 (br. d, J = 10.0 Hz, 2H), 2.87 (s, 3H), 1.89 - 1.79 (m, 4H), 1.32 (s, 9H); m/z ES+ [M+H] ⁺ 440.3. [0923] Step 6. Synthesis of (R)-N-((R)-1-(3-(difluoromethyl)-6-methyl-4-oxo-2-(tetrahydr o- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide [0924] To a solution of (NZ,R)-N-[1-[3-(difluoromethyl)-6-methyl-4-oxo-2-tetrahydrop yran- 4-yl-quinazolin-8-yl]ethylidene]-2-methyl-propane-2-sulfinam ide (750 mg, 1.71 mmol) in anhydrous tetrahydrofuran (10 mL) was added borane-methyl sulfide complex (10 M) dropwise at -78 °C and stirred at -30 °C for 4 hr. On completion, the mixture was quenched by adding methanol (5 mL) dropwise at 0 °C and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 250*50mm*10um;mobile phase: [water( ammonium bicarbonate)-acetonitrile];B%: 43%- 63%, 8 min) to give (R)-N-((R)-1-(3-(difluoromethyl)-6-methyl-4-oxo-2-(tetrahydr o-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide (190 mg, 430 μmol, 25%) as pink solid. m/z ES+ [M+H] ⁺ 442.2. [0925] Step 7. Synthesis of (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-methyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [0926] To a solution of (R)-N-[(1R)-1-[3-(difluoromethyl)-6-methyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl]ethyl]-2-methyl-propane -2-sulfinamide (130 mg, 294 μmol) in dichloromethane (1.2 mL) was added hydrochloric acid/dioxane (4 M) and stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( ammonium bicarbonate)-acetonitrile];B%: 23%-53%, 10 min) to give (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-methyl-2-(tetrahyd ro-2H-pyran-4- yl)quinazolin-4(3H)-one (60 mg, 176 μmol, 60%) as a yellow solid. m/z ES+ [M+H] ⁺ 338.1. [0927] [0928] Preparation of Intermediate 43: (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-fluoro-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (Int-43) [0929] [0930] Step 1. Synthesis of 2-amino-3-bromo-5-fluorobenzamide [0931] To a mxiture of 2-amino-3-bromo-5-fluoro-benzoic acid (180 g, 769 mmol) in N,N- dimethylformamide (1800 mL) was added tetramethylurea hexafluorophosphate (468 g, 1.23 mol) and diisopropylethylamine (994 g, 7.69 mol), the mixture was stirred for 20 min, then ammonium chloride (206 g, 3.85 mol) was added, the reaction mixtue was stirred at 25 °C for 12 hr. On completion, the reaction mixture was pured into water (3000 mL), then filtered and the filtered cake was concentrated in vacuo to give a residue, the residue was triturated with solvent (petroleum ether/ethyl acetate= 20/1, 4.2 L) at 25 °C for 1 hr to give 2-amino-3- bromo-5-fluoro-benzamide (155 g, 665 mmol, 86%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.06 - 7.92 (m, 1H), 7.63 - 7.50 (m, 2H), 7.48 (br. s, 1H), 6.51 (br. s, 2H); m/z ES+ [M+H] ⁺ 234.9. [0932] Step 2. Synthesis of N-(2-bromo-6-carbamoyl-4-fluorophenyl)tetrahydro-2H-pyran- 4-carboxamide [0933] To a mixture of tetrahydropyran-4-carboxylic acid (103 g, 798 mmol) in pyridine (1.60 L) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.27 kg, 2.00 mol, 50% purity), then 2-amino-3-bromo-5-fluoro-benzamide (155 g, 665 mmol) was added, the reaction mixture was stirred at 25 °C for 3 hr. On completion, the reaction mixture was added to water (2000 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure to give N-(2-bromo-6-carbamoyl-4- fluoro-phenyl)tetrahydropyran-4-carboxamide (160 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 7.75 (dd, J = 2.8, 8.0 Hz, 1H), 7.55 (br. d, J = 9.2 Hz, 2H), 7.34 (dd, J = 2.8, 8.4 Hz, 1H), 3.88 (br. d, J = 10.8 Hz, 2H), 3.35 (dt, J = 2.0, 11.2 Hz, 3H), 2.66 - 2.55 (m, 1H), 1.76 - 1.62 (m, 4H). [0934] Step 3. Synthesis of 8-bromo-6-fluoro-2-(tetrahydro-2H-pyran-4-yl)quinazolin- 4(3H)-one [0935] To a mixture of N-(2-bromo-6-carbamoyl-4-fluoro-phenyl)tetrahydropyran-4- carboxamide (160 g, 463 mmol) in methyl alcohol (700 mL) was added sodium methoxide (834 g, 4.64 mol), the reaction mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered and the filtered cake was concentrated in vacuo to give 8- bromo-6-fluoro-2-tetrahydropyran-4-yl-3H-quinazolin-4-one (120 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (dd, J = 2.8, 8.4 Hz, 1H), 7.62 (td, J = 1.2, 8.8 Hz, 1H), 3.91 (br dd, J = 2.0, 11.2 Hz, 2H), 3.40 (dt, J = 2.0, 11.6 Hz, 2H), 2.69 - 2.61 (m, 1H), 1.93 - 1.80 (m, 2H), 1.80 - 1.65 (m, 2H); m/z ES+ [M+H] ⁺ 329.0. [0936] Step 4. Synthesis of 8-acetyl-6-fluoro-2-(tetrahydro-2H-pyran-4-yl)quinazolin- 4(3H)-one [0937] To a mixture of 8-bromo-6-fluoro-2-tetrahydropyran-4-yl-3H-quinazolin-4-one (120 g, 367 mmol) and tributyl(1-ethoxyvinyl)stannane (397 g, 1.10 mol) in toluene (1.20 L) was added dichloropalladium;triphenylphosphane (12.9 g, 18.3 mmol) under nitrogen, the reaction mixture was stirred at 120 °C under nitrogen for 12 hr. On completion, the reaction mixture was quenched by saturated potassium fluoride solution 1000 ml, and then diluted with water (500 mL) and extracted with ethyl acetate (1000 mL x 2). The combined organic layers were washed with brine (300 mL) and concentrate under reduced pressure to give a residue. Then the mixture in hydrogen chloride (2 M, 200 mL) stirred at 25°C for 10 min and adjust to pH = 8 by saturated sodium bicarbonate solution, then the mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with (petroleum ether/ethyl acetate=1/1, 2.0 L) at 25 ^o C for 20 min to give 8-acetyl-6-fluoro-2- tetrahydropyran-4-yl-3H-quinazolin-4-one (94 g, 262 mmol, 73%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.94 - 7.83 (m, 1H), 7.65 (dd, J = 3.2, 8.8 Hz, 1H), 4.00 - 3.90 (m, 2H), 3.42 - 3.39 (m, 2H), 2.82 (s, 3H), 2.78 (br. d, J = 7.2 Hz, 1H), 1.90 - 1.74 (m, 4H); m/z ES+ [M+H] ⁺ 291.1. [0938] Step 5. Synthesis of 8-acetyl-3-(difluoromethyl)-6-fluoro-2-(tetrahydro-2H-pyran- 4- yl)quinazolin-4(3H)-one [0939] To a mixture of 8-acetyl-6-fluoro-2-tetrahydropyran-4-yl-3H-quinazolin-4-one (47.0 g, 162 mmol), sodium;2-chloro-2,2-difluoro-acetate (74.1 g, 486 mmol) and sodium carbonate (103 g, 971 mmol) in N,N-dimethylformamide (2500 mL), the reaction mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was partitioned between ethyl acetate (2000 mL) and water (1500 mL). The organic phase was separated, washed with brine (800 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 60/40) to give 8-acetyl-3- (difluoromethyl)-6-fluoro-2-tetrahydropyran-4-yl-quinazolin- 4-one (30 g, 88.2 mmol, 28%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 - 7.90 (m, 2H), 7.84 (dd, J = 3.2, 8.4 Hz, 1H), 4.11 (dd, J = 4.4, 12.0 Hz, 2H), 3.56 (dt, J = 1.6, 12.0 Hz, 2H), 3.45 - 3.34 (m, 1H), 2.90 (s, 3H), 2.12 (dq, J = 4.4, 12.4 Hz, 2H), 1.90 (br dd, J = 1.2, 12.8 Hz, 2H); m/z ES+ [M+H] ⁺ 341.3. [0940] Step 6. Synthesis of (R,Z)-N-(1-(3-(difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-meth ylpropane-2-sulfinamide [0941] To a mixture of 8-acetyl-3-(difluoromethyl)-6-fluoro-2-tetrahydropyran-4-yl- quinazolin-4-one (30 g, 88.1 mmo), (R)-2-methylpropane-2-sulfinamide (42.8 g, 353 mmol) and tetraethyl titanate (101 g, 441 mmol) in anhydrous tetrahydrofuran (300 mL), the reaction mixture was stirred at 75 °C for 12 hr. On completion, the reaction mixture was poured into water (300 mL), filtered and the filtered cake in ethyl acetate (400 mL) stirred for 5 min then filtered, the filtered liquor was partitioned between ethyl acetate (400 mL) and water (300 mL). The organic phase was separated, washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give (NZ,R)-N-[1-[3-(difluoromethyl)-6-fluoro-4-oxo-2-tetrahydrop yran-4-yl-quinazolin-8- yl]ethylidene]-2-methyl-propane-2-sulfinamide (36.0 g, 81.2 mmol, 92%) as a yellow oil. m/z ES+ [M+H] ⁺ 444.3. [0942] Step 7. Synthesis of (R)-N-((R)-1-(3-(difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydr o- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide [0943] To a mixture of (NZ,R)-N-[1-[3-(difluoromethyl)-6-fluoro-4-oxo-2-tetrahydrop yran- 4-yl-quinazolin-8-yl]ethylidene]-2-methyl-propane-2-sulfinam ide (33.0 g, 2.25 mmol) in anhydrous tetrahydrofuran (700 mL) was added borane-methyl sulfide complex (10 M, 37.2 mL) at -78 °C, the reaction mixture was stirred at -20 °C for 30 min. On completion, the mixture was quenched by addtion methanol (400 mL) dropwised at 0 °C, and then concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)-acetonitrile];gradient:52%-62% B over 9 min) to give (R)-N-[(1R)- 1-[3-(difluoromethyl)-6-fluoro-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl]ethyl]-2- methyl-propane-2-sulfinamide (18.0 g, 39.2 mmol, 53%) as a yellow solid. m/z ES+ [M+H] ⁺ 446.3 [0944] Step 8. Synthesis of (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-fluoro-2-(tetrahyd ro- 2H-pyran-4-yl)quinazolin-4(3H)-one [0945] To a mixture of (R)-N-[(1R)-1-[3-(difluoromethyl)-6-fluoro-4-oxo-2-tetrahydr opyran -4-yl-quinazolin-8-yl]ethyl]-2-methyl-propane-2-sulfinamide (18.0 g, 40.4 mmol) in dioxane (180 mL) was added hydrochloric acid/dioxane (4 M, 36 mL), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was filtered and the filtered cake was washed with dichloromethane, then the filtered cake was dissolved in water (100 mL) and adjust to pH = 8 by ammonium hydroxide, partitioned between ethyl acetate (100 mL x 2), and water (100 mL). The organic phase was separated, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)- 6-fluoro-2-tetrahydropyran-4-yl-quinazolin-4-one (10.0 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 342.1. [0946] [0947] Preparation of Intermediate 45: 8-acetyl-6-methyl-2-morpholinoquinazolin-4(3H)- one (Int-45) [0948] [0949] Step 1. Synthesis of 8-bromo-2-chloro-6-methylquinazolin-4(3H)-one [0950] To a solution of 2-amino-3-bromo-5-methyl-benzamide (10 g, 43.7 mmol) in dioxane (100 mL) was added thiocarbonyl dichloride (14.05 g, 122 mmol) at 25 °C. The mixture was stirred at 25 °C for 0.5 hr. Then the mixture was stirred at 105 °C for 1 hr. On completion, the mixture was filtered and filter liquid was concentrated under reduced pressure to give 8- bromo-2-chloro-6-methyl-3H-quinazolin-4-one (12.1 g, crude) as brown solid. m/z ES+ [M+H] ⁺ 272.9. [0951] Step 2. Synthesis of 8-bromo-6-methyl-2-morpholinoquinazolin-4(3H)-one [0952] 8-bromo-2-chloro-6-methyl-3H-quinazolin-4-one (12.1 g, 44.2 mmol) and morpholine (11.5 g, 133 mmol) in dichloromethane (120 mL) was added diisopropylethylamine (22.8 g, 177 mmol). The mixture was stirred at 40 °C for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 8-bromo-6-methyl-2-morpholino-3H-quinazolin-4-one (12.3 g, 37.6 mmol, 85%) as a white- off solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.6 - 11.4 (m, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 3.69 - 3.64 (m, 8H), 2.34 (s, 3H); m/z ES+ [M+H] ⁺ 324.0. [0953] Step 3. Synthesis of 8-acetyl-6-methyl-2-morpholinoquinazolin-4(3H)-one [0954] To a solution of 8-bromo-6-methyl-2-morpholino-3H-quinazolin-4-one (3 g, 9.25 mmol), 1-vinyloxybutane (2.78 g, 27.8 mmol), diacetoxypalladium (208 mg, 925 μmol), [2- (2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (5.03 g, 9.35 mmol), diacetoxypalladium (208 mg, 925 μmol) and N-ethyl-N-isopropyl-propan-2-amine (3.60 g, 27.9 mmol) in n-butyl alcohol (30 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 90 °C for 4.5 hr under nitrogen atmosphere. Then reaction mixture was added hydrochloric acid (1 M, 30 mL) and stirred at 25 °C for 0.5 hr. On completion, the mixture was neutralized with solid sodium hydroxide. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-acetyl-6-methyl-2-morpholino-3H-quinazolin-4-one (4.28 g, crude) as an off-white solid; m/z ES+ [M+H] ⁺ 288.1. [0955] [0956] Preparation of Intermediate 46: 8-(1-aminoethyl)-6-(difluoromethyl)-3-methyl-2- morpholinoquinazolin-4(3H)-one (Int-46) [0957] [0958] Step 1. Synthesis of 2-amino-3-bromo-5-iodobenzoic acid [0959] To a solution of 2-amino-3-bromo-benzoic acid (50 g, 231 mmol) in N, N- dimethylformamide (500 mL) was added N-iodosuccinimide (62.5 g, 278 mmol) portionwise. The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was poured into water (2000 mL), white precipitated solid formed, filtered and the filter cake was concentrated under reduced pressure to give 2-amino-3-bromo-5-iodo-benzoic acid (68 g, 199 mmol, 86%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 6.49 - 6.29 (m, 2H). [0960] Step 2. Synthesis of 2-amino-3-bromo-5-iodo-N-methyl-benzamide [0961] To a solution of 2-amino-3-bromo-5-iodo-benzoic acid (68 g, 198.87 mmol) in N,N- dimethylformamide (700 mL) was added methanamine;hydrochloride (26.9 g, 398 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene] dimethylammoniumhexafluorophosphate (90.7 g, 239 mmol) and diisopropylethylamine (103 g, 795 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (800 mL x 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-3-bromo-5-iodo-N- methyl-benzamide (23 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.48 (br. d, J = 4.0 Hz, 1H), 7.78 (dd, J = 1.6, 6.8 Hz, 2H), 6.59 (s, 2H), 2.72 (d, J = 4.4 Hz, 3H). [0962] Step 3. Synthesis of 8-bromo-2-chloro-6-iodo-3-methyl-quinazolin-4-one [0963] To a solution of 2-amino-3-bromo-5-iodo-N-methyl-benzamide (18 g, 50.7 mmol) in dioxane (200 mL) was added thiocarbonyl dichloride (11.7 g, 101 mmol). The mixture was stirred at 25 °C for 0.5 hr. Then the mixture was heated to 100 °C, the mixture was stirred at 100 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro-6-iodo-3-methyl-quinazolin-4-one (16 g, crude) as a yellow solid. [0964] Step 4. Synthesis of 8-bromo-6-iodo-3-methyl-2-morpholino-quinazolin-4-one [0965] To a solution of 8-bromo-2-chloro-6-iodo-3-methyl-quinazolin-4-one (16 g, 40.1 mmol) in dichloromethane (150 mL) was added morpholine (17.5 g, 200 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=3/1, 200 mL) at 25 °C for 20 min to give 8-bromo-6- iodo-3-methyl-2-morpholino-quinazolin-4-one (13.4 g, 29.8 mmol, 74%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 3.93 - 3.85 (m, 4H), 3.58 (s, 3H), 3.41 - 3.34 (m, 4H); m/z ES+ [M+H] ⁺ 449.9. [0966] Step 5. Synthesis of 8-bromo-3-methyl-2-morpholino-6-vinyl-quinazolin-4-one [0967] A mixture of 8-bromo-6-iodo-3-methyl-2-morpholino-quinazolin-4-one (13.4 g, 29.8 mmol), potassium;trifluoro(vinyl)boranuide (3.99 g, 29.8 mmol), cesium carbonate (29.1 g, 89.3 mmol) in dioxane (140 mL) and water (14 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.18 g, 2.98 mmol) under nitrogen atmosphere, then the mixture was stirred at 80 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-bromo-3-methyl-2-morpholino-6-vinyl-quinazolin- 4-one (8.80 g, 25.1 mmol, 84%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 6.76 – 6.69 (m, 1H), 5.36 - 5.31 (m, 2H), 3.91 - 3.89 (m, 4H), 3.58 (s, 3H), 3.38 - 3.36 (m, 4H). [0968] Step 6. Synthesis of 8-bromo-3-methyl-2-morpholino-4-oxo-quinazoline-6- carbaldehyde [0969] To a solution of 8-bromo-3-methyl-2-morpholino-6-vinyl-quinazolin-4-one (7.8 g, 22.3 mmol) in anhydrous tetrahydrofuran (200 mL) and water (50 mL) was added potassium osmate dihydrate (164 mg, 445 μmol) and sodium periodate (19.1 g, 89.1 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched with sodium sulfite solution 100 mL, then the mixture was added water (500 mL) and extracted with ethyl acetate (300 mL x 3), the combined organic layers was dried over anhydrous sodium sulfate. The residue was purified by flash silica gel chromatography (petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-bromo-3-methyl-2-morpholino-4-oxo-quinazoline- 6-carbaldehyde (4.2 g, 11.9 mmol, 53%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 3.92 - 3.89 (m, 4H), 3.59 (s, 3H), 3.50 - 3.47 (m, 4H). [0970] Step 7. Synthesis of 8-bromo-6-(1,3-dithiolan-2-yl)-3-methyl-2-morpholino- quinazolin-4-one [0971] To a solution of 8-bromo-3-methyl-2-morpholino-4-oxo-quinazoline-6-carbaldehy de (2.7 g, 7.67 mmol), 4-methylbenzenesulfonic acid (264 mg, 1.53 mmol) in toluene (60 mL) was added ethane-1,2-dithiol (939 mg, 9.97 mmol). The mixture was stirred at 110 °C for 6 hr. The reaction mixture was concentrated under reduced pressure to give a residue. It was diluted with water (100 mL) and extracted thrice with dichloromethane (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried anhydrous sodium sulfate, filtered, and concentrated in vacuo give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-bromo-6-(1,3-dithiolan-2-yl)-3-methyl-2-morpholino-quinazo lin-4-one (1.6 g, 3.70 mmol, 48%) as a white solid. m/z ES+ [M+H] ⁺ 428.1. [0972] Step 8. Synthesis of 8-bromo-6-(difluoromethyl)-3-methyl-2-morpholino-quinazolin- 4-one [0973] A solution of pyridine hydrofluoride (694 mg, 7.00 mmol) in dichloromethane (2 mL) was added to the mixture of N-Iodosuccinimide (315 mg, 1.40 mmol) in dichloromethane (2 mL) at -30 °C under nitrogen atmosphere. After stirring at -30 °C for 0.1 hr, a solution of 8-bromo-6-(1,3-dithiolan-2-yl)-3-methyl-2-morpholino-quinazo lin-4-one (150 mg, 350 μmol) in dichloromethane (2 mL) was added, and stirred at -30 °C for 0.15 hr. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];B%: 41%-71%, 10 min) to give 8- bromo-6-(difluoromethyl)-3-methyl-2-morpholino-quinazolin-4- one (40 mg, 86.6 μmol, 24%) as a white solid. m/z ES+ [M+H] ⁺ 374.1 [0974] [0975] Step 9. Synthesis of 8-acetyl-6-(difluoromethyl)-3-methyl-2-morpholino-quinazolin - 4-one [0976] To a solution of 8-bromo-6-(difluoromethyl)-3-methyl-2-morpholino-quinazolin- 4- one (120 mg, 320 μmol) and 1-vinyloxybutane (96.3 mg, 962 μmol) in n-butyl alcohol (5 mL) was added palladium acetate (7.20 mg, 32.0 μmol), diisopropylethylamine (124 mg, 962 μmol) and [2-(2-diphenylphosphanylphen-oxy)phenyl]-diphenyl-phosphane (34.5 mg, 64.1 μmol). The mixture was stirred at 95 °C for 12 hr. Then cooled down, added formic acid (14.6 mg, 305 μmol). The mixture was stirred at 25 °C for 10 min. On completion, the reaction was adjusted to pH = 7~8 by saturated sodium bicarbonate solution and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-acetyl-6-(difluoromethyl)-3-methyl-2-morpholino-quinazolin -4-one (50.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 338.1. [0977] Step 10. Synthesis of 8-(1-aminoethyl)-6-(difluoromethyl)-3-methyl-2-morpholino- quinazolin-4-one [0978] To a solution of 8-acetyl-6-(difluoromethyl)-3-methyl-2-morpholino-quinazolin -4- one (30.0 mg, 88.9 μmol) and ammonium acetate (137 mg, 1.78 mmol) in methanol (10 mL) and dichloromethane (5 mL) was added sodium cyanoborohydride (8.38 mg, 133 μmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was quenched by addition water 1 mL at 0 °C. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give 8-(1-aminoethyl)-6-(difluoromethyl)-3-me- thyl-2- morpholino-quinazolin-4-one (24.5 mg, 72.4 μmol, 81%) as white solid. m/z ES+ [M+H] ⁺ 339.2. [0979] [0980] Preparation of Intermediate 47: 8-bromo-6-fluoro-3-methyl-2- morpholinoquinazolin-4(3H)-one (Int-47) and Intermediate 48: (R)-8-(1-aminoethyl)-6- fluoro-3-methyl-2-morpholinoquinazolin-4(3H)-one (Int-48) [0981] [0982] Step 1. Synthesis of 2-amino-3-bromo-5-fluoro-N-methylbenzamide [0983] To a solution of 2-amino-3-bromo-5-fluoro-benzoic acid (20 g, 85.4 mmol) and methanamine hydrochloride (11.5 g, 170 mmol) in N,N-dimethylformamide (200 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethylammonium;hexafluorophosphate (39.0 g, 102 mmol) and diisopropylethylamine (33.1 g, 256 mmol). The mixture was stirred at 25 °C for 12 hr. The mixture was poured in water (800 mL) and then filter and the solid was collected and concentrated in vacuo to give 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (17 g, crude) as an off-white solid. m/z ES+ [M+H] ⁺ 247.0. [0984] Step 2. Synthesis of 8-bromo-2-chloro-6-fluoro-3-methylquinazolin-4(3H)-one [0985] To a solution of 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (2 g, 8.10 mmol) in dioxane (20 mL) was added thiocarbonyl dichloride (2.79 g, 24.2 mmol). The mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 105 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro-6-fluoro-3-methyl- quinazolin-4-one (2.19 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 290.9. [0986] Step 3. Synthesis of 8-bromo-6-fluoro-3-methyl-2-morpholinoquinazolin-4(3H)-one [0987] To a solution of 8-bromo-2-chloro-6-fluoro-3-methyl-quinazolin-4-one (1 g, 3.43 mmol) and morpholine (1.49 g, 17.1 mmol) in dichloromethane (10 mL) was added 4A molecular sieve (500 mg). The mixture was stirred at 40 °C for 12 hr. The reaction mixture was partitioned between dichloromethane (100 mL) and water (50 mL). The organic phase was separated, washed with brine (50 mL), washed with hydrochloric acid (25 mL x 2, 1M), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-6-fluoro-3-methyl-2-morpholino-quinazolin-4-one (1 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 2.8, 8.0 Hz, 1H), 7.72 (dd, J = 2.8, 8.0 Hz, 1H), 3.93 - 3.85 (m, 4H), 3.59 (s, 3H), 3.39 - 3.29 (m, 4H); m/z ES+ [M+H] ⁺ 342.0. [0988] Step 4. Synthesis of 8-(1-ethoxyvinyl)-6-fluoro-3-methyl-2-morpholinoquinazolin- 4(3H)-one [0989] To a solution of 8-bromo-6-fluoro-3-methyl-2-morpholino-quinazolin-4-one (6 g, 17.5 mmol) in toluene (60 mL) was added dichloropalladium triphenylphosphane (615 mg, 877 μmol) and tributyl(1-ethoxyvinyl)stannane (19.0 g, 52.6 mmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. The reaction was adjusted to pH = 7~8 by saturated sodium bicarbonate solution and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was dissolved in hydrochloric acid (2 M, 50 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was neutralized to pH = 9 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=3/1, 30 mL) at 25 °C for 30 min to give 8-acetyl-6-fluoro-3-methyl-2- morpholino-quinazolin-4-one (5 g, 16.4 mmol, 93%) as a white solid. m/z ES+ [M+H] ⁺ 306.1 [0990] Step 5. Synthesis of (RZ)-N-(1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [0991] To a solution of 8-acetyl-6-fluoro-3-methyl-2-morpholino-quinazolin-4-one (3.5 g, 11.5 mmol) in anhydrous tetrahydrofuran (35 mL) was added tetraethoxytitanium (13.1 g, 57.3 mmol, 11.9 mL) and (R)-2-methylpropane-2-sulfinamide (6.95 g, 57.3 mmol). The mixture was stirred at 75 °C for 12 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R,Z)-N-(1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (4.2 g, 8.74 mmol, 76%) as a yellow solid. m/z ES+ [M+H] ⁺ 409.2. [0992] Step 6. Synthesis of (R)-N-((R)-1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [0993] To a solution of (NZ,R)-N-[1-(6-fluoro-3-methyl-2-morpholino-4-oxo-quinazolin -8- yl)ethylidene]-2-methyl-propane-2-sulfinamide (4 g, 9.79 mmol) in anhydrous tetrahydrofuran (45 mL) was added borane-methyl sulfide complex (10 M, 4.90 mL) at - 78 °C. The mixture was stirred at -78 °C for 0.25 hr then stirred at 0 °C for 0.25 hr under nitrogen atmosphere. The mixture was added methanol (200 mL) dropwised at -10 °C. The mixture was stirred at 25 °C for 0.5 hr. Then the mixture was concentrated in vacuo to give a residue. The crude product was purified by reversed-phase HPLC (column: Kromasil Eternity XT 250*80mm*10um;mobile phase: [water (ammonia hydroxide v/v)- acetonitrile];gradient:32%-62% B over 20 min) to give (R)-N-[(1R)-1-(6-fluoro-3-methyl-2- morpholino-4-oxo-quinazolin-8-yl)ethyl]-2-methyl-propane-2-s ulfinamide (2 g, 4.87 mmol, 50%) as a white solid. m/z ES+ [M+H] ⁺ 411.3. [0994] Step 7. Synthesis of (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2- morpholinoquinazolin-4(3H)-one [0995] To a solution of (R)-N-[(1R)-1-(6-fluoro-3-methyl-2-morpholino-4-oxo-quinazol in-8- yl)ethyl]-2-methyl-propane-2-sulfinamide (1.5 g, 3.65 mmol) in dichloromethane (7.5 mL) was added hydrochloric acid/dioxane (4 M, 15 mL).The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was filtered and the cake concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2-morpholinoquinazoli n-4(3H)-one (1 g, 3.20 mmol, 88%) as a white solid. m/z ES+ [M+H] ⁺ 307.1. [0996] [0997] Preparation of Intermediate 50: (R)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-(methylth io)quinazolin-4(3H)-one (Int- 50) [0998] [0999] Step 1. Synthesis of (R)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(methylthio)quinazolin-4(3H)-one [1000] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl-quinazol in-4- one (0.50 g, 1.90 mmol) and 1,4-difluoro-2-methylsulfonyl-benzene (730 mg, 3.80 mmol) in dimethyl acetamide (5 mL) was added cesium carbonate (1.24 g, 3.80 mmol), then the mixture was stirred at 140 °C for 16 hr. On completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/1) to give (R)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl-2- (methylthio)quinazolin-4(3H)-one (0.80 g, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (m, 1H), 7.70 - 7.52 (m, 1H), 7.51 - 7.49 (m, 1H), 7.49 - 7.44 (m, 1H), 7.21 -7. 18 (m, 1H), 6.50 - 6.48 (m, 1H), 5.51- 5.49 (m, 1H), 3.60 (s, 3H), 3.15 (s, 3H), 2.69 (s, 3H), 2.39 (s, 3H), 1.53 - 1.52 (m, 3H); m/z ES+ [M+H] ⁺ 436.1. [1001] [1002] Preparation of Intermediate-53: 1-(2-bromophenyl)-4-((tert- butyldimethylsilyl)oxy)piperidine (Int-53) [1003] [1004] Step 1. Synthesis of 1-(2-nitrophenyl)piperidin-4-ol [1005] To a solution of piperidin-4-ol (5 g, 49.4 mmol) in dimethyl acetamide (50 mL) was 1-fluoro-2-nitro-benzene (5.81 g, 41.1 mmol) and cesium carbonate (40.2 g, 123 mmol), the mixture was stirred at 100 °C for 16 hr. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1-(2- nitrophenyl)piperidin-4-ol (10.5 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 223.1. [1006] Step 2. Synthesis of 1-(2-aminophenyl)piperidin-4-ol [1007] To a solution of 1-(2-nitrophenyl) piperidin-4-ol (10.5 g, 47.2 mmol) in ethanol (100 mL) and water (20 mL) was added iron (13.1 g, 236 mmol) and ammonium chloride (12.6 g, 236 mmol), the mixture was stirred at 80 °C for 2 hr. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 1-(2-aminophenyl)piperidin-4-ol (6.4 g, 33.2 mmol, 70%) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.86 (dd, J = 1.2, 7.6 Hz, 1H), 6.80 - 6.74 (m, 1H), 6.64 (dd, J = 1.6, 8.0 Hz, 1H), 6.53 - 6.45 (m, 1H), 4.71 - 4.59 (m, 3H), 3.62 - 3.50 (m, 1H), 3.01 - 2.89 (m, 2H), 2.59 - 2.51 (m, 2H), 1.87 - 1.78 (m, 2H), 1.60 - 1.50 (m, 2H); m/z ES+ [M+H] ⁺ 193.1. [1008] Step 3. Synthesis of 1-(2-bromophenyl)piperidin-4-ol [1009] Concentrated sulfuric acid (3.66 g, 36.6 mmol) was dropped slowly into water (40 mL) and cooled to 0 °C. 1-(2-aminophenyl) piperidin-4-ol (6.4 g, 33.2 mmol) was added slowly into the system, then a solution of sodium nitrite (2.53 g, 36.6 mmol) in water (10 mL)was slowly dropped into the raw material system while controlling the temperature to 0 to 10 °C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 1.5 hr to form a diazonium salt system. At last, a solution of sodium bromide (13.7 g, 133 mmol) and cuprous bromide (4.78 g, 33.2 mmol) in water (10 mL) was added to the diazonium salt system at 10 °C, the mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the mixture was quenched with ammonium hydroxide (40 mL), diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1011) to give 1-(2-bromophenyl)piperidin-4-ol (5.44 g, 21.1 mmol, 63%) as a yellow oil. m/z ES+ [M+H] ⁺ 256.0. [1010] Step 4. Synthesis of 1-(2-bromophenyl)-4-((tert-butyldimethylsilyl)oxy)piperidine [1011] To a solution of 1-(2-bromophenyl) piperidin-4-ol (5.44 g, 21.2 mmol) in N,N- dimethylformamide (40 mL) was added imidazole (3.61 g, 53.1 mmol) and tert- butylchlorodimethylsilane (4.80 g, 31.8 mmol), the mixture was stirred at 25 °C for 16 hr. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether) to give [1-(2-bromophenyl)-4-piperidyl]oxy-tert-butyl-dimethyl- silane (4.3 g, 10.4 mmol, 49%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 1.2, 8.0 Hz, 1H), 7.17 - 7.13 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.84 - 6.75 (m, 1H), 3.79 (d, J = 3.2 Hz, 1H), 3.14 (s, 2H), 2.83 - 2.68 (m, 2H), 1.83 (s, 2H), 1.75 - 1.61 (m, 2H), 0.85 - 0.81 (m, 9H), 0.03 - 0.02 (m, 6H); m/z ES+ [M+H] ⁺ 370.1. [1012] Preparation of Intermediate 54: [(3S)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy- tert-butyl-dimethyl-silane (Int-54) [1013] [1014] Step 1. Synthesis of (3S)-1-(5-fluoro-2-nitro-phenyl)piperidin-3-ol [1015] To a solution of (3S)-piperidin-3-ol (1.73 g, 12.5 mmol, hydrochloric acid salt) and 2,4-difluoro-1-nitro-benzene (2.00 g, 12.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (5.21 g, 37.7 mmol). The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was partitioned between water (200 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give (3S)-1-(5-fluoro-2-nitro-phenyl)piperidin-3-ol (2.20 g, 9.16 mmol, 72%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 6.0, 9.2 Hz, 1H), 6.81 (dd, J = 2.8, 10.4 Hz, 1H), 6.72 (ddd, J = 2.8, 6.4, 9.2 Hz, 1H), 4.06 - 3.91 (m, 1H), 3.19 (dd, J = 2.8, 11.6 Hz, 1H), 3.08 - 2.93 (m, 3H), 2.04 - 1.93 (m, 1H), 1.88 - 1.76 (m, 1H), 1.75 - 1.62 (m, 2H); m/z ES+ [M+H] ⁺ 241.1. [1016] Step 2. Synthesis of (3S)-1-(2-amino-5-fluoro-phenyl)piperidin-3-ol [1017] To a solution of (3S)-1-(5-fluoro-2-nitro-phenyl)piperidin-3-ol (2.20 g, 9.16 mmol) in ethanol (20 mL) and water (4 mL) was added iron (2.56 g, 45.7 mmol) and ammonium chloride (2.45 g, 45.7 mmol). The mixture was stirred at 80 °C for 3 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give (3S)-1-(2-amino-5-fluoro-phenyl)piperidin-3-ol (1.40 g, 6.59 mmol, 71%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 6.71 (d, J = 10.0 Hz, 1H), 6.68 - 6.63 (m, 2H), 4.01 - 3.90 (m, 1H), 3.02 (d, J = 10.0 Hz, 1H), 2.82 (s, 3H), 2.01 - 1.79 (m, 2H), 1.75 - 1.56 (m, 2H); m/z ES+ [M+H] ⁺ 211.1. [1018] Step 3. Synthesis of (3S)-1-(2-bromo-5-fluoro-phenyl)piperidin-3-ol [1019] Concentrated sulfuric acid (261 mg, 2.62 mmol) was dropped slowly into water (3 mL) and cooled to 0 ° C. (3S)-1-(2-amino-5-fluoro-phenyl)piperidin-3-ol (0.50 g, 2.38 mmol) was added slowly into the system. Then a solution of sodium nitrite (180 mg, 2.62 mmol) in water (1 mL) was slowly dropped into the raw material system while controlling the temperature to 0 to 10 °C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 0.5 h to form a diazonium salt system. Then a solution of sodium bromide (978 mg, 9.51 mmol) and copper(I) bromide (341 mg, 2.38 mmol) in water (1 mL) was added to the diazonium salt system, the mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition ammonium hydroxide (20 mL) at 0 °C, and then diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give (3S)-1-(2-bromo-5-fluoro- phenyl)piperidin-3-ol (460 mg, 1.64 mmol, 69%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 6.0, 8.8 Hz, 1H), 6.80 (dd, J = 2.8, 10.4 Hz, 1H), 6.69 (ddd, J = 2.8, 7.6, 8.8 Hz, 1H), 4.07 - 3.95 (m, 1H), 3.17 - 2.96 (m, 3H), 2.84 - 2.83 (m, 1H), 2.81 - 2.80 (m, 1H), 2.91 - 2.77 (m, 1H), 2.17 - 1.95 (m, 1H), 1.83 - 1.64 (m, 2H), 1.57 (ddd, J = 1.6, 4.4, 5.6 Hz, 1H); m/z ES+ [M+H] ⁺ 276.0. [1020] Step 4. Synthesis of [(3S)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl - dimethyl-silane [1021] To a solution of (3S)-1-(2-bromo-5-fluoro-phenyl)piperidin-3-ol (460 mg, 1.68 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (342. mg, 5.03 mmol) and tert-butylchlorodimethylsilane (505 mg, 3.36 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, washed with saturated sodium bicarbonate (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 10/1) to give [(3S)- 1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl-dimet hyl-silane (600 mg, 1.53 mmol, 91%) as brown oil. ¹ H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 6.4, 8.8 Hz, 1H), 6.81 - 6.73 (m, 1H), 6.67 - 6.60 (m, 1H), 3.89 (td, J = 5.2, 9.6 Hz, 1H), 3.44 - 3.34 (m, 1H), 3.27 - 3.16 (m, 1H), 2.59 - 2.48 (m, 1H), 2.41 (t, J = 10.0 Hz, 1H), 2.02 (dd, J = 4.0, 12.4 Hz, 1H), 1.86 - 1.69 (m, 2H), 1.38 - 1.31 (m, 1H), 0.94 - 0.81 (m, 9H), 0.10 (d, J = 6.0 Hz, 6H); m/z ES+ [M+H] ⁺ 389.8. [1022] [1023] Preparation of Intermediate 55: (R)-1-(2-bromo-5-fluorophenyl)-3-((tert- butyldimethylsilyl)oxy)piperidine (Int-55) [1024] [1025] Step 1. Synthesis of (3R)-1-(5-fluoro-2-nitro-phenyl)piperidin-3-ol [1026] To a solution of (3R)-piperidin-3-ol (3.00 g, 21.8 mmol) and 2,4-difluoro-1-nitro- benzene (3.47 g, 21.8 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (9.04 g, 65.40 mmol). The mixture was stirred at 80 °C for 3 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 4/1) to give (3R)-1-(5-fluoro-2-nitro-phenyl)piperidin-3-ol (3.50 g, 14.4 mmol, 66%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 6.0, 9.2 Hz, 1H), 6.73 (dd, J = 2.4, 10.4 Hz, 1H), 6.64 (ddd, J = 2.4, 6.8, 9.2 Hz, 1H), 3.96 - 3.86 (m, 1H), 3.11 (dd, J = 2.4, 11.6 Hz, 1H), 2.98 - 2.87 (m, 3H), 1.96 - 1.87 (m, 1H), 1.79 - 1.70 (m, 1H), 1.65 - 1.58 (m, 2H). m/z ES+ [M+H] ⁺ 241.0. [1027] Step 2. Synthesis of (3R)-1-(2-amino-5-fluoro-phenyl)piperidin-3-ol [1028] To a solution of (3R)-1-(5-fluoro-2-nitro-phenyl)piperidin-3-ol (3.50 g, 14.5 mmol) in ethanol (35 mL) was added ammonium chloride (8 M, 18.2 mL) and iron (4.07 g, 72.8 mmol), the mixture was stirred at 60 °C for 3 hr. On completion, the mixture was filtered and washed with ethyl acetate (30 mL × 3), then the filtrate adjust to pH = 8 by potassium carbonate. The organic phase was separated, washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give (3R)-1-(2-amino-5-fluoro-phenyl)piperidin-3-ol (2.00 g, 9.51 mmol, 65%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.73 (br. d, J = 10.4 Hz, 1H), 6.68 (br. d, J = 6.4 Hz, 2H), 3.98 (br. s, 1H), 3.04 (br. d, J = 9.2 Hz, 1H), 2.91 - 2.76 (m, 3H), 2.00 - 1.83 (m, 2H), 1.75 - 1.59 (m, 2H). m/z ES+ [M+H] ⁺ 211.1. [1029] Step 3. Synthesis of (3R)-1-(2-bromo-5-fluoro-phenyl)piperidin-3-ol [1030] Concentrated sulfuric acid (523 mg, 5.23 mmol) was dropped slowly into water (5 mL) at 0 °C. (3R)-1-(2-amino-5-fluoro-phenyl)piperidin-3-ol (1.00 g, 4.76 mmol) was added slowly into the system and stirred. A solution of sodium nitrite (360 mg, 5.23 mmol) in water (5 mL) was slowly dropped into the raw material system while controlling the temperature at 0 to 10 ° C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 1.5 hr to form a diazonium salt system. A mixture of sodium bromide (1.96 g, 19.0 mmol) and cuprous bromide (682 mg, 4.76 mmol) in water (2.5 mL) was added to the diazonium salt system at 25 °C, the mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by ammonium hydroxide until pH = 7, and then diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/1) to give (3R)-1-(2-bromo-5-fluoro-phenyl)piperidin-3-ol (900 mg, 3.28 mmol, 69%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (dd, J = 6.0, 8.8 Hz, 1H), 6.82 (dd, J = 2.4, 10.0 Hz, 1H), 6.71 (ddd, J = 2.8, 7.6, 8.8 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.16 - 2.96 (m, 3H), 2.91 - 2.80 (m, 1H), 2.09 - 2.02 (m, 1H), 1.78 - 1.67 (m, 3H). m/z ES+ [M+H] ⁺ 274.0. [1031] Step 4. Synthesis of [(3R)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl - dimethyl-silane [1032] To a solution of (3R)-1-(2-bromo-5-fluoro-phenyl)piperidin-3-ol (500 mg, 1.82 mmol) in N,N-dimethylformamide (5 mL) was added tert-butylchlorodimethylsilane (412 mg, 2.74 mmol) and imidazole (310 mg, 4.56 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), the combined organic layers were washed with sodium bicarbonate (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, ethyl acetate/petroleum ether =0/1 to 1/99) to give [(3R)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl - dimethyl-silane (600 mg, 1.54 mmol, 84%) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (dd, J = 6.0, 8.8 Hz, 1H), 6.79 (dd, J = 2.8, 10.4 Hz, 1H), 6.65 (ddd, J = 2.8, 7.6, 8.8 Hz, 1H), 3.98 - 3.85 (m, 1H), 3.46 - 3.37 (m, 1H), 3.29 - 3.18 (m, 1H), 2.55 (dt, J = 3.6, 11.2 Hz, 1H), 2.42 (t, J = 10.0 Hz, 1H), 2.10 - 1.99 (m, 1H), 1.88 - 1.72 (m, 2H), 1.42 - 1.32 (m, 1H), 0.92 (s, 9H), 0.11 (d, J = 6.0 Hz, 6H). m/z ES+ [M+H] ⁺ 390.1. Synthesis of Examples Example 1. Preparation of 2-((1-(3-ethyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1033] Step 1. Synthesis of 2-amino-3-bromo-N-ethyl-5-methyl-benzamide [1034] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (1 g, 4.35 mmol) and ethanamine (784 mg, 17.39 mmol) in N,N-dimethylformamide (2 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethylammonium;hexafluorophosphate (2.48 g, 6.52 mmol) and diisopropylethylamine (1.12 g, 8.69 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 2/1) to give 2-amino-3-bromo-N-ethyl-5-methyl-benzamide (900 mg, 3.50 mmol, 80%) as a white solid. m/z ES+ [M+H] ⁺ 257.1. [1035] Step 2. Synthesis of 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one [1036] To a solution of 2-amino-3-bromo-N-ethyl-5-methyl-benzamide (450 mg, 1.75 mmol) in 1,4-dioxane (5 mL) was added thiocarbonyl dichloride (423 mg, 3.68 mmol). The mixture was stirred at 105 °C for 2 hr. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one (300 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 303.1. [1037] Step 3. Synthesis of 8-bromo-3-ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-one [1038] To a solution of 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one (300 mg, 995 μmol) in dichloromethane (4 mL) was added morpholine (433 mg, 4.97 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-bromo- 3-ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-one (0.3 g, 852 μmol, 86%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 0.7, 1.6 Hz, 1H), 4.06 (q, J = 6.8 Hz, 2H), 3.83 - 3.71 (m, 4H), 3.23 - 3.16 (m, 4H), 2.39 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). [1039] Step 4. Synthesis of 8-acetyl-3-ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-one [1040] To a solution of 8-bromo-3-ethyl-6-methyl-2-morpholino-quinazolin-4-one (300 mg, 852 μmol) in toluene (5 mL) was added tetrakis(triphenylphosphine)palladium (98.4 mg, 85.2 μmol) and tributyl(1-ethoxyvinyl)stannane (923 mg, 2.56 mmol). The mixture was stirred at 130 °C under nitrogen for 12 hr. After cooled to room temperature, hydrochloric acid (1 M, 1.31 mL) was added to the mixture and stirred at 25 °C for 30 min. The mixture was poured in water (20 mL) and extracted with ethyl acetate (20 mLx2). The organic phase was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=20/1 to 5/1) to give 8-acetyl-3-ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-one (0.26 g, 824 μmol, 97%) as a yellow solid. m/z ES+ [M+H] ⁺ 316.3. [1041] Step 5. Synthesis of 8-(1-aminoethyl)-3-ethyl-6-methyl-2-morpholinoquinazolin- 4(3H)-one [1042] To a solution of 8-acetyl-3-ethyl-6-methyl-2-morpholino-quinazolin-4-one (200 mg, 634 μmol) in methanol (3 mL) was added ammonium acetate (978 mg, 12.7 mmol) and sodium cyanoborohydride (39.9 mg, 634 μmol). The mixture was stirred at 60 °C for 1 h. On completion, the mixture was quenched with water (1 mL) and then concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-(1- aminoethyl)-3-ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-on e (170 mg, 537 μmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 317.3. [1043] Step 6. Synthesis of methyl 2-((1-(3-ethyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1044] An oven-dried 15 mL vial equipped with magnetic stir bar was charged with 8-(1- aminoethyl)-3-ethyl-6-methyl-2-morpholino-quinazolin-4-one (170 mg, 537 μmol), methyl 2- oxocyclohexanecarboxylate (210 mg, 1.34 mmol), Ir(ppy) ₂ (dtbbpy)PF ₆ (9.82 mg, 10.8 μmol), chloro-bis[[(Z)-[(2Z)-2-hydroxyimino-1-methyl-propylidene]am ino]oxy]cobalt;pyridine (8.68 mg, 21.5 μmol), acetic acid (6.45 mg, 107 μmol, 6.15 ^L), 1,4-diazabicyclo[2.2.2]octane (90.4 mg, 806 μmol) in acetonitrile (3 mL). The reaction mixture was degassed by bubbling nitrogen stream, then irradiated with two 34 W blue LED lamps (at approximately 7 cm away) as the light source to keep the reaction temperature at 25 °C for 14 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give methyl 2-((1-(3-ethyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (85 mg, 189 μmol, 35%) as a yellow oil. m/z ES+ [M+H] ⁺ 451.3. [1045] Step 7. Synthesis of 2-((1-(3-ethyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1046] To a solution of methyl 2-[1-(3-ethyl-6-methyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoate (65 mg, 144 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (30.3 mg, 721 μmol). The mixture was stirred at 40 °C for 12 hr. On completion, the mixture was acidified with aqueous hydrochloric acid (1 M) to adjust pH = 3~4 and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (FA)- acetonitrile]; B%: 29%-32%, 2 min) to give 2-((1-(3-ethyl-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (30.7 mg, 69.6 μmol, 48%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 6.4 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.73 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.18 (br. t, J = 7.2 Hz, 1H), 6.59 - 6.43 (m, 2H), 5.38 (s, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.82 - 3.74 (m, 4H), 3.23 - 3.19 (m, 4H), 2.33 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.27 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 437.0. Example 2 and Example 3. Preparation of (R)-2-((1-(3-ethyl-6-methyl-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid and (S)-2-((1-(3-ethyl-6- methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)a mino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1047] Racemate 2-((1-(3-ethyl-6-methyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8- yl)ethyl)amino)benzoic acid (30.7 mg, 69.6 μmol) was separated by SFC (column: Daicel Chiral Pak IG (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide isopropanol]; B%: 25%-25%, 6.4 min, room temperature = 1.59 min) to give (R)-2-((1-(3-ethyl-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (7.72 mg, 17.7 μmol, 39%, >99% ee) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 - 8.45 (m, 1H), 7.83 - 7.75 (m, 1H), 7.73 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 6.62 - 6.42 (m, 2H), 5.47 - 5.29 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.85 - 3.72 (m, 4H), 3.24 - 3.18 (m, 4H), 2.33 (s, 3H), 1.57 (d, J = 6.8 Hz, 2H), 1.27 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 437.2 and (S)- 2-((1-(3-ethyl-6-methyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8- yl)ethyl)amino)benzoic acid (8.90 mg, 20.4 μmol, 45%, 97% ee) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (dd, J = 2.4, 6.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.50 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.50 (t, J = 8.4 Hz, 2H), 5.38 (d, J = 5.6 Hz, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.87 - 3.75 (m, 4H), 3.24 - 3.16 (m, 4H), 2.33 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.27 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 437.2. Example 4. Preparation of 2-((1-(3-isopropyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1048] Step 1. Synthesis of 2-amino-3-bromo-N-isopropyl-5-methylbenzamide [1049] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (5 g, 21.7 mmol) and propan-2-amine (2.57 g, 43.5 mmol) in N,N-dimethylformamide (50 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (12.4 g, 32.6 mmol) and diisopropylethylamine (5.62 g, 43.5 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was dilluted in water (500 mL) and filtered. The filter cake was collected to give 2-amino-3-bromo-N- isopropyl-5-methylbenzamide (5.1 g, 18.6 mmol, 85%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.07 (s, 1H), 5.99 - 5.71 (m, 1H), 2.24 (s, 3H), 1.28 (s, 6H). [1050] Step 2. Synthesis of 8-bromo-2-chloro-3-isopropyl-6-methylquinazolin-4(3H)-one [1051] To a solution of 2-amino-3-bromo-N-isopropyl-5-methylbenzamide (5.1 g, 18.8 mmol) in 1,4-dioxane (50 mL) was added thiocarbonyl dichloride (4.54 g, 39.5 mmol), the mixture was stirred at 25 °C for 1 hr under nitrogen amosphere. Then the mixture was stirred at 105 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 8-bromo-2-chloro-3- isopropyl-6-methylquinazolin-4(3H)-one (5.94 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 314.6. [1052] Step 3. Synthesis of 8-bromo-3-isopropyl-6-methyl-2-morpholinoquinazolin-4(3H)- one [1053] To a solution of 8-bromo-2-chloro-3-isopropyl-6-methyl-quinazolin-4-one (5.94 g, 18.8 mmol) in dichloromethane (60 mL) was added morpholine (4.92 g, 56.6 mmol). The mixture was stirred at 40 °C for 16 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent of 0~10% ethylacetate/petroleum ether, gradient @ 100 mL/min) to give 8-bromo-3-isopropyl-6-methyl-2-morpholinoquinazolin-4(3H)-on e (4 g, 10.9 mmol, 58%) as a yellow solid. m/z ES+ [M+H] ⁺ 367.8. [1054] Step 4. Synthesis of 8-acetyl-3-isopropyl-6-methyl-2-morpholinoquinazolin-4(3H)- one [1055] To a solution of 8-bromo-3-isopropyl-6-methyl-2-morpholinoquinazolin-4(3H)-on e (2.9 g, 7.92 mmol) in toluene (60 mL) was added tetrakis(triphenylphosphine)palladium (1.83 g, 1.58 mmol) and tributyl(1-ethoxyvinyl)stannane (8.58 g, 23.7 mmol). The mixture was stirred at 125 °C for 16 hr under nitrogen atmosphere. Then the mixture was added hydrochloric acid (1 M, 7.92 mL) at 25 °C and stirred for 30 min. On completion, the reaction was adjusted to pH = 7~8 with sat. sodium bicarbonate and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0~30% ethylacetate/petroleum ether gradient @ 50 mL/min) to give 8-acetyl-3-isopropyl-6-methyl-2- morpholinoquinazolin-4(3H)-one (2 g, 5.46 mmol, 69%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.17 - 8.03 (m, 1H), 7.85 (d, J = 2.0 Hz, 1H), 4.95 - 4.70(m, 1H), 3.94 - 3.77 (m, 4H), 3.30 - 3.11 (m, 4H), 2.86 (s, 3H), 2.45 (s, 3H), 1.67 (d, J = 6.8 Hz, 6H). [1056] Step 5. Synthesis of 8-(1-aminoethyl)-3-isopropyl-6-methyl-2-morpholinoquinazolin - 4(3H)-one [1057] To a solution of 8-acetyl-3-isopropyl-6-methyl-2-morpholinoquinazolin-4(3H)-o ne (700 mg, 2.13 mmol) in methanol (14 mL) was added ammonium acetate (1.64 g, 21.2 mmol) and sodium cyanoborohydride (133 mg, 2.13 mmol). The mixture was stirred at 120 °C for 1 hr under microwave irradiation. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% ammonium hydroxide conditions) to give 8-(1-aminoethyl)-3-isopropyl-6-methyl-2-morpholinoquinazolin -4(3H)-one (1 g, 3.03 mmol, 71%) as a gray solid. m/z ES+ [M+H] ⁺ 331.2. [1058] Step 6. Synthesis of methyl 2-((1-(3-isopropyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1059] An oven-dried 15 mL vial equipped with magnetic stir bar was charged with 8-(1- aminoethyl)-3-isopropyl-6-methyl-2-morpholinoquinazolin-4(3H )-one (200 mg, 605 μmol), methyl 2-oxocyclohexane-1-carboxylate (284 mg, 1.82 mmol), Ir(ppy) ₂ (dtbbpy)PF ₆ (9.22 mg, 10.1 μmol), chloro-bis[[(Z)-[(2Z)-2-hydroxyimino-1-methylpropylidene]ami no]oxy]cobalt pyridine (8.15 mg, 20.2 μmol), acetic acid (6.06 mg, 101 μmol), 1,4-diazabicyclo[2.2.2]octane (84.9 mg, 757 μmol) in acetonitrile (3 mL). The reaction mixture was degassed by bubbling nitrogen stream, then irradiated with two 34 W blue LED lamps (at approximately 7 cm away) as the light source to keep the reaction temperature at 25 °C for 14 hr. On completion, the reaction was concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give methyl 2-((1-(3-isopropyl-6-methyl-2-morpholino- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (90 mg, 193 μmol, 38%) as a yellow solid. m/z ES+ [M+H] ⁺ 465.3. [1060] Step 7. Synthesis of 2-((1-(3-isopropyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1061] To a solution of methyl 2-((1-(3-isopropyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (90 mg, 193 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (24.4 mg, 581 μmol). The mixture was stirred at 40 °C for 8 hr. On completion, the reaction was adjusted to pH = 7~8 with sat. sodium bicarbonate and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0~30% ethylacetate/petroleum ether gradient @ 50 mL/min) to give 2-((1-(3-isopropyl-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (2 g, 5.46 mmol, 69%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 - 8.05 (m, 1H), 8.02 - 7.95 (m, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.60 - 6.54 (m, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.50 - 5.40 (m, 1H), 4.97 - 4.86 (m, 1H), 3.91 (s, 4H), 3.34 - 3.18 (m, 4H), 2.37 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H), 1.68 - 1.63 (m, 6H); m/z ES+ [M+H] ⁺ 451.0. Example 5. Preparation of 2-((1-(3-(cyclobutylmethyl)-6-methyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1062] Step 1. Synthesis of 2-amino-3-bromo-N-(cyclobutylmethyl)-5-methylbenzamide [1063] To a solution of 2-amino-3-bromo-5-methylbenzoic acid (5 g, 21.7 mmol) and cyclobutylmethanamine (3.96 g, 32.6 mmol, HCl) in N,N-dimethylformamide (50 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (12.4 g, 32.6 mmol) and diisopropylethylamine (11.2 g, 86.9 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was dilluted in water (1 L) and filtered. And the filter cake was collected to give 2-amino-3-bromo-N- (cyclobutylmethyl)-5-methylbenzamide (5.85 g, 19.5 mmol, 90%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (s, 1H), 7.07 (s, 1H), 6.02 (s, 1H), 5.15 - 4.16 (m, 2H), 3.51 - 3.36 (m, 2H), 2.69 - 2.52 (m, 1H), 2.35 - 2.21 (m, 3H), 2.18 - 2.05 (m, 2H), 1.99 - 1.85 (m, 2H), 1.81 - 1.66 (m, 2H). [1064] Step 2. Synthesis of 8-bromo-2-chloro-3-(cyclobutylmethyl)-6-methylquinazolin- 4(3H)-one [1065] To a solution of 2-amino-3-bromo-N-(cyclobutylmethyl)-5-methylbenzamide (5.85 g, 19.7 mmol) in 1,4-dioxane (60 mL) was added thiocarbonyl dichloride (4.75 g, 41.3 mmol), the mixture was stirred at 25 °C for 1 hr under nitrogen amosphere. Then the mixture was stirred at 105 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 8- bromo-2-chloro-3-(cyclobutylmethyl)-6-methylquinazolin-4(3H) -one (5.94 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 343.1. [1066] Step 3. Synthesis of 8-bromo-3-(cyclobutylmethyl)-6-methyl-2- morpholinoquinazolin-4(3H)-one [1067] To a solution of 8-bromo-2-chloro-3-(cyclobutylmethyl)-6-methylquinazolin-4(3 H)- one (1.5 g, 4.39 mmol) in dichloromethane (30 mL) was added morpholine (1.15 g, 13.2 mmol). The mixture was stirred at 40 °C for 16 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0~10% ethylacetate/petroleum ether gradient @ 100 mL/min) to give 8-bromo-3-(cyclobutylmethyl)-6-methyl-2-morpholinoquinazolin -4(3H)-one (2.1 g, 5.33 mmol, 61%) as a yellow solid. m/z ES+ [M+H] ⁺ 393.8. [1068] Step 4. Synthesis of 8-acetyl-3-(cyclobutylmethyl)-6-methyl-2- morpholinoquinazolin-4(3H)-one [1069] To a solution of 8-bromo-3-(cyclobutylmethyl)-6-methyl-2-morpholinoquinazolin - 4(3H)-one (1 g, 2.55 mmol) in toluene (20 mL) was added tetrakis(triphenylphosphine)palladium (589 mg, 510 μmol) and tributyl(1- ethoxyvinyl)stannane (2.76 g, 7.65 mmol), the mixture was stirred at 125 °C for 16 hr under nitrogen atmosphere. Then the mixture was added hydrochloric acid (1 M, 5.10 mL) at 25 °C and stirred for 30 min. On completion, the reaction was adjusted to pH = 7~8 with sat. sodium bicarbonate and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0~30% ethylacetate/petroleum ether gradient @ 50 mL/min) to give 8-acetyl-3-(cyclobutylmethyl)-6-methyl-2-morpholinoquinazoli n- 4(3H)-one (670 mg, 1.88 mmol, 74%) as a yellow solid. m/z ES+ [M+H] ⁺ 355.9. [1070] Step 5. Synthesis of 8-(1-aminoethyl)-3-(cyclobutylmethyl)-6-methyl-2- morpholinoquinazolin-4(3H)-one [1071] To a solution of 8-acetyl-3-(cyclobutylmethyl)-6-methyl-2-morpholino-quinazol in-4- one (400 mg, 1.13 mmol) in methanol (4 mL) was added ammonium acetate (867 mg, 11.2 mmol) and sodium cyanoborohydride (70.7 mg, 1.13 mmol). Then the mixture was stirred at 120 °C for 1 hr under microwave irradiation. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% ammonium hydroxide conditions) to give 8-(1-aminoethyl)-3-(cyclobutylmethyl)-6-methyl-2-morpholinoq uinazolin- 4(3H)-one (400 mg, 1.12 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 357.2. [1072] Step 6. Synthesis of methyl 2-((1-(3-(cyclobutylmethyl)-6-methyl-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1073] To a solution of 8-(1-aminoethyl)-3-(cyclobutylmethyl)-6-methyl-2- morpholinoquinazolin-4(3H)-one (150 mg, 421 μmol) and methyl 2-bromobenzoate (181 mg, 842 μmol) in toluene (2 mL) was added tris(dibenzylideneacetone)dipalladium (38.5 mg, 42.1 μmol), cesium carbonate (411 mg, 1.26 mmol) and dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (19.6 mg, 42.1 μmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~30% ethylacetate/petroleum ether gradient @ 40 mL/min) to give methyl 2-((1-(3- (cyclobutylmethyl)-6-methyl-2-morpholino-4-oxo-3,4-dihydroqu inazolin-8- yl)ethyl)amino)benzoate (112 mg, 228 μmol, 54%) as a yellow solid. m/z ES+ [M+H] ⁺ 491.3. [1074] Step 7. Synthesis of 2-((1-(3-(cyclobutylmethyl)-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1075] To a solution of methyl 2-((1-(3-isopropyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (112 mg, 228 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (47.9 mg, 1.14 mmol). The mixture was stirred at 40 °C for 16 hr. On completion, the mixture was adjusted to pH ~ 6 by adding aqueous hydrochloric acid (1 N). Then the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water(FA)-acetonitrile]; B%: 50%-80%, 7 min) to give 2-((1-(3-(cyclobutylmethyl)-6- methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)a mino)benzoic acid (37.0 mg, 77.7 μmol, 34%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.39 - 8.05 (m, 1H), 8.02 - 7.95 (m, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.60 - 6.54 (m, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.50 - 5.39 (m, 1H), 4.95 - 4.86 (m, 1H), 3.91 (s, 4H), 3.34 - 3.18 (m, 4H), 2.37 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H), 1.68 - 1.62 (m, 6H); m/z ES+ [M+H] ⁺ 477.0. Example 6 and Example 7. Preparation of (R)-2-((1-(3-(cyclobutylmethyl)-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid and S)-2-((1-(3- (cyclobutylmethyl)-6-methyl-2-morpholino-4-oxo-3,4-dihydroqu inazolin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1076] Racemate 2-((1-(3-(Cyclobutylmethyl)-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (35 mg, 73.4 μmol) was purified by SFC (column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% NH3·H2O- MeOH]; B%: 45%-45%, 3.7 min) to give (R)-2-((1-(3-(cyclobutylmethyl)-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (5.29 mg, 11.1 μmol, 15%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.34 - 8.09 (m, 1H), 8.01 - 7.94 (m, 1H), 7.90 - 7.86 (m, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.22 - 7.16 (m, 1H), 6.59 - 6.54 (m, 1H), 6.49 (d, J = 8.8 Hz, 1H), 5.53 - 5.42 (m, 1H), 4.33 - 4.13 (m, 2H), 4.00 - 3.84 (m, 4H), 3.33 - 3.15 (m, 4H), 2.85 - 2.73 (m, 1H), 2.38 (s, 3H), 2.07 - 1.94 (m, 2H), 1.90 - 1.76 (m, 4H), 1.64 (d, J = 6.8 Hz, 3H); m/z ES ⁺ [M+H] ⁺ 477.0 and (S)-2-((1-(3-(cyclobutylmethyl)-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (10.07 mg, 21.1 μmol, 29%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 - 8.07 (m, 1H), 7.99 - 7.93 (m, 1H), 7.90 - 7.86 (m, 1H), 7.51 - 7.45 (m, 1H), 7.22 - 7.14 (m, 1H), 6.59 - 6.52 (m, 1H), 6.51 - 6.46 (m, 1H), 5.55 - 5.35 (m, 1H), 4.32 - 4.11 (m, 2H), 3.96 - 3.81 (m, 4H), 3.29 - 3.13 (m, 4H), 2.90 - 2.75 (m, 1H), 2.42 - 2.30 (m, 3H), 2.06 - 1.98 (m, 2H), 1.89 - 1.77 (m, 4H), 1.66 - 1.59 (m, 3H); m/z ES+ [M+H] ⁺ 477.0. Example 8. Preparation of 2-((1-(6-methyl-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1077] Step 1. Synthesis of 2-amino-3-bromo-5-methyl-N-(2,2,2-trifluoroethyl)benzamide [1078] To a mixture of 2-amino-3-bromo-5-methyl-benzoic acid (4 g, 17.4 mmol) and 2,2,2- trifluoroethanamine (2.58 g, 26.1 mmol, 2.05 mL) in N,N-dimethylformamide (50 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (9.92 g, 26.1 mmol), N,N- diisopropylethylamine (4.49 g, 34.7 mmol, 6.1 mL) in one portion. The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was triturated with water (500 mL) at 25 °C for 30 min to give 2-amino-3-bromo-5-methyl-N-(2,2,2-trifluoroethyl)benzamide (5 g, 16.1 mmol, 92%) as a yellow solid. m/z ES+ [M+H] ⁺ 311.1. [1079] Step 2. Synthesis of 8-bromo-2-chloro-6-methyl-3-(2,2,2-trifluoroethyl)quinazolin - 4(3H)-one [1080] To a solution of 2-amino-3-bromo-5-methyl-N-(2,2,2-trifluoroethyl)benzamide (5 g, 16.1 mmol) in 1,4-dioxane (50 mL) was added thiocarbonyl dichloride (3.88 g, 33.8 mmol). The mixture was stirred at 25 °C for 1 h. Then the mixture was stirred at 105 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give 8-bromo-2- chloro-6-methyl-3-(2,2,2-trifluoroethyl)quinazolin-4-one (5.7 g, 12.5 mmol, 78%) as a yellow solid. m/z ES+ [M+H] ⁺ 357.0. [1081] Step 3. Synthesis of 8-bromo-6-methyl-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one [1082] A mixture of 8-bromo-2-chloro-6-methyl-3-(2,2,2-trifluoroethyl)quinazolin -4-one (5.7 g, 16.0 mmol) and morpholine (4.19 g, 48.1 mmol, 4.2 mL) in dichloromethane (60 mL) was heated to 40 °C and stirred for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 3/1) to give 8-bromo-6-methyl-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4-one (5 g, 10.2 mmol, 64%) as a yellow solid. m/z ES+ [M+H] ⁺ 406.2. [1083] Step 4. Synthesis of 8-acetyl-6-methyl-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one [1084] To a solution of 8-bromo-6-methyl-2-morpholino-3-(2,2,2-trifluoroethyl)quinaz olin- 4-one (3 g, 7.39 mmolq) in toluene (30 mL) was added palladium(II)bis(triphenylphosphine) dichloride (1.04 g, 1.48 mmol) and tributyl(1-ethoxyvinyl)stannane (8.00 g, 22.2 mmol, 7.48 mL). The mixture was stirred at 130 °C for 12 hr under nitrogen. The reaction mixture was then added hydrogen chloride (1 M, 0.5 mL) at 25 °C and stirred for 30 min. On completion, the reaction mixture was quenched with water (100 mL) at 20 °C, and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-6-methyl- 2-morpholino-3-(2,2,2-trifluoroethyl)quinazolin-4-one (2.3 g, 5.54 mmol, 75%) as a yellow solid. m/z ES+ [M+H] ⁺ 370.3. [1085] Step 5. Synthesis of 8-(1-aminoethyl)-6-methyl-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one [1086] To a solution of 8-acetyl-6-methyl-2-morpholino-3-(2,2,2-trifluoroethyl)quina zolin-4- one (300 mg, 812 μmol) in methanol (10 mL) was added ammonium acetate (626 mg, 8.12 mmol) and sodium cyanoborohydride (66.4 mg, 1.06 mmol). The reaction mixture was stirred at 60 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1- aminoethyl)-6-methyl-2-morpholino-3-(2,2,2-trifluoroethyl)qu inazolin-4-one (160 mg, 428 μmol, 53%) as a yellow solid. m/z ES+ [M+H] ⁺ 371.2. [1087] Step 6. Synthesis of methyl 2-((1-(6-methyl-2-morpholino-4-oxo-3-(2,2,2- trifluoroethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzo ate [1088] To a mixture of 8-(1-aminoethyl)-6-methyl-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4-one (150 mg, 405. μmol) and methyl 2-bromobenzoate (131 mg, 608 μmol) in toluene (5 mL) was added cesium carbonate (396 mg, 1.22 mmol), tris(dibenzylideneacetone)dipalladium (37.1 mg, 40.5 μmol), methanesulfonato(2- dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2-amino -1,1-biphenyl-2-yl) (18.9 mg, 40.5 μmol) in one portion under nitrogen atmosphere. The mixture was then heated to 110 °C and stirred for 3 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=3/1) to give methyl 2-[1-[6-methyl-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)qu inazolin-8- yl]ethylamino]benzoate (110 mg, 212 μmol, 52%) as a yellow oil. m/z ES+ [M+H] ⁺ 505.4. [1089] Step 7. Synthesis of 2-((1-(6-methyl-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)- 3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1090] To a mixture of methyl 2-[1-[6-methyl-2-morpholino-4-oxo-3-(2,2,2- trifluoroethyl)quinazolin-8-yl]ethylamino]benzoate (100 mg, 198 μmol) in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (41.6 mg, 991 μmol) in one portion. The mixture was then heated to 80 °C and stirred for 2 hr. On completion, the reaction mixture was quenched with hydrochloric acid solution (1 N) to adjust pH ~ 5, and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)-acetonitrile]; B%: 48%-78%, 10 min) to give 2-[1-[6-methyl-2-morpholino-4-oxo-3-(2,2,2- trifluoroethyl)quinazolin-8-yl]ethylamino]benzoic acid (24.79 mg, 50.54 μmol, 26%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.92 - 12.46 (m, 1H), 8.47 - 8.46 (m, 1H), 7.78 - 7.76 (m, 2H), 7.59 (d, J = 1.6 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.60 - 6.46 (m, 2H), 5.38 (br. t, J = 6.4 Hz, 1H), 4.96 (br. dd, J = 6.0, 8.8 Hz, 2H), 3.77 (br. s, 4H), 3.22 - 3.13 (m, 4H), 2.35 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 491.0. Example 9 and Example 10. Preparation of 2-[[(1R)-1-[6-methyl-2-morpholino-4-oxo-3- (2,2,2-trifluoroethyl)quinazolin-8-yl]ethyl]amino]benzoic acid and 2-[[(1S)-1-[6-methyl- 2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)quinazolin-8-yl]e thyl]amino]benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1091] Racemate 2-[1-[6-methyl-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)qu inazolin-8- yl]ethylamino]benzoic acid (20 mg, 40.78 μmol) was separated by SFC (column: Daicel CHIRALPAK AD (250 x 30mm, 10 um); mobile phase: [0.1%NH3H2O IPA]; B%: 35%-35%, 2.2 min) to give 2-[[(1R)-1-[6-methyl-2-morpholino-4-oxo-3-(2,2,2-trifluoroet hyl)quinazolin- 8-yl]ethyl]amino]benzoic acid (6.48 mg, 13.21 μmol, 32%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.22 - 8.12 (m, 1H), 8.02 - 7.90 (m, 2H), 7.57 (d, J = 1.6 Hz, 1H), 7.26 - 7.11 (m, 1H), 6.58 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.55 - 5.42 (m, 1H), 5.03 - 4.81 (m, 2H), 3.90 (t, J = 4.8 Hz, 4H), 3.20 (q, J = 4.0 Hz, 4H), 2.40 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 491.2 and 2-[[(1S)-1-[6-methyl-2-morpholino-4-oxo-3-(2,2,2- trifluoroethyl)quinazolin-8-yl]ethyl]amino]benzoic acid (4.89 mg, 9.97 μmol, 24%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 - 8.12 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.58 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 8.8 Hz, 1H), 5.49 (q, J = 6.4 Hz, 1H), 5.01 - 4.78 (m, 2H), 3.90 (t, J = 4.8 Hz, 4H), 3.26 - 3.14 (m, 4H), 2.40 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 491.2. Example 11. Preparation of 3-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzonitrile [1092] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (80 mg, 265 μmol) in toluene (1 mL) was added 3-bromobenzonitrile (144 mg, 794 μmol), tris(dibenzylideneacetone)dipalladium (24 mg, 26.5 μmol), cesium carbonate (259 mg, 794 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (12.4 mg, 26.5 μmol). The mixture was stirred at 110 °C for 12 h under nitrogen. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The organic phase was dried over sodium sulfate, filtered and then concentrated in vacuo. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water (FA)- acetonitrile]; B%: 46%-76%, 2 min) to give 3-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzonitrile (27.3 mg, 67 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 7.6, 9.2 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.78 - 6.70 (m, 2H), 5.25 (q, J = 6.4 Hz, 1H), 4.82 (d, J = 2.0 Hz, 1H), 3.95 - 3.89 (m, 4H), 3.63 (s, 3H), 3.32 - 3.26 (m, 4H), 2.40 (s, 3H), 1.58 (s, 3H); m/z ES+ [M+H] ⁺ 404.0. Example 12. Preparation of 8-(1-((2-fluorophenyl)amino)ethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one [1093] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (100 mg, 331 μmol) in toluene (1 mL) was added 1-bromo-2-fluoro-benzene (174 mg, 992 μmol), tris(dibenzylideneacetone)dipalladium (30.3 mg, 33.1 μmol), cesium carbonate (323 mg, 992 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (15.4 mg, 33.1 μmol). The mixture was stirred at 110 °C for 12 hr. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resudue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 49%-79%, 10 min) to give 8-(1-((2-fluorophenyl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one (26.6 mg, 66.5 μmol, 20%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 6.99 - 6.89 (m, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.61 - 6.48 (m, 2H), 5.25 - 5.13 (m, 1H), 5.05 (br. d, J = 1.6 Hz, 1H), 3.95 - 3.86 (m, 4H), 3.61 (s, 3H), 3.32 - 3.24 (m, 4H), 2.40 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 396.9. Example 13. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzonitrile [1094] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (80 mg, 265 μmol) in toluene (1 mL) was added 2-bromobenzonitrile (144 mg, 794 μmol), tris(dibenzylideneacetone)dipalladium (24.2 mg, 26.5 μmol), cesium carbonate (259 mg, 794 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (12.4 mg, 26.5 μmol). The mixture was stirred at 110 °C for 12 h under nitrogen. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep- HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 50%-80%, 8 min) to give 2-((1-(3,6-dimethyl-2-morpholino- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzonitrile (40.1 mg, 94.1 μmol, 36%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 1.6, 7.6 Hz, 1H), 7.26 - 7.18 (m, 1H), 6.61 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 5.54 (br. d, J = 7.2 Hz, 1H), 5.27 (quin, J = 6.8 Hz, 1H), 3.91 (t, J = 4.8 Hz, 4H), 3.62 (s, 3H), 3.36 - 3.26 (m, 4H), 2.41 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 404.2. Example 14. Preparation of 8-(1-((3-fluorophenyl)amino)ethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one [1095] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-o ne (80 mg, 264 μmol) and 1-bromo-3-fluorobenzene (139 mg, 794 μmol) in toluene (1 mL) was added tris(dibenzylideneacetone)dipalladium (24.2 mg, 26.5 μmol), cesium carbonate (259 mg, 794 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (12.3 mg, 26.5 μmol). The mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50mm x 3 um; mobile phase: [water(FA)- acetonitrile]; B%: 45%-75%, 7 min) to give 8-(1-((3-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2-morpholinoquinazolin-4(3H)-one (17.8 mg, 44.4 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 0.8 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.06 - 6.97 (m, 1H), 6.35 - 6.20 (m, 3H), 5.26 - 5.18 (m, 1H), 4.91 - 4.65 (m, 1H), 3.99 - 3.78 (m, 4H), 3.62 (s, 3H), 3.37 - 3.22 (m, 4H), 2.40 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 397.2. Example 15. Preparation of 3,6-dimethyl-8-(1-((3-(methyls^Lfonyl)phenyl)amino)ethyl)- 2-morpholinoquinazolin-4(3H)-one [1096] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-o ne (80 mg, 265 μmol) and 1-bromo-3-(methylsulfonyl)benzene (187 mg, 794 μmol) in toluene (1 mL) was added tris(dibenzylideneacetone)dipalladium (24.2 mg, 26.5 μmol), cesium carbonate (259 mg, 794 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (12.3 mg, 26.5 μmol). The mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 um; mobile phase: [water(FA)-acetonitrile]; B%: 35%-65%, 7 min) to give 3,6-dimethyl-8-(1-((3- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one (34.3 mg, 75.1 μmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 0.8 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.16 - 7.10 (m, 2H), 6.74 - 6.70 (m, 1H), 5.35 - 5.26 (m, 1H), 5.17 - 4.85 (m, 1H), 3.94 - 3.88 (m, 4H), 3.62 (s, 3H), 3.33 - 3.26 (m, 4H), 2.92 (s, 3H), 2.39 (s, 3H), 1.61 (d, J = 6.7 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 16. Preparation of 3,6-Dimethyl-8-(1-((2-(methyls^Lfonyl)phenyl)amino)ethyl)- 2-morpholinoquinazolin-4(3H)-one [1097] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (80.0 mg, 265 μmol) in toluene (1 mL) was added 1-bromo-2-methylsulfonyl-benzene (187 mg, 794 μmol), tris(dibenzylideneacetone)dipalladium (24.2 mg, 26.5 μmol), cesium carbonate (259 mg, 794 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (12.4 mg, 26.5 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 44%-74%, 10 min) to give 3,6-dimethyl-8-(1-((2- (methyls^Lfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one (6.79 mg, 14.9 μmol, 6%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.26 - 7.21 (m, 1H), 6.77 (d, J = 6.8 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 5.49 - 5.36 (m, 1H), 3.92 - 3.87 (m, 4H), 3.62 (s, 3H), 3.33 - 3.26 (m, 4H), 3.11 (s, 3H), 2.38 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 17 and Example 18. Preparation of (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one and (S)-3,6- dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-morp holinoquinazolin-4(3H)- one (stereochemistry arbitrarily assigned for both enantiomers) [1098] Step 1. Synthesis of 3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2- morpholinoquinazolin-4(3H)-one [1099] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (0.32 g, 1.06 mmol) in toluene (5 mL) was added 1-bromo-2-methylsulfonyl-benzene (746 mg, 3.17 mmol), tris(dibenzylideneacetone)dipalladium (96.91 mg, 106 μmol), cesium carbonate (1.03 g, 3.17 mmol), and dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (49.4 mg, 106 μmol). The mixture was stirred at 110 °C for 12 h under nitrogen. On completion, the mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 45%-75%, 2 min) to give 3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one (50 mg, 104 μmol, 9.8%) as a white solid. m/z ES+ [M+H] ⁺ 457.3. [1100] Step 2. Chiral purification [1101] The racemate product was separated by prep-SFC (column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 60%-60%, 5.5 min) to give (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )-2- morpholinoquinazolin-4(3H)-one (20.49 mg, 44.9 μmol, 41%). ¹ H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 1.2 Hz, 1H), 7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.26 - 7.21 (m, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.75 - 6.67 (m, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.44 (q, J = 6.8 Hz, 1H), 3.94 - 3.87 (m, 4H), 3.62 (s, 3H), 3.32 - 3.26 (m, 4H), 3.11 (s, 3H), 2.38 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2 and and (S)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one (21.2 mg, 46.4 μmol, 42%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 1.2 Hz, 1H), 7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.26 - 7.19 (m, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.74 - 6.67 (m, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.44 (q, J = 6.8 Hz, 1H), 3.93 - 3.87 (m, 4H), 3.62 (s, 3H), 3.32 - 3.27 (m, 4H), 3.11 (s, 3H), 2.38 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 19. Preparation of 2-[1-(6-chloro-3-methyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoic acid [1102] Step 1. Synthesis of 2-amino-3-bromo-5-chloro-N-methyl-benzamide [1103] To a solution of 2-amino-3-bromo-5-chloro-benzoic acid (2.00 g, 7.98 mmol) in N,N- dimethylformamide (20 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (4.55 g, 12.0 mmol), methanamine;hydrochloride (1.08 g, 15.9 mmol) and diisopropylethylamine (4.13 g, 31.9 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was poured into water (50 mL) and then filtered. The filter cake was collected to give 2-amino-3- bromo-5-chloro-N-methyl-benzamide (2.50 g, crude) as a gray solid. m/z ES+ [M+H] ⁺ 262.9. [1104] Step 2. Synthesis of 8-bromo-2,6-dichloro-3-methyl-quinazolin-4-one [1105] To a solution of 2-amino-3-bromo-5-chloro-N-methyl-benzamide (1.00 g, 3.79 mmol) in 1,4-dioxane (10 mL) was added thiocarbonyl dichloride (916 mg, 7.97 mmol). The mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 105 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 8-bromo-2,6-dichloro-3- methyl-quinazolin-4-one (1.00 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 306.9. [1106] Step 3. Synthesis of 8-bromo-6-chloro-3-methyl-2-morpholino-quinazolin-4-one [1107] To a solution of 8-bromo-2,6-dichloro-3-methyl-quinazolin-4-one (1.00 g, 3.25 mmol) in dichloromethane (10 mL) was added morpholine (1.42 g, 16.2 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (water (0.1%FA)- acetonitrile]; B%: 30%-70%, 7 min) to give 8-bromo-6-chloro-3-methyl-2-morpholino- quinazolin-4-one (800 mg, 2.23 mmol, 68%) as a red solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 3.81 - 3.72 (m, 4H), 3.46 (s, 3H), 3.29 (s, 4H). [1108] Step 4. Synthesis of 8-acetyl-6-chloro-3-methyl-2-morpholino-quinazolin-4-one [1109] To a solution of 8-bromo-6-chloro-3-methyl-2-morpholino-quinazolin-4-one (700 mg, 1.95 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (451 mg, 390 μmol) and tributyl(1-ethoxyvinyl)stannane (1.41 g, 3.90 mmol). The mixture was stirred at 130 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was added hydrochloric acid (1 M, 5 mL) at 25 °C and stirred for 30 min. The reaction was adjusted to pH = 7~8 with saturated sodium bicarbonate and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-acetyl-6-chloro-3- methyl-2-morpholino-quinazolin-4-one (400 mg, 808 μmol, 41%) as a white solid. m/z ES+ [M+H] ⁺ 322.0. [1110] Step 5. Synthesis of 8-(1-aminoethyl)-6-chloro-3-methyl-2-morpholino-quinazolin-4 - one [1111] To a solution of 8-acetyl-6-chloro-3-methyl-2-morpholino-quinazolin-4-one (350 mg, 1.09 mmol) in methanol (4 mL) was added ammonium acetate (838 mg, 10.8 mmol) and sodium cyanoborohydride (102 mg, 1.63 mmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (water (0.1% FA)-acetonitrile]; B%: 1%-30%, 7 min) to give 8-(1-aminoethyl)-6-chloro-3-methyl-2-morpholino-quinazolin-4 -one (400 mg, 1.06 mmol, 97%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.09 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 5.23 - 5.06 (m, 1H), 3.91 - 3.85 (m, 4H), 3.60 (s, 3H), 3.40 - 3.33 (m, 4H), 1.74 (d, J = 6.8 Hz, 3H). [1112] Step 6. Synthesis of methyl 2-[1-(6-chloro-3-methyl-2-morpholino-4-oxo-quinazolin- 8-yl)ethylamino]benzoate [1113] An oven-dried 15 mL vial equipped with magnetic stir bar was charged with 8-(1- aminoethyl)-6-chloro-3-methyl-2-morpholino-quinazolin-4-one (350 mg, 1.08 mmol), methyl 2-oxocyclohexanecarboxylate (846 mg, 5.42 mmol), Ir(ppy) ₂ (dtbbpy)PF ₆ (19.8 mg, 21.6 μmol), chloro-bis[[(Z)-[(2Z)-2-hydroxyimino-1- methylpropylidene]amino]oxy]cobalt;pyridine (17.5 mg, 43.3 μmol), acetic acid (13.0 mg, 216 μmol) and 1,4-diazabicyclo[2.2.2]octane (364 mg, 3.25 mmol) in acetonitrile (15 mL). The reaction mixture was degassed by bubbling nitrogen stream, then irradiated with two 34 W blue LED lamps (at approximately 7 cm away) as the light source to keep the reaction temperature at 25 °C for 14 hr. On completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (water (0.1%FA)- acetonitrile]; B%: 60%-100%, 7 min) to give methyl 2-[1-(6-chloro-3-methyl-2-morpholino- 4-oxo-quinazolin-8-yl)ethylamino]benzoate (80.0 mg, 175 μmol, 16%) as a white solid. m/z ES+ [M+H] ⁺ 457.2. [1114] Step 7. Synthesis of 2-[1-(6-chloro-3-methyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoic acid [1115] To a solution of methyl 2-[1-(6-chloro-3-methyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoate (60.0 mg, 131 μmol) in tetrahydrofuran (0.2 mL), methanol (0.1 mL) and water (0.1 mL) was added lithium hydroxide monohydrate (15.7 mg, 656 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (FA)-acetonitrile]; B%:42%-72%, 7 min) to give 2-[1- (6-chloro-3-methyl-2-morpholino-4-oxo-quinazolin-8-yl)ethyla mino]benzoic acid (27.17 mg, 60.0 μmol, 45%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.81 - 7.70 (m, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.52 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.36 (s, 1H), 3.81 - 3.75 (m, 4H), 3.50 (s, 3H), 2.52 - 2.52 (m, 4H), 1.59 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 443.2. Example 20 and Example 21. Preparation of (R)-2-((1-(6-chloro-3-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid and (S)-2-((1-(6- chloro-3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1116] The racemic mixture, 2-[1-(6-chloro-3-methyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoic acid (0.023 g, 51.9 μmol) was separated by SFC (column: Daicel CHIRALCEL OD (250 mm x 30, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 60%-60%, 5.9 min) to give (R)-2-((1-(6-chloro-3-methyl-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (8.00 mg, 18.1 μmol, 35%) as a _{white solid.} ^{1H NMR (400 MHz, CD} ₃ ^{OD) į 8.00 - 7.80 (m, 2H), 7.59 (d, J = 1.6 Hz, 1H), 7.12} (t, J = 7.6 Hz, 1H), 6.52 (t, J = 7.2 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.46 (q, J = 6.4 Hz, 1H), 3.93 - 3.84 (m, 4H), 3.61 (s, 3H), 3.39 - 3.33 (m, 4H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 443.1 and give (S)-2-((1-(6-chloro-3-methyl-2-morpholino-4-oxo-3,4-dihydroq uinazolin-8- yl)ethyl)amino)benzoic acid (7.00 mg, 15.8 μmol, 30%) as a white solid. ¹ H NMR (400 MHz, CD3OD) δ 7.91 (s, 2H), 7.72 - 7.51 (m, 1H), 7.23 - 6.95 (m, 1H), 6.72 - 6.23 (m, 2H), 5.60 - 5.33 (m, 1H), 3.88 (s, 4H), 3.61 (s, 3H), 3.35 (s, 4H), 1.60 (s, 3H); m/z ES+ [M+H] ⁺ 443.1. Example 22. Preparation of 2-((1-(3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid

[1117] Step 1. Synthesis of 8-bromo-3-methyl-2-morpholinoquinazolin-4(3H)-one [1118] To a solution of 8-bromo-2-chloro-3-methylquinazolin-4(3H)-one (600 mg, 2.19 mmol) in dichloromethane (6 mL) was added morpholine (573 mg, 6.58 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give 8-bromo-3-methyl-2-morpholinoquinazolin-4(3H)-one (400 mg, 1.23 mmol, 56%) as a yellow solid. m/z ES+ [M+H] ⁺ 324.2. [1119] Step 2. Synthesis of 8-acetyl-3-methyl-2-morpholinoquinazolin-4(3H)-one [1120] To a solution of 8-bromo-3-methyl-2-morpholinoquinazolin-4(3H)-one (900 mg, 2.78 mmol) in toluene (9 mL) was added palladium(II)bis(triphenylphosphine) dichloride (390 mg, 555 μmol) and tributyl(1-ethoxyvinyl)stannane (3.01 g, 8.33 mmol). The mixture was stirred at 130 °C for 12 hr under nitrogen atmosphere. Then the reaction mixture was added aqueous hydrochloric acid (1 M, 5 mL) at 25 °C and stirred for 30 minutes. On completion, the reaction was adjusted to pH = 7~8 with saturated sodium bicarbonate and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 1/1) to give 8-acetyl-3-methyl-2-morpholinoquinazolin-4(3H)-one (450 mg, 1.57 mmol, 56%) as a yellow solid. m/z ES+ [M+H] ⁺ 288.2. [1121] Step 3. Synthesis of 8-(1-aminoethyl)-3-methyl-2-morpholinoquinazolin-4(3H)-one [1122] To a solution of 8-acetyl-3-methyl-2-morpholinoquinazolin-4(3H)-one (400 mg, 1.39 mmol) in methanol (4 mL) was added ammonium acetate (2.15 g, 27.8 mmol) and sodium cyanoborohydride (87.5 mg, 1.39 mmol). The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions, H2O:acetonitrile=20:1 to 1:1) to give 8-(1-aminoethyl)-3-methyl-2-morpholinoquinazolin- 4(3H)-one (120 mg, 416 μmol, 30%) as a yellow solid. m/z ES+ [M+H] ⁺ 289.4. [1123] Step 4. Synthesis of methyl 2-((1-(3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1124] To a solution of 8-(1-aminoethyl)-3-methyl-2-morpholinoquinazolin-4(3H)-one (100 mg, 347 μmol) and methyl 2-oxocyclohexanecarboxylate (270 mg, 1.73 mmol) in acetonitrile (3 mL) was added bis[2-(2-pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-b utyl-2- pyridyl)pyridine;hexafluorophosphate (6.34 mg, 6.94 μmol), Co(dmgH)2pyCl (4.81 mg, 13.8 μmol), acetic acid (4.17 mg, 69.3 μmol) and 1,4-diazabicyclo[2.2.2]octane (58.5 mg, 520 μmol). The reaction mixture was degassed by bubbling nitrogen stream, then irradiated with two 34 W blue LED lamps (at approximately 7 cm away) as the light source to keep the reaction temperature at 25 °C for 14 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions, H2O:acetonitrile=20:1 to 1:1) to give methyl 2-((1-(3-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oate (25.0 mg, 59.1 μmol, 17%) as a yellow solid. m/z ES+ [M+H] ⁺ 423.3. [1125] Step 5. Synthesis of 2-((1-(3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid [1126] To a solution of methyl 2-((1-(3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoate (20.0 mg, 47.3 μmol) in tetrahydrofuran (0.1 mL), methanol (0.05 mL) and water (0.05 mL) was added lithium hydroxide monohydrate (5.67 mg, 236 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was acidified with aqueous hydrochloric acid (1 N) to adjust the pH = 3~4 and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase: [water (FA)-acetonitrile]; B%: 38%-68%, 10 min) to give 2-((1-(3-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (6.14 mg, 14.9 μmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.41 - 8.18 (m, 1H), 8.12 - 8.05 (m, 1H), 8.00 - 7.80 (m, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.26 (s, 1H), 7.20 (t, J = 7.2 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 5.58 - 5.40 (m, 1H), 4.01 - 3.86 (m, 4H), 3.65 (s, 3H), 3.35 - 3.10 (m, 4H), 1.68 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 409.2. Example 23 and Example 24. Preparation of (R)-2-((1-(3-methyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid and (S)-2-((1-(3-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (stereochemistry arbitrarily assigned for both enantiomers) [1127] The enantiomers of racemate ,2-((1-(3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (70 mg, 171 μmol) were purified by SFC (column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% NH ₃ -water, methanol]; B%: 55%-55%, 5.2 min) to give (R)-2-((1-(3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (27.23 mg, 66.7 μmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 - 8.07 (m, 1H), 8.03 - 8.00 (m, 1H), 7.91 - 7.85 (m, 1H), 7.63 - 7.59 (m, 1H), 7.17 (s, 1H), 7.14 - 7.08 (m, 1H), 6.48 - 6.40 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.43 - 5.30 (m, 1H), 3.88 - 3.78 (m, 4H), 3.56 (s, 3H), 3.25 - 3.20 (m, 4H), 1.59 - 1.10 (m, 3H); m/z ES+ [M+H] ⁺ 409.3; and (S)-2-((1-(3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (39.10 mg, 95.7 μmol, 55%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.20 - 8.06 (m, 1H), 8.03- 8.00 (m, 1H), 7.91 - 7.80 (m, 1H), 7.61 - 7.55 (m, 1H), 7.17 (s, 1H), 7.14 - 7.08 (m, 1H), 6.48 - 6.40 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.43 - 5.40 (m, 1H), 3.88 - 3.80 (m, 4H), 3.56 (s, 3H), 3.25 - 3.20 (m, 4H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 409.3. Example 25. Preparation of 2-[1-[3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid [1128] Step 1. Synthesis of 8-bromo-3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7- yl)quinazolin-4-one [1129] To a mixture of 8-bromo-2-chloro-3-methyl-quinazolin-4-one (1.00 g, 367 μmol) and 2-oxa-7-azaspiro[3.4]octane (96.6 mg, 475 μmol, oxalic acid) in tetrahydrofuran (2 mL) was added diisopropylethylamine (236 mg, 1.83 mmol) in one portion. The mixture was then heated to 60 °C and stirred for 2 hr. On completion, the reaction mixture was quenched with water (50 mL) at 20 °C, and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-3-methyl-2-(2-oxa-7-azaspiro[3.4]octan- 7-yl)quinazolin-4-one (130 mg, 345 μmol, 94%) as a yellow solid. m/z ES+ [M+H] ⁺ 352.1. [1130] Step 2. Synthesis of 8-acetyl-3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7- yl)quinazolin-4-one [1131] To a mixture of 8-bromo-3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)quinazol in-4- one (400 mg, 1.14 mmol) and tributyl(1-ethoxyvinyl)stannane (825 mg, 2.28 mmol) in toluene (2 mL) was added palladium(II)bis(triphenylphosphine) dichloride (160 mg, 228 umo) in one portion under nitrogen. The mixture was then heated to 80 °C and stirred for 5 hr under nitrogen. Then the reaction mixture was added aqueous hydrochloric acid (1 M, 5 mL) at 25 °C and stirred for 30 min. On completion, the reaction mixture was quenched with aq. potassium fluoride solution (20 mL) at 20 °C, and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-3-methyl-2-(2-oxa-7- azaspiro[3.4]octan-7-yl)quinazolin-4-one (0.35 g, 793 μmol, 69%) as a yellow solid. m/z ES+ [M+H] ⁺ 314.0. [1132] Step 3. Synthesis of 8-(1-aminoethyl)-3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7- yl)quinazolin-4-one [1133] To a mixture of 8-acetyl-3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)quinazo lin-4- one (350 mg, 1.12 mmol) in methanol (8 mL) was added ammonium acetate (861 mg, 11.2 mmol) and sodium cyanoborohydride (105 mg, 1.68 mmol) in one portion. The mixture was then heated to 60 °C and stirred for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7- yl)quinazolin-4-one (160 mg, 445 μmol, 40%) as a yellow oil. m/z ES+ [M+H] ⁺ 315.2. [1134] Step 4. Synthesis of methyl 2-[1-[3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)-4- oxo-quinazolin-8-yl]ethylamino]benzoate [1135] To a mixture of 8-(1-aminoethyl)-3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7- yl)quinazolin-4-one (150 mg, 477 μmol) and methyl 2-bromobenzoate (513 mg, 2.39 mmol) in toluene (5 mL) was added methanesulfonato(2-dicyclohexylphosphino-2,6-di-i-propoxy- 1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl) (44.5 mg, 95.4 μmol), tris(dibenzylideneacetone)dipalladium (87.4 mg, 95.4 μmol) and cesium carbonate (466 mg, 1.43 mmol) in one portion at 20 °C under nitrogen. The mixture was then heated to 110 °C and stirred for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=3/1) to give methyl 2-[1-[3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)-4-oxo-qui nazolin-8- yl]ethylamino]benzoate (120 mg, 214 μmol, 45%) as a yellow solid. m/z ES+ [M+H] ⁺ 449.3. [1136] Step 5. Synthesis of 2-[1-[3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid [1137] To a mixture of methyl 2-[1-[3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)-4-oxo- quinazolin-8-yl]ethylamino]benzoate (100 mg, 223 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (46.8 mg, 1.11 mmol) in one portion. The mixture was heated to 60 °C and stirred for 2 hr. On completion, The reaction mixture was quenched with aqueous hydrochloric acid to adjust pH ~ 4.0, and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water (FA)-acetonitrile]; B%: 33%-63%, 10 min) to give 2-[1-[3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid (34.8 mg, 80.1 μmol, 36%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.64 - 12.59 (m, 1H), 8.46 - 8.43 (m, 1H), 7.85 (dd, J = 1.6, 8.0 Hz, 1H), 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.54 (dd, J = 1.2, 7.6 Hz, 1H), 7.20 - 7.09 (m, 2H), 6.52 - 6.40 (m, 2H), 5.42 - 5.32 (m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.56 - 4.50 (m, 2H), 3.93 - 3.77 (m, 2H), 3.62 (t, J = 6.8 Hz, 3H), 3.46 (s, 3H), 2.49 - 2.48 (m, 2H), 2.26 - 2.15 (m, 2H), 1.57 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 435.2. Example 26 and Example 27. Preparation of 2-[[(1R)-1-[3-methyl-2-(2-oxa-7- azaspiro[3.4]octan-7-yl)-4-oxo-quinazolin-8-yl]ethyl]amino]b enzoic acid and 2-[[(1S)-1- [3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)-4-oxo-quinazol in-8- yl]ethyl]amino]benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1138] The pure enantiomers of racemate 2-[1-[3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7- yl)-4-oxo-quinazolin-8-yl]ethylamino]benzoic acid (30 mg, 69.1 μmol) were separated with SFC (column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1%NH3- water methanol]; B%: 50%-50%, 4.1 min) to give 2-[[(1R)-1-[3-methyl-2-(2-oxa-7- azaspiro[3.4]octan-7-yl)-4-oxo-quinazolin-8-yl]ethyl]amino]b enzoic acid (15.2 mg, 34.9 μmol, 51%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 1.2, 8.0 Hz, 1H), 7.98 (dd, J = 1.6, 8.0 Hz, 1H), 7.66 - 7.62 (m, 1H), 7.21 - 7.15 (m, 2H), 6.55 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 8.8 Hz, 1H), 5.45 (q, J = 6.4 Hz, 1H), 4.80 - 4.74 (m, 2H), 4.73 - 4.68 (m, 2H), 3.85 (d, J = 1.6 Hz, 2H), 3.63 - 3.55 (m, 5H), 2.39 - 2.26 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H). m/z ES+ [M+H] ⁺ 435.4; and 2-[[(1S)-1-[3-methyl-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)-4-o xo- quinazolin-8-yl]ethyl]amino]benzoic acid (14.6 mg, 33.5 μmol, 49%) as a with solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J = 7.6 Hz, 1H), 7.98 (br. d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.18 (dt, J = 3.6, 7.2 Hz, 2H), 6.55 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 8.8 Hz, 1H), 5.45 (br. d, J = 6.8 Hz, 1H), 4.80 - 4.74 (m, 2H), 4.73 - 4.68 (m, 2H), 3.84 (s, 2H), 3.65 - 3.55 (m, 5H), 2.37 - 2.25 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 435.4. Example 28. Preparation of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1139] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one [1140] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (1.00 g, 3.48 mmol) in dichloromethane (10 mL) was added piperidine (1.48 g, 17.4 mmol). The mixture was stirred at 40 °C for 12 hr. The mixture was concentrated in vacuo. The residue was triturated in petroleum ether/ethyl acetate (10/1, 100 mL) for 10 min and then filtered. The filter cake was collected and concentrated in vacuo to give 8-bromo-3,6-dimethyl-2-(piperidin-1- yl)quinazolin-4(3H)-one (1.00 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 338.0. [1141] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one [1142] To a soltion of 8-bromo-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (500 mg, 1.49 mmol) in toluene (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.61 g, 4.46 mmol) and palladium(II)bis(triphenylphosphine) dichloride (104 mg, 148 μmol). The mixture was stirred at 110 °C for 12 hr. Then the reaction mixture was added aqueous hydrochloric acid (1 M, 5 mL) at 25 °C and stirred for 30 min. Then the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (0.33 g, 1.10 mmol, 74%) as a white solid. m/z ES+ [M+H] ⁺ 300.0. [1143] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin- 4(3H)-one [1144] To a solution of 8-acetyl-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (0.330 g, 1.10 mmol) in methanol (5 mL) was added ammonium acetate (1.70 g, 22.1 mmol) and sodium cyanoborohydride (69.3 mg, 1.10 mmol). The mixture was stirred at 60 °C for 1 hr. The mixture was quenched with water (1 mL) and then concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-(1-aminoethyl)-3,6-dimethyl-2- (piperidin-1-yl)quinazolin-4(3H)-one (300 mg, 866 μmol, 79%) as a white solid. m/z ES+ [M+H] ⁺ 301.2. [1145] Step 4. Synthesis of methyl 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1146] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-on e (300 mg, 866 μmol) in toluene (3.0 mL) was added methyl 2-bromobenzoate (559 mg, 2.60 mmol), tris(dibenzylideneacetone)dipalladium (79.3 mg, 86.6 μmol), cesium carbonate (846 mg, 2.60 mmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (40.4 mg, 86.6 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give methyl 2-((1-(3,6-dimethyl-4-oxo- 2-(piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoate (140 mg, 322 μmol, 37%) as a yellow solid. m/z ES+ [M+H] ⁺ 435.3. [1147] Step 5. Synthesis of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1148] To a solution of methyl 2-[1-[3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8- yl]ethylamino]benzoate (0.140 g, 322 μmol) in tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (67.6 mg, 1.61 mmol). The mixture was stirred at 40 °C for 12 hr. The reaction mixture was acidified with aqueous hydrochloric acid (1 N) to adjust the pH = 3~4 and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water (FA)- acetonitrile]; B%: 58%-88%, 2 min) to give 2-((1-(3,6-dimethyl-4-oxo-2- (piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (70.7 mg, 168 μmol, 52%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) 8.46 (s, 1H), 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.24 - 7.09 (m, 1H), 6.58 - 6.42 (m, 2H), 5.45 - 5.35 (m, 1H), 3.48 (s, 3H), 3.24 - 3.16 (m, 4H), 2.31 (s, 3H), 1.75 - 1.65 (m, 4H), 1.64 - 1.58 (m, 2H), 1.56 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 421.2. Example 29 and Example 30. Preparation of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(piperidin- 1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid & (S)-2-((1-(3,6-dimethyl-4- oxo-2-(piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amin o)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1149] The racemate product from Step 2 was separated by SFC (column (Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 35%-35%, 3.5 min) to give (R)-2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (25.34 mg, 60 μmol, 39%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.23 - 7.11 (m, 1H), 6.53 - 6.42 (m, 2H), 5.46 - 5.32 (m, 1H), 3.47 (s, 3H), 3.19 (d, J = 4.8 Hz, 4H), 2.31 (s, 3H), 1.69 (s, 4H), 1.61 (d, J = 4.8 Hz, 2H), 1.55 (d, J = 6.4 Hz, 3H); m/z ES + [M+H] ⁺ 421.2 and (S)-2-((1-(3,6-dimethyl- 4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)am ino)benzoic acid (27.2 mg, 65 μmol, 42%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 - 8.42 (m, 1H), 7.77 (dd, J = 1.2, 7.6 Hz, 1H), 7.70 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.22 - 7.07 (m, 1H), 6.53 - 6.39 (m, 2H), 5.40 (d, J = 6.8 Hz, 1H), 3.48 (s, 3H), 3.19 (d, J = 4.8 Hz, 4H), 2.31 (s, 3H), 1.69 (s, 4H), 1.62 (d, J = 5.2 Hz, 2H), 1.55 (d, J = 6.4 Hz, 3H); m/z ES + [M+H] ⁺ 421.2. Example 31. Preparation of 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1150] Step 1. Synthesis of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3,6-dimethylquinazoli n- 4(3H)-one [1151] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (1.00 g, 3.48 mmol) in dichloromethane (10 mL) was added 4,4-difluoropiperidine (2.11 g, 17.4 mmol). The mixture was stirred at 40 °C for 12 hr. The mixture was concentrated in vacuo. The residue was triturated in petroleum ether/ethyl acetate (10/1, 10 mL) and then filtered. The filter cake was concentrated in vacuo to give 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one (0.75 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 374.0. [1152] Step 2. Synthesis of 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3,6-dimethylquinazol in- 4(3H)-one [1153] To a solution of 8-bromo-2-(4,4-difluoro-1-piperidyl)-3,6-dimethyl-quinazolin -4-one (300 mg, 806 μmol) in toluene (6 mL) was added tributyl(1-ethoxyvinyl)stannane (873 mg, 2.42 mmol) and palladium(II)bis(triphenylphosphine) dichloride (56.6 mg, 80.6 μmol). The mixture was stirred at 110 °C for 12 h under nitrogen. Then the reaction mixture was quenched with aqueous hydrochloric acid (1 M, 5 mL) at 25 °C and stirred for 30 min. The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one (0.22 g, 636 μmol, 79%) as a white solid. m/z ES+ [M+H] ⁺ 336.2. [1154] Step 3. Synthesis of 8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one [1155] To a solution of 8-acetyl-2-(4,4-difluoro-1-piperidyl)-3,6-dimethyl-quinazoli n-4-one (220 mg, 656 μmol) in methanol (3 mL) was added ammonium acetate (1.01 g, 13.1 mmol) and sodium cyanoborohydride (41.2 mg, 656 μmol). The mixture was stirred at 60 °C for 1 hr. The mixture was quenched with water (3 mL) and then concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-(1-aminoethyl)-2- (4,4-difluoropiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-on e (0.17 g, 445 μmol, 68%) as a white solid. m/z ES+ [M+H] ⁺ 337.3. [1156] Step 4. Synthesis of methyl 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1157] To a solution of 8-(1-aminoethyl)-2-(4,4-difluoro-1-piperidyl)-3,6-dimethyl- quinazolin-4-one (170 mg, 445 μmol) in toluene (1 mL) was added methyl 2-bromobenzoate (287 mg, 1.33 mmol), tris(dibenzylideneacetone)dipalladium (40.7 mg, 44.5 μmol), cesium carbonate (435 mg, 1.33 mmol) and dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (20.7 mg, 44.5 μmol). The mixture was stirred at 110 °C for 12 h under nitrogen. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give methyl 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoate (140 mg, 298 μmol, 67%) as a white solid. m/z ES+ [M+H] ⁺ 471.3. [1158] Step 5. Synthesis of 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1159] To a solution of methyl 2-[1-[2-(4,4-difluoro-1-piperidyl)-3,6-dimethyl-4-oxo- quinazolin-8-yl]ethylamino]benzoate (140 mg, 298 μmol) in tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (62.4 mg, 1.49 mmol). The mixture was stirred at 40 °C for 12 h. The reaction mixture was acidified with aqueous hydrochloric acid (1 N) to adjust the pH = 3~4 and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water (FA)- acetonitrile]; B%: 52% - 82%, 2 min) to give 2-((1-(2-(4,4- difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-8-yl)ethyl)amino)benzoic acid (56.8 mg, 124 μmol, 42%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.48 (s, 1H), 7.15 (t, J = 7.2 Hz, 1H), 6.63 - 6.33 (m, 2H), 5.43 - 5.36 (m, 1H), 3.51 (s, 3H), 3.45 - 3.35 (m, 4H), 2.32 (s, 3H), 2.26 - 2.13 (m, 4H), 1.55 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 32 and Example 33. Preparation of (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoic acid and S)-2-((1- (2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1160] The racemic mixture was purified by SFC: [column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 45%-45%, 4 min] to give (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo -3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (15.0 mg, 33 μmol, 30%) as a yellow solid at retention time =1.992. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 1.2, 8.0 Hz, 1H), 7.73 (s, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.54 - 6.39 (m, 2H), 5.42 - 5.32 (m, 1H), 3.51 (s, 3H), 3.43 - 3.35 (m, 4H), 2.32 (s, 3H), 2.27 - 2.13 (m, 4H), 1.55 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2 and (S)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (18.4 mg, 40.0 μmol, 36%) as a yellow solid at retention time =2.295. ¹ H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.37 (m, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.48 (s, 1H), 7.14 (t, J = 7.2 Hz, 1H), 6.55 - 6.38 (m, 2H), 5.42 - 5.32 (m, 1H), 3.51 (s, 3H), 3.43 - 3.35 (m, 4H), 2.32 (s, 3H), 2.27 - 2.12 (m, 4H), 1.55 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 34. Preparation of 2-[1-[2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid

[1161] Step 1. Synthesis of 2-(6-azaspiro[3.4]octan-6-yl)-8-bromo-3-methyl-quinazolin-4- one [1162] To a mixture of 8-bromo-2-chloro-3-methyl-quinazolin-4-one (400 mg, 1.46 mmol) and 6-azaspiro[3.4]octane (353 mg, 877 μmol, oxalic acid) in tetrahydrofuran (8 mL) was added diisopropylethylamine (567 mg, 4.39 mmol) in one portion. The mixture was then heated to 60 °C and stirred for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 2-(6-azaspiro[3.4]octan-6-yl)-8-bromo-3-methyl-quinazolin-4- one (0.5 g, 1.38 mmol, 94%) as a yellow solid. m/z ES+ [M+H] ⁺ 350.2. [1163] Step 2. Synthesis of 8-acetyl-2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-quinazolin-4 - one [1164] To a mixture of 2-(6-azaspiro[3.4]octan-6-yl)-8-bromo-3-methyl-quinazolin-4- one (500 mg, 1.44 mmol) and tributyl(1-ethoxyvinyl)stannane (1.56 g, 4.31 mmol, 1.45 mL) in toluene (10 mL) was added palladium(II)bis(triphenylphosphine) dichloride (202 mg, 287 μmol) in one portion under nitrogen. The mixture was then heated to 80 °C and stirred for 4 hr. Then the reaction mixture was quenched with hydrochloric acid (1 M, 2 mL) at 25 °C and stirred for 30 minutes. On completion, the reaction mixture was quenched with sat. potassium fluoride solution (20 mL) at 20 °C, and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed- phase HPLC (0.1% formic acid condition) to give 8-acetyl-2-(6-azaspiro[3.4]octan-6-yl)-3- methyl-quinazolin-4-one (0.42 g, 1.15 mmol, 79%) as a yellow solid. m/z ES+ [M+H] ⁺ 312.1. [1165] Step 3. Synthesis of 8-(1-aminoethyl)-2-(6-azaspiro[3.4]octan-6-yl)-3-methyl- quinazolin-4-one [1166] To a mixture of 8-acetyl-2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-quinazolin-4 -one (400 mg, 1.28 mmol) in methanol (10 mL) was added ammonium acetate (990 mg, 12.9 mmol), sodium cyanoborohydride (96.9 mg, 1.54 mmol) in one portion. The mixture was then heated to 60 °C and stirred for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-quin azolin-4-one (0.2 g, 634 μmol, 49%) as a yellow solid. m/z ES+ [M+H] ⁺ 313.1. [1167] Step 4. Synthesis of tert-butyl 2-[1-[2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-4-oxo- quinazolin-8-yl]ethylamino]benzoate [1168] To a mixture of 8-(1-aminoethyl)-2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-quin azolin- 4-one (150 mg, 480 μmol) and tert-butyl 2-bromobenzoate (370 mg, 1.44 mmol) in toluene (5 mL) was added methanesulfonato(2-dicyclohexylphosphino-2,6-di-i-propoxy-1, 1- biphenyl)(2-amino-1,1-biphenyl-2-yl) (44.81 mg, 96.0 μmol), tris(dibenzylideneacetone)dipalladium (87.9 mg, 96.0 μmol) and cesium carbonate (469 mg, 1.44 mmol) in one portion under nitrogen atmosphere. The mixture was heated to 110 °C and stirred for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=3/1) to give tert-butyl 2-[1-[2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-4-oxo-quinazoli n-8- yl]ethylamino]benzoate (130 mg, 255 μmol, 53%) as a yellow solid. m/z ES+ [M+H] ⁺ 489.3. [1169] Step 5. Synthesis of 2-[1-[2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-4-oxo-quinazoli n- 8-yl]ethylamino]benzoic acid [1170] A mixture of tert-butyl 2-[1-[2-(6-azaspiro[3.4]octan-6-yl)-3-methyl-4-oxo- quinazolin-8-yl]ethylamino]benzoate (120 mg, 246 μmol) in trifluoroacetic acid (3 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)-acetonitrile]; B%: 55%-85%, 10 min) to give 2-[1-[2- (6-azaspiro[3.4]octan-6-yl)-3-methyl-4-oxo-quinazolin-8-yl]e thylamino]benzoic acid (46.69 mg, 107 μmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 - 7.95 (m, 2H), 7.62 (br. d, J = 6.8 Hz, 1H), 7.22 - 7.08 (m, 2H), 6.55 (t, J = 7.6Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.49 (q, J = 6.8 Hz, 1H), 3.72 - 3.49 (m, 7H), 2.14 - 1.91 (m, 8H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 433.2. Example 35. Preparation of 2-((1-(3,6-dimethyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1171] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(1,4-oxazepan-4-yl)quinazolin-4(3H)- one [1172] To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (1 g, 3.48 mmol) and 1,4-oxazepane hydrochloride (718 mg, 5.22 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (1.35 g, 10.4 mmol). The mixture was stirred at 40 °C for 16 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent of 0~50% ethylacetate/petroleum ether gradient @40 mL/min) to give 8-bromo-3,6-dimethyl-2-(1,4- oxazepan-4-yl)quinazolin-4(3H)-one (1.2 g, 3.41 mmol, 98%) as a yellow solid. m/z ES+ [M+H] ⁺ 352.1. [1173] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(1,4-oxazepan-4-yl)quinazolin-4(3H)- one [1174] To a solution of 8-bromo-3,6-dimethyl-2-(1,4-oxazepan-4-yl)quinazolin-4(3H)-o ne (1.2 g, 3.41 mmol) in toluene (10 mL) was added palladium(II)bis(triphenylphosphine) dichloride (589 mg, 510 μmol) and tributyl(1-ethoxyvinyl)stannane (2.46 g, 6.81 mmol). The mixture was stirred at 125 °C for 16 hr under nitrogen atmosphere. Then the mixture was quenched with formic acid (818 mg, 17.0 mmol) at 25 °C and stirred for 30 min. On completion, the reaction was adjusted to pH = 7~8 with sat. sodium bicarbonate and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 8-acetyl- 3,6-dimethyl-2-(1,4-oxazepan-4-yl)quinazolin-4(3H)-one (800 mg, 2.54 mmol, 75%) as a white solid. m/z ES+ [M+H] ⁺ 316.1. [1175] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(1,4-oxazepan-4-yl)quinazoli n- 4(3H)-one [1176] To a solution of 8-acetyl-3,6-dimethyl-2-(1,4-oxazepan-4-yl)quinazolin-4(3H)- one (400 mg, 1.27 mmol) in methanol (4 mL) was added ammonium acetate (978 mg, 12.7 mmol) and sodium cyanoborohydride (79.7 mg, 1.27 mmol). Then the mixture was stirred at 60 °C for 1 hr. On completion, the mixture was directly purified by reversed-phase HPLC (0.1% ammonium hydroxide conditions) to give 8-(1-aminoethyl)-3,6-dimethyl-2-(1,4-oxazepan-4- yl)quinazolin-4(3H)-one (280 mg, 873 μmol, 69%) as a yellow solid. m/z ES+ [M-NH ₂ ] ⁺ 300.1. [1177] Step 4. Synthesis of methyl 2-((1-(3,6-dimethyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1178] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-(1,4-oxazepan-4-yl)quinazoli n- 4(3H)-one (100 mg, 316 μmol) and methyl 2-bromobenzoate (204 mg, 949 μmol) in toluene (1 mL) was added tris(dibenzylideneacetone)dipalladium (28.9 mg, 31.6 μmol), cesium carbonate (309 mg, 948 μmol) and methanesulfonato(2-dicyclohexylphosphino-2,6-di-i- propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl) (14.7 mg, 3.16 μmol). The mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~30% ethylacetate/petroleum ether gradient @ 40 mL/min) to give methyl 2-((1-(3,6-dimethyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 155 μmol, 49%) as a light yellow solid. m/z ES+ [M-150] ⁺ 300.1. [1179] Step 5. Synthesis of 2-((1-(3,6-dimethyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1180] To a solution of methyl 2-((1-(3,6-dimethyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 155 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (32.6 mg, 777 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the mixture was adjusted to pH = 6 by adding formic acid, then the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 um; mobile phase: [water(FA)-acetonitrile]; B%: 40%-70%, 7 min) to give 2-((1-(3,6-dimethyl-2-(1,4-oxazepan- 4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (24.3 mg, 55.6 μmol, 35.8%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 - 8.05 (m, 1H), 8.01 - 7.96 (m, 1H), 7.88 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.62 - 6.52 (m, 1H), 6.45 (d, J = 8.4 Hz, 1H), 5.51 - 5.40 (m, 1H), 4.06 - 3.85 (m, 4H), 3.73 - 3.53 (m, 7H), 2.37 (s, 3H), 2.18 -2.09 (m, 2H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 437.2. Example 36 and Example 37. Preparation of (R)-2-((1-(3,6-dimethyl-2-(1,4-oxazepan-4- yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid and (S)-2-((1-(3,6- dimethyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1181] The racemic mixture, 2-[1-[3,6-dimethyl-2-(1,4-oxazepan-4-yl)-4-oxo-quinazolin-8- yl]ethylamino]benzoic acid (24 mg, 54.98 μmol) was separated by SFC to give (R)-2-((1-(3,6- dimethyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)amino)benzoic acid (3.73 mg, 8.55 μmol, 15.5%) as an off-with solid ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 7.2 Hz, 1H), 7.88 (s, 1H), 7.48 (s, 1H), 7.19 (s, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.45 (q, J = 6.4 Hz, 1H), 3.98 - 3.88 (m, 4H), 3.64 - 3.53 (m, 7H), 2.37 (s, 3H), 2.16 - 2.08 (m, 2H), 1.63 (d, J = 6.6 Hz, 3H); m/z ES+ [M+H] ⁺ 437.2and (S)-2-((1-(3,6-dimethyl-2- (1,4-oxazepan-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)a mino)benzoic acid (4.42 mg, 10.13 μmol, 18.4%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.99 - 7.94 (m, 1H), 7.88 (s, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.22 - 7.15 (m, 1H), 6.56 (t, J = 7.2 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 5.47 - 5.42 (m, 1H), 3.99 - 3.89 (m, 4H), 3.65 - 3.54 (m, 7H), 2.37 (s, 3H), 2.16 - 2.07 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 437.2. Example 38. Preparation of 2-((1-(2-(3,3-Difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1182] Step 1. Synthesis of 8-bromo-2-(3,3-difluoropiperidin-1-yl)-3,6-dimethylquinazoli n- 4(3H)-one [1183] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (1 g, 3.48 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (2.25 g, 17.4 mmol) and 3,3- difluoropiperidine;hydrochloride (1.64 g, 10.4 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 1/1) to give 8-bromo- 2-(3,3-difluoropiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)- one (0.6 g, 1.61 mmol, 46%) as a yellow solid. m/z ES+ [M+H] ⁺ 374.2. [1184] Step 2. Synthesis of 8-bromo-2-(3,3-difluoropiperidin-1-yl)-3,6-dimethylquinazoli n- 4(3H)-one [1185] To a solution of 8-bromo-2-(3,3-difluoropiperidin-1-yl)-3,6-dimethylquinazoli n- 4(3H)-one (0.6 g, 1.61 mmol) and tributyl(1-ethoxyvinyl)stannane (1.75 g, 4.84 mmol, 1.63 mL) in toluene (6 mL) was added palladium(II)bis(triphenylphosphine) dichloride (226 mg, 322 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen.Then the mixture was quenched with hydrochloric acid (1 N, 2.9 mL) and stirred at 25 °C for 0.5 hr. On completion, the reaction was adjusted to pH = 7~8, with sat. sodium bicarbonate and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions, water: acetonitrile=20:1 to 1:1) to give 8-acetyl-2-(3,3-difluoropiperidin-1-yl)-3,6-dimethylquinazol in-4(3H)-one (0.5 g, 1.49 mmol, 92%) as a yellow solid. m/z ES+ [M+H] ⁺ 336.4. [1186] Step 3. Synthesis of 8-(1-aminoethyl)-2-(3,3-difluoropiperidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one [1187] To a solution of 8-acetyl-2-(3,3-difluoropiperidin-1-yl)-3,6-dimethylquinazol in- 4(3H)-one (0.3 g, 895 μmol) in methanol (3 mL) was added ammonium acetate (1.03 g, 13.4 mmol) and sodium cyanoborohydride (56.2 mg, 895 μmol). The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions, water: acetonitrile=20:1 to 1:1) to give 8-(1-aminoethyl)-2-(3,3-difluoropiperidin-1-yl)-3,6-dimethyl quinazolin-4(3H)-one (0.14 g, 416 μmol, 47%) as a yellow solid. m/z ES+ [M+H] ⁺ 337.4. [1188] Step 4. Synthesis of methyl 2-((1-(2-(3,3-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1189] To a solution of 8-(1-aminoethyl)-2-(3,3-difluoropiperidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one (0.13 g, 386 μmol) and methyl 2-bromobenzoate (249 mg, 1.16 mmol) in toluene (2 mL) was added tris(dibenzylideneacetone)dipalladium (35.4 mg, 38.7 μmol), 2-dicyclohexylphosphino-2,6-dllsopropoxybiphenyl (18.0 mg, 38.7 μmol) and cesium carbonate (378 mg, 1.16 mmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions, water: acetonitrile=20:1 to 1:1) to give methyl 2-((1-(2-(3,3-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 148 μmol, 39%) as a yellow solid. m/z ES+ [M+H] ⁺ 471.3. [1190] Step 5. Synthesis of 2-((1-(2-(3,3-Difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1191] To a solution of methyl 2-((1-(2-(3,3-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 148 μmol) in tetrahydrofuran (0.1 mL), methanol (0.05 mL) and water (0.05 mL) was added lithium hydroxide monohydrate (17.8 mg, 744 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 um; mobile phase: [water(FA)-acetonitrile]; B%: 46%-76%, 7 min) to give 2-((1-(2-(3,3-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (29.10 mg, 63.1 μmol, 42%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.29 - 7.99 (m, 1H), 7.94 - 7.88 (m, 1H), 7.82 (s, 1H), 7.43 (s, 1H), 7.16 - 7.10 (m, 1H), 6.49 - 6.40 (m, 1H), 6.37 - 6.20 (m, 1H), 5.38 - 5.20 (m, 1H), 3.56 (s, 3H), 3.40 - 3.25 (m, 2H), 3.20 - 3.08 (m, 2H), 2.31 (s, 3H), 2.12 - 1.99 (m, 2H), 1.94 - 1.80 (m, 2H), 1.56 - 1.40 (m, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 39 and and Example 40. Preparation of (R)-2-((1-(2-(3,3-difluoropiperidin-1- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)benzoic acid and (S)-2- ((1-(2-(3,3-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-d ihydroquinazolin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1192] The racemic mixture, 2-((1-(2-(3,3-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (29.0 mg, 63.5 μmol) was purified by SFC ((column: Daicel CHIRALPAK IC (250 x 30 mm, 10 um); mobile phase: [IPA-acetonitrile]; B%: 35%-35%, 2.3 min) to give (R)-2-((1-(2-(3,3-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo - 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (4.29 mg, 9.39 μmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 - 7.85 (m, 1H), 7.82 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.12 - 7.00 (m, 1H), 6.48 - 6.40 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.40 - 5.34 (m, 1H), 3.55 (s, 3H), 3.44 - 3.37 (m, 2H), 3.19 - 3.11 (m, 2H), 2.30 (s, 3H), 2.08 - 1.98 (m, 2H), 1.97 - 1.91 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H). m/z ES+ [M+H] ⁺ 457.2 and (S)-2-((1-(2-(3,3-difluoropiperidin- 1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)am ino)benzoic acid (4.29 mg, 9.39 μmol, 14%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.89 - 7.85 (m, 1H), 7.82 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.16 - 7.10 (m, 1H), 6.49 - 6.40 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.41 - 5.34 (m, 1H), 3.55 (s, 3H), 3.45 - 3.35 (m, 2H), 3.17 - 3.11 (m, 2H), 2.30 (s, 3H), 2.10 - 1.99 (m, 2H), 1.95 - 1.90 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H). m/z ES+ [M+H] ⁺ 457.2. Example 41. Preparation of 2-({1-[6-methyl-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethyl}amino)benzoic acid

[1193] Step 1. Synthesis of 2-amino-3-bromo-5-methylbenzamide [1194] To a solution of 2-amino-3-bromo-5-methylbenzoic acid (10.0 g, 43.5 mmol) in N,N- dimethylformamide was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (7.75 g, 47.8 mmol). The mixture was stirred for 1 hour and then was cooled to 0 °C and ammonium hydroxide (19.3 g, 551 mmol, 20 mL) was added. The resulting solution was stirred for 24 hours at room temperature. Then the reaction solution was diluted with water and filtered. The filter cake was washed with water to give 2-amino-3-bromo-5-methylbenzamide (3.8 g, 16.6 mmol, 38.2%) as a light yellow solid. [1195] Step 2. Synthesis of 8-bromo-2-chloro-6-methyl-3,4-dihydroquinazolin-4-one [1196] To a stirred solution of 2-amino-3-bromo-5-methylbenzamide (3.8 g, 16.6 mmol) in 1,4-dioxane (50 mL) was added thiophosgene (4.01 g, 34.8 mmol) dropwise and the mixture was stirred at room temperature under argon for 1 hour and then at 105 °C for 1 hour. The resulting solution was concentrated in vacuo to give 8-bromo-2-chloro-6-methyl-3,4- dihydroquinazolin-4-one, which was used in the next step without additional purification. [1197] Step 3. Synthesis of 8-bromo-6-methyl-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4- one [1198] To a solution of crude 8-bromo-2-chloro-6-methylquinazolin-4-ol (4.54 g, 16.6 mmol) in ethyl acetate (100 mL) was added morpholine (4.34 g, 49.8 mmol). The reaction mixture was heated at 40 °C for 18 hours and then it was concentrated in vacuo. The residue was purified using flash column chromatography on silica gel to give 8-bromo-6-methyl-2- (morpholin-4-yl)-3,4-dihydroquinazolin-4-one (4.4 g, 13.6 mmol, 82%) as a white solid. Compound was used in the next step without additional purification. [1199] Step 4. Synthesis of 8-acetyl-6-methyl-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4 - one [1200] To a solution of 8-bromo-6-methyl-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4- one (500 mg, 1.54 mmol) in N,N-dimethylformamide (5 mL) was added tributyl(1- ethoxyethenyl)stannane (613 mg, 1.7 mmol). The mixture was stirred for 10 minutes and then dichloropalladium bis(triphenylphosphane) (54.1 mg, 77.1 μmol) was added under argon. The reaction mixture was heated at 40 °C for 12 hours and then it was concentrated in vacuo. The resulting residue was purified by prep-HPLC to give 8-acetyl-6-methyl-2-(morpholin-4-yl)- 3,4-dihydroquinazolin-4-one (900 mg, 3.13 mmol). Further purification by flash chromatography (ISCO® Interchim, 330 g SiO2, hexane/EtOAc with EtOAc from 0% to 79%, Cv=23-26) affords 8-acetyl-6-methyl-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4 -one (700 mg, 2.44 mmol). [1201] Step 5. Synthesis of 8-(1-hydroxyethyl)-6-methyl-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one [1202] To a solution of 8-acetyl-6-methyl-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4 -one (700 mg, 2.44 mmol) in methanol (30 mL) was added sodium borohydride (92.2 mg, 2.44 mmol) in one portion. The resulting mixture was stirred at room temperature overnight. The mixture was poured into water and filtered to afford the 8-(1-hydroxyethyl)-6-methyl-2- (morpholin-4-yl)-3,4-dihydroquinazolin-4-one (500 mg, 1.38 mmol, 57%). [1203] Step 6. Synthesis of 1-{1-[6-methyl-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethyl}-2,4-dihydro-1H-3,1-benzoxazine -2,4-dione [1204] To a solution of 8-(1-hydroxyethyl)-6-methyl-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one (250 mg, 864 μmol) in tetrahydrofuran (5 ml) was added triphenylphosphine (272 mg, 1.04 mmol). To an ice cooled resulting solution was added 2,4- dihydro-1H-3,1-benzoxazine-2,4-dione (282 mg, 1.73 mmol) and N- [(ethoxycarbonyl)imino]ethoxyformamide (180 mg, 1.04 mmol). The reaction mixture was stirred at 0 °C overnight and concentrated in vacuo. Crude product was used in the next step without purification. [1205] Step 7. Synthesis of 2-(1-[6-methyl-2-(morpholin-4-yl)-4-oxo-3,4-dihydroquinazoli n- 8-yl]ethylamino)benzoic acid [1206] To a solution of 1-1-[6-methyl-2-(morpholin-4-yl)-4-oxo-3,4-dihydroquinazolin -8- yl]ethyl-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (370 mg, 852 μmol) in methanol (10 mL) was added sodium hydroxide (341 mg, 8.52 mmol) and the mixture was heated for 1h. The residue was purified by HPLC to afford 2-(1-[6-methyl-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethylamino)benzoic acid (67.6 mg, 157 μmol, 18.5%). ¹ H NMR (400 MHz, DMSO-d6) δ 9.88 (d, J = 6.8 Hz, 1H), 7.73 (dd, J = 7.7, 1.8 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.75 (t, J = 7.9 Hz, 1H), 6.22 (t, J = 7.3 Hz, 1H), 6.13 (d, J = 8.2 Hz, 1H), 5.39 – 5.26 (m, 1H), 3.63 (s, 8H), 2.16 (s, 3H), 2.07 (s, 1H), 1.39 (d, J = 6.6 Hz, 3H); LC/MS [M+H] ⁺ 409.2. Example 42. Preparation of 2-(1-[6-chloro-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethylamino)benzoic acid [1207] Step 1. Synthesis of 2-amino-3-bromo-5-chlorobenzamide [1208] To a solution of 2-amino-3-bromo-5-chlorobenzoic acid (10.0 g, 39.9 mmol) in N,N- dimethylformamide was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (7.12 g, 43.9 mmol). The mixture was stirred for 1 hour and then was cooled to 0 °C and added ammonium hydroxide (19.3 g, 551 mmol, 20.0 mL). The resulting solution was stirred for 24 hours at room temperature. Then to the reaction solution was added water and filtered. The filter cake was washed with water to give 2-amino-3-bromo-5-chlorobenzamide (8.0 g, 32.1 mmol, 80.3%) as a white solid. [1209] Step 2. Synthesis of 8-bromo-2,6-dichloro-3,4-dihydroquinazolin-4-one [1210] To a stirred solution of 2-amino-3-bromo-5-chlorobenzamide (8.0 g, 32.1 mmol) substrate in 1,4-dioxane (50 mL) was added chloromethanecarbothioyl chloride (7.74 g, 67.3 mmol) dropwise and the mixture was stirred at room temperature under argon for 1 hour, then at 105 °C for 1 hour. The resulting solution was concentrated in vacuo to afford of 8-bromo- 2,6-dichloro-3,4-dihydroquinazolin-4-one, which was used in the next step without additional purification. [1211] Step 3. Synthesis of 8-bromo-6-chloro-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4- one [1212] To a solution of 8-bromo-2,6-dichloro-3,4-dihydroquinazolin-4-one (9.35 g, 32.07 mmol) in ethyl acetate (100 mL) was added morpholine (8.38 g, 96.2 mmol). The reaction mixture was heated at 40 °C for 18 hours and then it was concentrated in vacuo. The residue was purified using flash column chromatography on silica gel to give a 8-bromo-6-chloro-2- (morpholin-4-yl)-3,4-dihydroquinazolin-4-one (9.8 g, 28.4 mmol, 89%) as a white solid. [1213] Step 4. Synthesis of 8-acetyl-6-chloro-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4 - one [1214] To a reactor containing a solution of 8-bromo-6-chloro-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one (1.0 g, 2.9 mmol) in N,N-dimethylformamide (10 mL) was added tributyl(1-ethoxyethenyl)stannane (1.05 g, 2.9 mmol). The mixture was stirred for 10 min and then dichloropalladium bis(triphenylphosphane) (102 mg, 145 μmol) was added under argon. The reaction mixture was heated at 40 °C for 12 hours and then it was concentrated in vacuo. The resulting residue was purified by prep-HPLC to give 8-acetyl-6-chloro-2-(morpholin-4- yl)-3,4-dihydroquinazolin-4-one. [1215] Step 5. Synthesis of 6-chloro-8-(1-hydroxyethyl)-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one [1216] To a solution of 8-acetyl-6-chloro-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4 -one (1.7 g, 5.52 mmol) in methanol (30 mL) was added sodium borohydride (209 mg, 5.52 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was poured into water and filtered to afford the 6-chloro-8-(1-hydroxyethyl)-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one (1.0 g, 3.07 mmol, 56%). [1217] Step 6. Synthesis of 1-{1-[6-chloro-2-(morpholin-4-yl)-4-oxo-3,4-dihydroquinazoli n- 8-yl]ethyl}-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione [1218] To a solution of 6-chloro-8-(1-hydroxyethyl)-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one (250 mg, 807 μmol) in tetrahydrofuran (5 mL) was added triphenylphosphine (254 mg, 968 μmol). The resulting solution was cooled to 0 °C before 2,4- dihydro-1H-3,1-benzoxazine-2,4-dione (263 mg, 1.61 mmol) and N- [(ethoxycarbonyl)imino]ethoxyformamide (169 mg, 968 μmol) were added. The reaction mixture was stirred at 10 °C overnight and concentrated in vacuo. Crude product was used in the next step without purification. LC/MS [M-H] ⁺ 453.1. [1219] Step 7. Synthesis of 2-(1-[6-chloro-2-(morpholin-4-yl)-4-oxo-3,4-dihydroquinazoli n- 8-yl]ethylamino)benzoic acid [1220] To a solution of 1-1-[6-chloro-2-(morpholin-4-yl)-4-oxo-3,4-dihydroquinazolin -8- yl]ethyl-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (70.0 mg, 154 μmol) in methanol (10 mL) was added sodium hydroxide (61.6 mg, 1.54 mmol) and the mixture was heated for 1 h. The residue was purified by HPLC to afford 2-(1-[6-chloro-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethylamino)benzoic acid (13.1 mg, 29.0 μmol, 18.9%). ¹ H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.48 (d, J = 2.6 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.51 (t, J = 7.5 Hz, 1H), 6.40 (d, J = 8.5 Hz, 1H), 5.29 (d, J = 6.8 Hz, 1H), 3.70 (d, J = 5.1 Hz, 9H), 1.55 (d, J = 6.6 Hz, 3H); LC/MS [M+H] ⁺ 429.2. Example 43. Preparation of 2-({1-[7-methoxy-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethyl}amino)benzoic acid [1221] Step 1. Synthesis of 2-amino-3-bromo-4-methoxybenzamide [1222] To a solution of 2-amino-3-bromo-4-methoxybenzoic acid (3.21 g, 13.1 mmol) in tetrahydrofuran (50 mL) was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (2.54 g, 15.7 mmol) portionwise at room temperature. The mixture was stirred at 40 °C for 30 minutes. Afterwards, the solution was cooled down to 0 °C, and aqueous ammonia (20%, 15 mL) was added dropwise under ice cooling. Upon completion, the mixture was allowed to warm up to room temperature and stirred overnight. The solvent was concentrated, and the residue was portioned between ethyl acetate and water. The organic layer was separated, washed with aqueous NaHSO4 solution, brine, dried, filtered and evaporated in vacuo to obtain 2-amino-3- bromo-4-methoxybenzamide (1.9 g, 7.75 mmol, 59%). LC/MS [M+H] ⁺ 245.8. [1223] Step 2. Synthesis of 8-bromo-2-chloro-7-methoxy-3,4-dihydroquinazolin-4-one [1224] To a solution of 2-amino-3-bromo-4-methoxybenzamide (1.69 g, 6.91 mmol) in 50 mL of dry 1,4-dioxane was added a solution of carbonothioyl dichloride (1.67 g, 14.5 mmol) in 10 mL of 1,4-dioxane dropwise. The reaction mixture was heated at reflux for 3 h. Upon cooling to room temperature, the solvent was distilled off, and the residue was desiccated in high vacuum to yield 8-bromo-2-chloro-7-methoxy-3,4-dihydroquinazolin-4-one (2.0 g, 3.25 mmol, 47%). LC/MS [M+H] ⁺ 291.8. [1225] Step 3. Synthesis of 8-bromo-7-methoxy-2-(morpholin-4-yl)-3,4-dihydroquinazolin- 4-one [1226] A solution of 8-bromo-2-chloro-7-methoxy-3,4-dihydroquinazolin-4-one (1.7 g, 5.88 mmol) and morpholine (1.54 g, 17.6 mmol) were stirred in acetonitrile (50 mL) under reflux overnight. Upon cooling to room temperature, the solvent was concentrated, and the residue was portioned between ethyl acetate and water. The organic layer was separated, evaporated, and the residue was purified by HPLC to yield 8-bromo-7-methoxy-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one (210 mg, 617 μmol, 10.5%). LC/MS [M+H] ⁺ 341.2. [1227] Step 4. Synthesis of 8-acetyl-7-methoxy-2-(morpholin-4-yl)-3,4-dihydroquinazolin- 4- one [1228] To a solution of 8-bromo-7-methoxy-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4 -one (168 mg, 494 μmol) in N,N-dimethylformamdie (15 mL) was added tributyl(1- ethoxyethenyl)stannane (196 mg, 544 μmol) and Dichlorobis(triphenylphosphine)palladium(II) (34.8 mg, 49.5 μmol) under argon. The reaction mixture was heated at 100 °C overnight. Upon cooling to room temperature, the solvents were distilled off in vacuo. The residue was purified by HPLC to yield 8-acetyl-7- methoxy-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4-one (69.0 mg, 228 μmol, 46%). LC/MS [M+H] ⁺ 304.2. [1229] Step 5. Synthesis of 8-(1-hydroxyethyl)-7-methoxy-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one [1230] To the suspension of 8-acetyl-7-methoxy-2-(morpholin-4-yl)-3,4-dihydroquinazolin- 4-one (37.8 mg, 125 μmol) in methanol (40 mL) was added sodium borohydride (9.42 mg, 249 μmol) in several portions at 0 °C. The resulting slurry was stirred for 2 hours. After this, the solvent was evaporated, and the residue was purified by HPLC to yield 8-(1-hydroxyethyl)-7- methoxy-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4-one (19.0 mg, 62.2 μmol, 50%). LC/MS [M+H] ⁺ 306.2. [1231] Step 6. Synthesis of 1-{1-[7-methoxy-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethyl}-2,4-dihydro-1H-3,1-benzoxazine -2,4-dione [1232] A solution of 8-(1-hydroxyethyl)-7-methoxy-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one (19.7 mg, 64.4 μmol), 2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (13.7 mg, 83.7 μmol) and triphenylphosphine (33.8 mg, 129 μmol) were mixed together in tetrahydrofuran (20 mL) under argon. The mixture was cooled down to 0 °C before (Z)-N- [(ethoxycarbonyl)imino]ethoxyformamide (14.6 mg, 83.7 μmol) was added slowly, and the reaction mixture was kept at 4 °C overnight. Upon warming to room temperature, the reaction mixture, containing 1-1-[7-methoxy-2-(morpholin-4-yl)-4-oxo-3,4-dihydroquinazoli n-8- yl]ethyl-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (30.7% purity) was used in the next step with no isolation of the product. LC/MS [M-H] ⁺ 449.1. [1233] Step 7. Synthesis of 2-(1-[7-methoxy-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethylamino)benzoic acid [1234] The solution, containing 1-1-[7-methoxy-2-(morpholin-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl]ethyl-2,4-dihydro-1H-3,1-benzoxazine- 2,4-dione (28.7 mg, 63.6 μmol) was evaporated to a half of the initial volume. Water (10 mL) and methanol (5 mL) were added together with potassium hydroxide (35.7 mg, 636 μmol). The mixture was heated at reflux overnight. The solids formed were filtered out and discarded. The crude material was purified by HPLC to give 2-(1-[7-methoxy-2-(morpholin-4-yl)-4-oxo-3,4-dihydroquinazol in- 8-yl]ethylamino)benzoic acid (2.7 mg, 6.36 μmol, 10%). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.37 (s, 1H), 11.26 (s, 1H), 8.69 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 7.9, 1.7 Hz, 1H), 7.20 (s, 1H), 7.03 – 6.68 (m, 2H), 6.39 (t, J = 7.5 Hz, 1H), 3.88 (d, J = 26.8 Hz, 3H), 3.70 (s, 8H), 1.48 (d, J = 89.3 Hz, 4H); LC/MS [M+H] ⁺ 425.2. Example 44. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1235] Step 1. Synthesis of 2-amino-3-bromo-N,5-dimethylbenzamide [1236] To the solution of methylamine (22.9 g, 736 mmol, 146 mL) in methanol, ethyl 2- amino-3-bromo-5-methylbenzoate (19.0 g, 73.6 mmol) was added and the resulting solution was heated to 70 °C for 16 h. Upon completion the mixture was cooled down to room temperature, and was evaporated to dryness to afford 2-amino-3-bromo-N,5- dimethylbenzamide (17.5 g, 72.0 mmol, 98%). LC/MS [M+H] ⁺ 243.0. [1237] Step 2. Synthesis of 8-bromo-3,6-dimethyl-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one [1238] 2-Amino-3-bromo-N,5-dimethylbenzamide (17.5 g, 72.0 mmol) and chloromethanecarbothioyl chloride (12.4 g, 108 mmol, 8.23 mL) were dissolved in 1,4-dioxane and refluxed for 16 h. Then the reaction mixture was evaporated and dissolved in methylene chloride, morpholine (18.8 g, 216 mmol, 19 mL) was added dropwise and refluxed for 24 h. Solvent was removed under reduced pressure and the residue was washed with methyl tert- butyl ether to afford crude 8-bromo-3,6-dimethyl-2-(morpholin-4-yl)-3,4-dihydroquinazoli n- 4-one (6.1 g, 15.9 mmol, 22%) that was used in the next reaction without further purification. LC/MS [M+H] ⁺ 338.0. [1239] Step 3. Synthesis of 8-(1-ethoxyethenyl)-3,6-dimethyl-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one [1240] To a stirred solution of 8-bromo-3,6-dimethyl-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one (6.1 g, 18.0 mmol) in N,N-dimethylformamide were added tributyl(1- ethoxyethenyl)stannane (7.81 g, 21.6 mmol, 7.3 mL) and tetrakis(triphenylphosphine)palladium(0) (1.05 g, 902 μmol). The mixture was heated at 130 °C for 16 h, concentrated under reduced pressure and washed with methyl tert-butyl ether and hexane to afford the crude compound 8-(1-ethoxyethenyl)-3,6-dimethyl-2-(morpholin-4-yl)- 3,4-dihydroquinazolin-4-one (1.3 g, 2.6 mmol, 14%) that was used in the next reaction without further purification. [1241] Step 4. Synthesis of 8-acetyl-3,6-dimethyl-2-(morpholin-4-yl)-3,4-dihydroquinazol in- 4-one [1242] 8-(1-Ethoxyethenyl)-3,6-dimethyl-2-(morpholin-4-yl)-3,4-dihy droquinazolin-4-one (1.3 g, 3.95 mmol) was treated with water and hydrogen chloride (950 mg, 26.1 mmol, 5.2 mL). The resulting mixture was stirred at room temperature for 4 h, then the formed precipitate was washed and filtered off, washed with hexanes and dried to afford the crude 8-acetyl-3,6- dimethyl-2-(morpholin-4-yl)-3,4-dihydroquinazolin-4-one (800 mg, 2.26 mmol, 87%) that was used in the next reaction without further purification. LC/MS [M+H] ⁺ 302.2. [1243] Step 5. Synthesis of 8-(1-hydroxyethyl)-3,6-dimethyl-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one [1244] Sodium borohydride (128.14 mg, 3.39 mmol) was added portion wise to a stirred solution of 8-acetyl-3,6-dimethyl-2-(morpholin-4-yl)-3,4-dihydroquinazol in-4-one (800 mg, 2.65 mmol) in methanol at 0 °C and stirred overnight at room temperature. The reaction mixture was slowly quenched with water and extracted with ethyl acetae. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was evaporated to afford 8-(1- hydroxyethyl)-3,6-dimethyl-2-(morpholin-4-yl)-3,4-dihydroqui nazolin-4-one (560 mg, 1.66 mmol, 74%). [1245] Step 6. Synthesis of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin - 8-yl)ethyl)amino)benzoic acid [1246] To a solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-(morpholin-4-yl)-3,4- dihydroquinazolin-4-one (400 mg, 1.32 mmol) in water were added diphenylphosohinobenzene-3-sulfonic acid sodium salt (24.0 mg, 65.9 μmol), 2-aminobenzoic acid (271 mg, 1.98 mmol) and copper(II) dibromide (14.7 mg, 65.9 μmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours then the mixture was cooled to room temperature, evaporated and the crude mixture was purified by HPLC to afford the title compound 2-(1-[3,6-dimethyl-2-(morpholin-4-yl)-4-oxo-3,4-dihydroquina zolin-8- yl]ethylamino)benzoic acid (14.0 mg, 33.1 μmol, 2.5%). ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.97 – 7.84 (m, 1H), 7.86 – 7.75 (m, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.12 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 6.63 – 6.35 (m, 2H), 5.49 (q, J = 6.7 Hz, 1H), 3.97 – 3.83 (m, 4H), 3.62 (s, 3H), 3.33 (s, 4H), 2.36 (s, 3H), 1.62 (d, J = 6.7 Hz, 3H); LC/MS [M+H] ⁺ 423.0. Example 45 and Example 46. Preparation of (S)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid and (R)-2-((1-(3,6-dimethyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (stereochemistry arbitrarily assigned for both enantiomers) [1247] Supercritical fluid chromatography resolution of 2-((1-(3,6-dimethyl-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid afforded (S)-2-((1-(3,6-dimethyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (3.2 mg, 7.57 μmol, 23%). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 8.46 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.47 (q, J = 8.3, 7.5 Hz, 2H), 5.36 (s, 1H), 3.77 (t, J = 5.0 Hz, 4H), 3.48 (s, 3H), 3.25 (d, J = 5.0 Hz, 4H), 2.31 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H); LC/MS [M+H] ⁺ 423.4 and (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (3.2 mg, 7.81 μmol, 24%). ¹ H NMR (600 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.47 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.47 (q, J = 8.2, 7.5 Hz, 2H), 5.36 (s, 1H), 3.77 (t, J = 5.0 Hz, 4H), 3.48 (s, 3H), 3.25 (d, J = 5.0 Hz, 4H), 2.31 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H); LC/MS [M+H] ⁺ 423.4. Example 47. Preparation of 2-((1-(2-(4-methoxypiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1248] Step 1. Synthesis of 8-bromo-2-(4-methoxypiperidin-1-yl)-3,6-dimethylquinazolin- 4(3H)-one [1249] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (1.00 g, 3.48 mmol) in dichloromethane (10 mL) was added 4-methoxypiperidine (2.00 g, 17.4 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the mixture was quenched with water (15 mL) and extracted with dichloromethane (25 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 50/1 to 1/2) to give 8-bromo-2-(4-methoxy-1-piperidyl)-3,6-dimethyl-quinazolin-4- one (1.30 g, 3.28 mmol, 94%) as a yellow solid. m/z ES + [M+H] ⁺ 366.1. [1250] Step 2. Synthesis of 8-acetyl-2-(4-methoxy-1-piperidyl)-3,6-dimethyl-quinazolin-4 - one [1251] A mixture of 8-bromo-2-(4-methoxy-1-piperidyl)-3,6-dimethyl-quinazolin-4- one (1.10 g, 3.00 mmol), tributyl(1-ethoxyvinyl)stannane (3.53 g, 9.78 mmol) and dichloropalladium triphenylphosphane (440 mg, 627 μmol) in toluene (20 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. Then the reaction mixture was added hydrochloric acid (1 M, 5.50 mL) at 25 °C and stirred for 30 min. On completion, the reaction was adjusted pH = 7~8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (8 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 0/1) to give 8-acetyl-2-(4-methoxy-1-piperidyl)-3,6-dimethyl-quinazolin-4 -one (1.4 g, 2.85 mmol, 95%) as a yellow solid. m/z ES + [M+H] ⁺ 330.1. [1252] Step 3. Synthesis of 8-(1-aminoethyl)-2-(4-methoxy-1-piperidyl)-3,6-dimethyl- quinazolin-4-one [1253] To a solution of 8-acetyl-2-(4-methoxy-1-piperidyl)-3,6-dimethyl-quinazolin-4 -one (1.30 g, 3.95 mmol) in methanol (20 mL) was added ammonium acetate (6.08 g, 78.9 mmol) and sodium cyanoborohydride (260 mg, 4.14 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-2-(4-methoxy-1-piperidyl)-3,6-dimethyl-quin azolin-4-one (800 mg, 2.42 mmol, 61%) as a white solid. m/z ES + [M+H] ⁺ 331.4. [1254] Step 4. Synthesis of methyl 2-((1-(2-(4-methoxypiperidin-1-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1255] A mixture of 8-(1-aminoethyl)-2-(4-methoxy-1-piperidyl)-3,6-dimethyl-quin azolin-4- one (130 mg, 393 μmol), methyl 2-bromobenzoate (130 mg, 605 μmol), tris(dibenzylideneacetone)dipalladium (36.4 mg, 39.8 μmol), cesium carbonate (390 mg, 1.20 mmol) and dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (20.8 mg, 44.6 μmol) in toluene (1 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give methyl 2-[1-[2-(4- methoxy-1-piperidyl)-3,6-dimethyl-4-oxo-quinazolin-8-yl]ethy lamino]benzoate (130 mg, 280 μmol, 71%) as a yellow oil. m/z ES + [M+H] ⁺ 464.9. [1256] Step 5. Synthesis of 2-((1-(2-(4-methoxypiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1257] To a solution of methyl 2-[1-[2-(4-methoxy-1-piperidyl)-3,6-dimethyl-4-oxo- quinazolin-8-yl]ethylamino]benzoate (110 mg, 237 μmol) in anhydrous tetrahydrofuran (1 mL), methanol (0.5 mL) and water (0.5 mL) was added lithium hydroxide (27.5 mg, 1.15 mmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water (formic acid) - acetonenitrile]; B%: 45% - 75%, 7 min) to give 2-[1-[2-(4-methoxy-1-piperidyl)-3,6- dimethyl-4-oxo-quinazolin-8-yl]ethylamino]benzoic acid (71.5 mg, 158 μmol, 67%) as an off- white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 8.41 (s, 1H), 7.77 (dd, J = 1.2, 8.0 Hz, 1H), 7.70 (s, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.21 - 7.14 (m, 1H), 6.53 - 6.43 (m, 2H), 5.40 (s, 1H), 3.47 (s, 3H), 3.48 - 3.40 (m, 3H), 3.28 (s, 3H), 3.09 - 2.97 (m, 2H), 2.31 (s, 3H), 2.05 - 1.94 (m, 2H), 1.71 - 1.59 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H); m/z ES + [M+H] ⁺ 451.3. Example 48 and Example 49. Preparation of (R)-2-((1-(2-(4-methoxypiperidin-1-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid and (S)-2-((1-(2-(4- methoxypiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazo lin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1258] Compound 2-((1-(2-(4-methoxypiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (70 mg, 155 μmol) was separated by SFC to give (R)-2-((1-(2-(4-methoxypiperidin-1-yl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (22 mg, 48.8 μmol, 31%) as a yellow solid ¹ H NMR (400 MHz, DMSO-d6) δ 13.03 - 12.17 (m, 1H), 8.66 - 8.26 (m, 1H), 7.88 - 7.62 (m, 2H), 7.46 (s, 1H), 7.26 - 7.10 (m, 1H), 6.60 - 6.35 (m, 2H), 5.54 - 5.28 (m, 1H), 3.52 - 3.40 (m, 6H), 3.29 (s, 3H), 3.10 - 2.98 (m, 2H), 2.32 (s, 3H), 2.01 (dd, J = 1.6, 3.6 Hz, 2H), 1.69 - 1.51 (m, 5H); m/z ES+ [M+H] ⁺ 451.2 and (S)-2-((1-(2-(4-methoxypiperidin-1-yl)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (23 mg, 51.0 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.97 - 12.21 (m, 1H), 8.70 - 8.24 (m, 1H), 7.90 - 7.62 (m, 2H), 7.46 (s, 1H), 7.22 - 7.11 (m, 1H), 6.48 (d, J = 4.0 Hz, 2H), 5.40 (d, J = 2.4 Hz, 1H), 3.48 (s, 6H), 3.29 (s, 3H), 3.13 - 3.00 (m, 2H), 2.32 (s, 3H), 2.09 - 1.92 (m, 2H), 1.73 - 1.46 (m, 5H); m/z ES+ [M+H] ⁺ 451.2. Example 50. Preparation of 2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-7-azaspiro[3.5]nonan-7- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1259] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan-7- yl)quinazolin-4(3H)-one [1260] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (500 mg, 1.74 mmol) in dichloromethane (5 mL) was added 2-oxa-7-azaspiro[3.5]nonane;oxalic acid (755 mg, 3.48 mmol) and diisopropylethylamine (1.12 g, 8.69 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the solution was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1 to 3/1) to give 8-bromo-3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quin azolin-4(3H)-one (0.42 g, 955 μmol, 55%) as a yellow oil. m/z ES + [M+H] ⁺ 380.1. [1261] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan-7- yl)quinazolin-4(3H)-one [1262] To a solution of 8-bromo-3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan-7- yl)quinazolin-4-one (0.42 g, 1.11 mmol) in toluene (10 mL) was added tributyl(1- ethoxyvinyl)stannane (1.2 g, 3.33 mmol) and dichloropalladium triphenylphosphane (77.9 mg, 111 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the mixture was poured into water (30 mL) and then extracted with ethyl acetate (30 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-3,6-dimethyl- 2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)quinazolin-4(3H)-one (0.24 g, 703 μmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 4.36 (s, 3H), 3.46 (s, 2H), 3.32 (s, 3H), 3.12 (br. s, 4H), 2.76 (s, 2H), 2.40 (s, 3H), 1.98 - 1.91 (m, 4H). [1263] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan- 7- yl)quinazolin-4(3H)-one [1264] To a solution of 8-acetyl-3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan-7- yl)quinazolin-4-one (0.24 g, 703 μmol) in methanol (5 mL) was added ammonium acetate (1.08 g, 14.1 mmol) and sodium cyanoborohydride (44.2 mg, 703 μmol). The mixture was stirred at 60 °C for 1 hr. On completion, the mixture was quenched by water (3 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan- 7-yl)quinazolin-4(3H)-one (0.15 g, 438 μmol, 62%) as a white solid. m/z ES + [M+H] ⁺ 343.3. [1265] Step 4. Synthesis of methyl 2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-7- azaspiro[3.5]nonan-7-yl)-3,4-dihydroquinazolin-8-yl)ethyl)am ino)benzoate [1266] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan- 7- yl)quinazolin-4-one (0.15 g, 386 μmol) in toluene (3 mL) was added methyl 2-bromobenzoate (249 mg, 1.16 mmol), tris(dibenzylideneacetone)dipalladium (35.4 mg, 38.6 μmol), cesium carbonate (629 mg, 1.93 mmol) and dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (18 mg, 38.6 μmol). The mixture was stirred at 110 °C for 12 h under nitrogen atmosphere. On completion, the mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give methyl 2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl )-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (80 mg, 166 μmol, 43%) as a white solid. m/z ES + [M+H] ⁺ 477.1. [1267] Step 5. Synthesis of 2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl )- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1268] To a solution of methyl 2-[1-[3,6-dimethyl-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-4- oxo-quinazolin-8-yl]ethylamino]benzoate (80 mg, 168 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide (20.1 mg, 839 μmol). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 46%-76%, 2 min) to give 2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl )-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid (30.7 mg, 66.4 μmol, 40%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 - 8.37 (m, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.59 - 6.36 (m, 2H), 5.49 - 5.31 (m, 1H), 4.38 (s, 4H), 3.48 (s, 3H), 3.14 (s, 4H), 2.31 (s, 3H), 1.98 (s, 4H), 1.54 (d, J = 6.8 Hz, 3H); m/z ES + [M+H] ⁺ 463.2. Example 51 and Example 52. Preparation of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-7- azaspiro[3.5]nonan-7-yl)-3,4-dihydroquinazolin-8-yl)ethyl)am ino)benzoic acid and (S)-2- ((1-(3,6-dimethyl-4-oxo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)- 3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1269] The crude product was purified by SFC: [column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 60%-60%, 4.4 min] to give (R)-2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-7-azaspiro[3.5]nonan- 7-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (7.29 mg, 16.0 μmol, 29%) as a white solid at retention time=0.978 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 - 8.44 (m, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.70 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.52 - 6.38 (m, 2H), 5.42 - 5.32 (m, 1H), 4.38 (s, 4H), 3.48 (s, 3H), 3.18 - 3.10 (m, 4H), 2.31 (s, 3H), 2.02 - 1.94 (m, 4H), 1.54 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 463.3 and (S)-2-((1-(3,6-dimethyl-4- oxo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3,4-dihydroquinazoli n-8-yl)ethyl)amino)benzoic acid (9.99 mg, 22.0 μmol, 40%) as a white solid at retention time=1.528 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 - 8.55 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.46 (s, 1H), 7.12 (t, J = 7.2 Hz, 1H), 6.53 - 6.36 (m, 2H), 5.42 - 5.32 (d, J = 6.4 Hz, 1H), 4.38 (s, 4H), 3.48 (s, 3H), 3.18 - 3.10 (m, 4H), 2.31 (s, 3H), 2.02 - 1.94 (m, 4H), 1.54 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 463.2. Example 53. Preparation of 2-((1-(5-chloro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1270] Step 1. Synthesis of N-(5-chloro-2-iodo-phenyl)-2-hydroxyimino-acetamide [1271] To a solution of 5-chloro-2-iodo-aniline (25 g, 98.6 mmol) in water (667 mL) was added hydroxylammonium chloride (24.7 g, 355 mmol), sodium sulfate (112 g, 789 mmol), chloral hydrate (19.6 g, 118 mmol) and hydrochloride (2 M, 33.3 mL). The mixture was stirred at 70 °C for 18 hr. The reaction mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with 50 mL solution of petroleum ether/ethyl acetate=5/1, then filtered and filter cake was concentrated under reduced pressure to give N-(5-chloro-2-iodo-phenyl)-2-hydroxyimino- acetamide (17 g, 52.4 mmol, 53%) as a brown solid. m/z ES + [M+H] ⁺ 324.8. [1272] Step 2. Synthesis of 4-chloro-7-iodo-indoline-2,3-dione [1273] A solution of N-(5-chloro-2-iodo-phenyl)-2-hydroxyimino-acetamide (17 g, 52.4 mmol) in concentrated sulfuric acid (70 mL) was stirred at 85 °C for 0.5 hr. The reaction mixture was poured into ice, and then stirred for 30 min. The mixture was further extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with 50 mL mixture of petroleum ether/ethyl acetate=5/1, filtered and the filtrate was concentrated under reduced pressure to give 4-chloro-7-iodo-indoline-2,3-dione (11 g, 35.8 mmol, 68%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H). [1274] Step 3. Synthesis of 2-amino-6-chloro-3-iodobenzoic acid [1275] To a solution of 4-chloro-7-iodoindoline-2,3-dione (4.5 g, 14.6 mmol) in sodium hydroxide (25 mL, 2 N) was added hydrogen peroxide (7.24 g, 74.5 mmol, 35%) dropwise, then the mixture was stirred at 15 °C for 16 hr. On completion, the solution was adjusted the pH to 2 by adding 4 N aqueous hydrogen chloride. Then the mixture was filtered and the cake was collected to give 2-amino-6-chloro-3-iodobenzoic acid (4 g, 11.7 mmol, 80%) as a red solid. m/z ES + [M+H] ⁺ 297.9. [1276] Step 4. Synthesis of 2-amino-6-chloro-3-iodo-N-methylbenzamide [1277] To a solution of 2-amino-6-chloro-3-iodobenzoic acid (4 g, 13.5 mmol) and methanamine hydrochloride (2.72 g, 40.34 mmol, 3 eq) in N,N-dimethylformamide (40 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethylammonium;hexafluorophosphate (7.67 g, 20.2 mmol) and diisopropylethylamine (8.69 g, 67.2 mmol). The mixture was stirred at 15 °C for 16 hr. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (1 L x 1), dried over [anhydrous sodium sulfate], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0 ~ 50% ethylacetate/petroleum ether gradient @ 50 mL/min) to give 2-amino-6- chloro-3-iodo-N-methylbenzamide (3.4 g, 10.9 mmol, 81%) as a yellow solid. m/z ES + [M+H] ⁺ 311.0. [1278] Step 5. Synthesis of 2,5-dichloro-8-iodo-3-methylquinazolin-4(3H)-one [1279] To a solution of 2-amino-3-bromo-N-(cyclobutylmethyl)-5-methylbenzamide (3.4 g, 10.9 mmol) in 1,4-dioxane (34 mL) was added thiocarbonyl dichloride (2.64 g, 23.0 mmol), the mixture was stirred at 15 °C for 1 hr under nitrogen amosphere. Then the mixture was stirred at 105 °C for another 1 hr. On completion, the mixture was concentrated in vacuo to give 2,5-dichloro-8-iodo-3-methylquinazolin-4(3H)-one (3.7 g, crude) as a yellow solid. m/z ES + [M+H] ⁺ 354.9. [1280] Step 6. Synthesis of 5-chloro-8-iodo-3-methyl-2-morpholinoquinazolin-4(3H)-one [1281] To a solution of 2,5-dichloro-8-iodo-3-methylquinazolin-4(3H)-one (3.7 g, 4.42 mmol) in dichloromethane (40 mL) was added morpholine (4.54 g, 52.1 mmol). The mixture was stirred at 40 °C for 16 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0 ~ 10% ethylacetate/petroleum ether gradient @ 80 mL/min) to give 5-chloro-8-iodo-3-methyl-2-morpholinoquinazolin-4(3H)-one (3 g, 7.40 mmol, 71%) as a yellow solid. m/z ES + [M+H] ⁺ 406.0. [1282] Step 7. Synthesis of 8-acetyl-5-chloro-3-methyl-2-morpholinoquinazolin-4(3H)-one [1283] To a solution of 5-chloro-8-iodo-3-methyl-2-morpholinoquinazolin-4(3H)-one (1 g, 2.47 mmol) in touene (20 mL) was added dichloropalladium triphenylphosphane (346 mg, 493 μmol) and tributyl(1-ethoxyvinyl)stannane (1.34 g, 3.70 mmol), the mixture was stirred at 125 °C for 16 hr under nitrogen atmosphere. After cooled to room temperature, the mixture was added hydrochloric acid (1 M, 5.10 mL) at 25 °C and stirred for 30 min. On completion, the reaction was adjusted to pH = 7~8 with saturated sodium bicarbonate and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (300 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-5-chloro-3-methyl-2-morpholinoquinazolin-4(3H)-one (550 mg, 1.71 mmol, 69%) as a white solid. m/z ES + [M+H] ⁺ 322.1. [1284] Step 8. Synthesis of 8-(1-aminoethyl)-5-chloro-3-methyl-2-morpholinoquinazolin- 4(3H)-one [1285] To a solution of 8-acetyl-5-chloro-3-methyl-2-morpholinoquinazolin-4(3H)-one (550 mg, 1.71 mmol) in methanol (4 mL) was added ammonium acetate (1.32 g, 17.1 mmol) and sodium cyanoborohydride (107 mg, 1.71 mmol), then the mixture was stirred at 60 °C for 1 hr. On completion, the mixture was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give 8-(1-aminoethyl)-5-chloro-3-methyl-2-morpholinoquinazolin-4( 3H)-one (280 mg, 855 μmol, 50%) as a white solid. m/z ES + [M+H] ⁺ 306.0. [1286] Step 9. Synthesis of methyl 2-((1-(5-chloro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1287] To a solution of 8-(1-aminoethyl)-5-chloro-3-methyl-2-morpholinoquinazolin-4( 3H)- one (100 mg, 310 μmol) and methyl 2-bromobenzoate (200 mg, 929 μmol) in toluene (1 mL) was added tris(dibenzylideneacetone)dipalladium (28.4 mg, 31.0 μmol), cesium carbonate (303 mg, 929 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (14.5 mg, 30.1 μmol). The mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL x 1), dried over [anhydrous sodium sulfate], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~30% ethylacetate/petroleum ether gradient @ 40 mL/min) to give methyl 2-((1-(5-chloro-3-methyl-2-morpholino-4-oxo-3,4-dihydroquina zolin-8- yl)ethyl)amino)benzoate (78 mg, 171 μmol, 55%) as a light yellow solid. m/z ES + [M+H] ⁺ 457.1. [1288] Step 10. Synthesis of 2-((1-(5-chloro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1289] To a solution of methyl 2-((1-(5-chloro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (78 mg, 171 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide;hydrate (35.8 mg, 853 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the pH of the mixture was adjusted to 6 by adding formic acid, then the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 um; mobile phase: [water (FA) - acetonitrile]; B%: 40% - 70%, 7 min) to give 2-((1-(5-chloro-3- methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)a mino)benzoic acid (23.8 mg, 53.8 μmol, 32%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.39 - 8.05 (m, 1H), 8.01 - 7.96 (m, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.26 - 7.15 (m, 2H), 6.60 - 6.54 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.50 - 5.41 (m, 1H), 4.05 - 3.80 (m, 4H), 3.60 (s, 3H), 3.40 - 3.18 (m, 4H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES + [M+H] ⁺ 443.1. Example 54. Preparation of 2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-6-azaspiro[3.5]nonan-6- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1290] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5]nonan-8- yl)quinazolin-4-one [1291] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (500 mg, 1.74 mmol) and 2-oxa-8-azaspiro[3.5]nonane oxalic acid (779 mg, 2.26 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (1.12 g, 8.69 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=2/1 to 1/1) to give 8-bromo-3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5]nonan-8-yl)quin azolin-4-one (513 mg, 1.36 mmol, 78%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 4.39 - 4.33 (m, 2H), 4.33 - 4.28 (m, 2H), 3.45 (s, 2H), 3.43 (s, 3H), 3.10 - 2.99 (m, 2H), 2.39 (s, 3H), 1.86 (t, J = 6.0 Hz, 2H), 1.70 - 1.58 (m, 2H). [1292] Step 2. Synthesis of 8-bromo-3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5]nonan-8- yl)quinazolin-4-one [1293] A mixture of 8-bromo-3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5]nonan-8-yl)quin azolin- 4-one (510 mg, 1.35 mmol), tributyl(1-ethoxyvinyl)stannane (1.46 g, 4.04 mmol) and dichloropalladium triphenylphosphane (94.6 mg, 135 μmol) in toluene (8.0 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 130 °C for 12 h under nitrogen atmosphere. The reaction mixture was cooled to 25 °C, then formic acid (8.0 mL, 50% in dichloromethane) was added and the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was diluted with sat. sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 2/1) to give 8-acetyl-3,6-dimethyl-2-(2-oxa-8 -azaspiro[3.5]nonan- 8-yl)quinazolin-4-one (301 mg, 882 μmol, 65%) as a white solid. m/z ES + [M+H] ⁺ 342.2. [1294] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(2-oxa-6-azaspiro[3.5]nonan- 6- yl)quinazolin-4(3H)-one [1295] To a solution of 8-acetyl-3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5]nonan-8- yl)quinazolin-4-one (280 mg, 820 μmol) in methanol (3 mL) was added ammonium acetate (632 mg, 8.20 mmol) and sodium cyanoborohydride (51.5 mg, 820 μmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was quenched with water (3 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3,6-dimethyl-2-(2-oxa-8- azaspiro[3.5]nonan-8-yl)quinazolin-4-one (105 mg, 306 μmol, 37%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 4.93 - 4.86 (m, 1H), 4.36 - 4.30 (m, 4H), 3.46 (s, 3H), 3.43 - 3.35 (m, 2H), 3.01 (s, 2H), 2.41 (s, 3H), 1.85 (d, J = 5.6 Hz, 2H), 1.65 (s, 2H), 1.47 (d, J = 6.8 Hz, 3H); m/z ES + [M+H] ⁺ 343.2. [1296] Step 4. Synthesis of methyl 2-[1-[3,6-dimethyl-2-(2- oxa- 8-azaspiro[3.5]nonan-8-yl)- 4-oxo-quinazolin-8-yl]ethylamino]benzoate [1297] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5]nonan- 8-yl) quinazolin-4-one (100 mg, 292 μmol), methyl 2-bromobenzoate (314 mg, 1.46 mmol, 205 ^L) in toluene (5 mL) was added tris(dibenzylideneacetone)dipalladium (26.7 mg, 29.2 μmol), cesium carbonate (285 mg, 876 μmol) and methanesulfonato(2- dicyclohexylphosphino-2,6- di-i-propoxy-1,1-biphenyl) (13.6 mg, 29.2 μmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1:1) to give methyl 2-[1-[3,6-dimethyl-2-(2- oxa- 8- azaspiro[3.5]nonan-8-yl)-4-oxo-quinazolin-8-yl]ethylamino]be nzoate (70 mg, 147 μmol, 50%) as a yellow oil. m/z ES + [M+H] ⁺ 477.2. [1298] Step 5. Synthesis of 2-[1-[3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5]nonan-8-yl)-4-oxo - quinazolin-8-yl]ethylamino]benzoic acid [1299] To a solution of methyl 2-[1-[3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5]nonan-8-yl)-4- oxo- quinazolin-8-yl]ethylamino]benzoate (70 mg, 146 μmol) in anhydrous tetrahydrofuran (1 mL), methanol (0.5 mL) and water (0.5 mL) was added lithium hydroxide (17.6 mg, 734 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 42% - 72%, 7 min) to give 2-[1-[3,6-dimethyl-2-(2-oxa-8-azaspiro[3.5] nonan-8-yl)-4- oxo- quinazolin-8-yl]ethylamino]benzoic acid (52.2 mg, 113 μmol, 77%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 - 8.04 (m, 1H), 7.99 - 7.93 (m, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.25 - 7.18 (m, 1H), 6.59 - 6.49 (m, 2H), 5.46 - 5.32 (m, 1H), 4.60 (d, J = 6.0 Hz, 1H), 4.55 - 4.46 (m, 3H), 3.80 - 3.64 (m, 1H), 3.57 (s, 3H), 3.37 (d, J = 12.0 Hz, 1H), 3.21 - 3.06 (m, 1H), 3.02 - 2.86 (m, 1H), 2.40 (s, 3H), 2.07 - 1.98 (m, 1H), 1.89 - 1.82 (m, 1H), 1.78 - 1.73 (m, 2H), 1.71 (d, J = 6.8 Hz, 3H); m/z ES + [M+H] ⁺ 463.2. Example 55 and Example 56. Preparation of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-6- azaspiro[3.5]nonan-6-yl)-3,4-dihydroquinazolin-8-yl)ethyl)am ino)benzoic acid & (S)-2- ((1-(3,6-dimethyl-4-oxo-2-(2-oxa-6-azaspiro[3.5]nonan-6-yl)- 3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1300] The compound was separated by SFC (column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 60% - 60%, 6.2 min) to give (R)-2-((1-(3,6-dimethyl-4-oxo-2-(2-oxa-6-azaspiro[3.5]nonan- 6-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (14.2 mg, 30.6 μmol, 28.3%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 - 8.08 (m, 1H), 8.02 - 7.82 (m, 2H), 7.52 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.62 - 6.49 (m, 2H), 5.48 - 5.31 (m, 1H), 4.62 (d, J = 6.0 Hz, 1H), 4.56 - 4.48 (m, 3H), 3.73 (d, J = 11.2 Hz, 1H), 3.59 (s, 3H), 3.38 (d, J = 12.4 Hz, 1H), 3.19 - 3.09 (m, 1H), 2.95 (d, J = 1.6 Hz, 1H), 2.41 (s, 3H), 2.09 - 1.99 (m, 1H), 1.92 - 1.84 (m, 1H), 1.76 (d, J = 3.6 Hz, 2H), 1.72 (d, J = 6.8 Hz, 3H); m/z ES + [M+H] ⁺ 463.2 and (S)-2-((1-(3,6-dimethyl-4-oxo- 2-(2-oxa-6-azaspiro[3.5]nonan-6-yl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (16.7 mg, 36.0 μmol, 33.3%) as a white solid ¹ H NMR (400 MHz, CDCl3) δ 8.51 - 8.02 (m, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.52 (s, 1H), 7.26 - 7.21 (m, 1H), 6.60 - 6.51 (m, 2H), 5.39 (d, J = 5.6 Hz, 1H), 4.62 (d, J = 5.2 Hz, 1H), 4.53 (s, 3H), 3.79 - 3.67 (m, 1H), 3.59 (s, 3H), 3.38 (d, J = 12.0 Hz, 1H), 3.14 (d, J = 2.8 Hz, 1H), 2.95 (d, J = 2.0 Hz, 1H), 2.41 (s, 3H), 2.08 - 2.01 (m, 1H), 1.92 - 1.85 (m, 1H), 1.77 (s, 2H), 1.72 (d, J = 6.4 Hz, 3H); m/z ES + [M+H] ⁺ 463.3. Example 57. Preparation of 2-[1-[3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4- oxo-quinazolin-8-yl]ethylamino]benzoic acid [1301] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan-6- yl)quinazolin-4-one [1302] To a mixture of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (500 mg, 1.74 mmol) and 2-oxa-6-azaspiro[3.3]heptane;oxalic acid (362 mg, 1.91 mmol) in anhydrous tetrahydrofuran (10 mL) was added diisopropylethylamine (674 mg, 5.22 mmol) in one portion. The mixture was then heated to 60 °C and stirred for 3 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 8-bromo-3,6-dimethyl-2-(2-oxa-6- azaspiro[3.3]heptan-6-yl)quinazolin-4-one (0.6 g, 1.49 mmol, 86%) as a yellow solid. m/z ES + [M+H] ⁺ 352.0. [1303] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan-6- yl)quinazolin-4-one [1304] To a mixture of 8-bromo-3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan-6- yl)quinazolin-4-one (600 mg, 1.71 mmol) and tributyl(1-ethoxyvinyl)stannane (1.86 g, 5.14 mmol, 1.73 mL) in toluene (10 mL) was added dichloropalladium triphenylphosphane (241 mg, 343 μmol) in one portion under nitrogen atmosphere. The mixture was then heated to 80 °C and stirred for 5 hr under nitogen atmosphere. After cooled to room temperature, the reaction mixture was added fomic acid (20 mL) at 25 °C and stirred for 30 min. On completion, the reaction mixture was quenched by potassium fluoride solution (20 mL) at 20 °C, and then diluted with ethyl acetate (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-3,6-dimethyl-2-(2-oxa-6- azaspiro[3.3]heptan-6-yl)quinazolin-4-one (410 mg, 916 μmol, 53%) as a yellow solid. m/z ES + [M+H] ⁺ 314.1. [1305] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan - 6-yl)quinazolin-4-one [1306] To a mixture of 8-acetyl-3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan-6- yl)quinazolin-4-one (400 mg, 1.28 mmol) in methanol (15 mL) was added ammonium acetate (984 mg, 12.8 mmol), sodium cyanoborohydride (120 mg, 1.91 mmol) in one portion. The mixture was then heated to 60 °C and stirred for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3,6-dimethyl-2- (2-oxa-6-azaspiro[3.3]heptan-6-yl)quinazolin-4-one (0.1 g, 313 μmol, 25%) as a yellow solid. m/z ES + [M+H] ⁺ 315.1. [1307] Step 4. Synthesis of 2-[1-[3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-ox o- quinazolin-8-yl]ethylamino]benzoic acid [1308] To a mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan -6- yl)quinazolin-4-one (50 mg, 159 μmol) and 2-iodobenzoic acid (78.9 mg, 318 μmol) in dimethyl acetamide (1 mL) was added triethylamine (32.2 mg, 318 μmol), copper powder (10.1 mg, 159 μmol) in one portion under nitrogen atmosphere. The mixture was then heated to 110 °C and stirred for 3 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water (FA) - acetonitrile]; B%: 38%-68%, 10 min) to give 2-[1-[3,6-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-ox o- quinazolin-8-yl]ethylamino]benzoic acid (8.62 mg, 19.8 μmol, 12.5%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (br. d, J = 6.8 Hz, 1H), 7.85 (s, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.21 (br. t, J = 7.2 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.48 - 5.38 (m, 1H), 4.89 (s, 4H), 4.40 (s, 4H), 3.50 (s, 3H), 2.36 (s, 3H), 1.64 (br. d, J = 6.4 Hz, 3H); m/z ES + [M+H] ⁺ 435.2. Example 58. Preparation of 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1309] Step 1. Synthesis of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3,6- dimethylquinazolin-4(3H)-one [1310] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (0.5 g, 1.74 mmol) in dichloromethane (5 mL) was added 3-azabicyclo[3.1.0]hexane (416 mg, 3.48 mmol) and diisopropylethylamine (899 mg, 6.96 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 2-(3-azabicyclo[3.1.0]hexan-3- yl)-8-bromo-3,6-dimethylquinazolin-4(3H)-one (0.57 g, 1.65 mmol, 95%) as a white solid; m/z ES + [M+H] ⁺ 336.1. [1311] Step 2. Synthesis of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethylquinazolin-4(3H)-one [1312] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3,6-dimethyl-quina zolin- 4-one (0.3 g, 898 μmol) in n-butanol (3 mL) was added 1-vinyloxybutane (270 mg, 2.69 mmol), palladium acetate (20.2 mg, 89.8 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl- phosphane (48.3 mg, 89.8 μmol) and diisopropylethylamine (348 mg, 2.69 mmol). The mixture was stirred at 95 °C under nitrogen atmosphere for 12 hr. Then hydrochloric acid (1 M, 8.98 mL) was added to the mixture and stirred at 25 °C for 30 min. Then sodium carbonate (aq, sat.) was added to the mixture until pH = 8. The mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethylquina zolin-4(3H)-one (0.18 g, 605 μmol, 67%) as a white solid. m/z ES + [M+H] ⁺ 298.3. [1313] Step 3. Synthesis of 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethylquinazolin-4(3H)-one [1314] To a solution of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-quin azolin- 4-one (0.18 g, 605 μmol) in methanol (2 mL) was added ammonium acetate (933 mg, 12.1 mmol) and sodium cyanoborohydride (38 mg, 605 μmol). The mixture was stirred at 60 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-2-(3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethylquinazolin-4(3H)-on e (0.15 g, 436 μmol, 72%) as a white solid. m/z ES + [M+H] ⁺ 299.2. [1315] Step 4. Synthesis of methyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1316] To a solution of 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimet hyl- quinazolin-4-one (0.15 g, 436 μmol) in toluene (2 mL) was added methyl 2-bromobenzoate (281 mg, 1.31 mmol), tris(dibenzylideneacetone)dipalladium (39.9 mg, 43.6 μmol), dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (20.3 mg, 43.6 μmol) and cesium carbonate (710 mg, 2.18 mmol). The mixture was stirred at 110 °C under nitrogen atmosphere for 12 hr. On completion, the mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The organic layer was concentrated to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give methyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate (88 mg, 203 μmol, 47%) as a yellow oil. m/z ES + [M+H] ⁺ 433.3. [1317] Step 5. Synthesis of 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1318] To a solution of methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- quinazolin-8-yl]ethylamino]benzoate (88 mg, 203 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide (24.4 mg, 1.02 mmol). The mixture was stirred at 60 °C for 2 hr. On completion, hydrochloric acid (1 M) was added to the mixture until pH = 3. Then the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 56%-86%, 2 min) to give 2-((1-(2-(3-azabicyclo[3.1.0]hexan- 3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)am ino)benzoic acid (32.5 mg, 77.6 μmol, 38%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.21 - 7.13 (m, 1H), 6.52 - 6.40 (m, 2H), 5.41 - 5.29 (m, 1H), 3.99 (d, J = 10.4 Hz, 1H), 3.82 (d, J = 10.4 Hz, 1H), 3.53 (d, J = 9.6 Hz, 1H), 3.47 (d, J = 10.4 Hz, 1H), 3.42 (s, 3H), 2.29 (s, 3H), 1.66 - 1.59 (m, 2H), 1.54 (d, J = 6.4 Hz, 3H), 0.59 (dt, J = 4.4, 7.2 Hz, 1H), 0.37 (q, J = 4.0 Hz, 1H); m/z ES + [M+H] ⁺ 419.2. Example 59 and Example 60. Preparation of 2-(((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)benzoic acid & 2-(((1S)- 1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1319] The crude product was purified by SFC: column: Daicel CHIRALPAK IC (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide isopropanol]; B%: 50%-50%, 4.2 min to give 2-(((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4 -oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (9.29 mg, 22.2 μmol, 32%) as a white solid. ¹ H NMR (400 MHz, CDCl3) 7.98 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.45 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.47 (q, J = 6.4 Hz, 1H), 3.95 (d, J = 10.0 Hz, 1H), 3.79 (d, J = 10.0 Hz, 1H), 3.60 - 3.49 (m, 4H), 2.35 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.60 (d, J = 4.0 Hz, 2H), 0.69 - 0.58 (m, 1H), 0.51 (q, J = 4.0 Hz, 1H); m/z ES+ [M+H] ⁺ 419.2 and 2-(((1S)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4 -oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (9.90 mg, 23.7 μmol, 34%) as a white solid. ¹ H NMR (400 MHz, CDCl3) 7.98 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.45 (s, 1H), 7.23 - 7.15 (m, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.47 (q, J = 6.8 Hz, 1H), 3.95 (d, J = 10.4 Hz, 1H), 3.79 (d, J = 10.0 Hz, 1H), 3.59 - 3.49 (m, 4H), 2.35 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.60 (d, J = 4.0 Hz, 2H), 0.67 - 0.58 (m, 1H), 0.51 (q, = 4.0 Hz, 1H); m/z ES+ [M+H] ⁺ 419.2. Example 61. Preparation of 2-[1-[3,6-Dimethyl-2-(1-methyl-4-piperidyl)-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid [1320] Step 1. Synthesis of 2-amino-3-bromo-N,5-dimethyl-benzamide [1321] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (5 g, 21.7 mmol) and methanamine;hydrochloride (5.87 g, 86.9 mmol) in N,N-dimethylformamide (100 mL) was added diisopropylethylamine (14.4 g, 109 mmol) and [dimethylamino(triazolo[4,5-b]pyridin- 3-yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (12.4 g, 32.6 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was poured into water (500 mL), resulting much white precipitate. The precipitate was filtered and concentrated under reduced pressure to give 2-amino-3-bromo-N,5-dimethyl-benzamide (5 g, 20.6 mmol, 95%) as a white solid. m/z ES + [M+H] ⁺ 243.1. [1322] Step 2. Synthesis of tert-butyl 4-((2-bromo-4-methyl-6- (methylcarbamoyl)phenyl)carbamoyl)piperidine-1-carboxylate [1323] To a solution of 2-amino-3-bromo-N,5-dimethyl-benzamide (4.3 g, 17.7 mmol) and 1- tert-butoxycarbonylpiperidine-4-carboxylic acid (4.87 g, 21.2 mmol) in pyridine (30 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (33.7 g, 53.1 mmol, 50% purity). The mixture was stirred at 60 °C for 12 hr. On completion, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with 50 mL of petroleum ether/ethyl acetate=3/1 and then filtered. The filter cake was concentrated under reduced pressure to give tert-butyl 4-[[2-bromo-4-methyl-6- (methylcarbamoyl)phenyl]carbamoyl]piperidine-1-carboxylate (2.8 g, 6.16 mmol, 35%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.95 (br. d, J = 4.8 Hz, 1H), 7.59 (s, 1H), 7.24 (s, 1H), 3.95 (br. d, J = 11.6 Hz, 2H), 3.32 (s, 1H), 2.87 - 2.75 (m, 2H), 2.67 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 1.76 (br. d, J = 10.4 Hz, 2H), 1.50 - 1.44 (m, 2H), 1.41 (s, 9H). [1324] Step 3. Synthesis of tert-butyl 4-(8-bromo-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)piperidine-1-carboxylate [1325] To a solution of tert-butyl 4-[[2-bromo-4-methyl-6- (methylcarbamoyl)phenyl]carbamoyl]piperidine-1-carboxylate (2.2 g, 4.84 mmol) in methanol (60 mL) was added sodium methoxide (2.62 g, 48.4 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-(8-bromo-3,6-dimethyl-4-oxo-quinazolin-2-yl)piperidine-1-c arboxylate (2 g, 4.58 mmol, 95%) as a white solid. m/z ES + [M+H] ⁺ 438.1. [1326] Step 4. Synthesis of tert-butyl 4-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin- 2-yl)piperidine-1-carboxylate [1327] To a solution of tert-butyl 4-(8-bromo-3,6-dimethyl-4-oxo-quinazolin-2-yl)piperidine- 1-carboxylate (1 g, 2.29 mmol) and tributyl(1-ethoxyvinyl)stannane (2.48 g, 6.87 mmol, 2.3 mL) in toluene (15 mL) was added dichloropalladium triphenylphosphane (161 mg, 229 μmol). The mixture was stirred at 130 °C under nitrogen atmosphere for 12 hr. Then the reaction mixture was added hydrochloric acid (1 M, 5 mL) at 25 °C and stirred for 30 min. The reaction was adjusted to pH = 7~8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether/ethyl acetate (10 mL, 3/1), filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(8-acetyl-3,6-dimethyl-4-oxo- quinazolin-2-yl)piperidine-1-carboxylate (700 mg, 1.75 mmol, 77%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (d, J = 1.2 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 4.12 - 3.98 (m, 2H), 3.64 (s, 3H), 3.29 - 3.22 (m, 1H), 2.99 - 2.81 (m, 2H), 2.77 (s, 3H), 2.46 (s, 3H), 1.95 (br. d, J = 12.8 Hz, 2H), 1.68 - 1.58 (m, 2H), 1.42 (s, 9H); m/z ES + [M+H] ⁺ 400.2. [1328] Step 5. Synthesis of tert-butyl 4-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)piperidine-1-carboxylate [1329] To a solution of tert-butyl 4-(8-acetyl-3,6-dimethyl-4-oxo-quinazolin-2-yl)piperidine- 1-carboxylate (650 mg, 1.63 mmol) in methanol (5 mL) and dichloromethane (5 mL) was added ammonium acetate (1.88 g, 24.4 mmol) and sodium cyanoborohydride (153 mg, 2.44 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) and lyophilized to afford tert-butyl 4-[8-(1-aminoethyl)-3,6- dimethyl-4-oxo-quinazolin-2-yl]piperidine-1-carboxylate (420 mg, 1.05 mmol, 64%) as a yellow solid. m/z ES + [M+H] ⁺ 401.2. [1330] Step 6. Synthesis of tert-butyl 4-(8-(1-((2-(methoxycarbonyl)phenyl)amino)ethyl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-c arboxylate [1331] To a solution of tert-butyl 4-[8-(1-aminoethyl)-3,6-dimethyl-4-oxo-quinazolin-2- yl]piperidine-1-carboxylate (372 mg, 930 μmol) and methyl 2-bromobenzoate (1 g, 4.65 mmol) in toluene (10 mL) was added tris(dibenzylideneacetone)dipalladium (85.1 mg, 93.0 μmol), dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (65.1 mg, 139 μmol) and cesium carbonate (909 mg, 2.79 mmol). The mixture was stirred at 110 °C for 3 hr under nitrogen atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give tert-butyl 4-[8-[1-(2-methoxycarbonylanilino)ethyl]-3,6-dimethyl- 4-oxo-quinazolin-2-yl]piperidine-1-carboxylate (400 mg, 748 μmol, 80%) as a yellow solid. m/z ES + [M+H] ⁺ 535.3. [1332] Step 7. Synthesis of methyl 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-4-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1333] A solution of tert-butyl 4-[8-[1-(2-methoxycarbonylanilino)ethyl]-3,6-dimethyl-4- oxo-quinazolin-2-yl]piperidine-1-carboxylate (320 mg, 599 μmol) in hydrochloride-1,4- dioxane (5 mL) was stirred at 25 °C for 30 minutes. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 7~8 with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-[1-[3,6-dimethyl-4-oxo-2- (4-piperidyl)quinazolin-8-yl]ethylamino]benzoate (250 mg, 575 μmol, 96%) as a brown oil. m/z ES + [M+H] ⁺ 435.2. [1334] Step 8. Synthesis of methyl 2-[1-[3,6-dimethyl-2-(1-methyl-4-piperidyl)-4-oxo- quinazolin-8-yl]ethylamino]benzoate [1335] To a solution of methyl 2-[1-[3,6-dimethyl-4-oxo-2-(4-piperidyl)quinazolin-8- yl]ethylamino]benzoate (200 mg, 460 μmol) and paraformaldehyde (20.7 mg, 690 μmol) in methanol (5 mL) was added sodium cyanoborohydride (34.7 mg, 552 μmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (80 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-[1-[3,6-dimethyl-2-(1-methyl-4-piperidyl)-4-oxo-quinazolin -8- yl]ethylamino]benzoate (150 mg, 334 μmol, 73%) as a brown oil. m/z ES + [M+H] ⁺ 449.2. [1336] Step 9. Synthesis of 2-[1-[3,6-dimethyl-2-(1-methyl-4-piperidyl)-4-oxo-quinazolin -8- yl]ethylamino]benzoic acid [1337] To a solution of methyl 2-[1-[3,6-dimethyl-2-(1-methyl-4-piperidyl)-4-oxo- quinazolin-8-yl]ethylamino]benzoate (150 mg, 334 μmol) in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL) was added lithium hydroxide (40.0 mg, 1.67 mmol). The mixture was stirred at 60 °C for 12 hr. The reaction mixture was adjusted to pH = 2~3 with 1N hydrochloric acid and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 15% - 45%, 7 min) to afford 2-[1- [3,6-dimethyl-2-(1-methyl-4-piperidyl)-4-oxo-quinazolin-8-yl ]ethylamino]benzoic acid (99.7 mg, 229 μmol, 69%) as an off-white solid. ¹ H NMR (400 MHz, CD3OD) δ 7.88 (s, 1H), 7.82 (dd, J = 1.4, 7.6 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.10 - 7.05 (m, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 7.2 Hz, 1H), 5.18 (q, J = 6.4 Hz, 1H), 3.70 (s, 3H), 3.69 - 3.57 (m, 2H), 3.47 - 3.39 (m, 1H), 3.18 - 3.09 (m, 2H), 2.94 (s, 3H), 2.46 (s, 3H), 2.34 - 2.01 (m, 4H), 1.69 (d, J = 6.8 Hz, 3H); m/z ES + [M+H] ⁺ 435.2. Example 62. Preparation of 2-[1-[2-[1-(2,2-difluoroethyl)-4-piperidyl]-3,6-dimethyl-4- oxo-quinazolin-8-yl]ethylamino]benzoic acid [1338] Step 1. Synthesis of methyl 2-[1-[2-[1-(2,2-difluoroethyl)-4-piperidyl]-3,6-dimethyl- 4-oxo-quinazolin-8-yl]ethylamino]benzoate [1339] To a solution of methyl 2-[1-[3,6-dimethyl-4-oxo-2-(4-piperidyl)quinazolin-8- yl]ethylamino]benzoate (90.0 mg, 207 μmol) and 2,2-difluoroethyl trifluoromethanesulfonate (48.8 mg, 227 μmol) in N,N-dimethylformamide (1 mL) was added diisopropylethylamine (134 mg, 1.04 mmol). The mixture was stirred at 40 °C for 12 hr. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate = 3:1) to give methyl 2-[1-[2-[1-(2,2-difluoroethyl)-4-piperidyl]-3,6-dimethyl-4-o xo- quinazolin-8-yl]ethylamino]benzoate (80.0 mg, 158 μmol, 77%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J = 6.8 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.56 (d, J = 1.8 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.56 - 6.48 (m, 2H), 6.35 - 6.00 (m, 1H), 5.58 - 5.49 (m, 1H), 3.84 (s, 3H), 3.61 (s, 3H), 3.09 - 2.97 (m, 3H), 2.82 - 2.71 (m, 2H), 2.35 (s, 3H), 1.98 - 1.92 (m, 3H), 1.59 (d, J = 6.8 Hz, 3H). m/z ES+ [M+H] ⁺ 499.3. [1340] Step 2. Synthesis of 2-[1-[2-[1-(2,2-difluoroethyl)-4-piperidyl]-3,6-dimethyl-4-o xo- quinazolin-8-yl]ethylamino]benzoic acid [1341] To a solution of methyl 2-[1-[2-[1-(2,2-difluoroethyl)-4-piperidyl]-3,6-dimethyl-4- oxo-quinazolin-8-yl]ethylamino]benzoate (80 mg, 160 μmol) in tetrahydrofuran (0.8 mL), methanol (0.8 mL), water (0.8 mL) was added lithium hydroxide (33.7 mg, 802 μmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced presssrue. The residue was purified by prep-HPLC (formic acid condition; column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 16%-46%, 10 min) to give 2-[1-[2-[1-(2,2-difluoroethyl)-4-piperidyl]-3,6-dimethyl-4- oxo-quinazolin-8-yl]ethylamino]benzoic acid (27.0 mg, 53.9 μmol, 34%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.32 (m, 1H), 7.80 - 7.76 (m, 2H), 7.52 (s, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.51 - 6.40 (m, 2H), 6.34 - 6.00 (m, 1H), 5.60 - 5.54 (m, 1H), 3.61 (s, 3H), 3.08 - 3.00 (m, 3H), 2.82 - 2.71 (m, 2H), 2.38 - 2.30 (s, 5H), 2.02 - 1.88 (s, 4 H) 1.56 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 485.3. Example 63. Preparation of 2-[1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethylamino]benzoic acid

[1342] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(pyridin-4-yl)quinazolin-4(3H)-one [1343] A solution of 2-amino-3-bromo-N,5-dimethyl-benzamide (1.5 g, 6.17 mmol) and pyridine-4-carbaldehyde (991 mg, 9.26 mmol, 869 ^L) in dimethylsulfoxide (15 mL) was stirred at 120 °C for 12 hr. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (100 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with 50 mL of petroleum ether/ethyl acetate=3/1 and then filtered. The filter cake was collected and concentrated under reduced pressure to give 8-bromo-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one (1 g, 3.03 mmol, 49%) as a white solid. m/z ES+ [M+H] ⁺ 294.1. [1344] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(pyridin-4-yl)quinazolin-4(3H)-one [1345] To a solution of 8-bromo-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one (1 g, 3.03 mmol) and tributyl(1-ethoxyvinyl)stannane (3.28 g, 9.09 mmol) in toluene (15 mL) was added dichloropalladium triphenylphosphane (213 mg, 302 μmol). The mixture was stirred at 130 °C under nitrogen atmosphere for 12 hr. After cooled to room temperature, the reaction mixture was added aq. hydrochloric acid (1 M, 5 mL) at 25 °C and stirred for 30 min. Then the reaction was adjusted to pH = 7~8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with 10 mL petroleum ether/ethyl acetate=5/1 and then filtered. The filter cake was collected and dried under reduced pressure to give 8-acetyl-3,6-dimethyl-2-(4- pyridyl)quinazolin-4-one (450 mg, 1.53 mmol, 51%) as a white solid. ¹ HNMR (400 MHz, DMSO-d6) δ 8.81 (br. d, J = 5.6 Hz, 2H), 8.19 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 5.6 Hz, 2H), 3.40 (s, 3H), 3.34 (s, 3H), 2.71 (s, 3H). [1346] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one [1347] To a solution of 8-acetyl-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one (400 mg, 1.36 mmol) in methanol (10 mL) and dichloromethane (10 mL) was added ammonium acetate (1.58 g, 20.5 mmol) and sodium cyanoborohydride (128 mg, 2.05 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to afford 8-(1-aminoethyl)-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one (250 mg, 849 μmol, 62%) as a yellow solid. m/z ES+ [M+H] ⁺ 295.1. [1348] Step 4. Synthesis of methyl 2-[1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethylamino]benzoate [1349] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one (197 mg, 669 μmol) and methyl 2-bromobenzoate (600 mg, 2.79 mmol) in toluene (5 mL) was added tris(dibenzylideneacetone)dipalladium (51.1 mg, 55.8 μmol), dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl]phosphane (39.1 mg, 83.7 μmol) and cesium carbonate (545 mg, 1.67 mmol). The mixture was stirred at 110 °C under nitrogen atmosphere for 2 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give methyl 2-[1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8-yl]ethyla mino]benzoate (200 mg, 467 μmol, 84%) as a yellow solid. m/z ES+ [M+H] ⁺ 429.1. [1350] Step 5. Synthesis of 2-[1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethylamino]benzoic acid [1351] To a solution of methyl 2-[1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethylamino]benzoate (200 mg, 466 μmol) in tetrahydrofuran (3 mL), water (3 mL) and methanol (3 mL) was added lithium hydroxide (55.9 mg, 2.33 mmol). The mixture was stirred at 65 °C for 2 hr. On completion, the reaction mixture was adjusted to pH = 3~4 with 1 N aq. Hydrochloric acid. The residue was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 34%-64%, 10 min) to afford 2-[1-[3,6-dimethyl-4-oxo-2-(4- pyridyl)quinazolin-8-yl]ethylamino]benzoic acid (93.9 mg, 227 μmol, 49%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.85 - 8.78 (m, 2H), 8.44 (d, J = 4.8 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.82 - 7.76 (m, 3H), 7.61 (d, J = 2.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.50 (t, J = 7.6 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.45 (br. d, J = 5.2 Hz, 1H), 3.41 (s, 3H), 2.41 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 415.2. Example 64. Preparation of 5-cyano-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1352] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (0.1 g, 330 μmol) and 2-bromo-5-cyano-benzoic acid (150 mg, 661 μmol) in dimethyl acetamide (1 mL) was added copper powder (21 mg, 331 μmol), trimethylamine (100 mg, 992 μmol). The mixture was stirred at 110 °C for 1 hr under nitrogen. On completion, the mixture was poured in water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 48% - 78%, 2 min) to give 5-cyano-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (25.0 mg, 55.9 μmol, 17%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.83 - 8.69 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.94 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 2.0, 9.2 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 5.49 (t, J = 6.0 Hz, 1H), 3.92 (t, J = 4.8 Hz, 4H), 3.64 (s, 3H), 3.33 - 3.27 (m, 4H), 2.40 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 448.2. Example 65. Preparation of 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1353] Step 1. Synthesis of 8-bromo-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethylquinazoli n- 4(3H)-one [1354] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (1 g, 3.48 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (1.35 g, 10.4 mmol) and 3,3- dimethylpiperidine;hydrochloride (624.59 mg, 4.17 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure in vacuo to give 8-bromo-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethylquinazoli n- 4(3H)-one (1.25 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 364.0. [1355] Step 2. Synthesis of 8-acetyl-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethylquinazol in- 4(3H)-one [1356] A mixture of 8-bromo-2-(3,3-dimethyl-1-piperidyl)-3,6-dimethyl-quinazolin -4-one (1.2 g, 3.29 mmol), 1-vinyloxybutane (989 mg, 9.88 mmol), diacetoxypalladium (73.9 mg, 329 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (177 mg, 329 μmol) and diisopropylethylamine (1.28 g, 9.88 mmol) in n-butanol (10 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere. After cooled to room temperature, hydrochloric acid (1 M, 32.9 mL) was added in the mixture and stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 1/1) to give 8-acetyl-2-(3,3- dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (0.5 g, 1.53 mmol, 46%) as a white solid. m/z ES+ [M+H] ⁺ 328.4. [1357] Step 3. Synthesis of 8-(1-aminoethyl)-2-(3,3-dimethylpiperidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one [1358] To a solution of 8-acetyl-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethylquinazol in- 4(3H)-one (0.35 g, 1.07 mmol) in methanol (4 mL) was added sodium cyanoborohydride (67.1 mg, 1.07 mmol) and ammonium acetate (1.65 g, 21.3 mmol). The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-2-(3,3-dimethylpiperidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one (0.25 g, 761 μmol, 71%) as a white solid. m/z ES+ [M+H] ⁺ 330.4. [1359] Step 4. Synthesis of methyl 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate A mixture of 8-(1-aminoethyl)-2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl quinazolin-4(3H)- one (0.2 g, 608 μmol), methyl 2-bromobenzoate (393 mg, 1.83 mmol), tris(dibenzylideneacetone)dipalladium (55.7 mg, 60.8 μmol), dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl]phosphane (28.4 mg, 60.8 μmol) and cesium carbonate (595 mg, 1.83 mmol) in toluene (2 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 1/1) to give methyl 2- ((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-d ihydroquinazolin-8- yl)ethyl)amino)benzoate (0.15 g, 324 μmol, 53%) as a yellow solid. m/z ES+ [M+H] ⁺ 463.2. [1360] Step 5. Synthesis of 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1361] To 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 (0.12 g, 259 μmol) in anhydrous tetrahydrofuran (0.5 mL), methanol (0.25 mL) and water (0.25 mL) was added lithium hydroxide (18.4 mg, 778 μmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25mm, 10 um; mobile phase: [water (FA)- acetonitrile]; B%: 70%-100%, 10 min) to give 2-((1-(2-(3,3-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (59.57 mg, 131 μmol, 50%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 - 7.99 (m, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.23 - 7.19 (m, 1H), 6.61 - 6.55 (m, 1H), 6.50 (d, J = 8.8 Hz, 1H), 5.57 - 5.54 (m, 1H), 3.64 (s, 3H), 3.18 - 3.16 (m, 2H), 2.92 (s, 2H), 2.39 (s, 3H), 1.85 - 1.82 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H), 1.48 (t, J = 6.0 Hz, 2H), 1.09 (d, J = 1.6 Hz, 6H); m/z ES+ [M+H] ⁺ 449.3. Example 66. 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 [1362] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazolin - 4(3H)-one [1363] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (500 mg, 1.74 mmol) in dichloromethane (8 mL) was added diisopropylethylamine (1.12 g, 8.69 mmol) and 2-azaspiro [3.5]nonane (337 mg, 2.09 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-bromo-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazolin -4(3H)-one (620 mg, 1.53 mmol, 88%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 3.93 (s, 4H), 3.47 (s, 3H), 2.39 (s, 3H), 1.77 - 1.68 (m, 4H), 1.57 - 1.37 (m, 6H); m/z ES+ [M+H] ⁺ 378.1. [1364] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazoli n- 4(3H)-one [1365] A mixture of 2-(2-azaspiro [3.5] nonan-2-yl)-8-bromo-3, 6-dimethyl-quinazolin-4-one (500 mg, 1.33 mmol), 1-vinyloxybutane (399 mg, 3.99 mmol), diacetoxypalladium (29.8 mg, 133 μmol), diisopropylethylamine (515 mg, 3.99 mmol) and [2-(2- diphenylphosphanylphenoxy) phenyl]-diphenyl-phosphane (71.6 mg, 133 μmol) in n-butanol (8 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere. After cooled to room temperature, hydrochloric acid (1 M, 6.64 mL) was added to the mixture solution and the mixture solution was stirred at 20 °C for 2 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-acetyl-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2-yl)quinazoli n- 4(3H)-one (450 mg, 1.19 mmol, 89%) as a yellow solid. m/z ES+ [M+H] ⁺ 340.1. [1366] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(2-azaspiro[3.5]nonan-2- yl)quinazolin-4(3H)-one [1367] To a solution of 8-acetyl-2-(2-azaspiro [3.5] nonan-2-yl)-3, 6-dimethyl-quinazolin-4- one (350 mg, 1.03 mmol) in methanol (25 mL) and dichloromethane (25 mL) was added ammonium acetate (1.59 g, 20.6 mmol) and sodium cyanoborohydride (130 mg, 2.06 mmol). The mixture was stirred at 60 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3, 6-dimethyl-2- (2-azaspiro [3.5] nonan-2-yl) quinazolin-4(3H)-one (350 mg, 1.03 mmol, 99.7%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (s, 1H), 7.58 (d, J = 1.2 Hz, 1H), 4.82 (q, J = 6.8 Hz, 1H), 3.92 (s, 3H), 3.39 (s, 3H), 2.36 (s, 3H), 1.65 (d, J = 5.2 Hz, 4H), 1.50 - 1.31 (m, 10H); m/z ES+ [M+H] ⁺ 342.2. [1368] Step 4. Synthesis of methyl 2-((1-(3,6-dimethyl-4-oxo-2-(2-azaspiro[3.5]nonan-2-yl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1369] A mixture of 8-(1-aminoethyl)-2-(2-azaspiro[3.5]nonan-2-yl)-3,6-dimethyl- quinazolin-4-one (200 mg, 587 μmol), methyl 2-bromobenzoate (189 mg, 881 μmol), tris(dibenzylideneacetone)dipalladium (53.8 mg, 58.7 μmol), dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl] phosphane (27.4 mg, 58.7 μmol) and cesium carbonate (574 mg, 1.76 mmol) in toluene (5 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give methyl 2-((1-(3, 6-dimethyl-4-oxo-2-(2-azaspiro [3.5] nonan-2-yl)-3, 4-dihydroquinazolin-8-yl) ethyl) amino)benzoate (117 mg, 222 μmol, 38%) as a white solid. m/z ES+ [M+H] ⁺ 475.3. [1370] Step 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 [1371] To a solution of methyl 2-[1-[2-(2-azaspiro [3.5] nonan-2-yl)-3, 6-dimethyl-4-oxo- quinazolin-8-yl] ethylamino] benzoate (110 mg, 232 μmol) in anhydrous tetrahydrofuran (1.2 mL), water (0.7 mL) and methanol (0.7 mL) was added lithium hydroxide (27.8 mg, 1.16 mmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 32% - 62%, 8min) to give 3-((5-chloro-3-(1-((3, 3-difluorocyclobutyl) methyl)-1H-pyrazol-4-yl) quinoxalin-6-yl)oxy)-2-fluoro-6-nitroaniline (102 mg, 221 μmol, 95%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 - 8.41 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.17 - 7.13 (m, 1H), 6.51 - 6.41 (m, 2H), 5.38 - 5.35 (m, 1H), 3.95 (s, 4H), 3.40 (s, 3H), 2.28 (s, 3H), 1.66 (s, 4H), 1.53 (d, J = 6.8 Hz, 3H), 1.47 - 1.33 (m, 6H); m/z ES+ [M+H] ⁺ 461.3. Example 67. Preparation of 2-((1-(3-(difluoromethyl)-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1372] Step 1. Synthesis of 8-bromo-2-chloro-4-methoxy-6-methyl-quinazoline [1373] To a mixture of 8-bromo-2,4-dichloro-6-methyl-quinazoline (1.8 g, 6.17 mmol) in methanol (50 mL) was added sodium methylate (5 M, 986 ^L) in one portion at 0 °C. The mixture was stirred at 0 °C for 2 hr. On completion, the reaction mixture was quenched by addition water 50 mL at 20 °C, and then diluted with dichloromethane (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 8- bromo-2-chloro-4-methoxy-6-methyl-quinazoline (2 g, 6.12 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 289.0. [1374] Step 2. Synthesis of 4-(8-bromo-4-methoxy-6-methyl-quinazolin-2-yl)morpholine [1375] To a mixture of 8-bromo-2-chloro-4-methoxy-6-methyl-quinazoline (1 g, 3.48 mmol) and morpholine (909 mg, 10.4 mmol) in dichloromethane (20 mL) in one portion. The mixture was then heated to 40 °C and stirred for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether (20 mL) at 20 °C for 30 min to give 4-(8-bromo-4-methoxy-6-methyl- quinazolin-2-yl)morpholine (1 g, 2.96 mmol, 85%) as a white solid. m/z ES+ [M+H] ⁺ 338.1. [1376] Step 3. Synthesis of 1-(4-methoxy-6-methyl-2-morpholino-quinazolin-8-yl)ethanone [1377] To a mixture of 4-(8-bromo-4-methoxy-6-methyl-quinazolin-2-yl)morpholine (1 g, 2.96 mmol) and tributyl(1-ethoxyvinyl)stannane (3.20 g, 8.87 mmol) in toluene (15 mL) was added dichloropalladium triphenylphosphane (415 mg, 591 μmol) in one portion under nitrogen atmosphere.The mixture was then heated to 130 °C and stirred for 16 hr. Then the reaction mixture added hydrochloric acid (1 M, 5 mL) at 25 °C and stirred for 30 min. On completion, the reaction mixture was quenched by addition water (100 mL) at 20 °C, and then diluted with ethyl acetate (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 1-(4-methoxy-6- methyl-2-morpholino-quinazolin-8-yl)ethanone (0.4 g, 929 μmol, 31%) as a yellow solid. m/z ES+ [M+H] ⁺ 302.2. [1378] Step 4. Synthesis of 8-acetyl-6-methyl-2-morpholino-3H-quinazolin-4-one [1379] To a mixture of 1-(4-methoxy-6-methyl-2-morpholino-quinazolin-8-yl)ethanone (200 mg, 663 μmol) was added pyridine hydrochloride (1.53 g, 13.3 mmol) in one portion. The mixture was then heated to 180 °C and stirred for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water (FA) - acetonitrile]; B%: 13%-43%, 10 min) to give 8-acetyl-6-methyl-2-morpholino-3H-quinazolin- 4-one (35 mg, 109 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 12.35 - 11.50 (m, 1H), 8.38 - 8.15 (m, 1H), 8.05 - 7.92 (m, 1H), 3.81 (br. dd, J = 4.8, 16.8 Hz, 5H), 2.73 (d, J = 12.0 Hz, 3H), 2.48 (s, 3H); m/z ES+ [M+H] ⁺ 288.1. [1380] Step 5. Synthesis of 8-acetyl-3-(difluoromethyl)-6-methyl-2-morpholino-quinazolin - 4-one [1381] To a mixture of 1-(4-hydroxy-6-methyl-2-morpholino-quinazolin-8-yl)ethanone (50 mg, 174 μmol) and sodium;2-chloro-2,2-difluoro-acetate (79.6 mg, 522 μmol) in N,N- dimethylformamide (1 mL) was added potassium carbonate (72.2 mg, 522 μmol) in one portion. The mixture was then heated to 80 °C and stirred for 5 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to1/1,Rf = 0.5) to give 8-acetyl-3-(difluoromethyl)-6-methyl-2-morpholino-quinazolin -4-one (170 mg, 462 μmol, 66%) as a yellow solid. m/z ES+ [M+H] ⁺ 338.1. [1382] Step 6. Synthesis of 8-(1-aminoethyl)-3-(difluoromethyl)-6-methyl-2-morpholino- quinazolin-4-one [1383] To a mixture of 8-acetyl-3-(difluoromethyl)-6-methyl-2-morpholino-quinazolin -4-one (150 mg, 445 μmol) in methanol (10 mL) was added ammonium acetate (343 mg, 4.45 mmol), sodium cyanoborohydride (41.9 mg, 667 μmol) in one portion. The mixture was then heated to 60 °C and stirred for 2 hr. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3- (difluoromethyl)-6-methyl-2-morpholino-quinazolin-4-one (70 mg, 175 μmol, 40%) as a yellow solid. m/z ES+ [M+H] ⁺ 339.1. [1384] Step 7. Synthesis of 2-[1-[3-(difluoromethyl)-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid [1385] To a mixture of 8-(1-aminoethyl)-3-(difluoromethyl)-6-methyl-2-morpholino- quinazolin-4-one (60 mg, 177 μmol) and 2-iodobenzoic acid (132 mg, 532 μmol) in dimethyl acetamide (3 mL) was added copper (11.3 mg, 177 μmol), triethylamine (53.8 mg, 532 μmol) in one portion under nitrogen atmosphere. The mixture was then heated to 110 °C and stirred for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75 x 30mm, 3 um; mobile phase: [water (FA) - acetonitrile]; B%: 55%-85%, 7 min) to give 2- [1-[3-(difluoromethyl)-6-methyl-2-morpholino-4-oxo-quinazoli n-8-yl]ethylamino]benzoic acid (27.1 mg, 56.9 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (dd, J = 1.6, 8.0 Hz, 1H), 7.82 - 7.44 (m, 4H), 7.22 - 7.16 (m, 1H), 6.57 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.51 (dd, J = 6.8, 12.8 Hz, 1H), 3.89 (d, J = 4.8 Hz, 4H), 3.86 - 3.81 (m, 4H), 2.38 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 459.2. Example 68 and Example 69. Preparation of 2-[[(1R)-1-[3-(difluoromethyl)-6-methyl-2- morpholino-4-oxo-quinazolin-8-yl]ethyl]amino]benzoic acid and 2-[[(1S)-1-[3- (difluoromethyl)-6-methyl-2-morpholino-4-oxo-quinazolin-8-yl ]ethyl]amino]benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1386] The racemic mixture, 2-[1-[3-(difluoromethyl)-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid (24 mg, 52.4 μmol) was separated with SFC (column: Daicel CHIRALPAK AD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 20%-20%, 3.5 min) to give 2-[[(1R)-1-[3-(difluoromethyl)-6-methyl-2- morpholino-4-oxo-quinazolin-8-yl]ethyl]amino]benzoic acid (5.19 mg, 10.9 μmol, 21%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (dd, J = 1.2, 8.0 Hz, 1H), 7.84 - 7.43 (m, 3H), 7.21 - 7.13 (m, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.42 (d, J = 8.8 Hz, 1H), 5.55 - 5.45 (m, 1H), 3.89 (br. d, J = 5.2 Hz, 4H), 3.85 - 3.78 (m, 4H), 2.38 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 459.4 and 2-[[(1S)-1-[3-(difluoromethyl)-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethyl]amino]benzoic acid (5.14 mg, 11.2 μmol, 21%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 1H), 7.82 - 7.44 (m, 3H), 7.18 (t, J = 7.6 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.42 (d, J = 8.8 Hz, 1H), 5.51 (q, J = 6.8 Hz, 1H), 3.89 (br. d, J = 5.0 Hz, 4H), 3.86 - 3.82 (m, 4H), 2.38 (s, 3H), 1.66 (d, J = 6.6 Hz, 3H); m/z ES+ [M+H] ⁺ 459.4. Example 70. Preparation of 2-((1-(3-(2-methoxyethyl)-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1387] Step 1. Synthesis of 2-amino-3-bromo-N-(2-methoxyethyl)-5-methyl-benzamide [1388] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (2.00 g, 8.69 mmol) and 2- methoxyethanamine (979 mg, 13.0 mmol) in N,N-dimethylformamide (40 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl-ammonium (4.96 g, 13.0 mmol) and diisopropylethylamine (2.25 g, 17.4 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to give 2-amino-3-bromo-N-(2-methoxyethyl)-5-methyl-benzamide (3.50 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.41 (t, J = 5.2 Hz, 1H), 7.37 (d, J = 8.8 Hz, 2H), 6.21 (s, 2H), 3.47 - 3.42 (m, 2H), 3.40 - 3.35 (m, 2H), 3.26 (s, 3H), 2.18 (s, 3H). [1389] Step 2. Synthesis of 8-bromo-2-chloro-3-(2-methoxyethyl)-6-methyl-quinazolin-4- one [1390] To a solution of 2-amino-3-bromo-N-(2-methoxyethyl)-5-methyl-benzamide (3.80 g, 13.2 mmol) in 1,4-dioxane (30 mL) was added thiocarbonyl dichloride (3.20 g, 27.8 mmol). The mixture was stirred at 25 °C for 1 hr and then stirred at 105 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro-3-(2- methoxyethyl)-6-methyl-quinazolin-4-one (4.70 g, 10.6 mmol, 80%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (s, 1H), 7.91 (s, 1H), 4.38 (t, J = 6.0 Hz, 2H), 3.62 (t, J = 6.0 Hz, 2H), 3.26 (s, 3H), 2.44 (s, 3H). [1391] Step 3. Synthesis of 8-bromo-3-(2-methoxyethyl)-6-methyl-2-morpholino- quinazolin-4-one [1392] To a solution of 8-bromo-2-chloro-3-(2-methoxyethyl)-6-methyl-quinazolin-4-on e (4.70 g, 10.6 mmol) in dichloromethane (30.0 mL) was added morpholine (2.78 g, 31.9 mmol). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0~27% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give 8-bromo-3-(2-methoxyethyl)-6-methyl-2-morpholino- quinazolin-4-one (4.00 g, 10.5 mmol, 98%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.78 (s, 1H), 4.33 - 4.26 (m, 2H), 3.91 - 3.84 (m, 4H), 3.76 - 3.68 (m, 2H), 3.40 - 3.22 (m, 7H), 2.41 (s, 3H). [1393] Step 4. Synthesis of 8-(1-butoxyvinyl)-3-(2-methoxyethyl)-6-methyl-2-morpholino- quinazolin-4-one [1394] To a solution of 8-bromo-3-(2-methoxyethyl)-6-methyl-2-morpholino-quinazolin- 4- one (2.00 g, 5.23 mmol) and 1-vinyloxybutane (1.57 g, 15.7 mmol) in n-butanol (20 mL) was added diisopropylethylamine (2.03 g, 15.7 mmol), palladium(II) acetate (117 mg, 523 μmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (282 mg, 523 μmol). The mixture was stirred at 100 °C for 1 hr. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-(1- butoxyvinyl)-3-(2-methoxyethyl)-6-methyl-2-morpholino-quinaz olin-4-one (3.00 g, crude) as a yellow solid. [1395] Step 5. Synthesis of 8-acetyl-3-(2-methoxyethyl)-6-methyl-2-morpholino-quinazolin - 4-one [1396] To a solution of 8-(1-butoxyvinyl)-3-(2-methoxyethyl)-6-methyl-2-morpholino- quinazolin-4-one (3.00 g, 7.47 mmol) in n-butanol (20 mL) was added hydrochloric acid (1 M, 37.4 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0~40% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give 8-acetyl-3-(2-methoxyethyl)-6-methyl-2-morpholino-quinazolin -4-one (600 mg, 1.74 mmol, 23%) as a red solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.77 (s, 1H), 4.26 (t, J = 5.2 Hz, 2H), 3.79 - 3.73 (m, 4H), 3.64 (t, J = 5.2 Hz, 2H), 3.21 (s, 3H), 3.21 - 3.15 (m, 4H), 2.77 (s, 3H), 2.42 (s, 3H). [1397] Step 6. Synthesis of 8-(1-aminoethyl)-3-(2-methoxyethyl)-6-methyl-2-morpholino- quinazolin-4-one [1398] To a solution of 8-acetyl-3-(2-methoxyethyl)-6-methyl-2-morpholino-quinazolin -4- one (500 mg, 1.45 mmol) in methanol (5.0 mL) was added ammonium acetate (2.23 g, 29.0 mmol) and sodium cyanoborohydride (91.0 mg, 1.45 mmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.1% ammonium hydroxide condition) to give 8-(1- aminoethyl)-3-(2-methoxyethyl)-6-methyl-2-morpholino-quinazo lin-4-one (290 mg, 837 μmol, 58%) as a colourless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (s, 1H), 7.68 (s, 1H), 4.71 - 6.63 (m, 1H), 4.24 (t, J = 5.6 Hz, 2H), 3.80 - 3.72 (m, 4H), 3.62 (t, J = 5.2 Hz, 2H), 3.21 (s, 3H), 3.17 - 3.11 (m, 4H), 2.39 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H). [1399] Step 7. Synthesis of 2-[1-[3-(2-methoxyethyl)-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid [1400] To a solution of 8-(1-aminoethyl)-3-(2-methoxyethyl)-6-methyl-2-morpholino- quinazolin-4-one (120 mg, 346 μmol) and 2-iodobenzoic acid (430 mg, 1.73 mmol) in dimethyl acetamide (1.0 mL) was added copper (2.20 mg, 34.6 μmol) and triethylamine (105 mg, 1.04 mmol). The mixture was stirred at 100 °C for 1 hr under nitrogen. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (FA)-acetonitrile]; B%: 44%-74%, 10 min) to give 2-[1-[3-(2-methoxyethyl)-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid (31.5 mg, 66.6 μmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.45 (s, 1H), 7.80 - 7.70 (m, 2H), 7.51 (s, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.57 - 6.45 (m, 2H), 5.41 - 5.35 (m, 1H), 4.26 (t, J = 5.2 Hz, 2H), 3.71 - 3.75 (m, 4H), 3.66 (t, J = 5.2 Hz, 2H), 3.25 - 3.20 (m, 7H), 2.33 (s, 3H), 1.58 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 467.2. Example 71. Preparation 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 [1401] Step 1. Synthesis of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazoli n- 4(3H)-one [1402] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (600 mg, 2.09 mmol) and 4,4-dimethylpiperidine (937 mg, 6.26 mmol) in dichloromethane (10 mL) was added triethylamine (633 mg, 6.26 mmol). The reaction was stirred at 40 °C for 3 h. The mixture was added to water (25 mL) and extracted with dichloromethane (25 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give to give 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazoli n-4(3H)-one (714 mg, 1.80 mmol, 86%). m/z ES+ [M+H] ⁺ 363.9. [1403] Step 2. Synthesis of 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazol in- 4(3H)-one [1404] To a solution of 8-bromo-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-quinazolin -4-one (400 mg, 1.10 mmol) in n-butanol (8 mL) was added 1-vinyloxybutane (330 mg, 3.29 mmol), palladium acetate (24.7 mg, 110 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl- phosphane (59.1 mg, 110 μmol) and diisopropylethylamine (426 mg, 3.29 mmol). The mixture was stirred at 95 °C for 12 hr under nitrogen. Then hydrochloric acid (1 M, 15 mL) was added in the mixture and stirred at 25 °C for 30 min. Saturated sodium carbonate was added to the mixture until pH = 8. The mixture was poured in water (20 mL) then extracted with ethyl acetate (5 mL x 3). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 5/1) to give 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazol in-4(3H)-one (230 mg, 681 μmol, 62%) as a yellow solid. m/z ES+ [M+H] ⁺ 328.3. [1405] Step 3. Synthesis of 8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one [1406] To a solution of 8-acetyl-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-quinazoli n-4-one (230 mg, 702 μmol) in methanol (5 mL) was added ammonium acetate (1.08 g, 14.1 mmol) and sodium cyanoborohydride (66.2 mg, 1.05 mmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)- 2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)- one (123 mg, 374 μmol, 53%) as a white solid. m/z ES+ [M+H] ⁺ 329.1. [1407] Step 4. Synthesis 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 [1408] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (100 mg, 331 μmol) and 2-bromo-5-cyano-benzoic acid (150 mg, 661 μmol) in dimethyl acetamide (1 mL) was added copper (21.0 mg, 331 μmol), triethylamine (100 mg, 992 μmol). The mixture was stirred at 110 °C for 1 h. The mixture was poured in water (20 mL), then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC: [column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 48%-78%, 2 min] to give 5-cyano-2- ((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-d ihydroquinazolin-8- yl)ethyl)amino)benzoic acid (25.0 mg, 55.9 μmol, 17%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 13.24 (s, 1H), 9.07 (d, J = 6.8 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.73 (s, 1H), 7.61 - 7.55 (m, 1H), 7.50 (s, 1H), 6.69 (d, J = 8.8 Hz, 1H), 5.48 -5.40 (m, 1H), 3.46 (s, 3H), 3.25 - 3.15 (m, 4H), 2.33 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.52 - 1.42 (m, 4H), 1.00 (s, 6H); m/z ES+ [M+H] ⁺ 474.3. Example 72. Preparation of 2-[1-[6-methyl-2-morpholino-4-oxo-3-(tetrahydrofuran-3- ylmethyl)quinazolin-8-yl]ethylamino]benzoic acid [1409] Step 1. Synthesis of 2-amino-3-bromo-5-methyl-N-(tetrahydrofuran-3- ylmethyl)benzamide [1410] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (2.00 g, 8.69 mmol) and tetrahydrofuran-3-ylmethanamine (1.32 g, 13.0 mmol) in N,N-dimethylformamide (20 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (4.96 g, 13.0 mmol) and diisopropylethylamine (2.25 g, 17.4 mmol). The reaction was stirred at 25 °C for 2 h. On completion, the residue was diluted with water (30 mL). The suspension was filtered and filter cake was concentrated under reduced pressure to give 2-amino-3-bromo- 5-methyl-N-(tetrahydrofuran-3-ylmethyl)benzamide (1.50 g, 4.79 mmol, 55%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (t, J = 5.2 Hz, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 6.17 (s, 2H), 3.80 - 3.41 (m, 4H), 3.28 - 3.11 (m, 2H), 2.49 - 2.41 (m, 1H), 2.19 (s, 3H), 2.00 - 1.87 (m, 1H), 1.65 - 1.55 (m, 1H). [1411] Step 2. Synthesis of 8-bromo-2-chloro-6-methyl-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one [1412] To a solution of 2-amino-3-bromo-5-methyl-N-(tetrahydrofuran-3- ylmethyl)benzamide (1.90 g, 6.07 mmol) in 1,4-dioxane (20 mL) was dropwise added thiocarbonyl dichloride (1.46 g, 12.7 mmol). The reaction was stirred at 25 °C for 1 h. And then the reaction mixture was heated to 105 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 26~28% ethyl acetate/petroleum ether gradient @ 60 mL/min) to give 8-bromo-2-chloro-6-methyl-3- (tetrahydrofuran-3-ylmethyl)quinazolin-4-one (1.94 g, 5.15 mmol, 85%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 4.20 (d, J = 7.2 Hz, 2H), 3.83 - 3.78 (m, 1H), 3.71 - 3.59 (m, 2H), 3.57 - 3.49 (m, 1H), 2.77 - 2.67 (m, 1H), 2.44 (s, 3H), 2.02 - 1.92 (m, 1H), 1.72 - 1.62 (m, 1H). [1413] Step 3. Synthesis of 8-bromo-6-methyl-2-morpholino-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one [1414] To a solution of 8-bromo-2-chloro-6-methyl-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one (1.90 g, 5.31 mmol) in dichloromethane (20 mL) was added morpholine (1.39 g, 15.9 mmol). The reaction was stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (40 mL) and extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-6-methyl-2-morpholino-3- (tetrahydrofuran-3-ylmethyl)quinazolin-4-one (2.30 g, 5.13 mmol, 96%) as a yellow gum. ¹ H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 0.8 Hz, 1H), 4.06 (d, J = 7.2 Hz, 2H), 3.80 - 3.72 (m, 4H), 3.65 - 3.52 (m, 4H), 3.41 (dd, J = 5.2, 8.4 Hz, 1H), 3.21 - 3.13 (m, 3H), 2.70 - 2.61 (m, 1H), 2.40 (s, 3H), 1.86 - 1.74 (m, 1H), 1.56 - 1.45 (m, 1H). [1415] Step 4. Synthesis of 8-acetyl-6-methyl-2-morpholino-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one [1416] A mixture of 8-bromo-6-methyl-2-morpholino-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one (1.50 g, 3.67 mmol), 1-vinyloxybutane (1.10 g, 11.02 mmol), palladium(2+)diacetate (82.48 mg, 367.39 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]- diphenyl-phosphane (198 mg, 367 μmol) and diisopropylethylamine (1.42 g, 11.0 mmol) in n- butanol (30 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 95 °C for 12 h under nitrogen atmosphere. The residue was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 55~62% ethyl acetate/petroleum ether gradient @ 60 mL/min) to give 8-acetyl-6-methyl-2-morpholino-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one (902 mg, 2.43 mmol, 66%) as a yellow gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (s, 1H), 7.78 (d, J = 1.2 Hz, 1H), 4.09 (d, J = 7.2 Hz, 2H), 3.82 - 3.70 (m, 5H), 3.65 - 3.55 (m, 2H), 3.44 (dd, J = 5.2, 8.4 Hz, 1H), 3.22 - 3.07 (m, 4H), 2.78 (s, 3H), 2.71 - 2.63 (m, 1H), 2.43 (s, 3H), 1.88 - 1.77 (m, 1H), 1.58 - 1.49 (m, 1H). [1417] Step 5. Synthesis of 8-(1-aminoethyl)-6-methyl-2-morpholino-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one [1418] To a solution of 8-acetyl-6-methyl-2-morpholino-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one (600 mg, 1.62 mmol) in methanol (5 mL) was added azanium acetate (2.49 g, 32.3 mmol) and sodium cyanoborohydride (152 mg, 2.42 mmol). The reaction was stirred at 60 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reversed-phase HPLC (0.1 % FA condition) to give 8-(1-aminoethyl)-6-methyl-2-morpholino-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one (412 mg, 985 μmol, 61%, FA) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 4.88 (d, J = 5.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 2H), 3.81 - 3.71 (m, 5H), 3.64 - 3.55 (m, 2H), 3.46 - 3.39 (m, 1H), 3.14 (s, 4H), 2.69 - 2.61 (m, 1H), 2.41 (s, 3H), 1.88 - 1.75 (m, 1H), 1.61 - 1.39 (m, 4H). [1419] Step 6. Synthesis of methyl 2-[1-[6-methyl-2-morpholino-4-oxo-3-(tetrahydrofuran- 3-ylmethyl)quinazolin-8-yl]ethylamino]benzoate [1420] To a solution of 8-(1-aminoethyl)-6-methyl-2-morpholino-3-(tetrahydrofuran-3- ylmethyl)quinazolin-4-one (200 mg, 537 μmol), methyl 2-bromobenzoate (577 mg, 2.68 mmol) in toluene (4 mL) was added tris(dibenzylideneacetone)dipalladium (49.2 mg, 53.7 μmol), cesium carbonate (525 mg, 1.61 mmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl) phenyl]phosphane (50.1 mg, 107 μmol). The mixture was stirred at 110 °C for 0.5 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give methyl 2-[1-[6-methyl-2-morpholino-4-oxo-3- (tetrahydrofuran-3-ylmethyl)quinazolin-8-yl]ethylamino]benzo ate (150 mg, 296 μmol, 55%) as a white oil. m/z ES+ [M+H] ⁺ 507.2. [1421] Step 7. Synthesis of 2-[1-[6-methyl-2-morpholino-4-oxo-3-(tetrahydrofuran-3- ylmethyl)quinazolin-8-yl]ethylamino]benzoic acid [1422] To a solution of methyl 2-[1-[6-methyl-2-morpholino-4-oxo-3-(tetrahydrofuran-3- ylmethyl)quinazolin-8-yl]ethylamino]benzoate (140 mg, 276 μmol) in anhydrous tetrahydrofuran (3 mL), methanol (1.5 mL) and water (1.5 mL) was added lithium hydroxide (33.1 mg, 1.38 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 40%-70%, 7 min) to give 2-[1-[6-methyl-2-morpholino-4- oxo-3-(tetrahydrofuran-3-ylmethyl)quinazolin-8-yl]ethylamino ]benzoic acid (77.6 mg, 158 μmol, 57%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 13.02 - 12.20 (m, 1H), 8.57 - 8.36 (m, 1H), 7.83 - 7.70 (m, 2H), 7.54 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.50 (t, J = 7.6 Hz, 1H), 5.39 (d, J = 6.0 Hz, 1H), 4.14 - 4.05 (m, 2H), 3.84 - 3.74 (m, 5H), 3.65 - 3.57 (m, 2H), 3.49 - 3.44 (m, 1H), 3.20 (s, 4H), 2.70 - 2.66 (m, 1H), 2.35 (s, 3H), 1.88 - 1.77 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.58 - 1.52 (m, 1H); m/z ES+ [M+H] ⁺ 493.3. Example 73. Preparation of 2-[1-[3,6-dimethyl-2-(4-methyl-1-piperidyl)-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid

[1423] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(4-methyl-1-piperidyl)quinazolin-4-on e [1424] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (600 mg, 2.09 mmol) in dichloromethane (10 mL) was added 4-methylpiperidine (620 mg, 6.26 mmol). The mixture was stirred at 40 ^ for 3 hr. The mixture was stirred at 80 ^ for 12 hr. The mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with a mixture of (petroleum ether: ethyl acetate = 3:1, 20 mL) for 30 min to give 8-bromo- 3,6-dimethyl-2-(4-methyl-1-piperidyl)quinazolin-4-one (483 mg, 1.32 mmol, 63%) as a yellow solid. m/z ES+ [M+H] ⁺ 349.9. [1425] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(4-methyl-1-piperidyl)quinazolin-4-o ne [1426] To a solution of 8-bromo-3,6-dimethyl-2-(4-methyl-1-piperidyl)quinazolin-4-on e (540 mg, 1.54 mmol) in n-butyl alconhol (10 mL) was added 1-vinyloxybutane (463 mg, 4.63 mmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (83.1 mg, 154 μmol), palladium acetate (34.6 mg, 154 μmol) and diisopropylethylamine (597 mg, 4.63 mmol). The mixture was stirred at 95 °C for 12 hr. The reaction mixture was quenched by addition water (30 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 6/1) to give 8-acetyl-3,6-dimethyl-2-(4-methyl-1- piperidyl)quinazolin-4-one (200 mg, 599 μmol, 39%) was obtained as a brown solid. m/z ES+ [M+H] ⁺ 314.0. [1427] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(4-methyl-1- piperidyl)quinazolin-4-one [1428] To a solution of 8-acetyl-3,6-dimethyl-2-(4-methyl-1-piperidyl)quinazolin-4-o ne (150 mg, 478 μmol) in methanol (5 mL) was added ammonium acetate (738 mg, 9.57 mmol) and sodium cyanoborohydride (45.1 mg, 718 μmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was quenched by addition water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3,6-dimethyl-2- (4-methyl-1-piperidyl)quinazolin-4-one (75.0 mg, 206 μmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.95 (d, J = 0.8 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1 H), 4.72 - 4.67 (m, 1 H), 3.56 (s, 3 H), 3.51 - 3.47 (m, 2H), 2.91 - 2.81 (m, 2H), 2.42 (s, 3 H), 1.83 (d, J = 13.2 Hz, 2H), 1.75 (d, J = 6.8 Hz, 3H), 1.71 - 1.57 (m, 1H), 1.41 - 1.29 (m, 2 H), 1.03 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 315.2. [1429] Step 4. Synthesis of methyl 2-[1-[3,6-dimethyl-2-(4-methyl-1-piperidyl)-4-oxo- quinazolin-8-yl]ethylamino]benzoate [1430] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-(4-methyl-1-piperidyl)quinaz olin-4- one (50.0 mg, 159 μmol) and methyl 2-bromobenzoate (205 mg, 954 μmol) in toluene (1.5 mL) was added tris(dibenzylideneacetone)dipalladium (14.6 mg, 15.9 μmol) and cesium carbonate (155 mg, 477 μmol), dicyclohexyl-(2ƍ,6ƍ-diisopropoxy-[1,1ƍ-biphenyl]-2- yl)phosphine (7.42 mg, 15.9 μmol). The mixture was stirred at 110 °C for 12 hr. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate = 1:1) to give methyl 2-[1-[3,6-dimethyl-2-(4-methyl- 1-piperidyl)-4-oxo-quinazolin-8-yl]ethylamino]benzoate (30.0 mg, 65.5 μmol, 41%) as a white solid. m/z ES+ [M+H] ⁺ 449.2. [1431] Step 5. Synthesis of 2-[1-[3,6-dimethyl-2-(4-methyl-1-piperidyl)-4-oxo-quinazolin -8- yl]ethylamino]benzoic acid [1432] To a solution of methyl 2-[1-[3,6-dimethyl-2-(4-methyl-1-piperidyl)-4-oxo- quinazolin-8-yl]ethylamino]benzoate (30 mg, 66.9 μmol) in tetrahydrofuran (0.3 mL), methanol (0.3 mL), water (0.3 mL) was added lithium hydroxide (14.0 mg, 334 μmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (formic acid condition; column: Phenomenex luna C18150x25 mm, 10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 57%-87%, 10 min) to get compound 2-[1-[3,6-dimethyl-2-(4-methyl-1-piperidyl)-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid (20.2 mg, 46.6 μmol, 70%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.43 - 12.79 (m, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.71 - 7.69 (m, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.21 - 7.14 (m, 1H), 6.52 - 6.47 (m, 2H), 5.43 - 5.37 (m, 1H), 3.57 (d, J = 12.8 Hz, 2H), 3.47 (s, 3H), 2.92 - 2.81 (m, 2H), 2.31 (s, 3H), 1.76 - 1.70 (m, 2H), 1.66 - 1.58 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.43 - 1.26 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 435.2. Example 74. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-N-methoxybenzamide [1433] Step 1. Synthesis of tert-butyl 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1434] A mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (300 mg, 992 μmol), tert-butyl 2-bromobenzoate (331 mg, 1.29 mmol), tris(dibenzylideneacetone)dipalladium (90.8 mg, 99.2 μmol), dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl]phosphane (46.3 mg, 99.2 μmol) and cesium carbonate (969 mg, 2.98 mmol) in toluene (3 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 1/1) to give tert-butyl 2-((1-(3,6- dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl )amino)benzoate (0.12 g, 250 μmol, 25%) as a yellow solid. m/z ES+ [M+H] ⁺ 479.3. [1435] Step 2. Synthesis of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin - 8-yl)ethyl)amino)benzoic acid [1436] To a solution of tert-butyl 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (100 mg, 208 μmol) in trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin - 8-yl)ethyl)amino)benzoic acid (50.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 423.5. [1437] Step 3. Synthesis of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin - 8-yl)ethyl)amino)-N-methoxybenzamide [1438] To a solution of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin -8- yl)ethyl)amino)benzoic acid (40 mg, 94.8 μmol) and O-methylhydroxylamine (79.0 mg, 946 μmol) in N,N-dimethylformamide (0.5 mL) was added [dimethylamino(triazolo[4,5-b]pyridin- 3-yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (180 mg, 473 μmol) and diisopropylethylamine (61.1 mg, 473 μmol) at 0 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 38%-68%, 10 min) in vacuo to give 2-((1-(3,6- dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl )amino)-N- methoxybenzamide (39.6 mg, 86.9 μmol, 91%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.81 - 8.52 (m, 1H), 8.44 - 8.11 (m, 1H), 7.90 (s, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.24 - 7.10 (m, 1H), 6.61 - 6.43 (m, 2H), 5.50 - 5.39 (m, 1H), 3.97 - 3.89 (m, 7H), 3.63 (s, 3H), 3.31 - 3.20 (m, 4H), 2.38 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 452.3. Example 75 and and Example 76. Preparation of (R)-2-((1-(3,6-dimethyl-2-morpholino- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-N-methoxybenza mide and (S)-2-((1-(3,6- dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl )amino)-N- methoxybenzamide (stereochemistry arbitrarily assigned for both enantiomers) [1439] 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin -8-yl)ethyl)amino)- N-methoxybenzamide (39 mg, 86.3 μmol) was purified SFC ( (column: Daicel CHIRALPAK IG (250 * 30mm, 10 um); mobile phase: [0.1% ammonium hydroxide/ethanol]; B%: 40%-40%, 5 min) to give (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8- yl)ethyl)amino)-N-methoxybenzamide (18.7 mg, 41.5 μmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 7.98 - 7.88 (m, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.31 - 7.22 (m, 1H), 7.08 - 6.99 (m, 1H), 6.46 - 6.33 (m, 2H), 5.45 - 5.32 (m, 1H), 3.85 - 3.80 (m, 7H), 3.56 - 3.53 (m, 3H), 3.22 - 3.20 (m, 4H), 2.29 (s, 3H), 1.51 (d, J = 6.4 Hz, 3H). m/z ES+ [M+H] ⁺ 452.5 (S)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-N-methoxybenzamide (17.7 mg, 39 μmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.50 - 8.38 (m, 1H), 8.16 - 7.86 (m, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 7.04 - 7.00 (m, 1H), 6.50 - 6.34 (m, 2H), 5.43 - 5.30 (m, 1H), 3.87 - 3.80 (m, 7H), 3.54 (s, 3H), 3.22 - 3.20 (m, 4H), 2.29 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 452.5. Example 77. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-4-fluorobenzoic acid [1440] A mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (50 mg, 165.36 μmol), 4-fluoro-2-iodo-benzoic acid (66.0 mg, 248 μmol), copper (22.6 mg, 356 μmol), triethylamine (83.7 mg, 827 μmol) in dimethyl acetamide (1 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 8%-38%, 10 min) and prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 44%-74%, 10 min) to give 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin -8-yl)ethyl)amino)-4- fluorobenzoic acid (3.32 mg, 7.54 μmol, 4.6%) as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (dd, J = 6.8, 9.2 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.24 - 6.17 (m, 2H), 5.48 - 5.40 (m, 1H), 3.93 - 3.87 (m, 4H), 3.62 (s, 3H), 3.36 - 3.32 (m, 4H), 2.38 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 441.2. Example 78. Preparation of 2-[1-(3-cyclobutyl-6-methyl-2-morpholino-4-oxo-quinazolin- 8-yl)ethylamino]benzoic acid

[1441] Step 1. Synthesis of 2-amino-3-bromo-N-cyclobutyl-5-methyl-benzamide [1442] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (3.00 g, 13.0 mmol) and cyclobutanamine (1.39 g, 19.6 mmol) in N,N-dimethylformamide (40.0 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl-ammonium (7.44 g, 19.6 mmol) and diisopropylethylamine (3.37 g, 26.1 mmol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino- 3-bromo-N-cyclobutyl-5-methyl-benzamide (3.90 g, 12.7 mmol, 98%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 7.2 Hz, 1H), 7.37 (s, 2H), 6.17 (s, 2H), 4.49 - 4.22 (m, 1H), 2.26 - 2.15 (m, 5H), 2.11 - 1.98 (m, 2H), 1.73 - 1.60 (m, 2H); m/z ES+ [M+H] ⁺ 284.8. [1443] Step 2. Synthesis of 8-bromo-2-chloro-3-cyclobutyl-6-methyl-quinazolin-4-one [1444] To a solution of 2-amino-3-bromo-N-cyclobutyl-5-methyl-benzamide (3.90 g, 12.7 mmol) in 1,4-dioxane (30 mL) was dropwise added thiocarbonyl dichloride (3.07 g, 26.7 mmol). The mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 105 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro- 3-cyclobutyl-6-methyl-quinazolin-4-one (4.40 g, crude) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 (d, J = 1.6 Hz, 1H), 7.88 - 7.87 (m, 1H), 5.12 - 5.01 (m, 1H), 2.84 - 2.74 (m, 2H), 2.47 - 2.38 (m, 5H), 1.86 - 1.71 (m, 2H). [1445] Step 3. Synthesis of 8-bromo-3-cyclobutyl-6-methyl-2-morpholino-quinazolin-4-one [1446] To a solution of 8-bromo-2-chloro-3-cyclobutyl-6-methyl-quinazolin-4-one (4.40 g, 13.4 mmol) in dichloromethane (30 mL) was added morpholine (3.51 g, 40.3 mmol). The mixture was stirred at 40 °C for 2 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 4/1) to give 8-bromo-3-cyclobutyl-6-methyl-2-morpholino- quinazolin-4-one (4.60 g, 9.83 mmol, 73%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (s, 1H), 7.77 (s, 1H), 4.77-4.71 (m, 1H), 3.74 (s, 4H), 3.24 (s, 4H), 2.44 (t, J = 9.6 Hz, 4H), 2.37 (s, 3H), 1.74 - 1.65 (m, 2H); m/z ES+ [M+H] ⁺ 379.9. [1447] Step 4. Synthesis of 8-(1-butoxyvinyl)-3-cyclobutyl-6-methyl-2-morpholino- quinazolin-4-one [1448] To a solution of 8-bromo-3-cyclobutyl-6-methyl-2-morpholino-quinazolin-4-one (2.60 g, 5.55 mmol) and 1-vinyloxybutane (1.67 g, 16.7 mmol) in n-butanol (20 mL) was added diisopropylethylamine (2.15 g, 16.7 mmol), copper acetate (125 mg, 555 μmol) and [2-(2- diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (299 mg, 555 μmol). The mixture was stirred at 100 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give 8-(1-butoxyvinyl)-3-cyclobutyl-6-methyl-2-morpholino-quinazo lin-4-one (3.00 g, crude) as a brown solid. [1449] Step 5. Synthesis of 8-acetyl-3-cyclobutyl-6-methyl-2-morpholino-quinazolin-4-one [1450] To a solution of 8-(1-butoxyvinyl)-3-cyclobutyl-6-methyl-2-morpholino-quinazo lin- 4-one (3.00 g, 7.55 mmol) in n-butanol (5 mL) was added hydrochloric acid (1 M, 38 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0~25% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give 8-acetyl-3-cyclobutyl-6-methyl-2-morpholino-quinazolin-4-one (1.70 g, 4.98 mmol, 66%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 4.83 - 4.74 (m, 1H), 3.75 (s, 4H), 3.22 (s, 4H), 2.76 (s, 3H), 2.48 - 2.37 (m, 7H), 1.82 - 1.63 (m, 2H). [1451] Step 6. Synthesis of 8-(1-aminoethyl)-3-cyclobutyl-6-methyl-2-morpholino- quinazolin-4-one [1452] To a solution of 8-acetyl-3-cyclobutyl-6-methyl-2-morpholino-quinazolin-4-one (700 mg, 2.05 mmol) in methanol (7.00 mL) was added ammonium acetate (3.16 g, 41.0 mmol) and sodium cyanoborohydride (129 mg, 2.05 mmol). The mixture was stirred at 60 °C for 1 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.1% ammonium hydroxide condition) to give 8-(1-aminoethyl)-3-cyclobutyl- 6-methyl-2-morpholino-quinazolin-4-one (500 mg, 1.46 mmol, 71%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 4.81 (t, J = 8.4 Hz, 1H), 4.64 - 4.59 (m, 1H), 3.75 (s, 4H), 3.16 (s, 4H), 2.58 (s, 2H), 2.44 - 2.39 (m, 2H), 2.37 (s, 3H), 1.83 - 1.64 (m, 2H), 1.31 (d, J = 6.4 Hz, 3H). [1453] Step 7. Synthesis of methyl 2-[1-(3-cyclobutyl-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl)ethylamino]benzoate [1454] To a solution of 8-(1-aminoethyl)-3-cyclobutyl-6-methyl-2-morpholino-quinazol in-4- one (100 mg, 292 μmol) and methyl 2-bromobenzoate (314 mg, 1.46 mmol) in toluene (1.0 mL) was added dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (13.6 mg, 29.2 μmol), cesium carbonate (285 mg, 876 μmol) and tris(dibenzylideneacetone)dipalladium (26.7 mg, 29.2 μmol). The mixture was stirred at 100 °C for 1 hr. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0~25% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give methyl 2-[1-(3-cyclobutyl-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl)ethylamino]benzoate (70.0 mg, 147 μmol, 50%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J = 7.2 Hz, 1H), 7.78 (dd, J = 1.6, 8.0 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.28 - 7.20 (m, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 5.37 (t, J = 6.8 Hz, 1H), 4.89 - 4.81 (m, 1H), 3.83 (s, 3H), 3.77 (s, 4H), 3.23 (s, 4H), 2.71 - 2.55 (m, 2H), 2.45 - 2.37 (m, 2H), 2.31 (s, 3H), 1.82 - 1.67 (m, 2H), 1.57 (d, J = 6.8 Hz, 3H). [1455] Step 8. Synthesis of 2-[1-(3-cyclobutyl-6-methyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoic acid [1456] To a solution of methyl 2-[1-(3-cyclobutyl-6-methyl-2-morpholino-4-oxo-quinazolin- 8-yl)ethylamino]benzoate (70.0 mg, 147 μmol) in anhydrous tetrahydrofuran (1.0 mL), methanol (0.5 mL) and water (0.5 mL) was added lithium hydroxide (17.6 mg, 734 μmol). The mixture was stirred at 60 °C for 1 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (HCl)-acetonitrile]; B%: 48%-78%, 10 min) to give 2-[1- (3-cyclobutyl-6-methyl-2-morpholino-4-oxo-quinazolin-8-yl)et hylamino]benzoic acid (37.9 mg, 81.1 μmol, 55%) as a brown gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.91 - 12.39 (m, 1H), 8.72 - 8.36 (m, 1H), 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.68 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.25 - 7.17 (m, 1H), 6.55 - 6.46 (m, 2H), 5.38 - 5.31 (m, 1H), 4.88 - 4.82 (m, 1H), 3.95 - 3.82 (m, 4H), 3.77 (s, 4H), 2.70 - 2.62 (m, 2H), 2.62 - 2.58 (m, 2H), 2.31 (s, 3H), 1.84 - 1.65 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 463.0. Example 79 and Example 80. Preparation of 2-[[(1R)-1-(3-cyclobutyl-6-methyl-2- morpholino-4-oxo-quinazolin-8-yl)ethyl]amino]benzoic acid and 2-[[(1S)-1-(3- cyclobutyl-6-methyl-2-morpholino-4-oxo-quinazolin-8-yl)ethyl ]amino]benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1457] The crude product was purified by SFC (column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammounium hrdroxide methanol]; B%: 45%-45%, 4.3 min) to give 2-[[(1R)-1-(3-cyclobutyl-6-methyl-2-morpholino-4-oxo-quinazo lin-8- yl)ethyl]amino]benzoic acid (9.89 mg, 21.4 μmol, 26.0%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 - 8.07 (m, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.48 (s, 1H), 7.25 - 7.20 (m, 1H), 6.58 (t, J = 7.6 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.48 - 5.40 (m, 1H), 4.95 - 4.84 (m, 1H), 3.97 - 3.83 (m, 4H), 3.37 - 3.25 (m, 4H), 2.95 - 2.86 (m, 2H), 2.53 - 2.43 (m, 2H), 2.38 (s, 3H), 2.03 - 1.96 (m, 1H), 1.85 - 1.77 (m, 1H), 1.65 (br. d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 463.4; and 2-[[(1S)-1-(3-cyclobutyl-6-methyl-2-morpholino-4-oxo-quinazo lin-8- yl)ethyl]amino]benzoic acid (11.4 mg, 24.7 μmol, 30.0%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.28 - 8.00 (m, 1H), 7.90 (br. d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.39 (s, 1H), 7.12 (br. t, J = 7.6 Hz, 1H), 6.48 (br. t, J = 7.6 Hz, 1H), 6.40 (br. d, J = 8.8 Hz, 1H), 5.39 - 5.29 (m, 1H), 4.87 - 4.73 (m, 1H), 3.81 (br. s, 4H), 3.26 - 3.15 (m, 4H), 2.86 - 2.77 (m, 2H), 2.43 - 2.32 (m, 2H), 2.27 (s, 3H), 1.93 - 1.85 (m, 1H), 1.75 - 1.67 (m, 1H), 1.55 (br. d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 463.4. Example 81. Preparation of 3,6-Dimethyl-8-(1-((2-(methylsulfonyl) phenyl)amino)ethyl)- 2-(piperidin-1-yl)quinazolin-4(3H)-one [1458] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one [1459] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (1 g, 3.48 mmol) in dichloromethane (10 mL) was added piperidine (1.48 g, 17.4 mmol). The mixture was stirred at 40 °C for 12 hr. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in petroleum ether/ethyl acetate=10/1 (100 mL), then filtered and the solid was concentrated in vacuo to give 8-bromo-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (1 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 338.0. [1460] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one [1461] To a solution of 8-bromo-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (0.5 g, 1.49 mmol) in toluene (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.61 g, 4.46 mmol) and dichloropalladium triphenylphosphane (104 mg, 148 μmol). The mixture was stirred at 110 °C for 12 hr. The mixture was poured in water (50 mL) then extracted with ethyl acetate (50 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-3,6-dimethyl-2- (piperidin-1-yl)quinazolin-4(3H)-one (0.33 g, 1.10 mmol, 74%) as a white solid. m/z ES+ [M+H] ⁺ 300.0. [1462] Step 3. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin- 4(3H)-one [1463] To a solution of 8-acetyl-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (0.33 g, 1.10 mmol) in methanol (5 mL) was added ammonium acetate (1.70 g, 22.1 mmol) and sodium cyanoborohydride (69.3 mg, 1.10 mmol). The mixture was stirred at 60 °C for 1 hr. The mixture was quenched by water (1 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)- 3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (0.3 g, 866 μmol, 79%) as a white solid. m/z ES+ [M+H] ⁺ 301.2. [1464] Step 4. Synthesis of 3,6-dimethyl-8-(1-((2-(methylsulfonyl) phenyl)amino)ethyl)-2- (piperidin-1-yl)quinazolin-4(3H)-one [1465] A mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-on e (100 mg, 333 μmol), 1-bromo-2-methylsulfonyl-benzene (391 mg, 1.66 mmol), tris(dibenzylideneacetone)dipalladium (30.5 mg, 33.3 μmol), dicyclohexyl-[2-[2, 6-di(propan- 2-yloxy) phenyl] phenyl] phosphane (15.5 mg, 33.3 μmol) and cesium carbonate (325 mg, 999 μmol) in toluene (2 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (4 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 61%-91%, 10 min) to give 3,6-dimethyl-8-(1-((2- (methylsulfonyl) phenyl)amino)ethyl)-2-(piperidin-1-yl)quinazolin-4(3H)-one (14.8 mg, 30.9 μmol, 9.3%) as a white solid. ¹ H NMR (400 MHz, CD3OD) δ 7.80 (d, J = 1.2 Hz, 1H), 7.68 (dd, J = 1.6, 8.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.27 (t, J = 1.2 Hz, 1H), 6.76 - 6.60 (m, 2H), 5.47 (q, J = 6.8 Hz, 1H), 3.59 (s, 3H), 3.29 - 3.20 (m, 4H), 3.10 (s, 3H), 2.37 (s, 3H), 1.84 - 1.68 (m, 6H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 455.2. Example 82. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid [1466] A mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (50 mg, 165 μmol), 5-fluoro-2-iodo-benzoic acid (88.0 mg, 330 μmol), triethylamine (33.5 mg, 330 μmol), copper (10.5 mg, 165 μmol) in dimethyl acetamide (0.5 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (FA)-acetonitrile]; B%: 41%-71%, 10 min) in vacuo to give 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin -8- yl)ethyl)amino)-5-fluorobenzoic acid (3.76 mg, 8.45 μmol, 5.1%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.67 - 7.60 (m, 1H), 7.48 (s, 1H), 7.02 - 6.93 (m, 1H), 6.41 - 6.30 (m, 1H), 5.44 - 5.30 (m, 1H), 3.96 - 3.90 (m, 4H), 3.65 (s, 3H), 3.33 - 3.29 (m, 4H), 2.40 (s, 3H), 1.65 (d, J = 6.08 Hz, 3H); m/z ES+ [M+H] ⁺ 441.2. Example 83 and Example 84. Preparation of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid & (S)-2-((1-(3,6-dimethyl- 2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5 -fluorobenzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1467] The crude product (50 mg, 114 μmol) was purified by SFC (column: Daicel CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [acetonitrile/ methanol (0.1% ammonium hydroxide)]; B%: 25%-25%, 4.2 min) to give (R)-2-((1-(3,6-dimethyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-f luorobenzoic acid (18.6 mg, 42.2 μmol, 37%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.40 (s, 1H), 7.72 (s, 1H), 7.53 - 7.43 (m, 2H), 7.09 (dt, J = 2.8, 8.8 Hz, 1H), 6.47 (dd, J = 4.4, 9.2 Hz, 1H), 5.34 (q, J = 6.4 Hz, 1H), 3.79 (t, J = 4.4 Hz, 4H), 3.50 (s, 3H), 3.28 - 3.24 (m, 4H), 2.32 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 441.4; and (S)-2-((1-(3,6-dimethyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-f luorobenzoic acid (21.2 mg, 47.6 μmol, 42%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.41 (s, 1H), 7.72 (s, 1H), 7.54 - 7.43 (m, 2H), 7.09 (dt, J = 3.2, 8.8 Hz, 1H), 6.47 (dd, J = 4.4, 9.2 Hz, 1H), 5.35 (q, J = 6.4 Hz, 1H), 3.79 (t, J = 4.4 Hz, 4H), 3.50 (s, 3H), 3.28 - 3.23 (m, 4H), 2.32 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 441.4. Example 85. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-5-methylbenzoic acid [1468] A mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (50.0 mg, 165 μmol), 2-iodo-5-methyl-benzoic acid (86.0 mg, 330 μmol), triethylamine (33.4 mg, 330 μmol), copper (10.5 mg, 165 μmol) in dimethyl acetamide (0.5 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (FA)-acetonitrile]; B%: 43%-73%, 10 min) in vacuo to give 2-((1-(3,6- dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl )amino)-5-methylbenzoic acid (11.5 mg, 26.2 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.53 - 5.45 (m, 1H), 3.93 - 3.80 (m, 4H), 3.64 (s, 3H), 3.32 - 3.20 (m, 4H), 2.39 (s, 3H), 2.21 (s, 3H), 1.65 (d, J = 6.4 Hz, 3H). m/z ES+ [M+H] ⁺ 437.2. Example 86. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-3-fluorobenzoic acid [1469] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (0.07 g, 231 μmol), 3-fluoro-2-iodo-benzoic acid (307 mg, 1.16 mmol), triethylamine (117 mg, 1.16 mmol) in dimethyl acetamide (3 mL) was added copper powder (14.7 mg, 231 μmol). Then the mixture was stirred at 110 °C for 14 hr under nitrogen. On completion, the mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: YMC Triart C18 150 x 25 mm, 5 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 47%-77%, 10 min) to give 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin -8-yl)ethyl)amino)-3- fluorobenzoic acid (0.016 g, 36.0 μmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.76 (d, J = 1.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.08 - 6.96 (m, 1H), 6.60 - 6.54 (m, 1H), 5.87 - 5.79 (m, 1H), 3.87 (t, J = 4.8 Hz, 4H), 3.59 (s, 3H), 3.30 - 3.20 (m, 4H), 2.35 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 441.2. Example 87. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-4-methylbenzoic acid [1470] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (0.07 g, 231 μmol), 2-iodo-4-methyl-benzoic acid (181 mg, 694 μmol), triethylamine (117 mg, 1.16 mmol) in dimethyl acetamide (5 mL) was added copper powder (14.7 mg, 231 μmol). Then the mixture was stirred at 110 °C for 12 hr under nitrogen. On completion, the mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 18%- 48%, 9 min) to give 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin -8- yl)ethyl)amino)-4-methylbenzoic acid (20.0 mg, 45.8 μmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 7.80 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.35 - 6.30 (m, 2H), 5.50 (q, J = 6.8 Hz, 1H), 3.90 - 3.80 (m, 4H), 3.62 (s, 3H), 3.37 - 3.33 (m, 4H), 2.36 (s, 3H), 2.10 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 437.2. Example 88. Preparation of 2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]-6-fluoro-benzoic acid [1471] Step 1. Synthesis of methyl 2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl) ethylamino]- 6-fluoro-benzoate [1472] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (50 mg, 165 μmol), methyl 2-bromo-6-fluoro-benzoate (192 mg, 827 μmol) in toluene (4 mL) was added cesium carbonate (162 mg, 496 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl) phenyl]phosphane (15.4 mg, 33.0 μmol) and tris(dibenzylideneacetone)dipalladium (15.1 mg, 16.5 μmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1:2) to give methyl 2- [1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)ethylami no]-6-fluoro-benzoate (50.0 mg, 110 μmol, 67%) as a white oil; m/z ES+ [M+H] ⁺ 455.1. [1473] Step 2. Synthesis of 2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]-6-fluoro-benzoic acid [1474] To a solution of methyl 2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino] -6-fluoro-benzoate (50.0 mg, 110 μmol) in anhydrous tetrahydrofuran (2 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide (13.2 mg, 550 μmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 40%-70%, 7 min) to give 2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]-6-fluoro-benzoic acid (18.5 mg, 42.2 μmol, 38.3%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.39 (m, 1H), 7.92 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.16 - 7.05 (m, 1H), 6.34 - 6.25 (m, 2H), 5.51 - 5.41 (m, 1H), 3.95 - 3.90 (m, 4H), 3.64 (s, 3H), 3.34 - 3.29 (m, 4H), 2.40 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 441.2. Example 89. Preparation of 2-[1-(3,6-dimethyl-2-morpholino-4- oxo-quinazolin-8- yl)ethylamino]-6-methyl-benzoic acid [1475] Step 1. Synthesis of methyl 2-[1-(3,6-dimethyl-2-morpholino-4- oxo-quinazolin-8- yl)ethylamino]-6-methyl-benzoate [1476] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (50.0 mg, 165 μmol) and methyl 2-bromo-6-methyl-benzoate (189 mg, 827 μmol) in toluene (4 mL) was added tris(dibenzylideneacetone)dipalladium (15.1 mg, 16.5 μmol), cesium carbonate (162 mg, 497 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (15.4 mg, 33.1 μmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/2) to give methyl 2-[1-(3,6-dimethyl-2-morpholino-4- oxo-quinazolin-8-yl)ethylamino]-6- methyl-benzoate (50.0 mg, 111 μmol, 67%) as a white oil. m/z ES+ [M+H] ⁺ 451.1. [1477] Step 2. Synthesis of 2-[1-(3,6-dimethyl-2-morpholino-4- oxo-quinazolin-8-yl) ethylamino] -6-methyl-benzoic acid [1478] To a solution of methyl 2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]-6-methyl-benzoate (40.0 mg, 88.8 μmol) in anhydrous tetrahydrofuran (2 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide (10.6 mg, 444 μmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 42%-72%, 7 min) to give 2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]-6-methyl-benzoic acid (18.8 mg, 43.2 μmol, 49%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.55 (s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 5.47 - 5.39 (m, 1H), 3.92 (s, 4H), 3.63 (s, 3H), 3.30 (s, 4H), 2.58 (s, 3H), 2.41 (s, 3H), 1.67 (d, J = 6.0 Hz, 3H); m/z ES+ [M+H] ⁺ 437.2. Example 90. Preparation of 8-[1-(3-fluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2-morpholino-quinazolin-4-one [1479] Step 1. Synthesis of 1-bromo-3-fluoro-2-methylsulfonyl-benzene [1480] To a solution of 1-bromo-3-fluoro-2-methylsulfanyl-benzene (100 mg, 452 μmol) in dichloromethane (2 mL) was added 3-chlorobenzenecarboperoxoic acid (243 mg, 1.13 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was quenched by addition saturated sodium sulfite (10 mL) and saturated sodium bicarbonate (10 mL) at 0 °C and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 1-bromo-3-fluoro-2- methylsulfonyl-benzene (114 mg, 445 μmol, 98%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, J = 8.0 Hz, 1H), 7.47 - 4.39 (m, 1H), 7.23 (dd, J = 8.0, 10.0 Hz, 1H), 3.34 (s, 3H); m/z ES+ [M+H] ⁺ 252.8. [1481] Step 2. Synthesis of 8-[1-(3-fluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2- morpholino-quinazolin-4-one [1482] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (100 mg, 330 μmol) and 1-bromo-3-fluoro-2-methylsulfonyl-benzene (108 mg, 429 μmol) in toluene (1 mL) was added 2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl (15.4 mg, 33.0 μmol), cesium carbonate (323 mg, 992 μmol) and tris(dibenzylideneacetone)dipalladium (30.2 mg, 33.0 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate/methanol = 100/1/0 to 0/10/1) and then purified by reversed-phase HPLC (column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 45%-75%, 7 min) and normal phase HPLC (column: Welch Ultimate XB- CN 250 x 50, 10 um; mobile phase: [Hexane-ethanol]; B%: 10%-50%, 15 min and column: Welch Ultimate XB-CN 250*50*10 um; mobile phase: [Hexane-ethanol^0.1% ammonium hydroxide^]; B%: 10%-50%, 15 min) to give 8-[1-(3-fluoro-2-methylsulfonyl-anilino)ethyl]- 3,6-dimethyl-2-morpholino-quinazolin-4-one (3.74 mg, 7.88 μmol, 2%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 1.2 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.15 - 7.04 (m, 1H), 6.31 (dd, J = 8.0, 10.4 Hz, 1H), 6.25 (d, J = 8.8Hz, 1H), 5.43 - 5.33 (m, 1H), 3.93 - 3.87 (m, 4H), 3.62 (s, 3H), 3.31 (d, J = 0.8 Hz, 3H), 3.33 - 3.26 (m, 4H), 2.40 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 475.2. Example 91. Preparation of 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-4-methylbenzoic acid [1483] Step 1. Synthesis of 2-amino-3-bromo-5-fluoro-N-methylbenzamide [1484] To a solution of 2-amino-3-bromo-5-fluoro-benzoic acid (5.00 g, 21.4 mmol) and methanamine (2 M, 42.7 mL) in N,N-dimethylformamide (50.0 mL) was added diisopropylethylamine (5.52 g, 42.7 mmol) and [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammoniumhexafluorophosphate (12.2 g, 32.1 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturate brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by recrystallization with petroleum ether (150 mL) and filtered to give a compound 2-amino-3-bromo-5-fluoro-N- methylbenzamide (5.30 g, 20.3 mmol, 95%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J = 3.6 Hz, 1H), 7.56 (dd, J = 2.8, 8.0 Hz, 1H), 7.42 (dd, J = 2.8, 9.6 Hz, 1H), 6.37 - 6.27 (m, 2H), 2.76 - 2.72 (m, 3H). [1485] Step 2. Synthesis of 8-bromo-2-chloro-6-fluoro-3-methylquinazolin-4(3H)-one [1486] To a solution of 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (1.00 g, 4.05 mmol) in 1,4-dioxane (10 mL) was dropwise added thiocarbonyl dichloride (977 mg, 8.50 mmol). The mixture was stirred at 25 °C for 1 hr. Then heated to 105 °C stirred for 1 hr. The mixture was concentrated to give desired compound 8-bromo-2-chloro-6-fluoro-3-methylquinazolin- 4(3H)-one (1.20 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 293.0. [1487] Step 3. Synthesis of 8-bromo-6-fluoro-3-methyl-2-morpholinoquinazolin-4(3H)-one [1488] To a solution of 8-bromo-2-chloro-6-fluoro-3-methyl-quinazolin-4-one (1.20 g, 4.12 mmol) in dichloromethane (12 mL) was added morpholine (1.08 g, 12.4 mmol). The mixture was stirred at 40 °C for 12 hr. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 2/1) to give desired compound 8-bromo-6-fluoro-3-methyl-2- morpholinoquinazolin-4(3H)-one (850 mg, 2.24 mmol, 54%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 2.8, 8.4 Hz, 1H), 7.71 (dd, J = 2.8, 8.4 Hz, 1H), 3.80 - 3.74 (m, 4H), 3.46 (s, 3H), 3.29 - 3.24 (m, 4H). [1489] Step 4. Synthesis of 8-acetyl-6-fluoro-3-methyl-2-morpholinoquinazolin-4(3H)-one [1490] To a solution of 8-bromo-6-fluoro-3-methyl-2-morpholino-quinazolin-4-one (400 mg, 1.17 mmol) and 1-vinyloxybutane (351 mg, 3.51 mmol) in n-butanol (4.0 mL) was added diacetoxypalladium (26.3 mg, 117 μmol), diisopropylethylamine (453 mg, 3.51 mmol) and [2- (2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane (63.0 mg, 117 μmol). The mixture was stirred at 95 °C for 12 hr. Then hydrochloric acid (4 M, 1.0 mL) was added at 25 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction was adjusted pH = 7~8 with saturate sodium bicarbonate, the mixture was filtered to give a filtrate and the filtrate was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (C18, 0.1% formic acid condition, 10%~80%, acetonitrile/water, 15 min) to give desired compound 8-acetyl-6-fluoro-3-methyl- 2-morpholinoquinazolin-4(3H)-one (80.0 mg, 254 μmol, 22%) as a yellow solid. m/z ES+ [M+H] ⁺ 306.2. [1491] Step 5. Synthesis of 8-(1-aminoethyl)-6-fluoro-3-methyl-2-morpholinoquinazolin- 4(3H)-one [1492] To a solution of 8-acetyl-6-fluoro-3-methyl-2-morpholino-quinazolin-4-one (120 mg, 393 μmol) in methanol (3.0 mL) was added ammonium acetate (606 mg, 7.86 mmol) and sodium cyanoborohydride (24.7 mg, 393 μmol). The mixture was stirred at 60 °C for 1 hr. The mixture was quenched by water (1.0 mL) and then concentrated in vacuo to give a residue. The crude product was purified by reversed-phase HPLC (C18, 0.1% formic acid condition, 10%~80%, acetonitrile/water, 15 min) to give desired compound 8-(1-aminoethyl)-6-fluoro-3- methyl-2-morpholinoquinazolin-4(3H)-one (90.0 mg, 285 μmol, 73%) as a white solid. m/z ES+ [M+H] ⁺ 307.1. [1493] Step 6. Synthesis of methyl 2-((1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1494] To a solution of 8-(1-aminoethyl)-6-fluoro-3-methyl-2-morpholino-quinazolin-4 -one (90.0 mg, 294 μmol) and methyl 2-bromobenzoate (379 mg, 1.76 mmol) in toluene (3.0 mL) was added tris(dibenzylideneacetone)dipalladium (26.9 mg, 29.4 μmol), cesium carbonate (287 mg, 881 μmol) and dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (13.7 mg, 29.4 μmol). The mixture was stirred at 110 °C for 12 hr. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 5/1 to 1/1) to give desired compound methyl 2-((1-(6- fluoro-3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoate (80.0 mg, 182 μmol, 62%) as a yellow oil. m/z ES+ [M+H] ⁺ 441.2. [1495] Step 7. Synthesis of 2-((1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1496] To a solution of methyl 2-[1-(6-fluoro-3-methyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoate (80.0 mg, 182 μmol) in methanol (0.8 mL), anhydrous tetrahydrofuran (0.80 mL) and water (0.80 mL) was added lithium hydroxide (21.8 mg, 908 μmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid condition; column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water (FA)-acetonitrile]; B%: 37%-67%, 10 min) to give desired compound 2-((1-(6-fluoro-3-methyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (29.6 mg, 69.5 μmol, 38%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.83 - 12.58 (m, 1H), 8.44 (dd, J = 1.2, 5.2 Hz, 1H), 7.79 (dd, J = 1.6, 8.0 Hz, 1H), 7.58 (dd, J = 3.2, 8.4 Hz, 1H), 7.48 (dd, J = 2.8, 9.6 Hz, 1H), 7.23 - 7.16 (m, 1H), 6.55 - 6.43 (m, 2H), 5.42 - 5.34 (m, 1H), 3.82 - 3.75(m, 4H), 3.50 (s, 3H), 3.34 - 3.28 (m, 4H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 427.2. Example 92 and Example 93. Preparation of (R)-2-((1-(6-fluoro-3-methyl-2-morpholino- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid & (S)-2-((1-(6-fluoro-3- methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)a mino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1497] 2-((1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4-dihydroquina zolin-8- yl)ethyl)amino)benzoic acid (25 mg) was further separated by SFC (basic condition; column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonia methanol]; B%: 50%-50%, 7.5 min) to give desired compound (R)-2-((1-(6-fluoro-3-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (12.2 mg, 28.5 μmol, 49%) as a white solid ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 - 8.48 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.53 - 6.39 (m, 2H), 5.39 (d, J = 5.2 Hz, 1H), 3.79 (s, 4H), 3.50 (s, 3H), 3.28 (s, 4H), 1.59 (d, J = 6.0 Hz, 3H); m/z ES+ [M+H] ⁺ 427.2 and (S)-2-((1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (12.0 mg, 28.0 μmol, 48%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.48 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.54 - 6.38 (m, 2H), 5.38 (d, J = 6.4 Hz, 1H), 3.79 (s, 4H), 3.50 (s, 3H), 3.28 (s, 4H), 1.59 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 427.2. Example 94. Preparation of 8-(1-((3-chloro-2-(methylsulfonyl)phenyl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one [1498] Step 1. Synthesis of 1-bromo-3-chloro-2-methylsulfonyl-benzene [1499] To a mixture of 1-bromo-3-chloro-2-methylsulfanyl-benzene (0.5 g, 2.10 mmol) in dichloromethane (10 mL) was added 3-chloroperoxybenzoic acid (1.36 g, 6.31 mmol, 80% purity) in one portion. The mixture was then heated to 25 °C and stirred for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 1-bromo-3-chloro-2-methylsulfonyl-benzene (0.55 g, 2.02 mmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 270.0. [1500] Step 2. Synthesis of 8-[1-(3-chloro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2- morpholino-quinazolin-4-one [1501] To a mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (170 mg, 562 μmol) and 1-bromo-3-chloro-2-methylsulfonyl-benzene (455 mg, 1.69 mmol in toluene (5 mL) was added dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (26.2 mg, 56.2 μmol), tris(dibenzylideneacetone)dipalladium (51.5 mg, 56.2 μmol) and cesium carbonate (550 mg, 1.69 mmol) in one portion under N2.The mixture was then heated to110 °C and stirred for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 46%-76%, 10 min) to give 8-[1-(3-chloro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2-morpholino-quinazolin-4-one (17.4 mg, 34.5 μmol, 6.1%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 5.6 Hz, 1H), 7.90 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 5.45 - 5.35 (m, 1H), 3.90 (t, J = 4.4 Hz, 4H), 3.62 (s, 3H), 3.39 (s, 3H), 3.29 (d, J = 3.6 Hz, 4H), 2.40 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 491.2. Example 95. Preparation of 6-chloro-3-ethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one [1502] Step 1. Synthesis of 2-amino-3-bromo-5-chloro-N-ethylbenzamide [1503] To a solution of ethanamine (3.60 g, 79.8 mmol, 5.22 mL) and 2-amino-3-bromo-5- chloro-benzoic acid (10 g, 39.9 mmol) in N,N-dimethylformamide (100 mL) was added 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridi nium-3- oxidehexafluorophosphate (18.2 g, 47.9 mmol) and diisopropylethylamine (20.6 g, 160 mmol, 27.8 mL). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was poured into water (60 mL), filtered, the cake was collected and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3:1 to1:1) to give 2-amino-3-bromo-5-chloro-N-ethyl-benzamide (9.8 g, 34.9 mmol, 88%)as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 1 H) 7.63 (d, J =2.4 Hz, 1 H) 7.59 (d, J =2.4 Hz, 1 H) 6.52 - 6.60 (m, 2 H) 3.19 - 3.28 (m, 2 H) 1.11 (t, J =7.2 Hz, 3 H); m/z ES+ [M+H] ⁺ 279.0. [1504] Step 2. Synthesis of 8-bromo-2,6-dichloro-3-ethyl-quinazolin-4-one [1505] To a solution of 2-amino-3-bromo-5-chloro-N-ethyl-benzamide (9.8 g, 35.3 mmol) in 1,4-dioxane (100 mL) was dropwise added thiocarbonyl dichloride (8.53 g, 74.2 mmol), the reaction was stirred at 25 °C for 1 hr, then the reaction was warmed to 105 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 8-bromo-2,6-dichloro-3- ethyl-quinazolin-4-one (11 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 284.1. [1506] Step 3. Synthesis of 8-bromo-6-chloro-3-ethyl-2-morpholino-quinazolin-4-one [1507] A solution of 8-bromo-2,6-dichloro-3-ethyl-quinazolin-4-one (3 g, 9.32 mmol) and morpholine (2.44 g, 27.9 mmol, 2.5 mL) in dichloromethane (30 mL) was stirred at 40 °C for 12 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 5:1 to 1:1) to give 8-bromo-6-chloro-3-ethyl-2-morpholino-quinazolin-4-one (3 g, 7.97 mmol, 86%) as a yellow soild. m/z ES+ [M+H] ⁺ 374.0. [1508] Step 4. Synthesis of 8-acetyl-6-chloro-3-ethyl-2-morpholino-quinazolin-4-one [1509] To a solution of 8-bromo-6-chloro-3-ethyl-2-morpholino-quinazolin-4-one (1 g, 2.68 mmol) and 1-vinyloxybutane (806 mg, 8.05 mmol, 1.0 mL) in n-butanol (20 mL) was added palladium acetate (60.3 mg, 268 μmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]- diphenyl-phosphane (144 mg, 268 μmol), diisopropylethylamine (1.04 g, 8.05 mmol, 1.4 mL). The mixture was stirred at 95 °C for 12 hr. The pH of the reaction was adjusted to 2~3 with 50% formic acid (15 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated aqueous brine solution (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 3:1 to 0:1) to give 8-acetyl-6-chloro-3-ethyl-2-morpholino-quinazolin-4-one (0.8 g, 2.05 mmol, 76%) as a yellow solid. m/z ES+ [M+H] ⁺ 355.8. [1510] Step 5. Synthesis of 8-(1-aminoethyl)-6-chloro-3-ethyl-2-morpholino-quinazolin-4- one [1511] To a solution of 8-acetyl-6-chloro-3-ethyl-2-morpholino-quinazolin-4-one (300 mg, 893 μmol) in methanol (6 mL) and dichloromethane (6 mL) was added ammonium acetate (1.38 g, 17.8 mmol) and sodium cyanoborohydride (112 mg, 1.79 mmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8- (1-aminoethyl)-6-chloro-3-ethyl-2-morpholino-quinazolin-4-on e (350 mg, 1.04 mmol, 58%) as a white solid. m/z ES+ [M+H] ⁺ 337.1. [1512] Step 6. Synthesis of 6-chloro-3-ethyl-8-[1-(2-methylsulfonylanilino)ethyl]-2- morpholino-quinazolin-4-one [1513] To a solution of 8-(1-aminoethyl)-6-chloro-3-ethyl-2-morpholino-quinazolin-4- one (80 mg, 237 μmol) and 1-fluoro-2-methylsulfonyl-benzene (41.4 mg, 237 μmol) in N,N- dimethylformamide (1.5 mL) was added cesium carbonate (154 mg, 475 μmol). The mixture was stirred at 120 °C for 12 hr. The reaction mixture was filtered and was purified by prep- HPLC (formic acid condition; column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water(formic acid)- acetonitrile]; B%: 54%-84%, 10 min) to give 6-chloro-3-ethyl-8- [1-(2-methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4 -one (34.2 mg, 69.7 μmol, 29%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (d, J=2.4 Hz, 1 H) 7.77 (d, J = 2.4 Hz, 1 H) 7.62 (dd, J = 1.2, 7.6 Hz, 1 H) 7.36 (t, J = 8.0 Hz, 1 H) 6.66 - 6.80 (m, 3 H) 5.41-5.32 (m, 1 H) 4.13-4.05 (m, 2 H) 3.78 (t, J = 4.4 Hz, 4 H) 3.23 - 3.30 (m, 4 H) 3.19 (s, 3 H) 1.64 (d, J = 6.4 Hz, 3 H) 1.28 (t, J = 7.2 Hz, 3 H); m/z ES+ [M+H] ⁺ 491.2. Example 96. Preparation of 2-((1-(6-chloro-3-ethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1514] Step 1. Synthesis of methyl 2-((1-(6-chloro-3-ethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1515] To a solution of 8-(1-aminoethyl)-6-chloro-3-ethyl-2-morpholino-quinazolin-4- one (130 mg, 385 μmol) and methyl 2-bromobenzoate (415 mg, 1.93 mmol, 271 ^L) in toluene (3 mL) was added tris(dibenzylideneacetone)dipalladium (35.3 mg, 38.6 μmol) and dicyclohexyl- (2ƍ,6ƍ-diisopropoxy-[1,1ƍ-biphenyl]-2-yl)phosphine (18.0 mg, 38.6 μmol), cesium carbonate (377 mg, 1.16 mmol). The mixture was stirred at 110 °C for 12 hr. The pH of the reaction was adjusted to 2~3 with 50% formic acid (15 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated aqueous solution of brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 3:1 to 0:1) to get compound methyl 2-[1-(6-chloro-3-ethyl-2-morpholino- 4-oxo-quinazolin-8-yl)ethylamino]benzoate (140 mg, 291 μmol, 75%) as a white solid. m/z ES+ [M+H] ⁺ 417.2. [1516] Step 2. Synthesis of 2-((1-(6-chloro-3-ethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1517] To a solution of methyl 2-[1-(6-chloro-3-ethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoate (70 mg, 148 μmol) in tetrahydrofuran (0.7 mL), methanol (0.7 mL), water (0.7 mL) was added lithium hydroxide (31.2 mg, 743 μmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (formic acid condition; column: Phenomenex Luna C18 150 x 25 mm, 10 um; mobile phase: [water(formic acid)- acetonitrile]; B%: 48%-78%, 10 min) to get compound 2-[1-(6-chloro-3-ethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoic acid (30.2 mg, 66.0 μmol, 44%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.51 - 12.84 (m, 1H), 8.43 (d, J = 6.4 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.79 (dd, J = 1.6, 8.0 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.18 - 7.25 (m, 1H), 6.47 - 6.55 (m, 2H), 5.36 (t, J = 6.4 Hz, 1H), 4.08 (q, J = 6.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 4 H), 3.24 - 3.28 (m, 4 H), 1.60 (d, J = 6.4 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 97. Preparation of 8-(1-((1,1-dioxido-2,3-dihydrobenzo[b]thiophen-7- yl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-on e [1518] Step 1. Synthesis of 7-bromobenzo[b]thiophene 1,1-dioxide [1519] To a solution of 7-bromobenzothiophene (1 g, 4.69 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (2.38 g, 11.7 mmol, 85% purity) in portions. The mixture was stirred at 40 °C for 5 hr. The reaction mixture was slowly added to sodium sulfite (50 ml), and then was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with sodium bicarbonate (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7-bromobenzothiophene 1,1-dioxide (1.1 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77 (m, 1H), 7.57 - 7.61 (m, 3H), 7.44 (d, J = 6.8 Hz, 1H); m/z ES+ [M+H] ⁺ 247.0. [1520] Step 2. Synthesis of 7-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide [1521] To a solution of 7-bromobenzothiophene 1,1-dioxide (800 mg, 3.26 mmol) in ethanol (10 mL) was added sodium borohydride (154 mg, 4.08 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hr. The reaction mixture was slowly added to ammonium chloride (30 mL), was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous solution of brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 5:1 to 1:1) to get compound 7-bromo-2,3-dihydrobenzothiophene 1,1-dioxide (350 mg, 1.39 mmol, 43%) as a white solid. m/z ES+ [M+H] ⁺ 248.0. [1522] Step 3. Synthesis of 8-(1-((1,1-dioxido-2,3-dihydrobenzo[b]thiophen-7- yl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-on e [1523] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (50 mg, 165 μmol, 1 eq) and 7-bromo-2,3-dihydrobenzothiophene 1,1-dioxide (204 mg, 826 μmol) in toluene (1.5 mL) was added tris(dibenzylideneacetone)dipalladium (15 mg, 16.5 μmol) and dicyclohexyl-(2ƍ,6ƍ-diisopropoxy-[1,1ƍ-biphenyl]-2-yl)pho sphine (7.72 mg, 16.5 μmol), cesium carbonate (161 mg, 496 μmol). The mixture was stirred at 110 °C for 12 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1:5) to give 8-[1-[(1,1- dioxo-2,3-dihydrobenzothiophen-7-yl)amino]ethyl]-3,6-dimethy l-2-morpholino-quinazolin- 4-one (42.6 mg, 89.3 μmol, 54%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 1.2 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 7.4 Hz, 1H), 6.06 (d, J = 8.4 Hz, 1H), 5.21 - 5.32 (m, 1H), 3.78 (t, J = 4.4 Hz, 4 H), 3.52 (s, 2H), 3.50 (s, 3H), 3.33 - 3.39 (m, 2H), 3.14 - 3.25 (m, 4 H), 2.35 (s, 3H), 1.63 (d, J = 6.8 Hz, 3 H); m/z ES+ [M+H] ⁺ 469.2. Example 98 and Example 99. Preparation of (R)-8-(1-((1,1-dioxido-2,3- dihydrobenzo[b]thiophen-7-yl)amino)ethyl)-3,6-dimethyl-2-mor pholinoquinazolin- 4(3H)-one & compound (S)-8-(1-((1,1-dioxido-2,3-dihydrobenzo[b]thiophen-7- yl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-on e [1524] 8-[1-[(1,1-dioxo-2,3-dihydrobenzothiophen-7-yl)amino]ethyl]- 3,6-dimethyl-2- morpholino-quinazolin-4-one (35 mg, 74.7 μmol) was purfied by SFC ( basic condition column: Daicel CHIRALPAK AD (250 x 30 mm, 10 um); mobile phase: [0.1%NH ₃ -water IPA]; B%: 60%-60%, 9 min) to give 8-[(1R)-1-[(1,1-dioxo-2,3-dihydrobenzothiophen-7-yl)amino]et hyl]- 3,6-dimethyl-2-morpholino-quinazolin-4-one (16.0 mg, 34.2 μmol, 46%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (s, 1H), 7.61 (s, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 7.4 Hz, 1H), 6.06 (d, J =8.2Hz, 1H), 5.22 - 5.34 (m, 1H), 3.78 ( J = 4.2 Hz, 4 H), 3.51 - 3.54 (m, 2H), 3.50 (s, 3H), 3.33 - 3.40 (m, 2H), 3.14 - 3.25 (m, 4 H), 2.35 (s, 3H), 1.63 (d, J = 6.8 Hz, 3 H); m/z ES+ [M+H] ⁺ 469.2 and 8-[(1S)-1-[(1,1-dioxo-2,3- dihydrobenzothiophen-7-yl)amino]ethyl]-3,6-dimethyl-2-morpho lino-quinazolin-4-one (16.0 mg, 34.2 μmol, 46%)as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 1.0 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.23 - 7.31 (m, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 7.2 Hz, 1H), 6.06 (bd, J = 8.4 Hz, 1H), 5.22 - 5.32 (m, 1H), 3.78 (t, J = 4.8 Hz, 4 H), 3.51 - 3.54 (m, 2H), 3.50 (s, 3H), 3.33 - 3.38 (m, 2H), 3.15 - 3.26 (m, 4 H), 2.35 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 469.2. Example 100. Preparation of 2-((1-(6-chloro-3-(cyclobutylmethyl)-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1525] Step 1. Synthesis of 2-amino-3-bromo-5-chloro-N-(cyclobutylmethyl)benzamide [1526] To a solution of 2-amino-3-bromo-5-chloro-benzoic acid (5.8 g, 23.2 mmol) and cyclobutylmethanamine (3.94 g, 46.3 mmol) in dichloromethane (80 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (13.2 g, 34.7 mmol) and diisopropylethylamine (5.99 g, 46.3 mmol, 8.1 mL).The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate= 10/1 to 5/1) to give 2-amino-3-bromo-5-chloro-N- (cyclobutylmethyl)benzamide (5 g, 15.6 mmol, 67.1%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (t, J = 5.2 Hz, 1H), 7.71 - 7.54 (m, 2H), 6.63 - 6.45 (m, 2H), 3.24 (dd, J = 6.0, 6.8 Hz, 2H), 2.56 - 2.51 (m, 1H), 2.05 - 1.91 (m, 2H), 1.86 - 1.78 (m, 2H), 1.75 - 1.62 (m, 2H); m/z ES+ [M+H] ⁺ 318.9. [1527] Step 2. Synthesis of 8-bromo-2,6-dichloro-3-(cyclobutylmethyl)quinazolin-4(3H)-on e [1528] To a solution of 2-amino-3-bromo-5-chloro-N-(cyclobutylmethyl)benzamide (3 g, 9.45 mmol) in 1,4-dioxane (40 mL) was dropwise added thiocarbonyl dichloride (2.17 g, 18.9 mmol). The mixture was stirred at 25 °C for 1 hr. Then heated to 105 °C stirred for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 8-bromo-2, 6-dichloro-3-(cyclobutylmethyl) quinazolin-4(3H)-one (3.42 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 363.0. [1529] Step 3. Synthesis of 8-bromo-6-chloro-3-(cyclobutylmethyl)-2- morpholinoquinazolin-4(3H)-one [1530] To a solution of 8-bromo-2, 6-dichloro-3-(cyclobutylmethyl) quinazolin-4-one (3.42 g, 9.45 mmol) in dichloromethane (40 mL) was added morpholine (2.47 g, 28.3 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-bromo-6-chloro-3-(cyclobutylmethyl)-2- morpholinoquinazolin-4(3H)-one (4.03 g, 9.03 mmol, 95.6%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 4.09 (d, J = 6.8 Hz, 2H), 3.81 - 3.73 (m, 4H), 3.24 - 3.18 (m, 4H), 2.64 (td, J = 7.6, 14.8 Hz, 1H), 1.89 - 1.82 (m, 2H), 1.80 - 1.72 (m, 2H), 1.72 - 1.64 (m, 2H); m/z ES+ [M+H] ⁺ 414.1. [1531] Step 4. Synthesis of 8-acetyl-6-chloro-3-(cyclobutylmethyl)-2-morpholinoquinazoli n- 4(3H)-one [1532] A mixture of 8-bromo-6-chloro-3-(cyclobutylmethyl)-2-morpholino-quinazoli n-4-one (1 g, 2.42 mmol), 1-vinyloxybutane (728 mg, 7.27 mmol, 935 ^L), palladium acetate (54.4 mg, 242 μmol), diisopropylethylamine (939 mg, 7.27 mmol, 1.3 mL) and [2-(2- diphenylphosphanylphenoxy) phenyl]-diphenyl-phosphane (130 mg, 242 μmol) in n-butanol (10 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere, then added hydrogen chloride (1 M, 12.1 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with sodium bicarbonate 100 mL and extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-6-chloro-3-(cyclobutylmethyl)-2- morpholinoquinazolin-4(3H)-one (495 mg, 1.32 mmol, 54%) as a white solid. m/z ES+ [M+H] ⁺ 376.0. [1533] Step 5. Synthesis of 8-(1-aminoethyl)-6-chloro-3-(cyclobutylmethyl)-2- morpholinoquinazolin-4(3H)-one [1534] To a solutin of 8-acetyl-6-chloro-3-(cyclobutylmethyl)-2-morpholino-quinazol in-4- one (430 mg, 1.14 mmol) in dichloromethane (15 mL) and methanol (15 mL) was added ammonium acetate (1.76 g, 22.9 mmol) and sodium cyanoborohydride (71.9 mg, 1.14 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the mixture was quenched by water (2 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed- phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-6-chloro-3- (cyclobutylmethyl)-2-morpholinoquinazolin-4(3H)-one (0.4 g, 881 μmol, 77%) as a white solid. m/z ES+ [M+H] ⁺ 376.1. [1535] Step 6. Synthesis of methyl 2-((1-(6-chloro-3-(cyclobutylmethyl)-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1536] A mixture of 8-(1-aminoethyl)-6-chloro-3-(cyclobutylmethyl)-2-morpholino- quinazolin-4-one (100 mg, 265 μmol), methyl 2-bromobenzoate (85.6 mg, 398 μmol), dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (12.4 mg, 26.5 μmol), cesium carbonate (259 mg, 796 μmol) and tris(dibenzylideneacetone)dipalladium (24.3 mg, 26.5 μmol) in toluene (3 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purifiedby prep-TLC (petroleum ether/ethyl acetate = 2:1) to give methyl 2-((1-(6-chloro-3-(cyclobutylmethyl)-2- morpholino-4-oxo-3, 4-dihydroquinazolin-8-yl) ethyl) amino) benzoate (80 mg, 149 μmol, 56%) as a yellow solid. [1537] Step 7. Synthesis of 2-((1-(6-chloro-3-(cyclobutylmethyl)-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1538] To a solution of methyl 2-[1-[6-chloro-3-(cyclobutylmethyl)-2-morpholino-4-oxo- quinazolin-8-yl] ethylamino] benzoate (80 mg, 157 μmol) in anhydrous tetrahydrofuran (0.8 mL), methanol (0.5 mL) and water (0.5 mL) was added lithium hydroxide (19.2 mg, 801 μmol). The mixture was stirred at 60 °C for 50 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 28%-58%, 8 min) to give 2-((1-(6-chloro-3- (cyclobutylmethyl)-2-morpholino-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid (47.9 mg, 96.1 μmol, 61%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.52 (m, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.78 (dd, J = 1.2, 8.0 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.54 - 6.43 (m, 2H), 5.43 - 5.28 (m, 1H), 4.13 (tt, J = 6.8, 13.6 Hz, 2H), 3.79 (s, 4H), 3.24 (d, J = 4.0 Hz, 4H), 2.71 - 2.65 (m, 1H), 1.93 - 1.85 (m, 2H), 1.81 - 1.69 (m, 4H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 497.3. Example 101. Preparation of 3-ethyl-6-methyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one [1539] Step 1. Synthesis of 8-bromo-3-ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-one [1540] To a solution of 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one (300 mg, 995 μmol) in dichloromethane (4 mL) was added morpholine (433 mg, 4.97 mmol). The mixture was stirred at 40 °C for 12 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic condition) to give 8-bromo-3- ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-one (300 mg, 852 μmol, 86%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) 7.90 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 0.8, 1.6 Hz, 1H), 4.06 (q, J = 6.8 Hz, 2H), 3.83 - 3.71 (m, 4H), 3.23 - 3.16 (m, 4H), 2.39 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). [1541] Step 2. Synthesis of 8-acetyl-3-ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-one [1542] To a solution of 8-bromo-3-ethyl-6-methyl-2-morpholino-quinazolin-4-one (300 mg, 852 μmol) in toluene (5 mL) was added palladium triphenylphosphane (98.4 mg, 85.2 μmol) and tributyl(1-ethoxyvinyl)stannane (923 mg, 2.56 mmol). The mixture was stirred at 130 °C for 12 hr. Then hydrochloric acid (1 M, 1.3 mL) was added into the mixture and stirred at 25 °C for 30 min. The mixture was poured in water (20 mL) then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 5/1) to give 8-acetyl-3-ethyl-6-methyl-2-morpholinoquinazolin-4(3H)-one (0.260 g, 824 μmol, 97%) as a yellow solid. m/z ES+ [M+H] ⁺ 316.3. [1543] Step 3. Synthesis of 8-(1-aminoethyl)-3-ethyl-6-methyl-2-morpholinoquinazolin- 4(3H)-one [1544] To a solution of 8-acetyl-3-ethyl-6-methyl-2-morpholino-quinazolin-4-one (200 mg, 634 μmol) in methanol (3 mL) was added ammonium acetate (978 mg, 12.7 mmol) and sodium cyanoborohydride (39.9 mg, 634 μmol). The mixture was stirred at 60 °C for 1 h. Then 2- chloro-4-[(7-fluoro-6-nitro-quinazolin-4-yl)amino]phenol (400 mg, 1.2 mmol) was added in the reaction mixture was stirred at 0 °C for 1 hr. The mixture was quenched by water (1 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% fromic acid condition) to give 8-(1-aminoethyl)-3-ethyl-6-methyl-2- morpholinoquinazolin-4(3H)-one (170 mg, 537 μmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 317.3. [1545] Step 4. Synthesis of 3-ethyl-6-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )- 2-morpholinoquinazolin-4(3H)-one [1546] To a solution of 8-(1-aminoethyl)-3-ethyl-6-methyl-2-morpholino-quinazolin-4- one (50.0 mg, 158 μmol) and 1-fluoro-2-methylsulfonyl-benzene (27.5 mg, 158 μmol) in N,N- dimethylformamide (0.5 mL) was added cesium carbonate (102 mg, 316 μmol). The mixture was stirred at 120 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 50%-80%, 7 min) to give 3-ethyl-6-methyl-8-[1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (16.8 mg, 35.7 μmol, 22%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.76 (dd, J = 1.2, 8.0 Hz, 1H), 7.46 (s, 1H), 7.27 - 7.20 (m, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.59 - 5.35 (m, 1H), 4.31 - 4.14 (m, 2H), 3.96 - 3.83 (m, 4H), 3.26 (dd, J = 3.6, 5.6 Hz, 4H), 3.11 (s, 3H), 2.38 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 471.1. Example 102. Preparation of 2-((1-(3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1547] Step 1. Synthesis of 8-bromo-3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)quinazolin- 4(3H)-one [1548] To a solution of 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one (1.20 g, 3.98 mmol) and 1, 4-oxazepane (547 mg, 3.98 mmol, hydrochloric acid salt) in dicholomethane (12 mL) was added diisopropylethylamine (3.09 g, 23.8 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 0/1) to give 8-bromo-3-ethyl-6-methyl-2-(1,4- oxazepan-4-yl)quinazolin-4-one (1.00 g, 2.51 mmol, 63%) as a white solid; m/z ES+ [M+H] ⁺ 368.0. [1549] Step 2. Synthesis of 8-acetyl-3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)quinazolin- 4(3H)-one [1550] To a solution of 8-bromo-3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)quinazolin-4-o ne (0.90 g, 2.46 mmol) and 1-vinyloxybutane (738 mg, 7.37 mmol) in n-butanol (10 mL) was added palladium(II) acetate (55.1 mg, 245 μmol), diisopropylethylamine (952 mg, 7.37 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (132 mg, 245 μmol). The mixture was stirred at 95 °C for 11.5 hr under nitrogen atmosphere. Then hydrochloric acid (1 M, 24.5 mL) was added at 25 °C and stirred for 0.5 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 0/10) to give 8-acetyl-3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)quinazolin-4- one (0.80 g, 2.28 mmol, 92%) as a yellow solid; m/z ES+ [M+H] ⁺ 230.4. [1551] Step 3. Synthesis of 8-(1-aminoethyl)-3-ethyl-6-methyl-2-(1,4-oxazepan-4- yl)quinazolin-4(3H)-one [1552] To a solution of 8-acetyl-3-ethyl-6-methyl-2-(1, 4-oxazepan-4-yl)quinazolin-4-one (750 mg, 2.28 mmol) in methanol (50 mL) was added ammonium acetate (3.51 g, 45.5 mmol) and sodium cyanoborohydride (143 mg, 2.28 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate/methanol = 100/1/0 to 0/10/1) to give 8-(1-aminoethyl)-3-ethyl-6-methyl- 2-(1,4-oxazepan-4-yl)quinazolin-4-one (750 mg, 1.97 mmol, 86%) as a yellow solid; m/z ES+ [M+H] ⁺ 331.0. [1553] Step 4. Synthesis of tert-butyl 2-((1-(3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1554] To a solution of 8-(1-aminoethyl)-3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)quina zolin- 4-one (50.0 mg, 151 μmol) and tert-butyl 2-bromobenzoate (116 mg, 453 μmol) in toluene (1 mL) was added tris(dibenzylideneacetone)dipalladium (13.8 mg, 15.1 μmol), cesium carbonate (147 mg, 453 μmol) and dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (7.06 mg, 15.1 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 0/1) to give tert-butyl 2-[1-[3-ethyl-6-methyl-2-(1,4-oxazepan- 4-yl)-4-oxo-quinazolin-8-yl]ethylamino]benzoate (40 mg, 66.3 μmol, 43%) as a brown solid. m/z ES+ [M+H] ⁺ 507.2. [1555] Step 5. Synthesis of 2-((1-(3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1556] A solution of tert-butyl 2-[1-[3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)-4-oxo- quinazolin-8-yl]ethylamino]benzoate (40.0 mg, 78.9 μmol) in trifluoroacetic acid (1 mL) was stirred at 25 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 50%-80%,7 min) to give 2-[1-[3-ethyl-6-methyl-2-(1,4-oxazepan-4-yl)-4-oxo-quinazoli n-8- yl]ethylamino]benzoic acid (19.6 mg, 43.5 μmol, 55%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.76 - 12.48 (m, 1H), 8.56 - 8.28 (m, 1H), 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.70 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.54 - 6.45 (m, 2H), 5.35 (d, J = 6.4 Hz, 1H), 4.19 - 4.00 (m, 2H), 3.92 - 3.74 (m, 4H), 3.60 - 3.43 (m, 4H), 2.31 (s, 3H), 2.02 (dd, J = 5.6, 9.6 Hz, 2H), 1.56 (d, J = 6.4 Hz, 3H), 1.29 (t, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 451.2. Example 103. Preparation of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one [1557] Step 1. Synthesis of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3,6- dimethylquinazolin-4(3H)-one [1558] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (1.00 g, 3.48 mmol) and 3-azabicyclo[3.1.0]hexane;hydrochloride (1.25 g, 10.4 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (1.80 g, 13.9 mmol). The mixture was stirred at 40 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 2/1) to give desired compound 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3,6- dimethylquinazolin-4(3H)-one (940 mg, 2.50 mmol, 72%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d, J = 1.6 Hz, 1H), 7.75 - 7.72 (m, 1H), 3.91 (d, J = 10.4 Hz, 2H), 3.50 (d, J = 10.8 Hz, 2H), 3.39 (s, 3H), 2.34 (s, 3H), 1.64 - 1.56 (m, 2H), 0.58 (m, 1H), 0.25 (q, J = 4.0 Hz, 1H). [1559] Step 2. Synthesis of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethylquinazolin-4(3H)-one [1560] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3,6-dimethyl-quina zolin- 4-one (840 mg, 2.51 mmol) and 1-vinyloxybutane (755 mg, 7.54 mmol) in n-butanol (17 mL) was added diacetoxypalladium (56.4 mg, 251 μmol), [2-(2- diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (135 mg, 251 μmol) and diisopropylethylamine (975 mg, 7.54 mmol). The mixture was stirred at 95 °C for 12 hr. The mixture was cooled to 25 °C, then was added formic acid 17 mL and stirred for 0.5 hr. The reaction was adjusted pH=7~8 with saturated sodium bicarbonate, the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 2/1) to give desired compound 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethylquinazolin-4(3H)-one (680 mg, 2.19 mmol, 87%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 1.6 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 3.84 (d, J = 10.4 Hz, 2H), 3.49 (d, J = 10.4 Hz, 2H), 3.41 (s, 3H), 2.74 (s, 3H), 2.37 (s, 3H), 1.65 - 1.58 (m, 2H), 0.63 - 0.55 (m, 1H), 0.32 (q, J = 4.0 Hz, 1H). [1561] Step 3. Synthesis of 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethylquinazolin-4(3H)-one [1562] To a solution of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-quin azolin- 4-one (580 mg, 1.95 mmol) in methanol (12 mL) was added ammonium acetate (3.01 g, 39.0 mmol) and sodium cyanoborohydride (123 mg, 1.95 mmol). The mixture was stirred at 60 °C for 1 hr. The mixture was quenched by water (1.0 mL) and then concentrated in vacuo to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give desired compound 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethylquinazolin-4(3H)-one (550 mg, 1.82 mmol, 94%) as a white solid. m/z ES+ [M+H] ⁺ 299.2. [1563] Step 4. Synthesis of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one [1564] To a solution of 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimet hyl- quinazolin-4-one (80.0 mg, 268 μmol) and 1-fluoro-2-methylsulfonyl-benzene (46.7 mg, 268 μmol) in N,N-dimethylformamide (1.50 mL) was added cesium carbonate (175 mg, 536 μmol). The mixture was stirred at 120 °C for 16 hr. The reaction solution was diluted with water 30 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturate brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 3/1) to give 2-(3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-8-(1- ((2(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (25.0 mg, 55.2 μmol, 21%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.75 - 6.66 (m, 2H), 6.62 (d, J = 8.4 Hz, 1H), 5.41 - 5.31 (m, 1H), 3.98 (d, J = 10.4 Hz, 1H), 3.80 (d, J = 10.4 Hz, 1H), 3.51 (d, J = 9.6 Hz, 2H), 3.42 (s, 3H), 3.17 (s, 3H), 2.30 (s, 3H), 1.64 - 1.55 (m, 5H), 0.59 (d, J = 4.8 Hz, 1H), 0.37 (d, J = 3.6 Hz, 1H); m/z ES+ [M+H] ⁺ 453.2. Example 104 and Example 105. Preparation of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-8-((R)-1-((2(methylsulfonyl)phenyl)amino)ethyl)quin azolin-4(3H)-one and 2- (3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-8-((S)-1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (stereochemistry arbitrarily assigned for both enantiomers) [1565] 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (20 mg) was further separated by SFC (basic condition; column: Daicel CHIRALPAK IG (250 x 30 mm, 10 um); mobile phase: [0.1%NH ₃ -water IPA]; B%: 35%-35%, 4.2 min) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-8-((R)-1-((2-(methylsulfonyl)phenyl)amino)ethyl )quinazolin-4(3H)-one (10.0 mg, 21.3 μmol, 48%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.35 - 7.27 (m, 1H), 6.76 - 6.67 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 5.36 (t, J = 6.4 Hz, 1H), 3.98 (d, J = 10.4 Hz, 1H), 3.80 (d, J = 10.4 Hz, 1H), 3.51 (d, J = 10.0 Hz, 2H), 3.42 (s, 3H), 3.18 (s, 3H), 2.30 (s, 3H), 1.65 - 1.55 (m, 5H), 0.63 - 0.54 (m, 1H), 0.37 (d, J = 3.6 Hz, 1H); m/z ES+ [M+H] ⁺ 453.2 and 2-(3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-8-((S)-1-((2-(methylsulfonyl)phenyl)amino)ethyl )quinazolin-4(3H)-one (11.5 mg, 25.0 μmol, 57%) as a yellow gum. ¹ H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.63 - 7.58 (m, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.76 - 6.67 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 5.36 (t, J = 6.8 Hz, 1H), 3.98 (d, J = 10.4 Hz, 1H), 3.80 (d, J = 10.4 Hz, 1H), 3.51 (d, J = 10.4 Hz, 2H), 3.42 (s, 3H), 3.18 (s, 3H), 2.30 (s, 3H), 1.64 - 1.55 (m, 5H), 0.59 (d, J = 4.8 Hz, 1H), 0.37 (q, J = 4.0 Hz, 1H); m/z ES+ [M+H] ⁺ 453.2. Example 106. Preparation of 2-((1-(6-chloro-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1566] Step 1. Synthesis of 2-amino-3-bromo-5-chloro-N-(2,2,2-trifluoroethyl)benzamide [1567] To a solution of 2-amino-3-bromo-5-chloro-benzoic acid (6 g, 23.9 mmol) and 2,2,2- trifluoroethanamine (4.75 g, 47.1 mmol) in N,N-dimethylformamide (60 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl-ammonium hexafluorophosphate (11.8 g, 31.1 mmol) and diisopropylethylamine (12.3 g, 95.8 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction was adjusted pH = 7~8, with sat. sodium bicarbonate and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure in vacuo to give 2-amino-3-bromo-5-chloro-N-(2,2,2- trifluoroethyl)benzamide (7 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 333.2. [1568] Step 2. Synthesis of 8-bromo-2,6-dichloro-3-(2,2,2-trifluoroethyl)quinazolin-4(3H )- one [1569] To a solution of 2-amino-3-bromo-5-chloro-N-(2,2,2-trifluoroethyl)benzamide (2 g, 6.03 mmol) in 1,4-dioxane (20 mL) was added thiocarbonyl dichloride (1.39 g, 12.1 mmol, 925 ^L). The mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 105 °C for 1 hr. On completion, the reaction was mixture concentrated under reduced pressure in vacuo to give 8-bromo-2,6-dichloro-3-(2,2,2-trifluoroethyl)quinazolin-4(3H )-one (3 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 375.1. [1570] Step 3. Synthesis of 8-bromo-6-chloro-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one [1571] To a solution of 8-bromo-2,6-dichloro-3-(2,2,2-trifluoroethyl)quinazolin-4(3H )-one (3 g, 7.98 mmol) in dichloromethane (30 mL) was added morpholine (2.09 g, 23.9 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 1/1) to give 8-bromo-6-chloro-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one (1 g, 2.34 mmol, 29% ) as a white solid. m/z ES+ [M+H] ⁺ 428.1. [1572] Step 4. Synthesis of 8-acetyl-6-chloro-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one [1573] A mixture of 8-bromo-6-chloro-2-morpholino-3-(2,2,2-trifluoroethyl)quinaz olin- 4(3H)-one (1 g, 2.34 mmol), 1-vinyloxybutane (704 mg, 7.03 mmol), diacetoxypalladium (52.6 mg, 234 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (126 mg, 234 μmol) and diisopropylethylamine (908 mg, 7.03 mmol) in n-butanol (10 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 95 °C for 2 hr under nitrogen atmosphere. Then hydrochloric acid (4 M, 5.8 mL) was added in the mixture and stirred at 25 °C for 30 mins. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 1/1) to give 8-acetyl-6-chloro-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one (0.45 g, 1.15 mmol, 49%) as a yellow solid. m/z ES+ [M+H] ⁺ 390.0. [1574] Step 5. Synthesis of 8-(1-aminoethyl)-6-chloro-2-morpholino-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one [1575] To a solution of 8-acetyl-6-chloro-2-morpholino-3-(2,2,2-trifluoroethyl)quina zolin- 4(3H)-one (0.4 g, 1.03 mmol) in methanol (4 mL) was added sodium cyanoborohydride (64 mg, 1.03 mmol) and ammonium acetate (1.58 g, 20.5 mmol). The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (water/acetonitrile = 20:1 to 1:1) in vacuo to give 8-(1-aminoethyl)-6-chloro-2-morpholino-3- (2,2,2-trifluoroethyl)quinazolin-4(3H)-one (0.15 g, 383 μmol, 37%) as a white solid. m/z ES+ [M+H]+ 391.3. [1576] Step 6. Synthesis of methyl 2-((1-(6-chloro-2-morpholino-4-oxo-3-(2,2,2- trifluoroethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzo ate [1577] 8-(1-aminoethyl)-6-chloro-2-morpholino-3-(2,2,2-trifluoroeth yl)quinazolin-4-one (0.13 g, 332 μmol), tert-butyl 2-bromobenzoate (256 mg, 997 μmol), tris(dibenzylideneacetone)dipalladium (30.4 mg, 33.2 μmol), dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl]phosphane (15.5 mg, 33.2 μmol) and cesium carbonate (325 mg, 997 μmol) in toluene (1.5 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 1/1) to give methyl 2- ((1-(6-chloro-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)-3, 4-dihydroquinazolin-8- yl)ethyl)amino)benzoate (70 mg, 117 μmol, 35%) as a yellow solid. m/z ES+ [M+H] ⁺ 567.1. [1578] Step 7. Synthesis of 2-((1-(6-chloro-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)- 3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1579] A solution of methyl 2-((1-(6-chloro-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)- 3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (60 mg, 105 μmol) in trifluoroacetic acid (0.5 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)-acetonitrile]; B%: 50%-80%, 10 min) in vacuo to give 2-((1-(6-chloro-2-morpholino-4-oxo-3-(2,2,2-trifluoroethyl)- 3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (22.85 mg, 44.1 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 – 8.40 (m, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.22 - 7.15 (m, 1H), 6.57 - 6.50 (m, 2H), 5.42 - 5.32 (m, 1H), 5.03 - 4.92 (m, 2H), 3.78 - 3.70 (m, 4H), 3.23 - 3.20 (m, 4H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 511.2. Example 107. Preparation of 2-((1-(3,6-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1580] Step 1. Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(methylthio)quinazolin-4(3H) - one [1581] To a solution of 8-acetyl-3,6-dimethyl-2-methylsulfanyl-quinazolin-4-one (2.5 g, 9.53 mmol) in methanol (25 mL) was added ammonium acetate (14.7 g, 191 mmol) and sodium cyanoborohydride (599 mg, 9.53 mmol). The mixture was stirred at 60 °C for 1 hr. The mixture was quenched by water (1 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)- 3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (1.31 g, 4.06 mmol, 43%) as a white solid. m/z ES+ [M+H] ⁺ 264.2. [1582] Step 2. Synthesis of methyl 2-((1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1583] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-methylsulfanyl-quinazolin-4- one (1.21 g, 3.91 mmol) in toluene (10 mL) was added methyl 2-bromobenzoate (2.52 g, 11.7 mmol), tris(dibenzylideneacetone)dipalladium (358 mg, 391 μmol), cesium carbonate (3.82 g, 11.7 mmol) and dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (183 mg, 391 μmol). The mixture was stirred at 110 °C for 12 hr. The mixture was poured in water (50 mL) then extracted with ethyl acetate (50 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give methyl 2-((1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazol in-8- yl)ethyl)amino)benzoate (1 g, 2.52 mmol, 64%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.15 (t, J = 8.0 Hz, 2H), 6.54 (t, J = 7.6 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.61 - 5.51 (m, 1H), 3.93 (s, 3H), 3.65 (s, 3H), 2.69 (s, 3H), 2.37 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H). [1584] Step 3. Synthesis of methyl 2-((1-(3,6-dimethyl-2-(methylsulfonyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1585] To a solution of methyl 2-[1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8- yl)ethylamino]benzoate (0.3 g, 755 μmol) in tetrahydrofuran (3 mL) and water (3 mL) was added Oxone (1.39 g, 2.26 mmol). The mixture was stirred at 20 °C for 1 hr. The mixture was filter and the mixture was quenched by sodium sulfite (sat. 2 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give methyl 2-((1-(3,6-dimethyl-2-(methylsulfonyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (50 mg, 99 μmol, 13%) as a yellow oil. m/z ES+ [M+H] ⁺ 430.1. [1586] Step 4. Synthesis of methyl 2-((1-(3,6-dimethyl-2-((S)-2-methylmorpholino)-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1587] To a solution of methyl 2-[1-(3,6-dimethyl-2-methylsulfonyl-4-oxo-quinazolin-8- yl)ethylamino]benzoate (50 mg, 116 μmol) in N,N-dimethylformamide (1 mL) was added (2S)- 2-methylmorpholine (35.3 mg, 349 μmol) and diisopropylethylamine (75.2 mg, 582 μmol). The mixture was stirred at 60 °C for 12 h. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give methyl 2-((1-(3,6-dimethyl-2-((S)-2-methylmorpholino)- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (50 mg, 108 μmol, 92%) as a yellow oil. m/z ES+ [M+H] ⁺ 451.2. [1588] Step 5. Synthesis of 2-((1-(3,6-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1589] To a solution of methyl 2-[1-[3,6-dimethyl-2-[(2S)-2-methylmorpholin-4-yl]-4-oxo- quinazolin-8-yl]ethylamino]benzoate (50 mg, 111 μmol) in tetrahydrofuran (0.5 mL), methanol (0.5 mL), water (0.5 mL) was added lithium hydroxide (13.3 mg, 555 μmol). The mixture was stirred at 60 °C for 2 hr. hydrogenchloride (1 M) was added to the mixture until pH = 3. Then the mixture was poured in water (20 mL) then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 2-((1-(3,6-dimethyl-2- ((S)-2-methylmorpholino)-4-oxo-3,4-dihydroquinazolin-8-yl)et hyl)amino)benzoic acid (20.1 mg, 46 μmol, 41%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 - 8.09 (m, 1H), 8.01 - 7.94 (m, 1H), 7.90 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.24 - 7.17 (m, 1H), 6.57 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 8.8 Hz, 1H), 5.49 (q, J = 6.4 Hz, 1H), 4.07 - 3.96 (m, 1H), 3.93 - 3.80 (m, 2H), 3.62 (s, 3H), 3.39 (d, J = 12.8 Hz, 2H), 3.21 - 3.09 (m, 1H), 2.87 - 2.76 (m, 1H), 2.38 (s, 3H), 1.64 (d, J = 6.0 Hz, 3H), 1.27 (dd, J = 2.4, 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 437.3. Example 108. Preparation of 2-((1-(3-(2-hydroxy-2-methylpropyl)-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid [1590] Step 1. Synthesis of 2-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-1-amine [1591] To a solution of 1-amino-2-methyl-propan-2-ol (1 g, 11.2 mmol) and tert-butyl-chloro- diphenyl-silane (3.70 g, 13.5 mmol) in dichloromethane (10 mL) was added imidazole (2.29 g, 33.7 mmol). The reaction was stirred at 25 °C for 12 hr. The residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 36~40% ethyl acetate/petroleum ether gradient @ 60 mL/min) to give 2-[tert-butyl(diphenyl)silyl]oxy-2- methyl-propan-1-amine (2.32 g, 7.08 mmol, 63%) as a colorless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 (dd, J = 1.6, 7.6 Hz, 4H), 7.52 - 7.37 (m, 6H), 2.44 (s, 2H), 1.35 (s, 2H), 1.01 (s, 6H), 0.96 (s, 9H). [1592] Step 2. Synthesis of 2-amino-3-bromo-N-(2-((tert-butyldiphenylsilyl)oxy)-2- methylpropyl)-5-methylbenzamide [1593] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (811 mg, 3.53 mmol) and 2- [tert-butyl(diphenyl)silyl]oxy-2-methyl-propan-1-amine (2.31 g, 7.05 mmol) in N,N- dimethylformamide (10 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (2.01 g, 5.29 mmol) and diisopropylethylamine (1.37 g, 10.6 mmol, 1.8 mL). The reaction was stirred at 25 °C for 2 hr. The residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 12~16% ethyl acetate/petroleum ether gradient @ 60 mL/min) to give 2-amino-3- bromo-N-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl]-5 -methyl-benzamide (1.8 g, 3.34 mmol, 95%) as a colorless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (t, J = 6.0 Hz, 1H), 7.68 (d, J = 6.4 Hz, 4H), 7.53 - 7.26 (m, 8H), 6.11 (s, 2H), 3.35 - 3.32 (m, 2H), 2.19 (s, 3H), 1.05 (s, 6H), 0.97 (s, 9H). [1594] Step 3. Synthesis of 8-bromo-3-(2-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl)- 2- chloro-6-methylquinazolin-4(3H)-one [1595] To a solution of 2-amino-3-bromo-N-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl - propyl]-5-methyl-benzamide (2.2 g, 4.08 mmol) in 1,4-dioxane (30 mL) was added thiocarbonyl dichloride (984 mg, 8.56 mmol, 656 ^L). The reaction was stirred at 25 °C for 1 hr and then heated to 105 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 12~16% ethyl acetate/petroleum ether gradient @ 60 mL/min) to give 8-bromo-3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl] -2-chloro-6- methyl-quinazolin-4-one (1.7 g, 2.91 mmol, 71%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 7.91 (s, 1H), 7.50 (d, J = 6.4 Hz, 4H), 7.43 - 7.39 (m, 2H), 7.30 (d, J = 6.4 Hz, 4H), 4.58 - 4.35 (m, 2H), 2.45 (s, 3H), 1.10 - 1.03 (m, 6H), 0.87 (s, 9H). [1596] Step 4. Synthesis of 8-bromo-3-(2-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl)- 6- methyl-2-morpholinoquinazolin-4(3H)-one [1597] To a solution of 8-bromo-3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl] -2- chloro-6-methyl-quinazolin-4-one (1.5 g, 2.57 mmol) in tetrahydrofuran (15 mL) was added morpholine (671 mg, 7.71 mmol, 678 ^L). The reaction was stirred at 60 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®;20 g SepaFlash® Silica Flash Column, eluent of 22~26% ethyl acetate/petroleum ether gradient @ 60 mL/min) to give 8-bromo-3-[2- [tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl]-6-methyl-2-m orpholino-quinazolin-4-one (1.3 g, 1.90 mmol, 74%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 1.6 Hz, 1H), 7.78 (s, 1H), 7.56 - 7.25 (m, 11H), 3.68 (s, 5H), 3.38 - 2.88 (m, 5H), 2.35 (s, 3H), 0.97 (s, 6H), 0.76 (s, 9H). [1598] Step 5. Synthesis of 8-acetyl-3-(2-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl) -6- methyl-2-morpholinoquinazolin-4(3H)-one [1599] A mixture of 8-bromo-3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl] -6- methyl-2-morpholino-quinazolin-4-one (1.2 g, 1.89 mmol), 1-vinyloxybutane (568 mg, 5.67 mmol), palladium(2+) diacetate (42.5 mg, 189 μmol), [2-(2- diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (101.83 mg, 189 μmol) and diisopropylethylamine (733 mg, 5.67 mmol) in n-butanol (15 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. And then the reaction was cooled to 25 °C, hydrochloric acid (1 M, 4 mL) was added and stirred at 25 °C for 10 min. On completion, the residue was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 55~62% ethylacetate/petroleum ether gradient @ 60 mL/min) to give 8-acetyl-3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl- propyl]-6-methyl-2-morpholino-quinazolin-4-one (825 mg, 1.35 mmol, 72%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 2.0, 1H), 7.51 (d, J = 2.8 Hz, 4H), 7.44 - 7.39 (m, 2H), 7.35 - 7.27 (m, 4H), 3.69 (s, 4H), 3.30 (s, 4H), 3.20 - 3.07 (m, 2H), 2.77 (s, 3H), 2.39 (s, 3H), 0.99 (s, 6H), 0.76 (s, 9H). [1600] Step 6. Synthesis of 8-(1-aminoethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)-2- methylpropyl)-6-methyl-2-morpholinoquinazolin-4(3H)-one [1601] To a solution of 8-acetyl-3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl ]-6- methyl-2-morpholino-quinazolin-4-one (770 mg, 1.29 mmol) in methanol (8 mL) was added azanium acetate (1.99 g, 25.8 mmol) and sodium cyanoborohydride (162 mg, 2.58 mmol). The reaction was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methy l- propyl]-6-methyl-2-morpholino-quinazolin-4-one (500 mg, 775 μmol, 60%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 12.4 Hz, 2H), 7.54 (d, J = 7.2 Hz, 4H), 7.46 - 7.38 (m, 2H), 7.37 - 7.27 (m, 4H), 4.87 (s, 1H), 3.68 (s, 6H), 3.08 (s, 4H), 2.39 (s, 3H), 1.44 (d, J = 4.4 Hz, 3H), 0.98 (s, 6H), 0.78 (s, 9H). [1602] Step 7. Synthesis of 2-((1-(3-(2-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl)-6 - methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)a mino)benzoic acid [1603] A mixture of 8-(1-aminoethyl)-3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methy l-propyl]- 6-methyl-2-morpholino-quinazolin-4-one (200 mg, 310 μmol, FA salt) , 2-iodobenzoic acid (231 mg, 930 μmol), copper (19.7 mg, 310 μmol), triethylamine (94.2 mg, 930 μmol) in dimethyl acetamide (2 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 100 °C for 1 hr under nitrogen atmosphere. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was used in the next step without purification to give 2-[1-[3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl]-6 -methyl-2- morpholino-4-oxo-quinazolin-8-yl]ethylamino] benzoic acid (280 mg, 273 μmol, 88%) was obtained as green gum. m/z ES+ [M+H] ⁺ 582.2. [1604] Step 8. Synthesis of 2-((1-(3-(2-hydroxy-2-methylpropyl)-6-methyl-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1605] To a solution of 2-[1-[3-[2-[tert-butyl(diphenyl)silyl]oxy-2-methyl-propyl]-6 -methyl- 2-morpholino-4-oxo-quinazolin-8-yl]ethylamino]benzoic acid (115 mg, 112 μmol, 70% purity) in anhydrous tetrahydrofuran (2 mL) was added tetrabutylammonium;fluoride (1 M, 0.336 mL). The reaction was stirred at 25 °C for 12 hr. After the reaction was heated to 40 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(ammonium hydroxide)- acetonitrile]; B%: 8%-38%, 8 min) and by prep-TLC (silicon dioxide, dichloromethane/methanol = 10 :1) to give 2-[1-[3-(2- hydroxy-2-methyl-propyl)-6-methyl-2-morpholino-4-oxo-quinazo lin-8-yl]ethylamino] benzoic acid (3.63 mg, 7.33 μmol, 7%) as a yellow gum. ¹ H NMR (400 MHz, DMSO-d6) δ 13.15 - 12.03 (m, 1H), 8.83 - 8.29 (m, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.71 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.19 - 7.10 (m, 1H), 6.53 (d, J = 7.2 Hz, 1H), 6.47 (t, J = 7.2 Hz, 1H), 5.39 (s, 1H), 4.48 (s, 1H), 4.30 - 4.09 (m, 2H), 3.77 (s, 4H), 3.16 (s, 4H), 2.33 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.04 (s, 6H). Example 109. Preparation of 3-ethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2- morpholinoquinazolin-4(3H)-one [1606] A mixture of 8-(1-aminoethyl)-3-ethyl-2-morpholino-quinazolin-4-one (200 mg, 661 μmol), 1-fluoro-2-methylsulfonyl-benzene (230 mg, 1.32 mmol), cesium carbonate (647 mg, 1.98 mmol) in N,N-dimethylformamide (1 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 120 °C for 12 hr under nitrogen atmosphere. The mixture was poured in water (20 mL) then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 44%-74%, 10 min) to give 3-ethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2- morpholinoquinazolin-4(3H)-one (50 mg, 110 μmol, 17%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J = 1.2, 7.6 Hz, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.61 (dd, J = 1.2, 8.0 Hz, 1H), 7.38 - 7.28 (m, 2H), 6.79 (d, J = 7.2 Hz, 1H), 5.41 (t, J = 6.8 Hz, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 4H), 3.24 (q, J = 4.4 Hz, 4H), 3.18 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 110 and Example 111. Preparation of (R)-3-ethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one and (S)-3- ethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-morphol inoquinazolin-4(3H)-one (stereochemistry arbitrarily assigned for both enantiomers) [1607] The crude product was purified by SFC: column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide isopropanol]; B%: 35%-35%, 2.9 min to give (R)-3-ethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-m orpholinoquinazolin- 4(3H)-one (21.4 mg, 47.0 μmol, 43%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.98 - 7.90 (m, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.61 (dd, J = 1.2, 8.0 Hz, 1H), 7.38 - 7.28 (m, 2H), 6.79 (d, J = 7.2 Hz, 1H), 6.75 - 6.63 (m, 2H), 5.46 - 5.35 (m, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 4H), 3.28 - 3.21 (m, 4H), 3.18 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.31 - 1.22 (m, 3H); m/z ES+ [M+H] ⁺ 457.4; and (S)-3-ethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one (22.52 mg, 49 μmol, 45%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.36 - 7.29 (m, 2H), 6.79 (d, J = 6.8 Hz, 1H), 6.75 - 6.64 (m, 2H), 5.41 (t, J = 5.6 Hz, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 4H), 3.28 - 3.21 (m, 4H), 3.18 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 457.4. Example 112. Preparation of 2-((1-(3-ethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid [1608] A mixture of 8-(1-aminoethyl)-3-ethyl-2-morpholino-quinazolin-4-one (200 mg, 661 μmol), 2-iodobenzoic acid (492 mg, 1.98 mmol), triethylamine (201 mg, 1.98 mmol), copper (42 mg, 661 μmol) in toluene (200 mg, 1.98 mmol) dimethyl acetamide (2 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. The mixture was poured in water (20 mL) then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by prep-HPLCcolumn: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 43%-73%, 10 min) to give 2-((1-(3-ethyl- 2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoic acid (40 mg, 94.7 μmol, 14%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.85 - 12.40 (m, 1H), 8.68 - 8.35 (m, 1H), 7.92 (dd, J = 1.2, 8.0 Hz, 1H), 7.77 (dd, J = 1.2, 8.0 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.18 (br. t, J = 7.2 Hz, 1H), 6.54 - 6.43 (m, 2H), 5.48 - 5.34 (m, 1H), 4.15 - 4.04 (m, 2H), 3.84 - 3.74 (m, 4H), 3.27 - 3.18 (m, 4H), 1.59 (d, J = 6.4 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 423.2. Example 113 and Example 114. Preparation of (R)-2-((1-(3-ethyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid& (S)-2-((1-(3-ethyl-2-morpholino- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1609] The crude product was purified by SFC: column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 50%-50%, 4 min to give (R)-2-((1-(3-ethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid (14.84 mg, 35.1 μmol, 42%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) 8.58 - 8.41 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.77 (br. d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.35 - 7.24 (m, 1H), 7.23 - 7.11 (m, 1H), 6.48 (t, J = 6.0 Hz, 2H), 5.41 (d, J = 4.4 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.80 (s, 4H), 3.24 (d, J = 3.2 Hz, 4H), 1.59 (d, J = 6.4 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 423.4; and (S)-2-((1-(3-ethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (15.99 mg, 37.9 μmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.62 - 8.43 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.17 (br. t, J = 7.6 Hz, 1H), 6.52 - 6.42 (m, 2H), 5.45 - 5.37 (m, 1H), 4.14 - 4.06 (m, 2H), 3.83 - 3.76 (m, 4H), 3.26 - 3.21 (m, 4H), 1.59 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 423.4. Example 115. Preparation of 2-[1-[3-(Cyanomethyl)-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid [1610] Step 1. Synthesis of 2-amino-3-bromo-5-methyl-benzamide [1611] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (2.50 g, 10.8 mmol) and ammonium chloride (1.16 g, 21.7 mmol) in N,N-dimethylformamide (25 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (4.96 g, 13.0 mmol) and diisopropylethylamine (4.21 g, 32.6 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was poured into water (200 mL) and stirred at 25 °C for 0.5 hr. The resulting mixture was filtered, washed with water (100 mL) and dried to give 2-amino-3-bromo-5-methyl-benzamide (2.40 g, 9.11 mmol, 83%) as a white solid. m/z ES+ [M-15+H] ⁺ 214.1. [1612] Step 2. Synthesis of 8-bromo-2-chloro-6-methyl-3H-quinazolin-4-one [1613] To a solution of 2-amino-3-bromo-5-methyl-benzamide (2.20 g, 9.60 mmol) in 1,4- dioxane (22 mL) was added thiocarbonyl dichloride (2.32 g, 20.1 mmol). The mixture was stirred at 25 °C for 1 hr and then at 105 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro-6- methyl-3H-quinazolin-4-one (2.60 g, 6.84 mmol, 71%) as a white solid. m/z ES+ [M+H] ⁺ 274.7. [1614] Step 3. Synthesis of 2-(8-bromo-2-chloro-6-methyl-4-oxo-quinazolin-3- yl)acetonitrile [1615] To a solution of 8-bromo-2-chloro-6-methyl-3H-quinazolin-4-one (2.60 g, 9.51 mmol) in N,N-dimethylformamide (26 mL) was added sodium bicarbonate (2.40 g, 28.5 mmol) and 2-bromoacetonitrile (1.14 g, 9.51 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was poured into water (200 mL), filtered and dried to give 2- (8-bromo-2-chloro-6-methyl-4-oxo-quinazolin-3-yl)acetonitril e (2.40 g, 6.45 mmol, 67%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 5.27 (s, 2H), 2.45 (s, 3H); m/z ES+ [M+H] ⁺ 314.1. [1616] Step 4. Synthesis of 2-(8-bromo-6-methyl-2-morpholino-4-oxo-quinazolin-3- yl)acetonitrile [1617] To a solution of 2-(8-bromo-2-chloro-6-methyl-4-oxo-quinazolin-3-yl)acetonitr ile (1.00 g, 3.20 mmol) in dichloromethane (10 mL) was added morpholine (1.39 g, 16.0 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 0/1) to give 2-(8- bromo-6-methyl-2-morpholino-4-oxo-quinazolin-3-yl)acetonitri le (1.00 g, 2.51 mmol, 78%) as a white solid. m/z ES+ [M+H] ⁺ 363.1. [1618] Step 5. Synthesis of 2-(8-acetyl-6-methyl-2-morpholino-4-oxo-quinazolin-3- yl)acetonitrile [1619] To a solution of 2-(8-bromo-6-methyl-2-morpholino-4-oxo-quinazolin-3- yl)acetonitrile (0.90 g, 2.48 mmol) and 1-vinyloxybutane (744 mg, 7.43 mmol) in n-butanol (10 mL) was added palladium(II) acetate (55.6 mg, 247 μmol), diisopropylethylamine (960 mg, 7.43 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (133 mg, 247 μmol). The mixture was stirred at 95 °C for 11.5 hr under nitrogen atmosphere. Then hydrochloric acid (1 M, 25 mL) was added at 25 °C and stirred for 0.5 hr. On completion, the reaction mixture was quenched by addition saturated aqueous sodium bicarbonate (30 mL) at 0 °C, and then diluted with water (20 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate/Methanol = 100/1/0 to 0/10/1) to give 2-(8-acetyl-6-methyl-2-morpholino-4-oxo-quinazolin-3- yl)acetonitrile (1.10 g, 2.43 mmol, 97%) as a brown solid. m/z ES+ [M+H] ⁺ 327.3. [1620] Step 6. Synthesis of 2-[8-(1-aminoethyl)-6-methyl-2-morpholino-4-oxo-quinazolin-3 - yl]acetonitrile [1621] To a solution of 2-(8-acetyl-6-methyl-2-morpholino-4-oxo-quinazolin-3- yl)acetonitrile (1.00 g, 3.06 mmol) in methanol (50 mL) was added ammoniumacetate (4.72 g, 61.2 mmol) and sodium cyanoborohydride (192 mg, 3.06 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate/MeOH = 100/1/0 to 0/10/1) to give 2-[8-(1-aminoethyl)-6- methyl-2-morpholino-4-oxo-quinazolin-3-yl]acetonitrile (1.00 g, 1.99 mmol, 64%) as a brown solid. m/z ES+ [M+H] ⁺ 328.1. [1622] Step 7. Synthesis of 2-[1-[3-(cyanomethyl)-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid [1623] To a solution of 2-[8-(1-aminoethyl)-6-methyl-2-morpholino-4-oxo-quinazolin-3 - yl]acetonitrile (50.0 mg, 152 μmol) and 2-iodobenzoic acid (113 mg, 458 μmol)in dimethyl acetamide (0.5 mL) was added copper (9.71 mg, 152 μmol) and triethylamine (46.3 mg, 458 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition 1N hydrochloric acid at 0 °C to pH = 4, and then diluted with water (10 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide and column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 40%-70%, 7 min) to give 2-[1-[3-(cyanomethyl)-6-methyl-2-morpholino-4-oxo-quinazolin -8- yl]ethylamino]benzoic acid (10.0 mg, 22.1 μmol, 14%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 - 8.08 (m, 1H), 8.03 - 7.97 (m, 1H), 7.93 (s, 1H), 7.58 (s, 1H), 7.25 - 7.16 (m, 1H), 6.59 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.46 (d, J = 6.8 Hz, 1H), 5.01 (s, 2H), 4.04 - 3.87 (m, 4H), 3.43 - 3.27 (m, 4H), 2.40 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 448.2. Example 116. Preparation of 3,6-dimethyl-8-[1-(3-methyl-2-methylsulfonyl- anilino)ethyl]-2-morpholino-quinazolin-4-one [1624] Step 1. Synthesis of 1-bromo-3-chloro-2-methylsulfonyl-benzene [1625] To a mixture of 1-bromo-3-chloro-2-methylsulfanyl-benzene (0.5 g, 2.10 mmol) in dichloromethane (10 mL) was added 3-chloroperoxybenzoic acid (1.36 g, 6.31 mmol, 80% purity) in one portion. The mixture was then heated to 25 °C and stirred for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 1-bromo-3-chloro-2-methylsulfonyl-benzene (0.55 g, 2.02 mmol, 96%) was obtained as a yellow solid. m/z ES+ [M+H] ⁺ 270.0. [1626] Step 2. Synthesis of 8-[1-(3-chloro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2- morpholino-quinazolin-4-one [1627] To a mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (170 mg, 562 μmol) and 1-bromo-3-chloro-2-methylsulfonyl-benzene (455 mg, 1.69 mmo in toluene (5 mL) was added dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (26.2 mg, 56.2 μmol), tris(dibenzylideneacetone)dipalladium (51.5 mg, 56.2 μmol) cesium carbonate (549 mg, 1.69 mmol) in one portion under N ₂ .The mixture was then heated to 110 °C and stirred for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)-acetonitrile]; B%: 46%- 76%, 10 min) to give 8-[1-(3-chloro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2- morpholino-quinazolin-4-one (17.4 mg, 34.5 μmol, 6.1%) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (br. d, J = 5.9 Hz, 1H), 7.90 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.00 (t, J = 8.2 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 5.39 (t, J = 6.4 Hz, 1H), 3.90 (t, J = 4.4 Hz, 4H), 3.62 (s, 3H), 3.39 (s, 3H), 3.29 (br. d, J = 3.5 Hz, 4H), 2.40 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H); m/z ES+ [M+H] ⁺ 491.2. [1628] Step 3. Synthesis of 3,6-dimethyl-8-[1-(3-methyl-2-methylsulfonyl-anilino)ethyl]- 2- morpholino-quinazolin-4-one [1629] To a mixture To a mixture of 8-[1-(3-chloro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one (60 mg, 122 μmol) and methylboronic acid (73.2 mg, 1.22 mmol) in 1,4-dioxane (3 mL), water (0.5 mL) was added chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2 '-amino-1,1'-biphenyl-2-yl) palladium(II) (19.2 mg, 24.4 μmol), sodium carbonate (38.8 mg, 366 μmol) in one portion under nitrogen atmosphere. The mixture was then heated to 100 °C and stirred for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 46%-76%, 10 min) to give 3,6-dimethyl-8-[1-(3-methyl-2-methylsulfonyl-anilino)ethyl]- 2-morpholino-quinazolin-4-one (16.76 mg, 35.5 μmol, 29.%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.57 (br. d, J = 6.4 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.47 (br. t, J = 8.8 Hz, 2H), 5.40 - 5.28 (m, 1H), 3.83 - 3.73 (m, 4H), 3.50 (s, 3H), 3.29 - 3.24 (m, 4H), 2.53 - 2.51 (m, 3H), 2.34 (s, 3H), 1.55 (br. d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 471.4. Example 117. Preparation of 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1630] Step 1. Synthesis of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3-ethylquinazolin- 4(3H)-one [1631] To a solution of 8-bromo-2-chloro-3-ethyl-quinazolin-4-one (1 g, 3.48 mmol) in dichloromethane (10 mL) was added 3-azabicyclo[3.1.0]hexanehydrochloride (832 mg, 6.96 mmol) and diisopropylethylamine (1.8 g, 13.9 mmol). The mixture was stirred at 40 °C for 12 h. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in petroleum ether/ethyl acetate=10/1 (100 mL), then filter and the solid was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 10/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8- bromo-3-ethylquinazolin-4(3H)-one (1 g, 2.84 mmol, 82%) as a yellow oil; m/z ES+ [M+H] ⁺ 334.0. [1632] Step 2. Synthesis of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethylquinazolin - 4(3H)-one [1633] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3-ethyl-quinazolin -4-one (1 g, 2.99 mmol) and 1-vinyloxybutane (899 mg, 8.98 mmol) in n-butanol (10 mL) was added palladium acetate (67.2 mg, 299 μmol), diisopropylethylamine (1.16 g, 8.98 mmol) and [2-(2- diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (161 mg, 299 μmol). The mixture was stirred at 95 °C for 12 hr. Then hydrochloric acid (1 M, 15 mL) was added in the mixture and stirred at 25 °C for 30 min sodium bicarbonate (30 mL) was added to the mixture until pH = 8. Then the mixture was poured in water (30 mL) then extracted with ethyl acetate (50 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-acetyl-2-(3- azabicyclo[3.1.0]hexan-3-yl)-3-ethylquinazolin-4(3H)-one (750 mg, 2.51 mmol, 84%) as a white solid. m/z ES+ [M+H] ⁺ 298.2. [1634] Step 3. Synthesis of 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3- ethylquinazolin-4(3H)-one [1635] To a solution of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-quinazoli n-4-one (750 mg, 2.52 mmol) in methanol (8 mL) was added ammonium acetate (3.89 g, 50.5 mmol) and sodium cyanoborohydride (159 mg, 2.52 mmol). The mixture was stirred at 60 °C for 1 hr. The mixture was quenched by water (3 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1- aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethylquinazo lin-4(3H)-one (700 mg, 2.32 mmol, 92%) as a white solid. m/z ES+ [M+H] ⁺ 299.2. [1636] Step 4. Synthesis of methyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [1637] To a solution of 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl- quinazolin-4-one (0.4 g, 1.34 mmol), methyl 2-bromobenzoate (865 mg, 4.02 mmol) in toluene (5 mL) was added cesium carbonate (1.31 g, 4.02 mmol), tris(dibenzylideneacetone)dipalladium (123 mg, 134 μmol), dicyclohexyl-[2-[2,6-di(propan-2- yloxy)phenyl]phenyl]phosphane (62.6 mg, 134 μmol). The mixture was stirred at 110 °C for 12 hr under N2 atmosphere. The mixture was poured in water (5 mL) then extracted with ethyl acetate (10 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1) to give methyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-4-oxo-3,4-d ihydroquinazolin- 8-yl)ethyl)amino)benzoate (353 mg, 775 μmol, 58%) was obtained as a yellow solid. m/z ES+ [M+H] ⁺ 433.2. [1638] Step 5. Synthesis of 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1639] A mixture of methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-4-oxo- quinazolin-8-yl]ethylamino]benzoate (330 mg, 763 μmol), lithium hydroxide (91.4 mg, 3.81 mmol), in tetrahydrofuran (5 mL) and water (5 mL) methanol (5 mL), and then the mixture was stirred at 40 °C for 16 hr. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water formic acid- acetonitrile]; B%: 57%-87%, 10 min) to give 2-((1-(2-(3- azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-4-oxo-3,4-dihydroquinaz olin-8-yl)ethyl)amino)benzoic acid (0.1 g, 239 μmol, 31%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.74 - 12.58 (m, 1H), 8.51 - 8.28 (m, 1H), 7.85 (dd, J = 1.2, 8.0 Hz, 1H), 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.55 (dd, J = 1.2, 7.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 2H), 6.49 (t, J = 7.6 Hz, 1H), 6.41 (d, J = 8.3 Hz, 1H), 5.38 (d, J = 6.4 Hz, 1H), 4.09 - 3.86 (m, 3H), 3.78 (d, J = 10.4 Hz, 1H), 3.65 - 3.50 (m, 2H), 1.68 - 1.60 (m, 2H), 1.56 (d, J = 6.4 Hz, 3H), 1.32 (t, J = 6.8 Hz, 3H), 0.61 (dt, J = 4.8, 7.6 Hz, 1H), 0.41 (q, J = 4.0 Hz, 1H); m/z ES+ [M+H] ⁺ 419.4. Example 118. Preparation of 2-((1-(6-bromo-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1640] Step 1. Synthesis of 2-amino-5-bromo-3-iodobenzoic acid [1641] To a solution of 2-amino-5-bromo-benzoic acid (21 g, 97.1 mmol) in N,N- dimethylformamide (300 mL) was added 1-iodopyrrolidine-2,5-dione (39.4 g, 174 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction was concentrated under reduced pressure in vacuo to give 2-amino-5-bromo-3-iodobenzoic acid (30 g, crude) as a black solid. m/z ES+ [M+H] ⁺ 343.8. [1642] Step 2. Synthesis of 2-amino-5-bromo-3-iodo-N-methylbenzamide [1643] To a solution of 2-amino-5-bromo-3-iodo-benzoic acid (21 g, 61.4 mmol) and methanamine hydrochloride (8.29 g, 122 mmol) in N,N-dimethylformamide (200 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl-ammonium hexafluorophosphate (28 g, 73.7 mmol) and diisopropylethylamine (31.7 g, 245 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction was mixture concentrated under reduced pressure in vacuo to give 2-amino-5-bromo-3-iodo-N-methylbenzamide (20 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 354.8. [1644] Step 3. Synthesis of 6-bromo-2-chloro-8-iodo-3-methylquinazolin-4(3H)-one [1645] To a solution of 2-amino-5-bromo-3-iodo-N-methyl-benzamide (7 g, 19.7 mmol) in 1,4-dioxane (70 mL) was added thiocarbonyl dichloride (4.76 g, 41.4 mmol). The mixture was stirred at 25 °C for 12 hr. Then the mixture was stirred at 105 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-bromo-2-chloro-8-iodo-3- methylquinazolin-4(3H)-one (7 g, crude) as a black solid. m/z ES+ [M+H] ⁺ 401.0. [1646] Step 4. Synthesis of 6-bromo-8-iodo-3-methyl-2-morpholinoquinazolin-4(3H)-one [1647] To a solution of 6-bromo-2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (7 g, 17.5 mmol) in dichloromethane (70 mL) was added morpholine (4.58 g, 52.5 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 1/1) to give 6-bromo-8-iodo-3-methyl-2- morpholinoquinazolin-4(3H)-one (4 g, 8.89 mmol, 50%) as a black solid. m/z ES+ [M+H] ⁺ 449.9. [1648] Step 5. Synthesis of 8-acetyl-6-bromo-3-methyl-2-morpholinoquinazolin-4(3H)-one [1649] A mixture of 6-bromo-8-iodo-3-methyl-2-morpholinoquinazolin-4(3H)-one (2 g, 4.44 mmol), 1-vinyloxybutane (1.34 g, 13.3 mmol), diacetoxypalladium (99.7 mg, 444 μmol), [2- (2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (239 mg, 444 μmol) and diisopropylethylamine (1.72 g, 13.3 mmol) in n-butanol (20 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 85 °C for 12 hr under nitrogen atmosphere. Then hydrochloric acid (4 M, 11 mL) was added in the mixture and stirred at 25 °C for 30 mins. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 1/1) to give 8-acetyl-6-bromo-3-methyl-2-morpholinoquinazolin-4(3H)-one (1 g, 2.73 mmol, 61%) as a black solid. m/z ES+ [M+H] ⁺ 366.2. [1650] Step 6. Synthesis of 8-(1-aminoethyl)-6-bromo-3-methyl-2-morpholinoquinazolin- 4(3H)-one [1651] To a solution of 8-acetyl-6-bromo-3-methyl-2-morpholinoquinazolin-4(3H)-one (0.9 g, 2.46 mmol) in methanol (10 mL) was added sodium cyanoborohydride (154 mg, 2.46 mmol) and ammonium acetate (3.79 g, 49.1 mmol). The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (water/acetonitrile = 20:1 to 1:1) to give 8-(1-aminoethyl)-6-bromo-3-methyl-2-morpholinoquinazolin-4(3 H)-one (0.3 g, 816 μmol, 33%) as a white solid. m/z ES+ [M+H] ⁺ 350.2. [1652] Step 7. Synthesis of methyl 2-((1-(6-bromo-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1653] An oven-dried 15 mL vial equipped with magnetic stir bar was charged with 8-(1- aminoethyl)-6-bromo-3-methyl-2-morpholino-quinazolin-4-one (0.7 g, 1.91 mmol), methyl 2- oxocyclohexanecarboxylate (1.49 g, 9.53 mmol, 1.3 mL), bis[2-(2- pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridinehexafluorophosphate (34.8 mg, 38.12 μmol) , dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl]phosphane (26.5 mg, 76.2 μmol), acetic acid (22.9 mg, 381 μmol) 1,4- diazabicyclo[2.2.2]octane (320 mg, 2.86 mmol) in acetonitrile (7 mL). The reaction mixture was degassed by bubbling nitrogen stream, then irradiated with two 34 W blue LED lamps (at approximately 7 cm away) from the light source to keep the reaction temperature at 25 °C for 14 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (water/acetonitrile = 20:1 to 1:1) to give methyl 2-((1-(6-bromo-3-methyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8- yl)ethyl)amino)benzoate (0.3 g, 598 μmol, 31%) as a yellow solid. m/z ES+ [M+H] ⁺ 503.2. [1654] Step 8. Synthesis of 2-((1-(6-bromo-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1655] To a solution of methyl 2-[1-(6-bromo-3-methyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoate (50 mg, 99.7 μmol) in anhydrous tetrahydrofuran (0.4 mL) and methanol (0.2 mL) and water (0.2 mL) was added lithium hydroxide (11.9 mg, 498 μmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(fomic acid)-acetonitrile]; B%: 45%-75%, 10 min) to give 2-((1-(6-bromo-3-methyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8- yl)ethyl)amino)benzoic acid (10 mg, 20.3 μmol, 20%) as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 2.4 Hz, 1H), 8.21 - 8.11 (m, 1H), 8.01 – 8.00 (m, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.23 – 7.20 (m, 1H), 6.62 – 6.50 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.50 - 5.41 (m, 1H), 3.96 - 3.88 (m, 4H), 3.64 (s, 3H), 3.34 – 3.25 (m, 4H), 1.66 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 489.3. Example 119 and Example 120. Preparation of (R)-2-((1-(6-bromo-3-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid & (S)-2-((1-(6- bromo-3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl )ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1656] The racemic mixture, 2-((1-(6-bromo-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (25.0 mg, 51.1 μmol) was separated by SFC (column: Daicel CHIRALPAK AD (250 x 30 mm, 10 um); mobile phase:[0.1%NH3-H2O, ethanol]; B%: 35%-35%, 3.7 min) to give (R)-2-((1-(6-bromo-3-methyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (11.75 mg, 24.11 μmol, 47%) as a white solid. ¹ HNMR (400 MHz, CDCl3) δ 8.25 (d, J = 2.4 Hz, 1H), 8.19 (br. s, 1H), 8.01 – 8.00 (m, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.23 – 7.20 (m, 1H), 6.62 – 6.50 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.50 - 5.41 (m, 1H), 3.96 - 3.88 (m, 4H), 3.64 (s, 3H), 3.34 – 3.25 (m, 4H), 1.66 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H]+ 489.1; and (S)-2-((1-(6-bromo-3-methyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (11.44 mg, 23.47 μmol, 46%) as a white solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 2.4 Hz, 1H), 8.19 (br. s, 1H), 8.01 – 8.00 (m, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.23 – 7.20 (m, 1H), 6.62 – 6.50 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.50 - 5.41 (m, 1H), 3.96 - 3.88 (m, 4H), 3.64 (s, 3H), 3.34 – 3.25 (m, 4H), 1.66 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H]+ 489.1. Example 121. Preparation of 3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2- morpholinoquinazolin-4(3H)-one [1657] Step 1. Synthesis of 8-bromo-3-methyl-2-morpholino-quinazolin-4-one [1658] To a solution of 8-bromo-2-chloro-3-methyl-quinazolin-4-one (3 g, 10.9 mmol) in dichloromethane (30 mL) was added morpholine (3.82 g, 43.8 mmol), the mixture was stirred at 25 °C for 12 hr. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8- bromo-3-methyl-2-morpholino-quinazolin-4-one (1.8 g, 5.55 mmol) as a white solid. m/z ES+ [M+H] ⁺ 326.0. [1659] Step 2. Synthesis of 8-acetyl-3-methyl-2-morpholino-quinazolin-4-one [1660] To a solution of 8-bromo-3-methyl-2-morpholino-quinazolin-4-one (1.6 g, 4.94 mmol) in n-butanol (2 mL) was added 1-vinyloxybutane (1.48 g, 14.8 mmol), palladium acetate (110 mg, 0.50 mmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (265 mg, 0.50 mmol), diisopropylethylamine (3.19 g, 24.7 mmol) at 95 °C for 12 hr under nitrogen atmosphere. Then hydrochloric acid (1 M, 24.6 mL) was added and the mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by addition saturated sodium bicarbonate 100 mL at 25 °C and adjusted to pH = 7, and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (150 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silicagel column (petroleum ether/ethyl acetate = 20:1 to 1:1) to give 8-acetyl-3-methyl-2- morpholino-quinazolin-4-one (0.8 g, 2.65 mmol) as a white solid. m/z ES+ [M+H] ⁺ 228.4. [1661] Step 3. Synthesis of 8-(1-aminoethyl)-3-methyl-2-morpholino-quinazolin-4-one [1662] To a solution of 8-acetyl-3-methyl-2-morpholino-quinazolin-4-one (0.8 g, 2.78 mmol) in methanol (15 mL) was added ammonium acetate (2.15 g, 27.8 mmol), sodium cyanoborohydride (175 mg, 2.78 mmol), the mixture was stirred at 80 °C for 2 hr. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-3-methyl-2- morpholino-quinazolin-4-one (0.6 g, 2.08 mmol) as a white solid. m/z ES+ [M+H] ⁺ 288.1. [1663] Step 4. Synthesis of 8-(1-aminoethyl)-3-methyl-2-morpholino-quinazolin-4-one [1664] To a solution of 8-(1-aminoethyl)-3-methyl-2-morpholino-quinazolin-4-one (250 mg, 0.81 mmol) in N,N-dimethylformamide (0.4 mL) was added 1-fluoro-2-methylsulfonyl- benzene (227 mg, 1.30 mmol) and cesium carbonate (848 mg, 2.60 mmol), the mixture was stirred at 120 °C for 12 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase : [water (formic acid) - acetonitrile]; B%: 40%-70%, 2 min) to give 3-methyl-8-[1-(2-methylsulfonylanilino)ethyl]-2-morpholino- quinazolin-4-one (94.9 mg, 0.2 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.98 - 7.93 (m, 1H), 7.78 -7.72 (m, 1H), 7.64 - 7.60 (m, 1H), 7.36 - 7.26 (m, 2H), 6.80 (d, J = 6.8 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.44 - 5.41 (m, 1H), 3.80 (t, J = 4.4 Hz, 4H), 3.52 (s, 3H), 3.31 - 3.25 (m, 4H), 3.19 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 443.4. Example 122 and Example 123. Preparation of 3-methyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one & 3-methyl-8-[(1S)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (stereochemistry arbitrarily assigned for both enantiomers) [1665] A mixture of 3-methyl-8-[1-(2-methylsulfonylanilino)ethyl]-2-morpholino- quinazolin-4-one (90 mg, 0.21 mmol) was separated by SFC. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by SFC (column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 40%-40% , 4.2 min) to give 3-methyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (34.8 mg, 0.08 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J = 1.6, 7.6 Hz, 1H), 7.73 (dd, J = 1.2, 7.2 Hz, 1H), 7.61 (dd, J = 1.6, 8.0 Hz, 1H), 7.37 - 7.25 (m, 2H), 6.80 (d, J = 7.2 Hz, 1H), 6.74 - 6.69 (m, 1H), 6.65 (d, J = 8.8 Hz, 1H), 5.42 (t, J = 6.8 Hz, 1H), 3.80 (t, J = 4.4 Hz, 4H), 3.52 (s, 3H), 3.32 (s, 1H), 3.31 - 3.24 (m, 3H), 3.19 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 443.4; and 3-methyl-8-[(1S)-1-(2-methylsulfonylanilino)ethyl]-2-morphol ino- quinazolin-4-one (36.0 mg, 0.08 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J = 1.6, 7.6 Hz, 1H), 7.73 (dd, J = 1.2, 7.2 Hz, 1H), 7.61 (dd, J = 1.6, 8.0 Hz, 1H), 7.38 - 7.26 (m, 2H), 6.80 (d, J = 7.2 Hz, 1H), 6.74 - 6.69 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.42 (t, J = 6.8 Hz, 1H), 3.80 (t, J = 4.5 Hz, 4H), 3.52 (s, 3H), 3.32 (s, 1H), 3.31 - 3.25 (m, 3H), 3.19 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 443.4. Example 124. Preparation of 2-[1-[2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6-methyl-4- oxo-quinazolin-8-yl]ethylamino]benzoic acid [1666] Step 1. Synthesis of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3-ethyl-6-methyl- quinazolin-4-one [1667] To a solution of 8-bromo-2-chloro-3-ethyl-6-methyl-quinazolin-4-one (1.8 g, 5.97 mmol) in dichloromethane (30 mL) was added diisopropylethylamine (3.09 g, 23.8 mmol), 3- azabicyclo[3.1.0]hexane (2.14 g, 17.9 mmol). The mixture was stirred at 40 °C for 12 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 2-(3- azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3-ethyl-6-methyl-quinaz olin-4-one (1.4 g, 2.69 mmol, 67%) as a white solid. m/z ES+ [M+H] ⁺ 348.0. [1668] Step 2. Synthesis of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6-methyl- quinazolin-4-one [1669] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3-ethyl-6-methyl- quinazolin-4-one (1.3 g, 3.73 mmol) and 1-vinyloxybutane (1.12 g, 11.2 mmol) in n-butanol (30 mL) was added palladium(II)diacetate (83.8 mg, 373 μmol), diisopropylethylamine (1.45 g, 11.2 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (201 mg, 373 μmol). The mixture was stirred at 95 °C for 11.5 hr under nitrogen atmosphere. Then hydrochloride (1 M, 37.3 mL) was added at 25 °C and stirred for 0.5 hr. The reaction mixture was quenched by addition saturated aqueous solution of sodium bicarbonate (10 mL) at 0 °C, and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 0/1) to give 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6-methyl- quinazolin-4-one (1 g, 3.21 mmol, 86%) as a white solid. m/z ES+ [M+H] ⁺ 312.2. [1670] Step 3. Synthesis of 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6 - methyl-quinazolin-4-one [1671] To a solution of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6-methyl- quinazolin-4-one (900 mg, 2.89 mmol) in methanol (50 mL) was added ammonium acetate (4.46 g, 57.8 mmol) and sodium cyanoborohydride (363 mg, 5.78 mmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% TFA condition) to give 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6 -methyl- quinazolin-4-one (500 mg, 1.60 mmol, 55%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (d, J = 1.6, 4.6 Hz, 2H), 7.81 (s, 1H), 7.61 (d, J = 1.6 Hz, 1H), 5.00 (d, J = 2.8 Hz, 1H), 4.07 - 3.97 (m, 2H), 3.80-3.73 (m, 2H), 3.55 ( t, J = 8.4 Hz, 2H), 2.40 (s, 3H), 1.69 - 1.62 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H), 0.64-0.59 (m, 1H), 0.40-0.37 (m, 1H). [1672] Step 4. Synthesis of methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6- methyl-4-oxo-quinazolin-8-yl]ethylamino]benzoate [1673] To a solution of 8-(1-aminoethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6 - methyl-quinazolin-4-one (200 mg, 640 μmol), methyl 2-bromobenzoate (688 mg, 3.20 mmol) in toluene (10 mL) was added cesium carbonate (625 mg, 1.92 mmol) and tris(dibenzylideneacetone)dipalladium (58.6 mg, 64.0 μmol), dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl]phosphane (59.7 mg, 128 μmol). The mixture was stirred at 110 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layerswere washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue.The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/0 to 0/1) to give methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6-methyl-4-o xo- quinazolin-8-yl]ethylamino]benzoate (200 mg, 404 μmol, 90%) as a white solid. m/z ES+ [M+23] ⁺ 469.2. [1674] Step 5. Synthesis of 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6-methyl-4-o xo- quinazolin-8-yl]ethylamino]benzoic acid [1675] To a solution of methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6-methyl-4- oxo-quinazolin-8-yl]ethylamino]benzoate (180 mg, 403 μmol) in a mixture of tetrahydrofuran (5 mL), methanol (2.5 mL) and water (2.5 mL) was added lithium hydroxide (48.2 mg, 2.02 mmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine 15 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water(FA)-acetonitrile]; B%: 58%-88%, 7 min) to give 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-ethyl-6-methyl-4-o xo- 1 quinazolin-8-yl]ethylamino]benzoic acid (97 mg, 224 μmol, 100%) as a white solid. H NMR (400 MHz, DMSO-d6) δ 12.65 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H), 7.78-7.76 (m, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.22 - 7.13 (m, 1H), 6.53 - 6.41 (m, 2H), 5.45 - 5.26 (m, 1H), 4.08 - 3.95 (m, 2H), 3.89 (d, J = 10.4 Hz, 1H), 3.73 (d, J = 10.0 Hz, 1H), 3.62 - 3.49 (m, 2H), 2.29 (s, 3H), 1.66 - 1.58 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H), 1.30 (t, J = 6.8 Hz, 3H), 0.61-0.56 (m, 1H), 0.44-0.41 (m, 1H); m/z ES+ [M+H] ⁺ 433.1. Example 125. Preparation of 8-(1-((2-(2-hydroxyacetyl)phenyl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one

[1676] Step 1. Synthesis of 1-(2-bromophenyl)ethane-1,2-diol [1677] To a solution of 1-bromo-2-vinyl-benzene (2 g, 10.9 mmol) in tert-butyl alcohol (2 mL), water (4 mL) and acetone (10 mL) was added 4-methyl-4-oxido-morpholin-4-ium (1.92 g, 16.4 mmol, 1.7 mL). The mixture was added tetraoxoosmium (278 mg, 1.09 mmol) and stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched by addition aqueous solution of sodium sulfite (40 mL) at 25 °C, and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(2-bromophenyl)ethane-1,2-diol (2.1 g, crude) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.58 - 7.51 (m, 2H), 7.41 - 7.35 (m, 1H), 7.18 (dt, J = 1.6, 7.6 Hz, 1H), 5.47 (d, J = 4.4 Hz, 1H), 4.89 - 4.82 (m, 2H), 3.51 (ddd, J = 3.6, 6.4, 11.2 Hz, 1H), 3.30 (ddd, J = 5.6, 7.6, 11.2 Hz, 1H). [1678] Step 2. Synthesis of 4-(2-bromophenyl)-2,2-dimethyl-1,3-dioxolane [1679] To a solution of 1-(2-bromophenyl)ethane-1,2-diol (1 g, 4.61 mmol) in N,N- dimethylformamide (10 mL) was added p-toluenesulfonic acid (159 mg, 921 μmol) and 2,2- dimethoxypropane (816 mg, 7.83 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 10/1) to give 4-(2-bromophenyl)-2,2-dimethyl-1,3- dioxolane (1.3 g, 3.54 mmol, 77%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ 7.58 (ddd, J = 1.2, 7.6, 17.2 Hz, 2H), 7.46 - 7.40 (m, 1H), 7.26 (dt, J = 2.0, 7.6 Hz, 1H), 5.26 (t, J = 6.8 Hz, 1H), 4.48 (dd, J = 6.8, 8.2 Hz, 1H), 3.57 (dd, J = 6.8, 8.2 Hz, 1H), 1.50 (s, 3H), 1.42 (s, 3H). [1680] Step 3. Synthesis of 8-(1-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)phenyl)amino)ethyl) - 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [1681] A mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (380 mg, 1.26 mmol), 4-(2-bromophenyl)-2,2-dimethyl-1,3-dioxolane (969 mg, 3.77 mmol), cesium carbonate (1.23 g, 3.78 mmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (58.6 mg, 126 μmol) and tris(dibenzylideneacetone)dipalladium (115 mg, 126 μmol) in toluene (8 mL) was degassed and purged with nitrogen atmosphere 3 times, and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 3/1) to give 8-(1-((2-(2,2-dimethyl-1,3-dioxolan-4- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (650 mg, 951 μmol, 76%) as a yellow solid. m/z ES+ [M+H] ⁺ 479.2. [1682] Step 4. Synthesis of 8-(1-((2-(1,2-dihydroxyethyl)phenyl)amino)ethyl)-3,6-dimethy l- 2-morpholinoquinazolin-4(3H)-one [1683] To a solution of 8-(1-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)phenyl)amino)ethyl) -3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one (640 mg, 1.34 mmol) in hydrochloric acid/1,4- dioxane (4 M, 6 mL). The mixture was stirred at 20 °C for 1 hr. Then the reaction was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition, 65-70% acetonitrile, 6 min) to give 8-(1-((2-(1,2- dihydroxyethyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholino quinazolin-4(3H)-one (380 mg, 779 μmol, 58%) as a yellow solid. m/z ES+ [M+H] ⁺ 439.2. [1684] Step 5. Synthesis of 8-(1-((2-(2-((tert-butyldimethylsilyl)oxy)-1- hydroxyethyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoqu inazolin-4(3H)-one [1685] To a solution of 8-(1-((2-(1,2-dihydroxyethyl)phenyl)amino)ethyl)-3,6-dimethy l-2- morpholinoquinazolin-4(3H)-one (150 mg, 342 μmol) in dichloromethane (1 mL) was added tert-butylchlorodimethylsilane (61.9 mg, 410 μmol) and imidazole (46.6 mg, 684 μmol). The mixture was stirred at 40 °C for 2 hr. Then the reaction was added tert- butylchlorodimethylsilane (31.0 mg, 205 μmol) and stirred at 40 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 3:1) to give 8-(1- ((2-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)phenyl) amino)ethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (90 mg, 147 μmol, 43%) as a white solid. m/z ES+ [M+H] ⁺ 553.4. [1686] Step 6. Synthesis of 8-(1-((2-(2-((tert- butyldimethylsilyl)oxy)acetyl)phenyl)amino)ethyl)-3,6-dimeth yl-2-morpholinoquinazolin- 4(3H)-one [1687] To a solution of 8-(1-((2-(2-((tert-butyldimethylsilyl)oxy)-1- hydroxyethyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoqu inazolin-4(3H)-one (70 mg, 127 μmol) in dichloromethane (0.5 mL) was added (1,1-diacetoxy-3-oxo-1^5,2-benziodoxol- 1-yl) acetate (107 mg, 253 μmol). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition aqueous solution of sodium sulfite (10 mL) at 25 °C, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with aqueous sodium bicarbonate (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1:1) to give 8-(1-((2-(2-((tert- butyldimethylsilyl)oxy)acetyl)phenyl)amino)ethyl)-3,6-dimeth yl-2-morpholinoquinazolin- 4(3H)-one (30 mg, 49.0 μmol, 39%) as a yellow solid. m/z ES+ [M+H] ⁺ 551.2. [1688] Step 7. Synthesis of 8-(1-((2-(2-hydroxyacetyl)phenyl)amino)ethyl)-3,6-dimethyl-2 - morpholinoquinazolin-4(3H)-one [1689] To a solution of 8-(1-((2-(2-((tert-butyldimethylsilyl)oxy)acetyl)phenyl)amin o)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (25 mg, 45.4 μmol) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition aqueous sodium hydrogen carbonate 10 mL at 25 °C, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 42%-72%, 10 min) to give 8-(1-((2-(2- hydroxyacetyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoq uinazolin-4(3H)-one (16.5 mg, 37.8 μmol, 83%) as a blue solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (d, J = 6.8 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.47 (d, J = 1.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 6.53 (t, J = 7.6 Hz, 1H), 5.46 (q, J = 6.8 Hz, 1H), 4.87 - 4.71 (m, 3H), 3.79 (t, J = 4.0 Hz, 4H), 3.50 (s, 3H), 3.28 - 3.24 (m, 4H), 2.32 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 437.4. Example 126. Preparation of 6-chloro-3-methyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one [1690] Step 1. Synthesis of 8-bromo-2,6-dichloro-3-methylquinazolin-4(3H)-one [1691] To a solution of 2-amino-3-bromo-5-chloro-N-methyl-benzamide (1.4 g, 5.31 mmol) in 1,4-dioxane (2 mL) was added thiocarbonyl dichloride (1.28 g, 11.2 mmol). The mixture was stirred at 25 °C for 0.5 hr. Then the mixture was stirred at 105 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 8-bromo-2,6-dichloro-3- methylquinazolin-4(3H)-one (1.4 g, 4.55 mmol, 86%) as a yellow solid, which was used into the next step directly. m/z ES+ [M+H] ⁺ 308.9. [1692] Step 2. Synthesis of 8-bromo-6-chloro-3-methyl-2-morpholinoquinazolin-4(3H)-one [1693] To a solution of 8-bromo-2,6-dichloro-3-methyl-quinazolin-4-one (1.35 g, 4.38 mmol) in dichloromethane (13.5 mL) was added morpholine (1.15 g, 13.2 mmol). The mixture was stirred at 40 °C for 12 hr. The reaction mixture was diluted with aqueous hydrochloric acid (1 M, 30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine 20 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to compound 8-bromo-6-chloro-3-methyl-2-morpholino-quinazolin-4-one (1 g, 2.79 mmol, 64%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 3.79 - 3.76 (m, 4H), 3.47 (s, 3H), 3.32 - 3.30 (m, 4H); m/z ES+ [M+H] ⁺ 359.9. [1694] Step 3. Synthesis of 8-acetyl-6-chloro-3-methyl-2-morpholinoquinazolin-4(3H)-one [1695] To a solution of 8-bromo-6-chloro-3-methyl-2-morpholino-quinazolin-4-one (950 mg, 2.65 mmol) and 1-vinyloxybutane (796 mg, 7.95 mmol) in n-butanol (10 mL) was added palladium acetate (59.47 mg, 265 μmol), diisopropylethylamine (1.03 g, 7.95 mmol) and [2- (2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (143 mg, 265 μmol). The mixture was stirred at 95 °C for 12 hr under under nitrogen atmosphere. Then hydrochloric acid (1 M, 26.5 mL) was added and the mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 0/1) to give 8-acetyl-6-chloro-3-methyl-2-morpholinoquinazolin-4(3H)-one (420 mg, 1.31 mmol, 49%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 3.79 - 3.76 (m, 4H), 3.49 (s, 3H), 3.29 - 3.26 (m, 4H), 2.77 (s, 3H); m/z ES+ [M+H] ⁺ 322.1. [1696] Step 4. Synthesis of 8-(1-aminoethyl)-6-chloro-3-methyl-2-morpholinoquinazolin- 4(3H)-one [1697] To a solution of 8-acetyl-6-chloro-3-methyl-2-morpholino-quinazolin-4-one (400 mg, 1.24 mmol) in methanol (15 mL) and dichloromethane (15 mL) was added ammonium acetate (1.92 g, 24.9 mmol) and sodium cyanoborohydride (15.6 mg, 249 μmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-(1-aminoethyl)-6-chloro-3-methyl-2-morpholino-quinazolin-4 -one (260 mg, 805 μmol, 65%) as a white solid. m/z ES+ [M+H] ⁺ 323.1. [1698] Step 5. Synthesis of 6-chloro-3-methyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one [1699] To a solution of 8-(1-aminoethyl)-6-chloro-3-methyl-2-morpholino-quinazolin-4 -one (250 mg, 774 μmol) and 1-fluoro-2-methylsulfonyl-benzene (202 mg, 1.16 mmol) in dimethyl acetamide (1 mL) was added cesium carbonate (505 mg, 1.55 mmol). The mixture was stirred at 120 °C for 2 hr. The reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine 30 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water(FA)-acetonitrile]; B%: 48%-78%, 7 min) to give 6-chloro-3-methyl-8- [1-(2-methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4 -one (103 mg, 216 μmol, 28%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 2.4 Hz, 1H), 7.84 - 7.73 (m, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.28 - 7.24 (m, 1H), 6.82 - 6.71 (m, 2H), 6.49 (d, J = 8.4 Hz, 1H), 5.45 - 5.34 (m, 1H), 3.94 - 3.89 (m, 4H), 3.64 (s, 3H), 3.36 - 3.32 (m, 4H), 3.14 (s, 3H), 1.66 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 477.4. Example 127 and Example 128. Preparation of (R)-6-chloro-3-methyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one & (S)-6-chloro- 3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-morp holinoquinazolin-4(3H)- one (stereochemistry arbitrarily assigned for both enantiomers) [1700] The crude product (~100 mg) was separated by SFC (column: Daicel CHIRALPAK AD (250 x 30 mm, 10 um); mobile phase: [0.1%NH3-water, ethanol]; B%: 35%-35%, 3.5 min) to give (R)-6-chloro-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino) ethyl)-2- morpholinoquinazolin-4(3H)-one (40.4 mg, 84.7 μmol, 40%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 2.4 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.26 - 7.22 (m, 1H), 6.81 - 6.72 (m, 2H), 6.47 (d, J = 8.4 Hz, 1H), 5.44 - 5.33 (m, 1H), 3.92 - 3.88 (m, 4H), 3.62 (s, 3H), 3.34 - 3.30 (m, 4H), 3.13 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 477.4; and (S)-6-chloro-3-methyl-8-(1-((2-(methylsulfonyl)phenyl)amino) ethyl)-2- morpholinoquinazolin-4(3H)-one (46.6 mg, 97.7 μmol, 47%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.08 (d, J = 2.4 Hz, 1H), 7.80 - 7.76 (m, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.26 - 7.22 (m, 1H), 6.79 - 6.73 (m, 2H), 6.47 (d, J = 8.4 Hz, 1H), 5.38 (t, J = 6.4 Hz, 1H), 3.92 - 3.88 (m, 4H), 3.62 (s, 3H), 3.34 - 3.31 (m, 4H), 3.13 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 477.4. Example 129. Preparation of 2-((1-(2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[1701] Step 1. Synthesis of 8-bromo-2-(3,3-dimethylpyrrolidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one [1702] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (550 mg, 1.53 mmol) and 3,3-dimethylpyrrolidine (220 mg, 1.62 mmol) in dichloromethane (3 mL) was added diisopropylethylamine (395 mg, 3.06 mmol). The mixture was stirred at 40 °C for 4 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate =1/0 to 5/1) to give 8-bromo-2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl- quinazolin-4-one (450 mg, 1.21 mmol, 79%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 3.71 (t, J = 7.2 Hz, 2H), 3.53 (s, 3H), 3.34 (s, 2H), 2.39 (s, 3H), 1.79 (t, J = 7.2 Hz, 2H), 1.17 (s, 6H); m/z ES+ [M+H] ⁺ 352.0. [1703] Step 2. Synthesis of 8-acetyl-2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethylquinazo lin- 4(3H)-one [1704] A mixture of 8-bromo-2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-quinazo lin-4-one (400 mg, 1.14 mmol), 1-vinyloxybutane (343 mg, 3.43 mmol), palladium acetate (25.6 mg, 114 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (61.5 mg, 114 μmol) and diisopropylethylamine (442 mg, 3.43 mmol) in n-butanol (4 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 90 °C for 1 hr under nitrogen atmosphere. Then the reaction was cooled to 25 °C. Hydrochloric acid (1 M, 1.08 mL) was added and the mixture was stirred at 25 °C for 10 min. On completion, the reaction mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 10/1 to 2/1) to give 8-acetyl-2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-quinaz olin-4-one (410 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 3.69 (t, J = 7.2 Hz, 2H), 3.55 (s, 3H), 3.29 (s, 2H), 2.86 (s, 3H), 2.42 (s, 3H), 1.79 (t, J = 7.2 Hz, 2H), 1.16 (s, 6H); m/z ES+ [M+H] ⁺ 314.3. [1705] Step 3. Synthesis of 8-(1-aminoethyl)-2-(3,3-dimethylpyrrolidin-1-yl)-3,6- dimethylquinazolin-4(3H)-one [1706] To a solution of 8-acetyl-2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-quinaz olin-4- one (390 mg, 1.24 mmol) in methanol (4 mL) was added sodium cyanoborohydride (117 mg, 1.87 mmol) and ammonium acetate (1.92 g, 24.8 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition, 10%- 20% acetonitrile/water, 10 min) to give 8-(1-aminoethyl)-2-(3,3-dimethylpyrrolidin-1-yl)-3,6- dimethyl-quinazolin-4-one (230 mg, 729 μmol, 58%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.92 (s, 1H), 7.23 (br. s, 2H), 4.69 (q, J = 6.8 Hz, 1H), 3.73 - 3.58 (m, 2H), 3.54 (s, 3H), 3.31 - 3.21 (m, 2H), 2.40 (s, 3H), 1.89 - 1.68 (m, 5H), 1.16 (s, 6H); m/z ES+ [M+H] ⁺ 315.2. [1707] Step 4. Synthesis of 2-((1-(2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1708] A mixture of 8-(1-aminoethyl)-2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethy l- quinazolin-4-one (100 mg, 318 μmol), 2-iodobenzoic acid (394 mg, 1.59 mmol), triethylamine (96.5 mg, 954 μmol) and copper powder (20.2 mg, 318 μmol) in dimethyl acetamide (2 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 100 °C for 2 hr under nitrogen atmosphere. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 56%-86%, 10 min) to give 2-[1-[2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-4-oxo-qui nazolin-8- yl]ethylamino]benzoic acid (25.0 mg, 53.6 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.08 – 7.92 (m, 1H), 7.85 (s, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.56 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.56 - 5.32 (m, 1H), 3.86 - 3.74 (m, 1H), 3.74 – 3.62 (m, 1H), 3.58 (s, 3H), 3.39 - 3.30 (m, 1H), 3.30 - 3.24 (m, 1H), 2.35 (s, 3H), 1.80 (t, J = 7.2 Hz, 2H), 1.63 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 4.4 Hz, 6H); m/z ES+ [M+H] ⁺ 435.0. Example 130 and Example 131. Preparation of (R)-2-((1-(2-(3,3-dimethylpyrrolidin-1-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoic acid & (S)-2-((1-(2- (3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1709] The racemate (R)-2-((1-(2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (21.6 mg, 49.8 μmol) was separated by SFC (column: Daicel CHIRALPAK AD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 20%-28%; 8 min) to give 2-[[(1R)-1-[2-(3,3-dimethylpyrrolidin-1- yl)-3,6-dimethyl-4-oxo-quinazolin-8-yl]ethyl]amino]benzoic acid (11.2 mg, 24.8 μmol, 49%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 – 7.92 (m, 1H), 7.85 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.56 – 5.33 (m, 1H), 3.78 (td, J = 7.4, 10.3 Hz, 1H), 3.88 – 3.72 (m, 1H), 3.57 (s, 3H), 3.40 - 3.19 (m, 2H), 2.35 (s, 3H), 1.80 (t, J = 7.2 Hz, 2H), 1.63 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 4.8 Hz, 6H) ; m/z ES+ [M+H] ⁺ 435.1; S)-2-((1-(2-(3,3-dimethylpyrrolidin-1-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (9.01 mg, 19.9 μmol, 39%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 – 7.92 (m, 1H), 7.85 (d, J = 0.8 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.24 - 7.13 (m, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 5.56 – 5.37 (m, 1H), 3.89 - 3.59 (m, 2H), 3.57 (s, 3H), 3.41 - 3.18 (m, 2H), 2.35 (s, 3H), 1.80 (t, J = 7.2 Hz, 2H), 1.63 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 4.8 Hz, 6H); m/z ES+ [M+H] ⁺ 435.3. Example 132. Preparation of 8-(1-((2-(isopropylsulfonyl)phenyl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one [1710] Step 1. Synthesis of (2-fluorophenyl)(isopropyl)sulfane [1711] To a solution of 2-fluorobenzenethiol (500 mg, 3.90 mmol) and 2-iodopropane (795 mg, 4.68 mmol) in acetonitrile (5 mL) was added potassium carbonate (1.08 g, 7.80 mmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (100 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1-fluoro-2- isopropylsulfanyl-benzene (550 mg, 3.23 mmol, 82%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 - 7.37 (m, 1H), 7.30 - 7.21 (m, 1H), 7.15 - 7.02 (m, 2H), 3.51 – 3.36 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H); m/z ES+ [M+H] ⁺ 171.2. [1712] Step 2. Synthesis of 1-fluoro-2-(isopropylsulfonyl)benzene [1713] To a solution of 1-fluoro-2-isopropylsulfanyl-benzene (450 mg, 2.64 mmol) in anhydrous tetrahydrofuran (5 mL) and water (5 mL) was added potassium peroxomono sulfate (4.06 g, 6.61 mmol) at 0 °C. The reaction was stirred at 25 °C for 3 h. On completion, the reaction mixture was quenched with aqueous sodium sulfite solution (40 mL) and extracted with ethyl acetate (40 x 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-fluoro-2-isopropylsulfonyl- benzene (500 mg, 2.47 mmol, 93%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 - 7.89 (m, 1H), 7.72 - 7.59 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.26 - 7.21 (m, 1H), 3.55 - 3.35 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H); m/z ES+ [M+H] ⁺ 203.2. [1714] Step 3. Synthesis of 8-(1-((2-(isopropylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl -2- morpholinoquinazolin-4(3H)-one [1715] To a solution of 1-fluoro-2-isopropylsulfonyl-benzene (104 mg, 516 μmol) and 8-(1- aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (120 mg, 344 μmol, formic acid) in N,N-dimethylformamide (2 mL) was added cesium carbonate (224 mg, 688 μmol). The mixture was stirred at 120 °C for 12 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water(formic acid)- acetonitrile]; B%: 52%-82%, 10 min) to give 8-[1-(2-isopropylsulfonylanilino)ethyl]- 3,6-dimethyl-2-morpholino-quinazolin-4-one (50.0 mg, 103 μmol, 29%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.70 – 7.58 (m, 1H), 7.46 (s, 1H), 7.24 - 7.17 (m, 1H), 7.03 – 6.90 ( m, J = 6.4 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.48 – 5.34 (m, 1H), 3.96 - 3.83 (m, 4H), 3.62 (s, 3H), 3.42 – 3.33 (m, 1H), 3.32 - 3.26 (m, 4H), 2.37 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.44 – 1.27 (m, 6H); m/z ES+ [M+H] ⁺ 485.2. Example 133 and Example 134. Preparation of (R)-8-(1-((2- (isopropylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpho linoquinazolin-4(3H)- one & (S)-8-(1-((2-(isopropylsulfonyl)phenyl)amino)ethyl)-3,6-dime thyl-2- morpholinoquinazolin-4(3H)-one (stereochemistry arbitrarily assigned for both enantiomers) [1716] The racemate 8-[1-(2-isopropylsulfonylanilino)ethyl]-3,6-dimethyl-2-morph olino- quinazolin-4-one (47.0 mg, 97.0 μmol) was purified by SFC (column: column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 40%-40%, 8 min) to give (R)-8-(1-((2- (isopropylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpho linoquinazolin-4(3H)-one (21.0 mg, 43.4 μmol, 44%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.70 – 7.60 (m, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.25 - 7.16 (m, 1H), 7.03 – 6.93 (m, 1H), 6.66 (t, J = 7.6 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.42 (t, J = 6.8 Hz, 1H), 3.96 - 3.85 (m, 4H), 3.62 (s, 3H), 3.42 – 3.33 (m, 1H), 3.32 - 3.27 (m, 4H), 2.37 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.42 – 1.31 (m, 6H); m/z ES+ [M+H] ⁺ 485.3; and (S)-8-(1-((2- (isopropylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpho linoquinazolin-4(3H)-one (25.0 mg, 51.0 μmol, 52%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J = 0.8 Hz, 1H), 7.70 – 7.60 (m, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.24 - 7.16 (m, 1H), 7.02 - 6.92 (m, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.42 (t, J = 6.8 Hz, 1H), 3.94 - 3.84 (m, 4H), 3.62 (s, 3H), 3.43 – 3.33 (m, 1H), 3.32 - 3.27 (m, 4H), 2.37 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H), 1.43 – 1.31 (m, 6H); m/z ES+ [M+H] ⁺ 485.3. Example 135. Preparation of isopropyl 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1717] Step 1. Synthesis of isopropyl 2-bromobenzoate [1718] To a mixture of 2-bromobenzoic acid (2 g, 9.95 mmol) and 2-iodopropane (2.03 g, 11.9 mmol) in acetonitrile (30 mL) was added potassium carbonate (2.75 g, 19.9 mmol), then the mixture was stirred at 60 °C for 12 hr. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give isopropyl 2- bromobenzoate (0.8 g, 3.29 mmol, 33%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 - 7.68 (m, 1H), 7.63 (m, J = 0.8, 7.6 Hz, 1H), 7.38 - 7.24 (m, 2H), 5.35 - 5.20 (m, 1H), 1.41 - 1.35 (m, 6H). [1719] Step 2. Synthesis of isopropyl 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1720] To a mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (150 mg, 430 μmol, FA) in toluene (2 mL) was added isopropyl 2-iodobenzoate (624 mg, 2.15 mmol), cesium carbonate (420 mg, 1.29 mmol), methanesulfonato(2-dicyclohexylphosphino- 2,6-di-i-propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl) (20.1 mg, 43.0 μmol) and tris(dibenzylideneacetone)dipalladium (39.4 mg, 43.0 μmol) under nitrogen, the mixture was stirred at 110 °C for 2 hr under nitrogen. On completion, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate= 1/0 to 5:1) to give a residue. The residue was further purified by prep-TLC (petroleum ether/ethyl acetate = 2:3) to give isopropyl 2-[1-(3,6-dimethyl-2-morpholino-4- oxo-quinazolin-8-yl)ethylamino]benzoate (28.2 mg, 58.4 μmol, 13%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.92 (dd, J = 1.2, 8.0 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.16 - 7.11 (m, 1H), 6.52 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.52 - 5.41 (m, 1H), 5.32 – 5.20 (m, 1H), 3.94 - 3.85 (m, 4H), 3.62 (s, 3H), 3.33 - 3.26 (m, 4H), 2.37 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.4 Hz, 6H); m/z ES+ [M+H] ⁺ 465.1. Example 136 and Example 137. Preparation of isopropyl (R)-2-((1-(3,6-dimethyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oate & isopropyl (S)-2- ((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)amino)benzoate (stereochemistry arbitrarily assigned for both enantiomers) [1721] The racemic mixture, isopropyl 2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoate (25 mg, 53.8 μmol) was separated by SFC (column: Daicel CHIRALPAK AD (250 x 30 mm, 10 um); mobile phase: [0.1%NH3-water, ethanol]; B%: 25%- 25%, 7 min) to give isopropyl (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (6.92 mg, 14.8 μmol, 27%) as a yellow gum. ¹ H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 5.6 Hz, 1H), 7.95 - 7.90 (m, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 8.8 Hz, 1H), 5.52 - 5.42 (m, 1H), 5.31 -5.21 (m, 1H), 3.94 - 3.86 (m, 4H), 3.62 (s, 3H), 3.33 - 3.26 (m, 4H), 2.37 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.0 Hz, 6H); m/z ES+ [M+H] ⁺ 465.3; and isopropyl (S)- 2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin -8-yl)ethyl)amino)benzoate (7.64 mg, 16.1 μmol, 30%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, J = 6.4 Hz, 1H), 7.93 (dd, J = 1.6, 8.0 Hz, 1H), 7.88 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.18 - 7.10 (m, 1H), 6.52 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.47 (t, J = 6.4 Hz, 1H), 5.30 – 5.22 (m, 1H), 3.93 - 3.88 (m, 4H), 3.62 (s, 3H), 3.32 - 3.28 (m, 4H), 2.37 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.4 Hz, 6H); m/z ES+ [M+H] ⁺ 465.2. Example 138. Preparation of 2-((1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid [1722] Step 1. Synthesis of 8-bromo-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethylquinazolin-4(3H)-one [1723] To a mixture of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (500 mg, 1.39 mmol) in N,N-dimethylformamide (8 mL) was added diisopropylethylamine (539 mg, 4.17 mmol) and 6,6-difluoro-3-azabicyclo[3.1.0]hexane (238 mg, 1.53 mmol). The mixture was stirred at 80 °C for 2 hour. The mixture was poured into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1/0 to 2/1) to give 8-bromo-2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-quinazolin-4-one (529 mg, 1.01 mmol, 73%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.75 (s, 1H), 4.05 - 3.96 (m, 2H), 3.95 - 3.85 (m, 2H), 3.52 (s, 3H), 2.42 - 2.35 (m, 5H); m/z ES+ [M+H] ⁺ 371.6. [1724] Step 2. Synthesis of 8-acetyl-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethylquinazolin-4(3H)-one [1725] To a solution of 8-bromo-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-quinazolin-4-one (479 mg, 1.29 mmol) in n-butanol (8 mL) was added 1- vinyloxybutane (388 mg, 3.87 mmol), diisopropylethylamine (500 mg, 3.87 mmol), palladium acetate (29.0 mg, 129 μmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl- phosphane (69.5 mg, 129 μmol). The mixture was stirred at 95 °C for 1 hr under nitrogen. On completion, hydrochloric acid (1 M, 1.28 mL) was added and the mixture was stirred at 25 °C for 0.5 h. The mixture was then pured into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1/0 to 2/1) to give 8-acetyl-2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-quinazolin-4-one (310 mg, 930 μmol, 72%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (dd, J = 0.8, 2.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 4.01 (d, J = 10.8 Hz, 2H), 3.87 - 3.80 (m, 2H), 3.55 (s, 3H), 2.84 (s, 3H), 2.44 (s, 3H), 2.42 - 2.40 (m, 1H), 2.39 -2.37 (m, 2.8 Hz, 1H). [1726] Step 3. Synthesis of 8-(1-aminoethyl)-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)- 3,6-dimethylquinazolin-4(3H)-one [1727] To a mixture of 8-acetyl-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-quinazolin-4-one (290 mg, 870 μmol) in methanol (10 mL) was added ammonium acetate (1.34 g, 17.4 mmol) and sodium cyanoborohydride (82.0 mg, 1.31 mmol), then the mixture was stirred at 60 °C for 1 hr. The mixture was poured into water (40 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was purified by reversed- phase HPLC (0.1% NH ₃ •H ₂ O) to give 8-(1-aminoethyl)-2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-quinazolin-4-one (170 mg, 508 μmol, 58%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.47 (s, 1H), 4.76 -4.62 (m, 1H), 4.05 - 3.93 (m, 2H), 3.86 - 3.78 (m, 2H), 3.54 (s, 3H), 2.42 (s, 3H), 2.40 – 2.33 (m, 2H), 1.51 (d, J = 6.8 Hz, 3H). [1728] Step 4. Synthesis of 2-((1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid [1729] To a solution of 8-(1-aminoethyl)-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3- yl)-3,6- dimethyl-quinazolin-4-one (150 mg, 449 μmol) and 2-iodobenzoic acid (334 mg, 1.35 mmol) in dimethyl acetamide (3 mL) was added triethylamine (136 mg, 1.35 mmol) and copper powder (28.5 mg, 449 μmol). The mixture was stirred at 110 °C for 2 hours under nitrogen atmosphere. The mixture was then filtered and concentrated under vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water(FA)-acetonitrile]; B%: 54%-84%, 10 min) to give 2-[1-[2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-quinazolin-8 -yl]ethylamino]benzoic acid (75.0 mg, 163 μmol, 36%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.55 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 8.8 Hz, 1H), 5.49 - 5.38 (m, 1H), 4.14 - 3.75 (m, 4H), 3.58 (s, 3H), 2.42 – 2.34 (m, 2H), 2.36 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 454.2 Example 139 and Example 140. Preparation of 2-(((1R)-1-(2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8- yl)ethyl)amino)benzoic acid & 2-(((1S)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1730] The racemic mixture, 2-[1-[2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-4-oxo-quinazolin-8-yl]ethylamino]benzoic acid (70.0 mg, 154 μmol) was separated by SFC [column: Daicel CHIRALPAK AD (250 x 30 mm, 10 um); mobile phase: [0.1% NH3- water, ethanol]; B%: 35%-35%, 4.9 min] to give 2-[[(1R)-1-[2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-quinazolin-8 -yl]ethyl]amino]benzoic acid (24.0 mg, 52.9 μmol, 34%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.52 - 8.07 (m, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.48 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.49 -5.38 (m, 1H), 4.17 - 4.08 (m, 1H), 4.01 - 3.78 (m, 3H), 3.58 (s, 3H), 2.44 - 2.30 (m, 5H), 1.64 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 454.2; and 2-[[(1S)-1-[2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3 ,6-dimethyl-4-oxo-quinazolin-8- yl]ethyl]amino]benzoic acid (23.4 mg, 51.4 μmol, 33%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 - 8.09 (m, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.48 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.49 - 5.38 (m, 1H), 4.12 (d, J = 10.8 Hz, 1H), 4.02 - 3.79 (m, 3H), 3.58 (s, 3H), 2.45 - 2.30 (m, 5H), 1.64 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 454.2. Example 141. Preparation of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)-N-methoxybenzamide [1731] Step 1. Synthesis of tert-butyl 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate [1732] To a mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-on e (100 mg, 333 μmol) and tert-butyl 2-bromobenzoate (428 mg, 1.66 mmol) in toluene (5 mL) was added tris(dibenzylideneacetone)dipalladium (60.97 mg, 66.6 μmol), dicyclohexyl-[2-[2,6- di(propan-2-yloxy)phenyl]phenyl]phosphane (31.07 mg, 66.6 μmol) and cesium carbonate (271 mg, 832 μmol) in one portion under nitrogen. The mixture was then heated to 110 °C and stirred for 16 hours under nitrogen. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 3/1) to give tert-butyl 2-[1-[3,6-dimethyl-4-oxo-2- (1-piperidyl)quinazolin-8-yl]ethylamino]benzoate (100 mg, 191 μmol, 57%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 8.45 - 8.21 (m, 1H), 7.92 - 7.81 (m, 2H), 7.50 (d, J = 2.0 Hz, 1H), 7.12 (ddd, J = 1.6, 7.2, 8.4 Hz, 1H), 6.55 - 6.41 (m, 2H), 5.53 - 5.43 (m, 1H), 3.60 (s, 3H), 3.26 - 3.16 (m, 4H), 2.36 (s, 3H), 1.85 – 1.75 (m, 4H), 1.81 - 1.59 (m, 14H); m/z ES+ [M+H] ⁺ 477.1. [1733] Step 2. Synthesis of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1734] A mixture of tert-butyl 2-[1-[3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8- yl]ethylamino]benzoate (90 mg, 189 μmol) in trifluoroacetic acid (5 mL) was stirred at 20 °C for 5 hours. On completion, the reaction mixture was concentrated under reduced pressure to give 2-[1-[3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8-yl]ethy lamino]benzoic acid (80 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 421.1. [1735] Step 3. Synthesis of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)-N-methoxybenzamide [1736] To a mixture of 2-[1-[3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8- yl]ethylamino]benzoic acid (70 mg, 166 μmol) and O-methylhydroxylamine (41.71 mg, 499 μmol) in dichloromethane (5 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (127 mg, 333 μmol) and diisopropylethylamine (108 mg, 832 μmol) in one portion. The mixture was stirred at 20 °C for 3 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue.The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)-acetonitirle]; B%: 48%-78%, 10 min) to give 2-[1-[3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8-yl]ethy lamino]-N-methoxy- benzamide (33 mg, 73.4 μmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.08 (br. s, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 1.6, 8.0 Hz, 1H), 7.15 - 7.07 (m, 1H), 6.52 - 6.41 (m, 2H), 5.34 (br. dd, J = 1.6, 4.4 Hz, 1H), 3.71 (s, 3H), 3.47 (s, 3H), 3.21 (br. s, 4H), 2.31 (s, 3H), 1.76 - 1.58 (m, 6H), 1.52 (d, J = 6.6 Hz, 3H); m/z ES+ [M+H] ⁺ 450.2. Example 142 and Example 143. Preparation of (R)-2-((1-(3,6-dimethyl-4-oxo-2- (piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-N-m ethoxybenzamide & (S)-2- ((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinaz olin-8-yl)ethyl)amino)-N- methoxybenzamide (stereochemistry arbitrarily assigned for both enantiomers) [1737] The racemic mixture, 2-[1-[3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8- yl]ethylamino]-N-methoxy-benzamide (30 mg, 66.73 μmol) was separated by SFC (column: Daicel CHIRALPAK AD (250 x 30 mm, 10 um); mobile phase: [0.1%NH ₃ H ₂ O, IPA]; B%: 55%-55%, 6.3 min) to give (R)-2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)-N-methoxybenzamide (11.6 mg, 25.3 μmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 7.99 (br. d, J = 5.4 Hz, 1H), 7.85 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.30 (dd, J = 1.2, 7.6 Hz, 1H), 7.13 - 7.06 (m, 1H), 6.54 - 6.40 (m, 2H), 5.47 (br. t, J = 6.4 Hz, 1H), 3.91 (s, 3H), 3.59 (s, 3H), 3.27 - 3.15 (m, 4H), 2.34 (s, 3H), 1.81 - 1.71 (m, 6 H), 1.57 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 450.2; and (S)-2- ((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinaz olin-8-yl)ethyl)amino)-N- methoxybenzamide (9.92 mg, 20.96 μmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.00 (br. s, 1H), 7.85 (d, J = 0.8 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.31 (br. d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.53 - 6.41 (m, 2H), 5.47 (br. d, J = 6.4 Hz, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.25 - 3.13 (m, 4H), 2.34 (s, 3H), 1.83 - 1.63 (m, 6H), 1.58 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 450.2. Example 144. Preparation of 8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one [1738] A suspension of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (150 mg, 496 μmol), 1,4-difluoro-2-methylsulfonyl-benzene (143 mg, 744 μmol) and cesium carbonate (323 mg, 992 μmol) in dimethyl acetamide (1.5 mL) was stirred at 140 °C for 16 hr. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purificated by prep-HPLC (column: Welch Ultimate C18150 x 25 mm, 5 um; mobile phase: [water(FA)-acetonitrile]; B%: 50%-80%, 10 min) to give 8-[1-(4-fluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2-morpholino- quinazolin-4-one (90 mg, 189 μmol, 38%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 1.1 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.00 (ddd, J = 3.1, 7.7, 9.2 Hz, 1H), 6.64 - 6.48 (m, 2H), 5.39 (quin, J = 6.5 Hz, 1H), 3.97 - 3.88 (m, 4H), 3.64 (s, 3H), 3.36 - 3.27 (m, 4H), 3.15 (s, 3H), 2.40 (s, 3H), 1.64 (d, J = 6.6 Hz, 3H); m/z ES+ [M+H] ⁺ 475.3. Example 145 and Example 146. Preparation of (R)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholin oquinazolin-4(3H)-one & (S)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl-2- morpholinoquinazolin-4(3H)-one (stereochemistry arbitrarily assigned for both enantiomers) [1739] The racemic mixture, 8-[1-(4-fluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2- morpholino-quinazolin-4-one (80 mg, 168 μmol) was separated by SFC [column: Daicel CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1%NH3H2O, IPA]; B%: 35%-35%, 7.8 min] to give (R)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl-2- morpholinoquinazolin-4(3H)-one (29.7 mg, 62.0 μmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 3.2, 8.4 Hz, 1H), 7.39 - 7.29 (m, 1H), 6.76 - 6.63 (m, 2H), 5.34 (q, J = 6.8 Hz, 1H), 3.79 (t, J = 4.8 Hz, 4H), 3.51 (s, 3H), 3.30 - 3.19 (m, 7H), 2.38 - 2.32 (m, 3H), 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 475.0; and (S)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl- 2-morpholinoquinazolin-4(3H)-one (38.3 mg, 79.9 μmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.39 (dd, J = 3.2, 8.4 Hz, 1H), 7.39 - 7.29 (m, 1H), 6.76 - 6.63 (m, 2H), 5.34 (q, J = 6.8 Hz, 1H), 3.79 (t, J = 4.8 Hz, 4H), 3.51 (s, 3H), 3.23 (s, 4H), 2.35 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H); m/z ES+ [M+H]+ 475.2. Example 147. Preparation of 2-((1-(2-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-6-fluoro-3- methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1740] Step 1. Synthesis of 2-amino-3-bromo-5-fluoro-N-methylbenzamide [1741] To a solution of 2-amino-3-bromo-5-fluoro-benzoic acid (5 g, 21.4 mmol) and methanamine hydrochloride (2.89 g, 42.7 mmol) in N,N-dimethylformamide (50 mL) was added diisopropylethylamine (11.1 g, 85.5 mmol) and dimethylamino(triazolo[4,5-b]pyridin- 3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (9.75 g, 25.6 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was poured into water (500 mL) and then filtered. The filtered cake was collected and concentrated in vacuo to give 2-amino-3- bromo-5-fluoro-N-methyl-benzamide (3.2 g, crude) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34 (dd, J = 2.8, 7.6 Hz, 1H), 7.06 (dd, J = 2.8, 8.8 Hz, 1H), 6.14 - 5.68 (m, 2H), 3.00 (d, J = 4.8 Hz, 3H). [1742] Step 2. Synthesis of 8-bromo-2-chloro-6-fluoro-3-methylquinazolin-4(3H)-one [1743] To a solution of 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (500 mg, 2.02 mmol) in 1,4-dioxane (5 mL) was added thiophogene (487 mg, 4.25 mmol). The mixture was stirred at 25 °C for 1 hour. Then the mixture was stirred at 105 °C for another 1 hour. The mixture was concentrated in vacuo to give 8-bromo-2-chloro-6-fluoro-3-methyl-quinazolin-4-one (3.1 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 292.9. [1744] Step 3. Synthesis of 2-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-6-fluoro-3 - methylquinazolin-4(3H)-one [1745] To a solution of 8-bromo-2-chloro-6-fluoro-3-methyl-quinazolin-4-one (3.5 g, 12.1 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (4.31 g, 36.0 mmol) in dichloromethane (40 mL) was added diisopropylethylamine (6.21 g, 48.0 mmol). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was partitioned between water (40 mL) and dichloromethane (40 mL). The organic phase was separated, washed with brine (40 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 30/1 to 1/1) to give 2-[(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]-8-bromo- 6-fluoro-3-methyl-quinazolin-4-one (4 g, 10.7 mmol, 89%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 2.8, 8.4 Hz, 1H), 7.47 (dd, J = 2.8, 8.0 Hz, 1H), 3.71 (s, 1H), 3.68 (s, 1H), 3.37 (br. d, J = 10.4 Hz, 2H), 3.30 (s, 3H), 1.46 - 1.38 (m, 2H), 0.49 - 0.42 (m, 1H), 0.22 (q, J = 4.4 Hz, 1H). [1746] Step 4. Synthesis of 8-acetyl-2-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-6-fluoro- 3- methylquinazolin-4(3H)-one [1747] To a solution of 2-[(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]-8-bromo-6-fluoro-3 - methyl-quinazolin-4-one (2 g, 5.91 mmol) and 1-vinyloxybutane (1.78 g, 17.7 mmol, 2.28 mL) in n-butanol (20 mL) was added palladium acetate (133 mg, 591 μmol), diisopropylethylamine (2.29 g, 17.7 mmol, 3.09 mL) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl- phosphane (318 mg, 591 μmol). The mixture was stirred at 95 °C for 12 hours under nitrogen atmosphere. Then hydrochloric acid (1 M, 59.14 mL) was added and the mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was extracted with ethyl acetate (100 mL x 2). Then the water phase was adjusted to pH ~ 7 with saturated aqueous solution of sodium bicarbonate, and then extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-acetyl-2-[(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]-6-fluoro- 3-methyl-quinazolin-4-one (1.2 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 3.2, 8.0 Hz, 1H), 7.78 (dd, J = 3.2, 8.9 Hz, 1H), 3.86 (s, 1H), 3.83 (s, 1H), 3.56 (br. s, 1H), 3.54 (s, 3H), 2.88 (s, 3H), 1.67 - 1.56 (m, 3H), 0.73 - 0.63 (m, 1H), 0.45 (q, J = 4.4 Hz, 1H). [1748] Step 5. Synthesis of 8-(1-aminoethyl)-2-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-6 - fluoro-3-methylquinazolin-4(3H)-one [1749] To a solution of 8-acetyl-2-[(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]-6-fluoro- 3- methyl-quinazolin-4-one (1.1 g, 3.65 mmol) in methanol (100 mL) and dichloromethane (50 mL) was added ammonium acetate (5.63 g, 73.0 mmol) and sodium cyanoborohydride (344 mg, 5.48 mmol). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 8-(1-aminoethyl)-2-[(1R,5S)-3- azabicyclo[3.1.0] hexan-3-yl]-6-fluoro-3-methyl-quinazolin-4-one (830 mg, 2.75 mmol, 75%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.69 (dd, J = 2.8, 9.6 Hz, 1H), 7.65 - 7.59 (m, 1H), 5.09 - 4.76 (m, 1H), 3.87 (d, J = 10.4 Hz, 2H), 3.56 - 3.47 (m, 2H), 3.43 (s, 3H), 1.70 - 1.58 (m, 2H), 1.53 - 1.45 (m, 3H), 0.60 (dt, J = 5.2, 7.6 Hz, 1H), 0.32 (q, J = 4.0 Hz, 1H). [1750] Step 6. Synthesis of 2-((1-(2-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-6-fluoro-3- methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1751] To a solution of 8-(1-aminoethyl)-2-[(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]-6 - fluoro-3-methyl-quinazolin-4-one (300 mg, 992 μmol) and 2-iodobenzoic acid (1.97 g, 7.94 mmol, 46.5 uL) in dimethyl acetamide (6 mL) was added copper powder (126 mg, 1.98 mmol) and triethylamine (803 mg, 7.94 mmol). The mixture was stirred at 120 °C for 12 hours under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 um; mobile phase: [water (FA)-acetonitrile]; B%: 52%-82%, 10 min) to give 2-[1-[2- [(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]-6-fluoro-3-methyl-4- oxo-quinazolin-8- yl]ethylamino]benzoic acid (40 mg, 94.7 μmol, 9.5%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.92 - 12.53 (m, 1H), 8.42 (br. d, J = 4.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 3.2, 8.8 Hz, 1H), 7.40 (dd, J = 2.8, 9.6 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.35 (br. d, J = 5.2 Hz, 1H), 4.01 (d, J = 10.8 Hz, 1H), 3.86 (d, J = 10.4 Hz, 1H), 3.58 - 3.48 (m, 2H), 3.45 - 3.42 (m, 3H), 1.65 - 1.60 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H), 0.67 - 0.54 (m, 1H), 0.36 (q, J = 4.0 Hz, 1H); m/z ES+ [M+H] ⁺ 423.1. Example 148 and Example 149. Preparation of 2-(((R)-1-(2-((1R,5S)-3- azabicyclo[3.1.0]hexan-3-yl)-6-fluoro-3-methyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethyl)amino)benzoic acid & 2-(((S)-1-(2-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-6- fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino )benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1752] The racemate product (30.0 mg, 71.0 μmol) was separated by SFC (column: Daicel CHIRALCEL OD-H (250 x 30 mm, 5 um); mobile phase: [0.1%NH3H2O, methanol]; B%: 30%-30%, 4.5 min) to give 2-(((R)-1-(2-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-6-fluor o-3- methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (13.4 mg, 31.8 μmol, 45%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 - 8.43 (m, 1H), 7.85 - 7.75 (m, 1H), 7.55 - 7.46 (m, 1H), 7.39 (dd, J = 3.2, 9.2 Hz, 1H), 7.17 (br. t, J = 7.6 Hz, 1H), 6.51 (t, J = 7.6 Hz, 1H), 6.37 (d, J = 8.8 Hz, 1H), 5.35 (br. d, J = 6.4 Hz, 1H), 4.01 (d, J = 10.8 Hz, 1H), 3.86 (d, J = 10.4 Hz, 1H), 3.61 - 3.47 (m, 2H), 3.44 (s, 3H), 1.66 - 1.60 (m, 2H), 1.57 (d, J = 6.8 Hz, 3H), 0.60 (dt, J = 5.2, 7.2 Hz, 1H), 0.36 (q, J = 4.0 Hz, 1H); m/z ES+ [M+H] ⁺ 423.2. and 2-(((S)-1-(2-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-6-fluor o-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (14.2 mg, 32.7 μmol, 46%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.74 (br. s, 1H), 8.55 - 8.37 (m, 1H), 7.80 (dd, J = 1.6, 8.0 Hz, 1H), 7.52 (dd, J = 3.2, 8.8 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.19 (br. t, J = 7.2 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.35 (br. d, J = 6.0 Hz, 1H), 4.01 (d, J = 10.8 Hz, 1H), 3.86 (d, J = 10.4 Hz, 1H), 3.57 - 3.47 (m, 2H), 3.44 (s, 3H), 1.67 - 1.61 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H), 0.60 (dt, J = 4.8, 7.6 Hz, 1H), 0.36 (q, J = 4.0 Hz, 1H); m/z ES+ [M+H] ⁺ 423.2. Example 150. Preparation of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-4,5-difluorobenzoic acid [1753] Step 1. Synthesis of methyl (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-4,5-difluorobenzoate [1754] To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3 H)- one (20 mg, 66.1 μmol) in toluene (1 mL) was added methyl 2-bromo-4,5-difluoro-benzoate (83.0 mg, 331 μmol), tris(dibenzylideneacetone)dipalladium (12.1 mg, 13.2 μmol), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (6.17 mg, 13.2 μmol) and cesium carbonate (64.7 mg, 198 μmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1:1) to give methyl (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8- yl)ethyl)amino)-4,5-difluorobenzoate (15 mg, 31.8 μmol, 48%) as a white solid. m/z ES+ [M+H] ⁺ 473.1. [1755] Step 2. Synthesis of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-4,5-difluorobenzoic acid [1756] To a solution of methyl (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-4,5-difluorobenzoate (15 mg, 31.8 μmol) in anhydrous tetrahydrofuran (1 mL), methanol (0.3 mL) and water (0.3 mL) was added lithium hydroxide (3.8 mg, 159 μmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water(FA)-acetonitrile]; B%: 48%-78%, 7 min) to give (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-4,5-difluorobenzoic acid (8.08 mg, 17.6 μmol, 56%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.27 - 8.07 (m, 1H), 7.93 (s, 1H), 7.82 - 7.72 (m, 1H), 7.46 (d, J = 1.6 Hz, 1H), 6.40 - 6.31 (m, 1H), 5.46 - 5.33 (m, 1H), 3.95 - 3.89 (m, 4H), 3.64 (s, 3H), 3.35 - 3.27 (m, 4H), 2.40 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 459.2. Example 151. Preparation of (R)-3,6-dimethyl-8-(1-((3-(methylsulfonyl)pyridin-2- yl)amino)ethyl)-2-morpholinoquinazolin-4(3H)-one [1757] To a solution of 2-chloro-3-methylsulfonyl-pyridine (95.1 mg, 496 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (161 mg, 496 μmol) and (R)-8-(1-aminoethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (50 mg, 165 μmol). The mixture was stirred at 130 °C for 16 hours. On completion, the mixture was filtered to remove the solid. The filtrate was concentrated in vacuo. The obtained residue was purified by prep-HPLC (column: YMC Triart C 18150 x 25 mm, 5 um; mobile phase: [water (formic acid)-acetonitrile]; B %: 46%- 76 %, 10 min) to give (R)-3,6-dimethyl-8-(1-((3-(methylsulfonyl)pyridin-2-yl)amino )ethyl)-2- morpholinoquinazolin-4(3H)-one (18.5 mg, 40.5 μmol, 24%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 1.6 Hz, 1H), 8.35 - 8.30 (m, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.94 - 7.88 (m, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 4.8, 7.6 Hz, 1H), 5.92 - 5.82 (m, 1H), 3.82 - 3.73 (m, 4H), 3.50 (s, 3H), 3.40 - 3.33 (m, 2H), 3.18 - 3.12 (m, 2H), 3.10 (s, 3H), 2.36 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H); m/z ES ⁺ [M+H] ⁺ 458.2. Example 152. Preparation of (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1758] A mixture of 4, 4-dimethylpiperidine (70.8 mg, 625 μmol) and 2-(((1R)-1-(3,6- dimethyl-2-(methylsulfinyl)-4-oxo-3,4-dihydroquinazolin-8-yl )ethyl)amino)benzoic acid (50.0 mg, 125 μmol) was stirred at 100 °C for 12 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25 mm, 10 um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 33%-63%, 9 min) and further purified by prep-TLC (SiO ₂ , petroleum ether/ethyl acetate = 0/1) to give (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (5.40 mg, 11.7 μmol, 9.4%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 1.6, 8.0 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.27 - 7.18 (m, 1H), 6.56 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.51 (q, J = 6.8 Hz, 1H), 3.59 (s, 3H), 3.23 (br. d, J = 3.6 Hz, 4H), 2.37 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.57 (br. dd, J = 3.6, 6.8 Hz, 4H), 1.05 (s, 6H); m/z ES+ [M+H] ⁺ 449.3. Example 153. Preparation of (R)-5-chloro-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1759] To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3 H)- one (50 mg, 165 μmol), 5-chloro-2-iodo-benzoic acid (233 mg, 826 μmol) in dimethylacetamide (2 mL) was added copper powder (21.0 mg, 330 μmol) and triethylamine (83.6 mg, 826 μmol). The mixture was stirred at 120 °C for 2 hr under nitrogen. The reaction mixture was quenched by brine (40 mL) at 25 °C, and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (3 x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water(FA)-acetonitrile]; B%: 50%-80%, 7 min) and repurified by prep-HPLC (column: 3 Phenomenex Luna C1875 x 30 mm, 3 um; mobile phase: [water(TFA)-acetonitrile]; B%: 55%- 75%, 9 min) to give (R)-5-chloro-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (17.3 mg, 37.6 μmol, 23%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 - 8.25 (m, 1H), 7.76 - 7.68 (m, 2H), 7.48 (s, 1H), 7.26- 7.23 (m, 1H), 6.56 (d, J = 9.2 Hz, 1H), 5.35 (d, J = 6.8 Hz, 1H), 3.78 (t, J = 4.4 Hz, 4H), 3.60 (s, 3H), 3.30 - 3.20 (m, 4H), 2.33 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 457.1. Example 154. Preparation of (R)-3,6-dimethyl-8-(1-((2-((methyl- d ₃ )sulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one [1760] Step 1. Synthesis of (2-fluorophenyl)(methyl-d3)sulfane [1761] To a solution of 2-fluorobenzenethiol (500 mg, 3.90 mmol) in acetonitrile (5 mL) was added potassium carbonate (1.08 g, 7.80 mmol) and trideuterio(iodo)methane (848 mg, 5.85 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours under nitrogen atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2- fluorophenyl)(methyl-d3)sulfane (566 mg, 3.59 mmol, 91%) as a brown oil. ¹ H NMR (400 MHz, CDCl3) δ 7.40 - 7.33 (m, 1H), 7.30 - 7.18 (m, 2H), 7.17 - 7.09 (m, 1H). [1762] Step 2. Synthesis of 1-fluoro-2-((methyl-d ₃ )sulfonyl)benzene [1763] To a solution of 1-fluoro-2-(trideuteriomethylsulfanyl)benzene (200 mg, 1.38 mmol) in anhydrous tetrahydrofuran (3 mL) and water (1 mL) was added Oxone (2.54 g, 4.13 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 3/1) to give 1-fluoro- 2-((methyl-d3)sulfonyl)benzene (200 mg, 1.13 mmol, 81%) as a brown oil. ¹ H NMR (400 MHz, CDCl3) δ 7.97 (dt, J = 1.6, 7.6 Hz, 1H), 7.70 - 7.62 (m, 1H), 7.38 - 7.32 (m, 1H), 7.30 - 7.23 (m, 1H); m/z ES+ [M+H] ⁺ 178.1. [1764] Step 3. Synthesis of (R)-3,6-dimethyl-8-(1-((2-((methyl- d3)sulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4(3H) -one [1765] (R)-8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3 H)-one (50.0 mg, 143 μmol, formic acid salt) was dissolved in methanol-d4 (0.5 mL) and stirred at 25 ºC for 0.5 h. Then the mixture was concentrated in vacuo. The resulting residue and 1-fluoro-2-((methyl- d ₃ )sulfonyl)benzene (25.4 mg, 143 μmol) were dissolved in dimethyl sulfoxide-d ₆ (0.5 mL) and then cesium carbonate (140 mg, 430 μmol) was added. The mixture was stirred at 140 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 45%-75%, 7 min) to give (R)-3,6-dimethyl-8-(1-((2-((methyl- d ₃ )sulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one (30.8 mg, 66.5 μmol, 46%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (d, J = 0.8 Hz, 1H), 7.75 (dd, J = 1.6, 8.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.26 - 7.18 (m, 1H), 6.77 (d, J = 6.8 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.43 (t, J = 6.8 Hz, 1H), 3.95 - 3.85 (m, 4H), 3.62 (s, 3H), 3.34 - 3.26 (m, 4H), 2.38 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 460.2. Example 155. Preparation of (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)- one [1766] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one [1767] To a solution of 2-amino-3-bromo-N-5-dimethyl-benzamide (2.00 g, 8.23 mmol) in ethanol (15 mL) was added tetrahydropyran-4-carbaldehyde (1.13 g, 9.87 mmol) and iodine (2.30 g, 9.05 mmol). The mixture was stirred at 80 °C for 17 hr. On completion, the reaction mixture was quenched with saturated aqueous solution of sodium sulfite (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1:0 to 2:1) to give 8-bromo-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (1.60 g, 4.53 mmol, 55%) as yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 - 7.93 (m, 1H), 7.92 - 7.86 (m, 1H), 4.02 - 3.88 (m, 2H), 3.60 (s, 3H), 3.56 - 3.40 (m, 2H), 3.32 - 3.18 (m, 1H), 2.42 (s, 3H), 1.98 - 1.79 (m, 4H); m/z ES+ [M+H] ⁺ 336.9. [1768] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-on e [1769] A mixture of 8-bromo-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (1.3 g, 3.86 mmol), 1-vinyloxybutane (1.16 g, 11.5 mmol), palladium acetate (86.5 mg, 386 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (207 mg, 385 μmol) and diisopropylethylamine (1.49 g, 11.5 mmol) in n-butanol (10 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 95 °C for 2 hr under nitrogen atmosphere. And then the reaction was cooled to 25 °C, hydrochloric acid (1 M, 4.6 mL) was added and stirred at 25°C for 10 min. On completion, the reaction mixture was quenched with water (100 mL) and extracted ethyl acetate (50 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1:0 to 3:2) to give 8-acetyl-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (1.15 g, 3.71 mmol, 96%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 4.05 - 3.86 (m, 2H), 3.63 (s, 3H), 3.56 - 3.40 (m, 2H), 3.30 (s, 1H), 2.80 (s, 3H), 2.45 (s, 3H), 1.88 - 1.79 (m, 4H); m/z ES+ [M+H] ⁺ 300.9. [1770] Step 3. Synthesis of (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide [1771] To a solution of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-on e (1.28 g, 4.26 mmol) in 2-methyltetrahydrofuran (12 mL) was added tetraethoxytitanium (4.86 g, 21.3 mmol) and (R)-2-methylpropane-2-sulfinamide (2.58 g, 21.3 mmol). The mixture was stirred at 85 °C for 12 hr. On completion, the mixture was poured in water (100 mL) and was extracted with ethyl acetate (50 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1:0 to 0:1) to give (NZ,R)-N-[1-(3,6- dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethyli dene]-2-methyl-propane-2- sulfinamide (1.60 g, 3.82 mmol, 89%) as yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 8.17 - 8.02 (m, 1H), 7.65 (s, 1H), 4.17 - 4.05 (m, 2H), 3.78 – 3.61 (m, 5H), 3.62 – 3.42 (m, 3H), 3.17 - 3.00 (m, 1H), 2.90 (s, 2H), 2.63 - 2.53 (m, 1H), 2.49 (s, 3H), 2.45 - 2.45 (m, 1H), 2.13 - 1.94 (m, 3H), 1.34 (s, 5H), 1.24 (s, 13H), 1.20 (s, 3H); m/z ES+ [M+H] ⁺ 404.1. [1772] Step 4. Synthesis of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethyl]-2-methylpropane-2-sulfinamide & (R)-N-[(1S)-1-(3,6-dimethyl-4-oxo- 2-tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]-2-methyl-propa ne-2-sulfinamide [1773] To a mixture of (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quina zolin- 8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (1.1 g, 2.73 mmol) in anhydrous tetrahydrofuran (10 mL) was added sodium borohydride (206 mg, 5.45 mmol). The mixture was stirred at -40 °C for 2 hr, then the mixture was stirred at 15 °C for 12 hr. On completion, the mixture was quenched by water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The product purified by prep-HPLC (column: YMC Triart C18250 x 50 mm, 7 um; mobile phase: [water(ammonium hydroxide)-acetonitrile]; B%: 20%-20%, 15 min) to give (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethyl]-2-methylpropane-2-sulfinamide (380 mg, 936 μmol, 34%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J = 0.8 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 5.81 (d, J = 8.8 Hz, 1H), 5.16 - 5.05 (m, 1H), 4.02 - 3.91 (m, 2H), 3.61 (s, 3H), 3.55 - 3.45 (m, 2H), 3.29 (s, 1H), 2.43 (s, 3H), 1.86 (d, J = 2.8 Hz, 4H), 1.47 (d, J = 6.8 Hz, 3H), 1.11 (s, 9H); m/z ES+ [M+H] ⁺ 406.6; and (R)-N-[(1S)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (370 mg, 912 μmol, 33%) as yellow solid. [1774] Step 5. Synthesis of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one [1775] To a solution of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (370 mg, 912 μmol) in hydrochloric acid/1,4-dioxane (3 mL) was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide, 10%-30% acetonitrile/water, 10 min) to give 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-qu inazolin-4-one (240 mg, 795 μmol, 87%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.83 - 7.51 (m, 2H), 3.96 (d, J = 11.2 Hz, 2H), 3.60 (s, 3H), 3.56 – 3.44 (m, 2H), 3.31 - 3.24 (m, 3H), 2.41 (s, 3H), 1.85 (s, 4H), 1.49 - 1.25 (m, 2H); m/z ES+ [M+H] ⁺ 302.3. [1776] Step 6. Synthesis of (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )- 2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [1777] To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one (50.0 mg, 165 μmol) and 1-fluoro-2-methylsulfonyl-benzene (43.3 mg, 248 μmol) in N,N-dimethylformamide (1 mL) was added cesium carbonate (108 mg, 331 μmol). The mixture was stirred at 140 °C for 12 hr. On completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(formic acid)- acetonitrile]; B%: 42%-72%, 15 min) to give (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (49.2 mg, 108 μmol, 65%) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 0.8 Hz, 1H), 7.79 – 7.71 (m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.25 - 7.16 (m, 1H), 6.76 - 6.67 (m, 2H), 6.53 (d, J = 8.4 Hz, 1H), 5.69 – 5.53 (m, 1H), 4.23 - 4.09 (m, 2H), 3.71 (s, 3H), 3.67 – 3.54 (m, 2H), 3.18 - 3.11 (m, 4H), 2.40 (s, 3H), 2.29 - 2.11 (m, 2H), 1.92 (d, J = 13.6 Hz, 2H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 456.4. Example 156. Preparation of (S)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)- one [1778] Step 1. Synthesis of 8-[(1S)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one [1779] To a solution of (R)-N-[(1S)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (370 mg, 912 umol) in hydrochloride/1,4-dioxane (3 mL) was stirred at 25 °C for 30 minutes. The reaction mixture was quenched with ethyl acetate (20 mL x 3) and saturated aqueous solution of sodium bicarbonate (20 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 8-[(1S)-1-aminoethyl]-3,6-dimethyl-2- tetrahydropyran-4-yl-quinazolin-4-one (250 mg, 827 umol, 91%) as yellow solid. m/z ES+ [M+H] ⁺ 302.1. [1780] Step 2. Synthesis of (S)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )- 2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [1781] To a solution of (S)-8-(1-aminoethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one (50.0 mg, 165 μmol) and 1-fluoro-2-methylsulfonyl-benzene (52.0 mg, 298 μmol) in N,N-dimethylformamide (1 mL) was added cesium carbonate (108 mg, 331 μmol). The mixture was stirred at 140 °C for 12 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 42%-72%, 10 min) to give (S)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (35.0 mg, 76.9 μmol, 46%) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.78 - 7.71 (m, 1H), 7.52 - 7.47 (m, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.80 - 6.66 (m, 2H), 6.53 (d, J = 8.4 Hz, 1H), 5.67 - 5.59 (m, 1H), 4.21-4.10 (m, 2H), 3.71 (s, 3H), 3.65 - 3.57 (m, 2H), 3.19 - 3.12 (m, 4H), 2.40 (s, 3H), 2.26 - 2.15 (m, 2H), 1.96-1.89 (m, 2H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 456.4. Example 157. Preparation of 2-(((R)-1-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoic acid [1782] To a solution of 2-(((1R)-1-(3,6-dimethyl-2-(methylsulfinyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (40.0 mg, 100 μmol) and (1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (27.2 mg, 200 μmol) was added diisopropylethylamine (64.7 mg, 501 μmol). The mixture was stirred at 100 °C for 0.5 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep- HPLC (column: Waters xbridge 150 x 25 mm, 10 um; mobile phase: [water (NH ₄ HCO ₃ )- acetonitrile]; B%: 10%-40%, 10 min) to give 2-(((R)-1-(2-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8- yl)ethyl)amino)benzoic acid (9.14 mg, 20.6 μmol, 21%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.30 - 8.01 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.47 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.51 - 5.34 (m, 1H), 4.83 - 4.75 (m, 1H), 4.69 (s, 1H), 4.37 (d, J = 7.6 Hz, 1H), 3.93 (d, J = 6.8 Hz, 1H), 3.60 (d, J = 10.0 Hz, 1H), 3.57 (s, 3H), 3.46 (d, J = 9.6 Hz, 1H), 2.35 (s, 3H), 2.03 - 1.96 (m, 2H), 1.61 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 434.9. Example 158. Preparation of (R)-2-((1-(2-(4-methoxy-4-methylpiperidin-1-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid [1783] To a solution of 2-(((1R)-1-(3,6-dimethyl-2-(methylsulfinyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (40.0 mg, 100 μmol) and 4-methoxy-4- methyl-piperidine hydrochloride (33.2 mg, 200 μmol) was added diisopropylethylamine (64.7 mg, 500 μmol). The mixture was stirred at 100 °C for 0.5 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25 mm, 10 um; mobile phase: [water (NH ₄ HCO ₃ )-acetonitrile]; B%: 18%-48%, 8 min) to give (R)-2-((1-(2-(4-methoxy-4-methylpiperidin-1-yl)-3,6-dimethyl -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (3.94 mg, 8.40 μmol, 8.4%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.60 - 8.02 (m, 1H), 8.01 - 7.94 (m, 1H), 7.88 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.23 - 7.16 (m, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.49 (q, J = 6.8 Hz, 1H), 3.60 (s, 3H), 3.35 - 3.21 (m, 7H), 2.36 (s, 3H), 1.93 (m, 2H), 1.79 - 1.71 (m, 2H), 1.63 (d, J = 6.4 Hz, 3H), 1.27 - 1.23 (m, 3H); m/z ES+ [M+H] ⁺ 465.1. Example 159. Preparation of 2-(((R)-1-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoic acid [1784] To a solution of 2-(((1R)-1-(3,6-dimethyl-2-(methylsulfinyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (40.0 mg, 100 μmol) and (1R, 4R)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (40.7 mg, 300 μmol) was added diisopropylethylamine (64.7 mg, 500 μmol). The mixture was stirred at 100 °C for 2 hours. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25 mm, 10 um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 5%-35%, 8 min) to give 2-(((R)-1-(2-((1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8- yl)ethyl)amino)benzoic acid (6.80 mg, 15.6 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.02 - 8.00 (m, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 7.24 - 7.20 (m, 1H), 6.58 (t, J = 7.2 Hz, 1H), 6.49 - 6.41 (m, 1H), 5.40 (q, J = 6.8 Hz, 1H), 4.82 (s, 1H), 4.70 (s, 1H), 4.48 (d, J = 7.6 Hz, 1H), 3.98 - 3.89 (m, 1H), 3.67 (d, J = 9.2 Hz, 1H), 3.56 (s, 3H), 3.44 (d, J = 9.6 Hz, 1H), 2.37 (s, 3H), 2.05 - 1.98 (m, 2H), 1.63 (br. d, J = 6.4 Hz, 3H). m/z ES+ [M+H] ⁺ 434.9. Example 160. Preparation of (R)-4-chloro-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [1785] To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3 H)- one (10.0 mg, 28.7 μmol, formic acid salt) and 4-chloro-2-fluoro-benzoic acid (15.0 mg, 86.1 μmol) in dimethyl acetamide (0.5 mL) was added cesium carbonate (37.4 mg, 114 μmol). The mixture was stirred at 140 °C for 12 hours under nitrogen. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 50%-80%, 7 min) to give (R)-4-chloro-2-((1-(3,6- dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl )amino)benzoic acid (5.44 mg, 11.0 μmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.2 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 2.0, 8.4 Hz, 1H), 5.48 (dd, J = 1.6, 3.2 Hz, 1H), 3.98 - 3.87 (m, 4H), 3.63 (s, 3H), 3.33 (d, J = 2.8 Hz, 4H), 2.41 (s, 3H), 1.68 - 1.58 (m, 3H); m/z ES+ [M+H] ⁺ 457.2. Example 161. Preparation of (R)-6-fluoro-3-methyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one [1786] Step 1. Synthesis of 8-bromo-2-chloro-6-fluoro-3-methylquinazolin-4(3H)-one [1787] To a solution of 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (1 g, 4.05 mmol) in 1,4-dioxane (10 mL) was added thiocarbonyl dichloride (977 mg, 8.50 mmol, 0.652 mL) dropwise. The mixture was stirred at 25 °C for 1 hour. Then the mixture was heated to 105 °C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give 8-bromo-6-fluoro-3-methyl-2-morpholinoquinazolin-4(3H)-one (1.2 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 292.8. [1788] Step 2. Synthesis of 8-bromo-6-fluoro-3-methyl-2-morpholinoquinazolin-4(3H)-one [1789] To a mixture of 8-bromo-2-chloro-6-fluoro-3-methyl-quinazolin-4-one (1.2 g, 4.12 mmol) in dichloromethane (12 mL) was added morpholine (1.08 g, 12.4 mmol) in one portion. The mixture was then heated to 40 °C and stirred for 16 hours. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to give 8-bromo-6-fluoro-3-methyl-2- morpholinoquinazolin-4(3H)-one (1.1 g, 2.54 mmol, 62%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.00 (dd, J = 2.8, 8.4 Hz, 1H), 7.66 (dd, J = 2.8, 8.4 Hz, 1H), 3.82 - 3.71 (m, 4H), 3.45 (s, 3H), 3.28 - 3.21 (m, 4H); m/z ES+ [M+H] ⁺ 341.9. [1790] Step 3. Synthesis of 8-acetyl-6-fluoro-3-methyl-2-morpholinoquinazolin-4(3H)-one [1791] To a solution of 8-bromo-6-fluoro-3-methyl-2-morpholino-quinazolin-4-one (0.5 g, 1.46 mmol) and 1-vinyloxybutane (439 mg, 4.38 mmol) in n-butanol (5 mL) was added palladium acetate (32.8 mg, 146 μmol), diisopropylethylamine (567 mg, 4.38 mmol) and [2- (2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (78.7 mg, 146 μmol). The mixture was stirred at 95 °C for 32 hours under nitrogen. Then hydrochloric acid (4 M, 1.0 mL) was added at 25 °C. The mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was quenched by sat. sodium bicarbonate solution (5 mL) at 20 °C, and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-acetyl-6-fluoro-3- methyl-2-morpholinoquinazolin-4(3H)-one (260 mg, 766 μmol, 53%) as a yellow solid. m/z ES+ [M+H] ⁺ 306. [1792] Step 4. Synthesis of (R)-N-(1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [1793] To a mixture of 8-acetyl-6-fluoro-3-methyl-2-morpholino-quinazolin-4-one (240 mg, 786 μmol) and (R)-2-methylpropane-2-sulfinamide (476 mg, 3.93 mmol) in anhydrous tetrahydrofuran (5 mL) was added tetraethyl titanate (897 mg, 3.93 mmol) in one portion. The mixture was then heated to 80 °C and stirred for 16 hours. On completion, the reaction mixture was quenched by water 10 mL at 20 °C, and then diluted with ethyl acetate 10 mL and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 10/1 to 1/1) to give (R)-N-(1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (0.2 g, 426 μmol, 87%) as a yellow oil. m/z ES+ [M+H] ⁺ 409.1. [1794] Step 5. Synthesis of (R)-N-((R)-1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [1795] To a mixture of (R)-N-(1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (170 mg, 416 μmol) in anhydrous tetrahydrofuran (6 mL) was added sodium borohydride (31.5 mg, 832 μmol) in portions at -40 °C under nitrogen. The mixture was stirred at -40 °C for 60 min, then warmed to 20 °C and stirred for 16 hours. On completion, the reaction mixture was quenched by sat. ammonium chloride solution (5 mL) at 20 °C, and then diluted with ethyl acetate (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water (ammonia hydroxide)- acetonitrile]; B%: 33%-63%, 9 min) and repurified by prep-HPLC (column: Waters Xbridge C18 150 x 50 mm, 10 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 38%-58%, 10 min) to give (R)-N-((R)-1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4-dihyd roquinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (40 mg, 97.1 μmol) as a white solid. m/z ES ⁺ [M+H] ⁺ 411.1. [1796] Step 6. Synthesis of (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2- morpholinoquinazolin-4(3H)-one [1797] A solution of (R)-N-((R)-1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (40 mg, 97.4 μmol) in hydrochloric acid/1,4-dioxane (4 M, 0.4 mL) was stirred at 30 °C for 1 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2- morpholinoquinazolin-4(3H)-one (30 mg, 96.9 μmol, 99%) as a yellow solid. m/z ES ⁺ [M+H] ⁺ 307.1. [1798] Step 7. Synthesis of (R)-6-fluoro-3-methyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one [1799] To a solution of (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2-morpholinoquinazoli n- 4(3H)-one (15 mg, 49 μmol) and 1-fluoro-2-methylsulfonyl-benzene (17.1 mg, 97.9 μmol) in dimethyl acetamide (0.2 mL) was added cesium carbonate (47.9 mg, 147 μmol). The mixture was stirred at 140 °C for 16 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a crude product. The residue was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm, 3 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 45%-75%, 7 min) to give (R)-6-fluoro-3-methyl-8-(1- ((2(methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazoli n-4(3H)-one (7.58 mg, 15.8 μmol, 32%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.6 - 7.58 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 6.80 - 6.71 (m, 2H), 6.64 (d, J = 8.8 Hz, 1H), 5.43 - 5.34 (m, 1H), 3.79 (t, J = 4.4 Hz, 4H), 3.51 (s, 3H), 3.31 - 3.22 (m, 4H), 3.20 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES ⁺ [M+H] ⁺ 461.0. Example 162. Preparation of (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(pyridin-3-yl)quinazol in-4(3H)-one [1800] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one [1801] To a mixture of 3-bromo-N,5-dimethyl-2-[(E)-3-pyridylmethyleneamino]benzamid e (0.96 g, 2.89 mmol) in ethanol (10 mL) was added iodine (806 mg, 3.18 mmol), the mixture was stirred at 80 °C for 20 hr. On completion, the mixture was quenched by saturated sodium sulfite solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 1/9) to give 8-bromo-3,6-dimethyl-2-(3- pyridyl)quinazolin-4-one (400 mg, 1.13 mmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 4.8 Hz, 1H), 8.16 (br. d, J = 7.9 Hz, 1H), 8.02 (d, J = 14.6 Hz, 2H), 7.61 (dd, J = 4.9, 7.9 Hz, 1H), 3.39 (s, 3H), 2.47 (s, 3H); m/z ES+ [M+H] ⁺ 331.7. [1802] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one [1803] To a mixture of 8-bromo-3,6-dimethyl-2-(3-pyridyl)quinazolin-4-one (400 mg, 1.21 mmol) in n-butanol (4 mL) was added 1-vinyloxybutane (606 mg, 6.06 mmol), palladium acetate (27.2 mg, 121 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (65.2 mg, 121 μmol) and diisopropylethylamine (469 mg, 3.63 mmol) under nitrogen, then the mixture was stirred at 95 °C for 16 hr under nitrogen. On completion, the mixture was quenched by hydrochloric acid (1 M, 6.1 mL) and further stirred at 25 °C for 0.5 hr. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=1/0 to 1/8) to give 8-acetyl-3,6-dimethyl-2-(3- pyridyl)quinazolin-4-one (300 mg, 1.02 mmol, 84%) as a yellow gum. m/z ES+ [M+H] ⁺ 294.3. [1804] Step 3. Synthesis of (R)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [1805] To a mixture of 8-acetyl-3,6-dimethyl-2-(3-pyridyl)quinazolin-4-one (0.3 g, 1.02 mmol) in 2-methyl tetrahydrofuran (4 mL) was added (R)-2-methylpropane-2-sulfinamide (619 mg, 5.11 mmol) and tetraethoxytitanium (1.17 g, 5.11 mmol), the mixture was stirred at 85 °C for 16 hr. On completion, the reaction mixture was diluted water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 0/1) to give (R)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4-dihydroqui nazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (310 mg, 750 μmol, 73%) as a yellow gum. m/z ES+ [M+H] ⁺ 397.5. [1806] Step 4. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [1807] To a mixture of (R)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (520 mg, 1.31 mmol) in tetrahydrofuran (7 mL) was added sodium borohydride (99.2 mg, 2.62 mmol) portionwise at - 40 °C. The mixture was stirred at -40 °C for 3 hr. Then the mixture was stirred at 15 °C for 16 hr. On completion, the mixture was quenched by water (50 mL) and saturated ammonium chloride solution (50 mL). Then the mixture was extracted with ethyl acetate (70 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (Welch Xtimate C18 150 x 25 mm, 5 um; mobile phase: [water (ammonia hydroxide v/v)- acetonitrile]; B%: 24%-54%, 2 min) to give (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-3- yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide (45 mg, 112 μmol, 8%) as a yellow oil. m/z ES+ [M+H] ⁺ 454.2. [1808] Step 5. Synthesis of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-3-yl)quinazolin - 4(3H)-one [1809] A mixture of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (40 mg, 100 μmol) in hydrogen chloride/dioxane (4 M, 0.5 mL) was stirred at 20 °C for 1 hr. On completion, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-3,6- dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one (35 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 295.0. [1810] Step 6. Synthesis of (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )- 2-(pyridin-3-yl)quinazolin-4(3H)-one [1811] To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-3-yl)quinazolin -4(3H)- one (30 mg, 101 μmol) in N,N-dimethylformamide (0.5 mL) was added 1-fluoro-2- methylsulfonyl-benzene (26.6 mg, 153 μmol) and cesium carbonate (99.6 mg, 305 μmol), the mixture was stirred at 140 °C for 20 hr. On completion, the mixture was filtered and the filtrate was directly purified by prep-HPLC (Waters xbridge 150 x 25 mm, 10 um; mobile phase: [water( NH4HCO3)-acetonitrile]; B%: 34%-64%, 9 min) to give (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(pyridin-3-yl)quinazol in-4(3H)-one (7.28 mg, 16.2 μmol, 16%) as a brown gum. ¹ H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 1.6 Hz, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.51 (dd, J = 4.8, 7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 6.8 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.57 - 5.48 (m, 1H), 3.59 (s, 3H), 3.07 (s, 3H), 2.45 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 449.3. Example 163. Preparation of (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(pyridin-2-yl)quinazol in-4(3H)-one

[1812] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(pyridin-2-yl)quinazolin-4(3H)-one [1813] To a solution of 2-amino-3-bromo-N,5-dimethyl-benzamide (2 g, 8.23 mmol) in ethanol (30 mL) was added pyridine-2-carbaldehyde (1.06 g, 9.87 mmol) and iodine (4.18 g, 16.4 mmol), the mixture was stirred at 90 °C for 12 hours. On completion, the crude product was triturated in water (30 mL) at 25 ^o C for 10 min and then filtered. The filtered cake was collected and dried in vacuo to give 8-bromo-3,6-dimethyl-2-(2-pyridyl)quinazolin-4-one (2.1 g, 3.18 mmol, 39%) as a white solid. m/z ES+ [M+H] ⁺ 331.8. [1814] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(pyridin-2-yl)quinazolin-4(3H)-one [1815] To solution of 8-bromo-3,6-dimethyl-2-(2-pyridyl)quinazolin-4-one (2 g, 6.06 mmol) in n-butanol (20 mL) was added 1-vinyloxybutane (1.82 g, 18.1 mmol), palladium acetate (135 mg, 605 μmol), diisopropylethylamine (2.35 g, 18.1 mmol) and [2-(2- diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (326 mg, 605 μmol). The mixture was stirred at 90 °C for 2 hr under nitrogen atmosphere. On completion, the mixture was quenched by hydrochloric acid (1 M, 5.7 mL) and further stirred at 25 °C for 0.1 hr. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1/0 to 5/1) to give 8-acetyl-3,6-dimethyl-2-(2- pyridyl)quinazolin-4-one (880 mg, 2.79 mmol, 49%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) 8.69 - 8.62 (m, 1H), 8.23 (d, J = 1.2 Hz, 1H), 7.92 - 7.76 (m, 3H), 7.43 - 7.36 (m, 1H), 3.62 (s, 3H), 2.77 (s, 3H), 2.46 (s, 3H); m/z ES+ [M+H] ⁺ 294.2. [1816] Step 3. Synthesis of (R)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [1817] To a solution of 8-acetyl-3,6-dimethyl-2-(2-pyridyl)quinazolin-4-one (880 mg, 3.00 mmol) in anhydrous tetrahydrofuran (10 mL) was added (R)-2-methylpropane-2-sulfinamide (1.82 g, 15.0 mmol) and tetraethoxytitanium (3.42 g, 15.0 mmol), the mixture was stirred at 80 °C for 16 hours under nitrogen atmosphere. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1/0 to 10/1) to give (R)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4-dihydroqui nazolin-8-yl)ethylidene)- 2-methylpropane-2-sulfinamide (1.13 g, 2.76 mmol, 92%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (d, J = 4.0 Hz, 1H), 8.15 (s, 1H), 7.87 - 7.78 (m, 2H), 7.59 (s, 1H), 7.41 - 7.35 (m, 1H), 3.60 (s, 3H), 2.80 (s, 3H), 2.45 (s, 3H), 1.16 (s, 8H); m/z ES+ [M+H] ⁺ 397.3. [1818] Step 4. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [1819] To a mixture of (R)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.00 g, 2.52 mmol) in anhydrous tetrahydrofuran (15 mL) was added sodium borohydride (114 mg, 3.03 mmol) portionwise at -60 °C. The mixture was stirred at -60 °C for 4 hours. Then the mixture was stirred at 0~25 °C for 12 hr. On completion, the mixture was quenched with water (100 mL) and saturated ammonium chloride solution (300 mL). Then the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue The residue was purified by prep-HPLC [column: Phenomenex C18250 x 50 mm, 10 um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 27%-57%, 8 min] to give (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2- (pyridin-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide (200 mg, 476 μmol, 19%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.79 - 8.65 (m, 1H), 8.08 (d, J = 1.2 Hz, 1H), 7.99 - 7.90 (m, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.50 - 7.42 (m, 1H), 5.18 - 4.99 (m, 2H), 3.66 (s, 3H), 2.52 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.15 (s, 9H); m/z ES+ [M+H] ⁺ 399.1. [1820] Step 5. Synthesis of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-2-yl)quinazolin - 4(3H)-one [1821] A solution of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (180 mg, 451 μmol) in hydrochloric acid/1,4-dioxane (3 mL) was stirred at 20 °C for 1 hr. On completion, the mixture was basified with sat. sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-2-yl)quinazolin -4(3H)-one (180 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 294.9. [1822] Step 6. Synthesis of (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )- 2-(pyridin-2-yl)quinazolin-4(3H)-one [1823] A suspension of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-2-yl)quinazolin - 4(3H)-one (180 mg, 611 μmol), 1-fluoro-2-methylsulfonyl-benzene (213 mg, 1.22 mmol) and cesium carbonate (398 mg, 1.22 mmol) in N,N-dimethylformamide (2 mL) was stirred at 140 °C for 16 hr. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC [column: Waters xbridge 150 x 25 mm, 10 um; mobile phase: [water (NH ₄ HCO ₃ )-acetonitrile]; B%: 36%-66%, 11 min] to give (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(pyridin-2-yl)quinazol in-4(3H)-one (80.6 mg, 177 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 - 8.69 (m, 1H), 8.12 - 8.04 (m, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.34 - 7.26 (m, 1H), 6.78 - 6.66 (m, 2H), 6.62 (d, J = 8.4 Hz, 1H), 5.46 (q, J = 6.4 Hz, 1H), 3.51 (s, 3H), 3.12 (s, 3H), 2.43 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 449.3. Example 164. Preparation of (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(1,4-oxazepan-4-yl)qui nazolin-4(3H)-one [1824] To a mixture of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (70 mg, 161 μmol) in diisopropylethylamine (371 mg, 2.87 mmol) was added 1,4-oxazepane (66.6 mg, 484 μmol, HCl). The mixture was stirred at 40 °C for 1 hr and then stirred at 60 °C for 16 hr. On completion, the mixture was purified by prep-HPLC (Waters xbridge 150 x 25mm, 10 um; mobile phase: [water(NH4HCO3)-acetonitrile]; B%: 39%-69%, 7min) to give (R)-3,6- dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2-(1,4 -oxazepan-4-yl)quinazolin- 4(3H)-one (8.83 mg, 18.8 μmol, 11%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J = 0.8 Hz, 1H), 7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.26 - 7.21 (m, 1H), 6.78 (d, J = 6.4 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 5.44 - 5.34 (m, 1H), 3.96 - 3.90 (m, 4H), 3.64 - 3.55 (m, 7H), 3.11 (s, 3H), 2.37 (s, 3H), 2.16 - 2.09 (m, 2H), 1.62 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 471.3. Example 165. Preparation of O-(2-(((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoyl)-L-serine [1825] Step 1. Synthesis of (S)-3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxoprop yl 2-(((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8- yl)ethyl)amino)benzoate [1826] To a solution of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin- 8-yl)ethyl)amino)benzoic acid (50 mg, 118 μmol) and tert-butyl (2S)-2-(tert- butoxycarbonylamino)-3-hydroxy-propanoate (46.4 mg, 178 μmol) in dichloromethane (1 mL) was added 3-(ethyliminomethylideneamino)propyl-dimethylazanium;chlorid e (27.2 mg, 142 μmol) and 4-dimethylaminopyridine (2.89 mg, 23.7 μmol). The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic phases were concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give (S)-3-(tert- butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl 2-(((R)-1-(3,6-dimethyl-2-morpholino- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (30 mg, 27 μmol, 23%) as a white solid. m/z ES+ [M+H] ⁺ 666.3. [1827] Step 2. Synthesis of O-(2-(((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoyl)-L-serine [1828] To a solution of (S)-3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxoprop yl 2- (((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazol in-8-yl)ethyl)amino)benzoate (30 mg, 45.1 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.7 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 22%-42%, 2 min) to give O-(2-(((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroqui nazolin-8- yl)ethyl)amino)benzoyl)-L-serine (13.9 mg, 27.2 μmol, 60%) as a white solid. ¹ H NMR (400 MHz, CD3OD) 8.00 (dd, J = 1.2, 8.0 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.21 - 7.11 (m, 1H), 6.55 - 6.47 (m, 2H), 5.49 (q, J = 6.4 Hz, 1H), 4.74 (dd, J = 2.8, 12.0 Hz, 1H), 4.66 - 4.54 (m, 1H), 3.99 (dd, J = 2.8, 6.0 Hz, 1H), 3.89 (t, J = 4.4 Hz, 4H), 3.62 (s, 3H), 3.38 - 3.32 (m, 4H), 2.35 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 510.3. Example 166. Preparation of (R)-8-(1-((5-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [1829] Step 1. Synthesis of 2,4-difluoro-1-(methylsulfonyl)benzene [1830] To a solution of (2,4-difluorophenyl)(methyl)sulfane (100 mg, 624 μmol) in dichloromethane (3 mL) was added 3-chloroperoxybenzoic acid (634 mg, 3.12 mmol, 85%). The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was quenched by saturated solution of sodium sulfite (10 mL) at 25 °C, and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2,4-difluoro-1- (methylsulfonyl)benzene (100 mg, crude) as a colorless oil. [1831] Step 2. Synthesis of (R)-8-(1-((5-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6- dimethyl-2-morpholinoquinazolin-4(3H)-one [1832] A solution of 2,4-difluoro-1-methylsulfonyl-benzene (90.0 mg, 468 μmol), (R)-8-(1- aminoethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (142 mg, 468 μmol) and cesium carbonate (305 mg, 937 μmol) in dimethyl acetamide (2 mL) was stirred at 120 °C for 12 hr. On completion, the reaction mixture was quenched by water (10 mL) at 25 °C, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18150 x 50mm, 10 um; mobile phase: [water( NH ₄ HCO ₃ )-acetonitrile]; B%: 46%-76%, 10 min) and further purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1/1) to give (R)-8-(1-((5-fluoro- 2-(methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morphol inoquinazolin-4(3H)-one (1.43 mg, 3.01 μmol, 7.2%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 1.2 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.45 (d, J = 2.0 Hz, 1H), 6.94 (br. d, J = 6.0 Hz, 1H), 6.44 - 6.33 (m, 2H), 5.45 - 5.36 (m, 1H), 3.96 - 3.86 (m, 4H), 3.63 (s, 3H), 3.35 - 3.27 (m, 4H), 3.08 (s, 3H), 2.40 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 475.2. Example 167. Preparation of 2-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)-3,6-dimethyl-8- ((R)-1-((2-(methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3 H)-one [1833] To a mixture of (R)-3,6-dimethyl-2-(methylsulfonyl)-8-(1-((2-(methylsulfonyl )- phenyl)amino)ethyl)quinazolin-4(3H)-one (30 mg, 66.7 μmol) in diisopropylethylamine (371 mg, 2.87 mmol) was added (3S,4R)-3,4-dimethylpyrrolidine (27.1 mg, 200 μmol, HCl). The mixture was stirred at 40 °C for 4 hr. On completion, the mixture was purified by prep-HPLC (Waters xbridge 150 x 25 mm, 10 um; mobile phase: [water( NH ₄ HCO ₃ )-acetonitrile]; B%: 53%-83%, 8 min) to give 2-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)-3,6-dimethyl-8-((R)- 1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one (16.6 mg, 35.3 μmol, 53%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.79 - 6.65 (m, 2H), 6.59 (d, J = 8.4 Hz, 1H), 5.47 - 5.36 (m, 1H), 3.76 – 3.64 (m, 2H), 3.56 (s, 3H), 3.38 - 3.26 (m, 2H), 3.10 (s, 3H), 2.44 - 2.29 (m, 5H), 1.62 (d, J = 6.4 Hz, 3H), 1.03 (t, J = 5.6 Hz, 6H); m/z ES+ [M+H] ⁺ 469.3. Example 168. Preparation of (R)-2-(4-methoxypiperidin-1-yl)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)quinazolin-4(3H)-one [1834] A solution of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2-(methylsulfonyl )phenyl)- amino)ethyl)quinazolin-4(3H)-one (80.0 mg, 178 μmol) and 4-methoxypiperidine (81.0 mg, 533 μmol) in diisopropylethylamine (115 mg, 889 μmol) was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)-acetonitrile]; B%: 51%-81%, 10 min) to give 2-(4-methoxy-1- piperidyl)-3,6-dimethyl-8-[(1R)-1-(2-methylsulfonylanilino)e thyl]quinazolin-4-one (30.2 mg, 62.3 μmol, 35%) as yellow gum. ¹ H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.71 - 7.64 (m, 1H), 7.35 (s, 1H), 7.17 - 7.13 (m, 1H), 6.77 - 6.68 (m, 1H), 6.62 (t, J = 7.6 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.43 - 5.25 (m, 1H), 3.52 (s, 3H), 3.44 - 3.35 (m, 3H), 3.33 (s, 3H), 3.09 - 2.95 (m, 5H), 2.29 (s, 3H), 2.07 - 1.94 (m, 2H), 1.76 - 1.65 (m, 2H), 1.56 - 1.53 (m, 3H); m/z ES+ [M+H] ⁺ 485.3. Example 169. Preparation of N-(4-fluoro-2-(methylsulfonyl)phenyl)-3,6-dimethyl-4-oxo- 2-(piperidin-1-yl)-3,4-dihydroquinazoline-8-sulfonamide (Compound 531) [1835] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one [1836] To a solution of 8-bromo-2-chloro-3,6-dimethyl-quinazolin-4-one (5.2 g, 18.08 mmol) and piperidine (2.31 g, 27.1 mmol, 2.68 mL) in dichloromethane (50 mL) was added diisopropylethylamine (7.01 g, 54.3 mmol, 9.45 mL) and 4A molecular sieve (1 g). The mixture was stirred at 40 °C for 12 hr under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate =100/1 to 1/1) to give 8-bromo- 3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (5.5 g, 15.2 mmol, 84%) as a white solid. m/z ES+ [M+H] ⁺ 337.9/335.9. [1837] Step 2. Synthesis of methyl 3-((3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)sulfonyl)propanoate [1838] To a solution of 8-bromo-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (500 mg, 1.49 mmol) and (3-methoxy-3-oxo-propyl)sulfinyloxysodium (1.29 g, 7.44 mmol) in dimethylsulfoxide (5 mL) was added copper iodide (1.42 g, 7.44 mmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give methyl 3-[3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8-yl]sulfony lp-ropanoate (360 mg, 795 μmol, 53%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.66 (s, 3H), 3.55 (s, 3H), 3.33 - 3.24 (m, 4H), 2.80 - 2.71 (m, 2H), 2.49 (s, 3H), 1.81 - 1.65 (m, 6H); m/z ES+ [M+H] ⁺ 408.2. [1839] Step 3. Synthesis of Sodium 3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazoline-8-sulfinate [1840] To a solution of methyl 3-[3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8- yl]sulfonylpropanoate (310 mg, 760 μmol) in anhydrous tetrahydrofuran (30 mL) and methanol (3 mL) was added dropwise sodium methanolate (5 M, 152 ^L). The mixture was stirred at 25 °C for 0.2 hr. On completion, the reaction mixture was added Petroleum ether (30 mL), then filtered and concentrated under reduced pressure to give sodium 3,6-dimethyl-4-oxo-2- (piperidin-1-yl)-3,4-dihydroquinazoline-8-sulfinate (230 mg, 602 μmol, 79%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J = 1.2 Hz, 1H), 7.67 (s, 1H), 3.44 (s, 3H), 3.12 (d, J = 4.4 Hz, 4H), 2.41 - 2.34 (m, 3H), 1.72 - 1.53 (m, 6H); m/z ES+ [M+H] ⁺ 344.1. [1841] Step 4. Synthesis of 3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinazoline -8- sulfonyl chloride [1842] To a solution of [3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazolin-8- yl]sulfinyloxysodium (230 mg, 669 μmol) in dichloromethane (15 mL) was added N- chlorosuccinimide (134 mg, 1.00 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazoline-8- sulfonyl chloride (160 mg, 409 μmol, 61%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.16 (s, 1H), 3.56 (s, 3H), 3.46 - 3.35 (m, 4H), 2.50 (s, 3H), 1.85 - 1.65 (m, 6H); m/z ES+ [M+H] ⁺ 356.1. [1843] Step 5. Synthesis of N-(4-fluoro-2-(methylsulfonyl)phenyl)-3,6-dimethyl-4-oxo-2- (piperidin-1-yl)-3,4-dihydroquinazoline-8-sulfonamide [1844] To a solution of 3,6-dimethyl-4-oxo-2-(1-piperidyl)quinazoline-8-sulfonyl chloride (50.0 mg, 140 μmol) and 4-fluoro-2-methylsulfonyl-aniline (265 mg, 1.41 mmol) in dioxane (1 mL) was added 4-dimethylaminopyridine (51.5 mg, 421 μmol) at 25 °C. The mixture was stirred at 100 °C for 1.5 hr. On completion, the reaction mixture was partitioned between dichloromethane (20 mL) and water (5 mL). The organic phase was separated, washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water(formic acid)-acetonitrile];B%: 56%-86%, 10 min) to give N-(4-fluoro-2-methylsulfonyl-phenyl)-3,6-dimethyl-4-oxo-2-(1 - piperidyl)quinazoline-8-sulfonamide (44.0 mg, 86.5 μmol, 61%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (s, 1H), 8.21 (s, 2H), 7.64 (dd, J = 3.2, 7.6 Hz, 1H), 7.46 (dd, J = 4.4, 9.2 Hz, 1H), 7.25 - 7.18 (m, 1H), 3.55 (s, 3H), 3.35 (d, J = 5.6 Hz, 4H), 3.09 (s, 3H), 2.53 (s, 3H), 1.79 - 1.67 (m, 6H); m/z ES+ [M+H] ⁺ 509.1. Example 170. Preparation of 8-(2-((4-fluoro-2-(methylsulfonyl)phenyl)amino)propan-2- yl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 492)

[1845] Step 1. Synthesis of 8-(2-((4-fluoro-2-(methylsulfonyl)phenyl)amino)propan-2-yl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [1846] A mixture of 8-(1-amino-1-methyl-ethyl)-3,6-dimethyl-2-morpholino-quinazo lin-4- one (50 mg, 158 μmol), 1,4-difluoro-2-methylsulfonyl-benzene (151 mg, 790 μmol), cesium carbonate (154 mg, 474 μmol), 4A molecular sieve (50 mg) in dimethyl acetamide (0.5 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 140 °C for 12 hr under nitrogen atmosphere. The reaction mixture was partitioned between water (5 mL) and ethyl acetate (20 mL). The organic phase was separated, dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water(formic acid)- acetonitrile];B%: 55%-85%, 10 min) and the residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=1/2 ) to give 8-(2-((4- Fluoro-2-(methylsulfonyl)phenyl)amino)propan-2-yl)-3,6-dimet hyl-2-morpholinoquinazolin- 4(3H)-one (12.0 mg, 22.8 μmol, 14%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.58 (s, 1H), 7.53 (dd, J = 3.2, 8.0 Hz, 1H), 6.90 - 6.82 (m, 1H), 6.61 (s, 1H), 6.38 (dd, J = 4.0, 9.2 Hz, 1H), 3.91 - 3.84 (m, 4H), 3.56 (s, 3H), 3.26 - 3.20 (m, 4H), 3.17 (s, 3H), 2.45 (s, 3H), 1.96 (s, 6H); m/z ES+ [M+H] ⁺ 489.2. Example 171. Preparation of 2-((2-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)propan-2-yl)amino)-5-fluorobenzoic acid (Compound 509) [1847] Step 1. Synthesis of methyl 2-((2-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)propan-2-yl)amino)-5-fluorobenzoate [1848] A mixture of 8-(1-amino-1-methyl-ethyl)-3,6-dimethyl-2-morpholino-quinazo lin-4- one (50 mg, 158 μmol), methyl 2-bromo-5-fluoro-benzoate (184 mg, 790 μmol), cesium carbonate (154 mg, 474 μmol), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H- imidazol-1-ium-2-ide;3-chloropyridinedichloropalladium (15.3 mg, 15.8 μmol) in dioxane (3 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The organic phase was separated, dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=1/2) to give methyl 2-[[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)-1-me thyl- ethyl]amino]-5-fluoro-benzoate (15 mg, 24.0 μmol, 15%) as a yellow solid. m/z ES+ [M+H] ⁺ 469.2. [1849] Step 2. Synthesis of 2-((2-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin - 8-yl)propan-2-yl)amino)-5-fluorobenzoic acid [1850] To a solution of methyl 2-[[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)-1- methyl-ethyl]amino]-5-fluoro-benzoate (15 mg, 32.0 μmol) in water (0.1 mL), anhydrous tetrahydrofuran (0.1 mL) and methanol (0.1 mL) was added lithium hydroxide (2.30 mg, 96.0 μmol). The mixture was stirred at 25 °C for 3 hr. The reaction mixture was quenched by addition hydrochloric acid (1N) to PH = 6 at 25 °C, and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm,10um; mobile phase: [water(formic acid)- acetonitrile];B%: 36%-56%,9 min) to give 2-((2-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazolin -8- yl)propan-2-yl)amino)-5-fluorobenzoic acid (7.70 mg, 14.7 μmol, 46%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.97 (dd, J = 3.2, 8.8 Hz, 1H), 7.35 (d, J = 1.6 Hz, 1H), 6.87 - 6.80 (m, 1H), 6.23 (dd, J = 4.8, 8.8 Hz, 1H), 3.91 - 3.87 (m, 4H), 3.64 (s, 3H), 3.24 - 3.19 (m, 4H), 2.45 (s, 3H), 1.72 (s, 6H); m/z ES+ [M+H] ⁺ 455.2. Example 172. Preparation of 8-(1-((2-(2-hydroxy-2- methylpropanoyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholin oquinazolin-4(3H)-one (Compound 212)

[1851] Step 1. Synthesis of 1-bromo-2-(2-methylprop-1-enyl)benzene [1852] To a solution of isopropyl(triphenyl)phosphonium iodide (7.71 g, 17.8 mmol) in anhydrous tetrahydrofuran (80 mL) at 0 °C was added n-butyllithium (2.5 mol/L in n-hexane, 7.46 mL) dropwise. The reaction mixture was maintained at 0 °C and 2-bromobenzaldehyde (3 g, 16.2 mmol) was added dropwise. Then the mixture was stirred at 20 °C for 2 hr under nitrogen atmosphere. The reaction mixture was quenched by addition saturated ammonium chloride (100 mL) at 0 °C, and then diluted with water (100 mL) and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 1-bromo-2-(2-methylprop-1-enyl)benzene (3 g, 14.2 mmol, 88%) as white oil. ¹ H NMR (400 MHz, CDCl3) δ 7.63 - 7.53 (m, 1H), 7.30 - 7.29 (m, 1H), 7.28 - 7.27 (m, 1H), 7.15 - 7.04 (m, 1H), 6.28 (s, 1H), 1.97 (d, J = 1.2 Hz, 3H), 1.79 (d, J = 1.2 Hz, 3H). [1853] Step 2. Synthesis of 1-(2-bromophenyl)-2-methyl-propane-1,2-diol [1854] To a solution of 1-bromo-2-(2-methylprop-1-enyl)benzene (1.5 g, 7.11 mmol) in tertiary butanol (2 mL) and water (4 mL), acetone (10 mL)was added 4-methyl-4-oxido- morpholin-4-ium (1.25 g, 10.7 mmol, 1.12 mL). The reaction mixture was added tetraoxoosmium (181 mg, 711 μmol) portionwise at 25 °C and stirred at 25 °C for 1 hr. The reaction mixture was quenched by saturated sodium sulfite (40 mL) at 25 °C, and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(2-bromophenyl)-2-methyl- propane-1,2-diol (1.2 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 - 7.60 (m, 1H), 7.56 - 7.51 (m, 1H), 7.36 - 7.31 (m, 1H), 7.18 - 7.12 (m, 1H), 5.08 (s, 1H), 2.75 (s, 1H), 2.18 (s, 1H), 1.37 (s, 3H), 1.14 (s, 3H). [1855] Step 3. Synthesis of 5-(2-bromophenyl)-2,2,4,4- tetramethyl- 1,3-dioxolane [1856] To a solution of 1-(2-bromophenyl)-2-methyl-propane-1,2-diol (1.18 g, 4.81 mmol) in N,N-dimethylformamide (12 mL) was added p-toluenesulfonic acid (166 mg, 963 μmol) and 2,2-dimethoxypropane (852 mg, 8.18 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 3/1) to give 5-(2-bromophenyl)-2,2,4,4- tetramethyl- 1,3-dioxolane (1.2 g, 4.21 mmol, 87%) as a white oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.67 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.22 - 7.11 (m, 1H), 5.37 (s, 1H), 1.61 (s, 3H), 1.58 (s, 3H), 1.51 (s, 3H), 0.91 (s, 3H). [1857] Step 4. Synthesis of 3,6-dimethyl-2-morpholino-8-[1-[2-(2,2,5,5-tetramethyl-1,3- dioxolan-4-yl)anilino]ethyl]quinazolin-4-one [1858] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (220 mg, 728 μmol) and 5-(2-bromophenyl)-2,2,4,4-tetramethyl-1,3-dioxolane (623 mg, 2.18 mmol) in toluene (6 mL) was added cesium carbonate (711 mg, 2.18 mmol), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (33.9 mg, 72.8 μmol) and tris(dibenzylideneacetone)dipalladium (66.6 mg, 72.8 μmol). The mixture was stirred at 120 °C for 12 hr under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 3,6-dimethyl-2-morpholino-8-[1-[2-(2,2,5,5- tetramethyl-1,3-dioxolan-4-yl)anilino]ethyl]quinazolin-4-one (250 mg, 494 μmol, 68%) as a yellow solid. m/z ES+ [M+H] ⁺ 507.1 [1859] Step 5. Synthesis of 8-[1-[2-(1,2-dihydroxy-2-methyl-propyl)anilino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one [1860] To a solution of 3,6-dimethyl-2-morpholino-8-[1-[2-(2,2,5,5-tetramethyl-1,3- dioxolan-4-yl)anilino]ethyl]quinazolin-4-one (210 mg, 415 μmol) in hydrochloric acid/dioxane (4 M, 3 mL) was stirred at 20 °C for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic acid)- acetonitrile];B%: 25%-55%, 7 min) to give 8-[1-[2-(1,2-dihydroxy-2-methyl- propyl)anilino]ethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (190 mg, 407 μmol, 98%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.57 - 7.48 (m, 1H), 7.15 - 7.03 (m, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.69 - 6.60 (m, 1H), 6.49 - 6.39 (m, 1H), 5.40 - 5.32 (m, 1H), 4.73 - 4.62 (m, 1H), 3.89 (br. t, J = 4.4 Hz, 4H), 3.62 (s, 3H), 3.29 (br. d, J = 4.4 Hz, 4H), 2.36 (s, 3H), 1.55 (br. d, J = 6.4 Hz, 3H), 1.41 - 1.38 (m, 3H), 1.34 - 1.28 (m, 3H); m/z ES+ [M+H] ⁺ 467.2. [1861] Step 6. Synthesis of 8-[1-[2-(2-hydroxy-2-methyl-propanoyl)anilino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one [1862] To a solution of 8-[1-[2-(1,2-dihydroxy-2-methyl-propyl)anilino]ethyl]-3,6-di methyl- 2-morpholino-quinazolin-4-one (60 mg, 129 μmol) in dimethylsulfoxide (1 mL) was added 1- hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione (180 mg, 643 μmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic acid)-acetonitrile];B%: 52%-82%, 7 min) to give 8-[1-[2-(2-hydroxy-2-methyl-propanoyl)anilino]ethyl]-3,6-dim ethyl-2-morpholino- quinazolin-4-one (54 mg, 116 μmol, 90%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 9.47 - 9.27 (m, 1H), 7.97 - 7.93 (m, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.21 - 7.15 (m, 1H), 6.59 - 6.51 (m, 2H), 5.56 - 5.45 (m, 1H), 4.96 - 4.49 (m, 1H), 3.93 - 3.87 (m, 4H), 3.63 (s, 3H), 3.33 - 3.27 (m, 4H), 2.38 (s, 3H), 1.72 (d, J = 1.6 Hz, 6H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 465.2. Example 173. Preparation of 3,6-dimethyl-8-(1-((2-(S- methylsulfonimidoyl)phenyl)amino)-ethyl)-2-morpholinoquinazo lin-4(3H)-one (Compound 165) [1863] Step 1. Synthesis of 3,6-dimethyl-8-(1-((2-(S- methylsulfonimidoyl)phenyl)amino)ethyl)-2-morpholinoquinazol in-4(3H)-one [1864] To a mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (150 mg, 496 μmol) and (2-fluorophenyl)-imino-methyl-oxo-^ ⁶ -sulfane (129 mg, 744 μmol) in dimethyl acetamide (5 mL) was added cesium carbonate (323 mg, 992 μmol) in one portion. The mixture was heated to 135 °C and stirred for 16 hr. On completion, the reaction mixture was quenched by water (50 mL) at 20 °C, and then diluted with ethyl acetate (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx10um;mobile phase: [water(fomic acid)-acetonitrile];B%: 35%-65%, 10 min) to give 3,6-dimethyl-8-(1-((2-(S-methylsulfonimidoyl)phenyl)amino)et hyl)-2- morpholinoquinazolin-4(3H)-one (43 mg, 94.4 μmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.84 - 7.68 (m, 2H), 7.66 (dd, J = 1.6, 8.0 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.53 (dd, J = 1.6, 15.2 Hz, 1H), 7.29 - 7.15 (m, 1H), 6.66 (q, J = 7.2 Hz, 1H), 6.52 (dd, J = 8.8, 12.4 Hz, 1H), 5.50 - 5.30 (m, 1H), 4.71 - 4.51 (m, 1H), 3.78 (br. s, 4H), 3.50 (s, 3H), 3.26 (br. d, J = 4.0 Hz, 4H), 3.08 (s, 3H), 2.33 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 456.2. Example 174. Preparation of 3,6-dimethyl-8-((R)-1-((2-((S)-S- methylsulfonimidoyl)phenyl)amino) ethyl)-2-morpholinoquinazolin-4(3H)-one and 3,6- dimethyl-8-((S)-1-((2-((S)-S-methylsulfonimidoyl)phenyl)amin o)ethyl)-2-morpholino- quinazolin-4(3H)-one and 3,6-dimethyl-8-((R)-1-((2-((R)-S-methylsulfonimidoyl)phenyl) - amino)ethyl)-2-morpholinoquinazolin-4(3H)-one and 3,6-dimethyl-8-((S)-1-((2-((R)-S- methylsulfonimidoyl)phenyl)amino)ethyl)-2-morpholinoquinazol in-4(3H)-one (Compounds 181, 182, 183, and 184) (stereochemistry arbitrarily assigned for all enantiomers) [1865] Step 1. Chiral purification [1866] A mixture of 3,6-dimethyl-8-[1-[2-(methylsulfonimidoyl)anilino]ethyl]-2- morpholino-quinazolin-4-one (40 mg, 87.8 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10um);mobile phase: [0.1% ammonium hydroxide methanol];B%: 50%-50%,7.1min)(column: REGIS(S,S)WHELK- O1(250mmx25mm,10um);mobile phase: [0.1% ammonium hydroxide methanol];B%: 45%- 45%,5.0min) to give peak 1: 3,6-dimethyl-8-((R)-1-((2-((S)-S- methylsulfonimidoyl)phenyl)amino)ethyl)-2-morpholinoquinazol in-4(3H)-one (6.06 mg, 13.2 μmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H),7.81 (d, J = 7.6 Hz, 1H), 7.48 (br. d, J = 6.8 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.23 - 7.14 (m, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 5.50 (quin, J = 6.4 Hz, 1H), 3.95 - 3.87 (m, 4H), 3.63 (s, 3H), 3.34 - 3.26 (m, 4H), 3.19 (s, 3H), 2.38 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 456.2; and peak 2: 3,6-dimethyl-8-((S)-1-((2-((S)-S-methylsulfonimidoyl)phenyl) amino)ethyl)-2- morpholinoquinazolin-4(3H)-one (8.46 mg, 18.4 μmol, 21%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.82 (dd, J = 1.2, 8.0 Hz, 1H), 7.49 (br. d, J = 5.6 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.23 - 7.14 (m, 1H), 6.69 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 5.51 (br. d, J = 5.6 Hz, 1H), 3.93 - 3.85 (m, 4H), 3.63 (s, 3H), 3.32 - 3.26 (m, 4H), 3.19 (s, 3H), 2.38 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 456.2; and peak 3: 3,6-dimethyl-8-((R)-1- ((2-((R)-S-methylsulfonimidoyl)phenyl)amino)ethyl)-2-morphol inoquinazolin-4(3H)-one (13.2 mg, 29 μmol, 33%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 1.2 Hz, 1H), 7.82 (dd, J = 1.6, 8.0 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.41 (br. d, J = 5.6 Hz, 1H), 7.24 - 7.12 (m, 1H), 6.74 - 6.65 (m, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.48 (t, J = 6.4 Hz, 1H), 3.94 - 3.85 (m, 4H), 3.63 (s, 3H), 3.33 - 3.25 (m, 4H), 3.20 (s, 3H), 2.37 (s, 3H), 1.60 (d, J = 6.8 Hz 3H); m/z ES+ [M+H] ⁺ 456.2; and peak 4: 3,6-dimethyl-8-((S)-1-((2-((R)-S- methylsulfonimidoyl)phenyl)amino)ethyl)-2-morpholinoquinazol in-4(3H)-one (10.2 mg, 22.3 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 1.0 Hz, 1H), 7.82 (dd, J = 1.6, 8.0 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.69 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.47 (t, J = 6.4 Hz, 1H), 3.95 - 3.85 (m, 4H), 3.62 (s, 3H), 3.33 - 3.25 (m, 4H), 3.20 (s, 3H), 2.37 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 456.2. Example 175. Preparation of (R)-3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(morpholino-d ₈ )quinazolin-4(3H)-one (Compound D5)

[1867] Step 1. Synthesis of 1-fluoro-2-(methylsulfonyl)benzene [1868] To a solution of 1-fluoro-2-methylsulfanyl-benzene (4.50 g, 31.6 mmol, 3.83 mL) in water (45 mL) and acetonitrile (45 mL) was added potassium peroxomonosulfate (58.3 g, 94.9 mmol) portionwise at 25 °C. The mixture was stirred at 100 °C for 24 hr. The reaction mixture was filtered and the filtrate was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-fluoro- 2-methylsulfonyl-benzene (5.00 g, 28.7 mmol, 91%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.04 - 7.95 (m, 1H), 7.74 - 7.62 (m, 1H), 7.43 - 7.34 (m, 1H), 7.32 - 7.26 (m, 1H), 3.25 (s, 3H). [1869] Step 2. Synthesis of (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )- 2-(methylthio)quinazolin-4(3H)-one [1870] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-methylsulfanyl-quinazol in-4- one (500 mg, 1.90 mmol) in dimethyl acetamide (5 mL) was added cesium carbonate (1.86 g, 5.70 mmol) and 1-fluoro-2-methylsulfonyl-benzene (992 mg, 5.70 mmol). The mixture was stirred at 140 °C for 12 hr. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [water(formic acid)- acetonitrile];gradient:53%-83% B over 15 min) to give (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )-2- (methylthio)quinazolin-4(3H)-one (300 mg, 718 μmol, 38%) as a white solid. m/z ES+ [M+H] ⁺ 418.1. [1871] Step 3. Synthesis of 3,6-dimethyl-2-(methylsulfinyl)-8-((R)-1-((2-(methylsulfonyl )- phenyl)amino)ethyl)quinazolin-4(3H)-one [1872] To a solution of 3,6-dimethyl-2-methylsulfanyl-8-[(1R)-1-(2-methylsulfonylani lino) ethyl] quinazolin-4-one (150 mg, 359 μmol) in anhydrous tetrahydrofuran (1.5 mL) was added a solution of potassium peroxomonosulfate (441 mg, 718 μmol) in water (0.4 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3,6-dimethyl-2-methylsulfinyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]quinazolin-4-one (150 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 434.1. [1873] Step 4. Synthesis of (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )- 2-(morpholino-d ₈ )quinazolin-4(3H)-one [1874] To a solution of 2,2,3,3,5,5,6,6-octadeuteriomorpholine (29.1 mg, 221 μmol, hydrogen chloride salt) in diisopropylethylamine (2 mL) was added 3,6-dimethyl-2-methylsulfinyl-8- [(1R)-1-(2-methylsulfonylanilino)ethyl]quinazolin-4-one (80.0 mg, 184 μmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:46%-76% B over 10 min) to give (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )-2- (morpholino-d8)quinazolin-4(3H)-one (33.6 mg, 71.6 μmol, 39%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 1.2 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.26 - 7.21 (m, 1H), 6.78 (br. d, J = 6.4 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.49 - 5.37 (m, 1H), 3.62 (s, 3H), 3.11 (s, 3H), 2.38 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 465.2. Example 176. Preparation of 3,6-dimethyl-8-[(1R)-1-(3-methyl-2-methylsulfonyl- anilino)ethyl]-2-morpholino-quinazolin-4-one (Compound 324) [1875] Step 1. Synthesis of 1-bromo-3-chloro-2-(methylsulfonyl)benzene [1876] To a solution of 1-bromo-3-chloro-2-methylsulfanyl-benzene (0.9 g, 3.79 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (2.31 g, 11.4 mmol, 80% purity). The mixture was stirred at 25 °C for 16 hr. On completion. The reaction mixture was quenched by saturated sodium sulfite solution (150 mL) at 25 °C, and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated sodium carbonate solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-bromo-3-chloro-2-methylsulfonyl-benzene (1.00 g, 3.71 mmol, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.29-7.33 (m, 1H), 3.35 (s, 3H). [1877] Step 2. Synthesis of 8-[(1R)-1-(3-bromo-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one [1878] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (100 mg, 330 μmol) , 1-bromo-3-chloro-2-methylsulfonyl-benzene (267 mg, 992 μmol), cesium carbonate (323 mg, 992 μmol) in dimethyl acetamide (0.3 mL) was degassed and purged with nitrogen for 2 times, and then the mixture was stirred at 140 °C for 2 hr under nitrogen atmosphere. On completion. The mixture was diluted with water 30 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 0/1) to give 8-[(1R)-1-(3-bromo-2-methylsulfonyl-anilino)ethyl]-3,6-dimet hyl-2-morpholino- quinazolin-4-one (70 mg, 114 μmol, 34%) as a yellow solid. m/z ES+ [M+H] ⁺ 535.0. [1879] Step 3. Synthesis of 3,6-dimethyl-8-[(1R)-1-(3-methyl-2-methylsulfonyl- anilino)ethyl]-2-morpholino-quinazolin-4-one [1880] A mixture of 8-[(1R)-1-(3-bromo-2-methylsulfonyl-anilino)ethyl]-3,6-dimet hyl-2- morpholino-quinazolin-4-one (120 mg, 224 μmol), methylboronic acid (134 mg, 2.24 mmol), cesium carbonate (219 mg, 672 μmol), chloro(2-dicyclohexylphosphino-2ƍ,4ƍ,6ƍ-triisopropyl- 1,1ƍ-biphenyl)[2-(2ƍ-amino-1,1ƍ-biphenyl)]palladium(II) (35 mg, 44.8 μmol) in dioxane (5 mL) and water (1 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 100 °C for 2 hr under nitrogen atmosphere. On completion. The mixture was diluted with water 20 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic acid)-acetonitrile];B%: 45%-75%, 7 min) to give 3,6-dimethyl-8-[(1R)-1-(3-methyl-2-methylsulfonyl-anilino)et hyl]-2-morpholino-quinazolin- 4-one (36.8 mg, 78.2 μmol, 35%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J = 1.2 Hz, 1H), 7.56 (br. d, J = 6.4 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.46 (d, J = 7.2 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.41 (t, J = 6.4 Hz, 1H), 3.98 - 3.83 (m, 4H), 3.62 (s, 3H), 3.29 (dd, J = 3.6, 5.6 Hz, 4H), 3.15 (s, 3H), 2.62 (s, 3H), 2.38 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 471.2. Example 177. Preparation of 8-[(1R)-1-[2-(N,S-dimethylsulfonimidoyl)anilino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one (Compound 251) [1881] Step 1. Synthesis of (2-fluorophenyl)-methyl-methylimino-oxo-^6-sulfane [1882] To a solution of (2-fluorophenyl)-imino-methyl-oxo-^6-sulfane (200 mg, 1.15 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (92.4 mg, 2.31 mmol, 60% purity) at 0 °C and after 0.5 hr added methyl iodide (197 mg, 1.39 mmol). The mixture was stirred at 25 °C for 11.5 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition water (10 mL) at 0 °C, and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give (2-fluorophenyl)-methyl-methylimino-oxo-^6-sulfane (220 mg, 1.15 mmol, 99%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.03 - 7.92 (m, 1H), 7.67 - 7.55 (m, 1H), 7.38 - 7.33 (m, 1H), 7.28 - 7.23 (m, 1H), 3.26 (s, 3H), 2.66 (s, 3H). [1883] Step 2. Synthesis of 8-[(1R)-1-[2-(N,S-dimethylsulfonimidoyl)anilino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one [1884] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (100 mg, 331 μmol) and (2-fluorophenyl)-methyl-methylimino-oxo-^6-sulfane (80.5 mg, 429 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (162 mg, 496 μmol). The mixture was stirred at 140 °C for 12 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic acid)-acetonitrile];B%: 35%-65%, 7 min) to give 8-[(1R)-1-[2-(N,S- dimethylsulfonimidoyl)anilino]-ethyl]-3,6-dimethyl-2-morphol ino-quinazolin-4-one (43.03 mg, 91.6 μmol, 28%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.77 - 7.72 (m, 1H), 7.48 - 7.45 (m, 1H), 7.32 - 7.28 (m, 1H), 7.25 - 7.20 (m, 1H), 6.74 - 6.67 (m, 1H), 6.57 - 6.49 (m, 1H), 5.54 - 5.45 (m, 1H), 3.92 - 3.88 (m, 4H), 3.63 (s, 3H), 3.31 - 3.27 (m, 4H), 3.19 (d, J = 3.6 Hz, 3H), 2.76 (d, J = 1.6 Hz, 3H), 2.37 (d, J = 4.8 Hz, 3H), 1.61-1.58 (m, 3H); m/z ES+ [M+H]+470.1. Example 178. Preparation of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-N-methylbenzenesulfonami de (Compound 260) [1885] Step 1. Synthesis of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquin- nazolin-8-yl)ethyl)amino)-N-methylbenzenesulfonamide [1886] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (50 mg, 165 μmol) in dimethylacetamide (3 mL) was added 2-bromo-N-methyl- benzenesulfonamide (62 mg, 248 μmol), copper power (10.5 mg, 165 μmol) and triethylamine (50.2 mg, 496 μmol). The mixture was stirred at 110 °C for 12 hr. The mixture was poured in water (5 mL) then extracted with ethyl acetate (10 mL x 2). The organic phase was concentrated in vacuo to give (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquin-n azolin-8- yl)ethyl)amino)-N-methylbenzenesulfonamide (6.72 mg, 14.2 μmol, 9%) as a white solid. ¹ H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.63 (d, J = 6.4 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.20 - 7.11 (m, 1H), 6.67 - 6.50 (m, 2H), 5.56 - 5.43 (m, 1H), 3.93 - 3.87 (m, 4H), 3.62 (s, 3H), 3.34 (d, J = 4.8 Hz, 4H), 2.53 (s, 3H), 2.35 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 472.2. Example 179. Preparation of (R)-8-(1-((3-Hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 335) [1887] Step 1. Synthesis of 4-bromobenzo[d]isoxazol-3-ol [1888] To a solution of 1,2-benzoxazol-3-ol (800 mg, 5.92 mmol) in acetic acid (8 mL) was added sodium acetate (485 mg, 5.92 mmol) and bromine (1.89 g, 11.8 mmol) at 0 °C. The mixture was stirred at 0 -25 °C for 12 hr. The reaction mixture were filtered, washed with water (20 mL) and filter cake concentrated under reduced pressure to give 4-bromo-1,2-benzoxazol- 3-ol (600 mg, 2.80 mmol, 47%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.6 ( s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.75 (dd, J = 1.6, 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H); m/z ES+ [M+H] ⁺ 213.9. [1889] Step 2. Synthesis of 4-bromo-3-(methoxymethoxy)benzo[d]isoxazole [1890] To a solution of 4-bromo-1,2-benzoxazol-3-ol (400 mg, 1.87 mmol) in N,N- dimethylformamide (4 mL) was added sodium hydride (149 mg, 3.74 mmol, 60% purity) at 0 °C and the mixture was stirred at 25 °C for 1 hr under nitrogen atmosphere. Then chloro(methoxy)methane (180 mg, 2.24 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by saturated ammonium chloride solution (20 mL) at 0 °C, and then extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=40/1 to 0/1) to give 4-bromo- 3-(methoxymethoxy)-1,2-benzoxazole (330 mg, 1.28 mmol, 68%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 2.0, 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 5.55 (s, 2H), 3.54 (s, 3H); m/z ES+ [M+H] ⁺ 258.0. [1891] Step 3. Synthesis of (R)-8-(1-((3-(methoxymethoxy)benzo[d]isoxazol-4- yl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-on e [1892] To a solution of 4-bromo-3-(methoxymethoxy)-1,2-benzoxazole (330 mg, 1.28 mmol) and 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (77.3 mg, 255 μmol) in toluene (9 mL) was added cesium carbonate (249 mg, 767 μmol), dicyclohexyl-[2-[2,6- di(propan-2-yloxy)phenyl]phenyl]phosphane (23.9 mg, 51.1 μmol) and tris(dibenzylideneacetone)-dipalladium (46.8 mg, 51.1 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate (90 mL) and water (90 mL). The organic phase was separated, washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=40/1 to 1/1) to give (R)-8-(1-((3- (methoxymethoxy)benzo[d]isoxazol-4-yl)amino)ethyl)-3,6-dimet hyl-2- morpholinoquinazolin-4(3H)-one (70 mg, 103 μmol, 40%) as a yellow gum. m/z ES+ [M+H] ⁺ 480.2. [1893] Step 4. Synthesis of (R)-8-(1-((3-hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one [1894] To a solution of 8-[(1R)-1-[[3-(methoxymethoxy)-1,2-benzoxazol-4-yl]amino]eth yl]- 3,6-dimethyl-2-morpholino-quinazolin-4-one (55 mg, 114 μmol) in dioxane (5.6 mL) was added hydrochloric acid (3 M, 1.08 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 34%-54%, 10 min) to give (R)-8-(1-((3- hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)-3,6-dimethyl-2-mor pholinoquinazolin-4(3H)- one (9.86 mg, 21.3 μmol, 18%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 1.2 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.91 (dd, J = 2.4, 9.2 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 5.28 - 5.20 (m, 1H), 3.95 - 3.88 (m, 4H), 3.62 (s, 3H), 3.33 - 3.27 (m, 4H), 2.37 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 436.2. Example 180. Preparation of 8-[(1R)-1-[2-(fluoromethylsulfonyl)anilino]ethyl]-3,6- dimethyl-2- morpholino-quinazolin-4-one (Compound 208) [1895] Step 1. Synthesis of 1-fluoro-2-(fluoromethylsulfanyl)benzene [1896] To a solution of 2-fluorobenzenethiol (500 mg, 3.90 mmol) in acetonitrile (8 mL) was added cesium carbonate (3.81 g, 11.7 mmol) and fluoro(iodo)methane (936 mg, 5.85 mmol). The mixture was stirred at 20 °C for 6 hr. Then the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/1) to give 1-fluoro-2- (fluoromethylsulfanyl)benzene (440 mg, 2.75 mmol, 70%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 - 7.54 (m, 1H), 7.36 - 7.30 (m, 1H), 7.19 - 7.10 (m, 2H), 5.78 (s, 1H), 5.65 (s, 1H). [1897] Step 2. Synthesis of 1-fluoro-2-(fluoromethylsulfonyl)benzene [1898] To a solution of 1-fluoro-2-(fluoromethylsulfanyl)benzene (400 mg, 2.50 mmol) in dichloromethane (10 mL) was added 3-chloroperoxybenzoic acid (1.52 g, 7.49 mmol, 85% purity). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water (100 mL) and neutralized to pH = 8 with aqueous sodium sulfite solution then extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 2/1) to give 1-fluoro-2-(fluoromethylsulfonyl)benzene (400 mg, 2.08 mmol, 83%) as white oil. ¹ H NMR (400 MHz, CDCl3) δ 8.09 - 7.97 (m, 1H), 7.82 - 7.71 (m, 1H), 7.48 - 7.39 (m, 1H), 7.37 - 7.29 (m, 1H), 5.41 (s, 1H), 5.30 (s, 1H). [1899] Step 3. Synthesis of 8-[(1R)-1-[2-(fluoromethylsulfonyl)anilino]ethyl]-3,6-dimeth yl- 2-morpholino-quinazolin-4-one [1900] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (30 mg, 99.2 μmol) in dimethyl acetamide (1.5 mL) was added cesium carbonate (97 mg, 298 μmol) and 1-fluoro-2-(fluoromethylsulfonyl)benzene (57.2 mg, 298 μmol). The mixture was stirred at 120 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75x30mmx3um;mobile phase: [water (formic acid)-acetonitrile];B%: 48%-78%, 7 min) to give 8-[(1R)-1-[2-(fluoromethylsulfonyl)anilino]ethyl]-3,6-dimeth yl-2- morpholino-quinazolin-4- one (11.8 mg, 24.8 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 6.93 - 6.84 (m, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 5.46 - 5.36 (m, 1H), 5.30 - 5.21 (m, 1H), 5.20 - 5.09 (m, 1H), 3.90 (br. t, J = 4.4 Hz, 4H), 3.62 (s, 3H), 3.31 - 3.26 (m, 4H), 2.39 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 475.2. Example 181. Preparation of (R)-3,6-dimethyl-2-morpholino-8-(1-((2- ((trifluoromethyl)sulfonyl) phenyl)amino)ethyl)quinazolin-4(3H)-one (Compound 185) [1901] Step 1. Synthesis of (R)-3,6-dimethyl-2-morpholino-8-(1-((2- ((trifluoromethyl)sulfonyl)phenyl)amino)ethyl) quinazolin-4(3H)-one [1902] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (50 mg, 165 μmol) and 1-fluoro-2-(trifluoromethylsulfonyl)benzene (113 mg, 496 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (269 mg, 827 μmol). The mixture was stirred at 140 °C for 4 hr. The mixture was filtered to remove cesium carbonate. The mixture was purified by prep-HPLC: column: YMC Triart C18150*25 mm*5 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 70%-100%, 10 min to give (R)-3,6-dimethyl-2-morpholino- 8-(1-((2-((trifluoromethyl)sulfonyl)phenyl)amino)ethyl)quina zolin-4(3H)-one (9.11 mg, 17.8 μmol, 11%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.07 (d, J = 6.4 Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 5.50 - 5.38 (m, 1H), 3.94 - 3.88 (m, 4H), 3.63 (s, 3H), 3.32 - 3.27 (m, 4H), 2.39 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 511.2. Example 182. Preparation of 8-[(1R)-1-[2-(difluoromethylsulfonyl)anilino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one (Compound 207) [1903] Step 1. Synthesis of 1-(difluoromethylsulfinyl)-2-fluoro-benzene [1904] To a solution of 1-(difluoromethylsulfanyl)-2-fluoro-benzene (260 mg, 1.46 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was added oxone (2.69 g, 4.38 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was quenched by addition sat.sodium sulfite (20 mL) at 0 °C, and then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 5/1) to give 1-(difluoromethylsulfinyl)-2-fluoro-benzene (130 mg, 602 μmol, 41%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 - 7.89 (m, 1H), 7.65 - 7.61 (m, 1H), 7.49 - 7.43 (m, 1H), 7.25 - 7.19 (m, 1H), 6.42 - 6.10 (m, 1H). [1905] Step 2. Synthesis of 1-(difluoromethylsulfonyl)-2-fluoro-benzene [1906] To a solution of 1-(difluoromethylsulfinyl)-2-fluoro-benzene (130 mg, 669 μmol) in dichloromethane (3 mL) was added 3-chloroperoxybenzoic acid (173 mg, 803 μmol, 80% purity) at 0 °C. The mixture was stirred at 25 °C for 12 hr. On completion. The reaction mixture was quenched with saturated sodium sulfite solution (10 mL) and extracted with ethyl acetate (30 mL x 3), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 1-(difluoromethylsulfonyl)-2- fluoro-benzene (90 mg, 385 μmol, 57%) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 8.01 - 7.82 (m, 1H), 7.97 - 7.80 (m, 1H), 7.46 - 7.40 (m, 1H), 7.35 - 7.29 (m, 1H), 6.48 - 6.19 (m, 1H). [1907] Step 3. Synthesis of 8-[(1R)-1-[2-(difluoromethylsulfonyl)anilino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one [1908] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (20 mg, 57.4 μmol) and 1-(difluoromethylsulfonyl)-2-fluoro-benzene (18.1 mg, 86.1 μmol) in dimethyl acetamide (0.2 mL) was added diisopropylethylamine (29.7 mg, 229 μmol). On completion, the mixture was stirred at 80 °C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic aced)-acetonitrile];B%: 52%-82%, 7 min) to give 8-[(1R)-1-[2- (difluoromethylsulfonyl)anilino]ethyl]-3,6-dimethyl-2-morpho lino-quinazolin-4-one (10.56 mg, 21.2 μmol, 37%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 0.8 Hz, 1H), 7.67 (dd, J = 1.6, 8.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.05 (d, J = 6.4 Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 6.22 (t, J = 53.6 Hz, 1H), 5.43 (q, J = 6.4 Hz, 1H), 3.95 - 3.87 (m, 4H), 3.62 (s, 3H), 3.35 - 3.25 (m, 4H), 2.38 (s, 3H), 1.61 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 493.2. Example 183. Preparation of methyl 3,6-dimethyl-8-[(1R)-1-[(4-methylsulfonyl-3- pyridyl)amino]ethyl] -2-morpholino-quinazolin-4-one (Compound 321) [1909] Step 1. Synthesis of methyl 3-fluoro-4-methylsulfonyl-pyridine [1910] To a mixture of 4-chloro-3-fluoro-pyridine (2.00 g, 15.2 mmol) and sodium methanesulfinate (1.86 g, 18.2 mmol) in dimethylsulfoxide (10 mL) was added copper iodide (289 mg, 1.52 mmol) and L-Proline (350 mg, 3.04 mmol), the reaction mixture was stirred at 100 °C under nitrogen for 12 hr. On completion, the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL x 2), filtered and the combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/2) to give 3-fluoro-4-methylsulfonyl- pyridine (1.10 g, 6.28 mmol, 41%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.75 (br. s, 2H), 7.87 (br. s, 1H), 3.28 (s, 3H). [1911] Step 2. Synthesis of (R)-3,6-dimethyl-8-(1-((4-(methylsulfonyl)pyridin-3- yl)amino)ethyl)-2-morpholinoquinazolin-4(3H)-one [1912] To a mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (50.0 mg, 165 μmol) and 3-fluoro-4-methylsulfonyl-pyridine (144mg, 826 μmol) in dimethyl acetamide (3 mL) was added cesium carbonate (161 mg, 496 μmol) and cesium fluoride (37.6 mg, 248 μmol), the reactin mixture was stirred at 140 °C for 2 hr. On completion, the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];B%: 8%-38%, 10 min) to give (R)-3,6- dimethyl-8-(1-((4-(methylsulfonyl)-pyridin-3-yl)amino)ethyl) -2-morpholinoquinazolin- 4(3H)-one (12.1 mg, 26.6 μmol, 16%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.20 (d, J = 6.0 Hz, 1H), 7.94 (s, 1H), 7.43 (br. d, J = 6.8 Hz, 1H), 7.39 (s, 1H), 6.47 (d, J = 6.0 Hz, 1H), 5.43 (br. t, J = 6.8 Hz, 1H), 3.90 (br. t, J = 4.4 Hz, 4H), 3.63 (s, 3H), 3.37 - 3.22 (m, 4H), 3.11 (s, 3H), 2.41 (s, 3H), 1.68 (br. d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 458.2. Example 184. Preparation of [2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin- 8-yl)ethyl]amino]phenyl]boronic acid (Compound 345) [1913] Step 1. Synthesis of 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-morpholino- quinazolin-4-one [1914] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (100 mg, 330 μmol) and (2-bromophenyl)boronic acid (664 mg, 3.31 mmol) in dichloromethane (20 mL) was added copper acetate (120 mg, 661 μmol) and triethylamine (334 mg, 3.31 mmol) and 4A molecular sieve (0.1 g). The mixture was stirred at 25 °C for 12 hr under oxygen. On completion, the mixture was filtered with celatom and concentrated in vacuo. The residue was purified by flash silica gel chromatography (petroleum ether/ethyl acetate = 3/1) to give 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-morp-holino- quinazolin-4-one (90.0 mg, 196 μmol, 59%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 1.2 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.03 - 6.96 (m, 1H), 6.53 - 6.47 (m, 1H), 6.46 - 6.42 (m, 1H), 5.34 - 5.24 (m, 1H), 5.12 (d, J = 6.4 Hz, 1H), 3.95- 3.85 (m, 4H), 3.62 (s, 3H), 3.37 - 3.23 (m, 4H), 2.39 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 459.0. [1915] Step 2. Synthesis of 3,6-dimethyl-2-morpholino-8-[(1R)-1-[2-(4,4,5,5-tetramethyl- 1,3,2-dioxaboro-lan-2-yl)anilino]ethyl]quinazolin-4-one [1916] To a solution of 8-[(1R)-1-(2-bromoanilino)ethyl]-3,6-dimethyl-2-morpholino- quinazolin-4-one (80.0 mg, 174 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxabo-rolane (88.8 mg, 349 μmol) in dioxane (8 mL) was added [1,1'-Bis(diphenylphosphino)ferrocene]dich-loropalladium(II) (12.8 mg, 17.4 μmol) and potassium acetate (68.6 mg, 699 μmol). The mixture was stirred at 130 °C for 5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (formic acid)- acetonitrile]; B%: 24%-54%, 10min) to give 3,6-dimethyl-2-morpholino-8-[(1R)-1-[2- (4,4,5,5-tetrame-thyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl] quinazolin-4-one (68 mg, 128 μmol, 73%) as a yellow oil. m/z ES+ [M+H] ⁺ 505.3. [1917] Step 3. Synthesis of [2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]phenyl]boronic acid [1918] To a solution of 3,6-dimethyl-2-morpholino-8-[(1R)-1-[2-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)anilino]ethyl]quinazolin-4-one (50.0 mg, 99.1 μmol) and methylboronic acid (59.3 mg, 991 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 6 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water (formic acid)- acetonitrile]; B%: 21%-51%, 10 min) to give [2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]phenyl]boronic acid (8 mg, 18.0 μmol, 18%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (s, 2H), 7.69 (s, 1H), 7.59 - 7.51 (m, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 6.4 Hz, 1H), 7.00 - 6.90 (m, 1H), 6.45-6.36 (m, 1H), 6.18 (d, J = 8.4 Hz, 1H), 5.35-5.25 (m, 1H), 3.78 (s, 4H), 3.50 (s, 3H), 3.25 (d, J = 4.0 Hz, 4H), 2.33 - 2.30 (m, 3H), 1.47 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 423.2. Example 185. Preparation of 8-[(1R)-1-(4,5-difluoro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2- morpholino-quinazolin-4-one (Compound 370) [1919] Step 1. Synthesis of 1-bromo-4,5-difluoro-2-methylsulfanyl-benzene [1920] To a solution of 1-bromo-2,4,5-trifluoro-benzene (1 g, 4.74 mmol) in dimethylsulfoxide (7.5 mL) was added sodium methanthiol (1.66 g, 23.7 mmol) at 0 °C. The mixture was stirred at 25°C for 4 hr. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-bromo-4,5-difluoro-2-meth-ylsulfanyl-benzene (800 mg, crude) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 7.26 - 7.21 (m, 1H), 7.02 - 6.96 (m, 1H), 2.47 (s, 3H). [1921] Step 2. Synthesis of 1-bromo-4,5-difluoro-2-methylsulfonyl-benzene [1922] To a solution of 1-bromo-4,5-difluoro-2-methylsulfanyl-benzene (400 mg, 1.67 mmol) in dichloromethane (6 mL) was added 3-chloroperoxybenzoic acid (1.02 g, 5.02 mmol, 85% purity). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (100 mL) and quenched by saturated sodium sulfite solution (20 mL), then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 4/1) to give 1-bromo-4,5-difluoro-2-methylsulfonyl-benzene (205 mg, 718 μmol, 43%) as a white solid. [1923] Step 3. Synthesis of 8-[(1R)-1-(4,5-difluoro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one [1924] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (45 mg, 149 μmol) and 1-bromo-4,5-difluoro-2-methylsulfonyl-benzene (202 mg, 744 μmol) in toluene (1 mL) was added cesium carbonate (146 mg, 446 μmol), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phos-phane (6.94 mg, 14.9 μmol) and tris (dibenzylideneacetone) dipalladium (13.6 mg, 14.9 μmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate 45 mL (15 mL x 3). The combined organic layers were washed with brine 15 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75 x 30mm x 3um; mobile phase: [water(formic acid)- acetonitrile];B%: 45%-75%, 7 min) to give 8-[(1R)-1-(4,5-difluoro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2-morpholino- quinazolin-4-one (41.4 mg, 81.5 μmol, 54%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.2 Hz, 1H), 7.49 - 7.39 (m, 2H), 6.49 - 6.35 (m, 1H), 6.00 - 5.59 (m, 1H), 5.29 - 5.11 (m, 1H), 3.96 - 3.85 (m, 4H), 3.63 (s, 3H), 3.31 - 3.24 (m, 4H), 3.12 (s, 3H), 2.43 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 493.2. Example 186. Preparation of 8-[(1R)-1-(2,5-difluoro-4-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2- morpholino-quinazolin-4-one (Compound 305) [1925] Step 1. Synthesis of 1,2,4-trifluoro-5-methylsulfonyl-benzene [1926] To a solution of 1,2,4-trifluoro-5-methylsulfanyl-benzene (100 mg, 561 μmol) in dichloromethane (2 mL) was added 3-chloroperoxybenzoic acid (341 mg, 1.68 mmol, 85% purity). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water 20 mL and neutralized to pH = 8 with aqueous sodium sulfite solution, then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated salt solution 20 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1,2,4-trifluoro-5-methylsulfonyl-benzene (100 mg, 476 μmol, 84%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 - 7.80 (m, 1H), 7.21 - 7.11 (m, 1H), 3.24 (s, 3H). [1927] Step 2. Synthesis of 8-[(1R)-1-(2,5-difluoro-4-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one [1928] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (38.4 mg, 127 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (124 mg, 381 μmol) and 1,2,4-trifluoro-5-methylsulfonyl-benzene (80 mg, 381 μmol). The mixture was stirred at 120 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic acid)- acetonitrile];B%: 45%-75%, 7 min) to give 8-[(1R)-1-(2,5-difluoro-4-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2-morpholino- quinazolin-4-one (34.9 mg, 68.6 μmol, 54%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.48 - 7.40 (m, 2H), 6.46 - 6.38 (m, 1H), 5.82 (br. d, J = 6.0 Hz, 1H), 5.18 (t, J = 6.8 Hz, 1H), 3.93 - 3.88 (m, 4H), 3.62 (s, 3H), 3.29 - 3.25 (m, 4H), 3.11 (s, 3H), 2.42 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 493.1. Example 187. Preparation of (R)-8-(1-((2-Fluoro-6-(methylsulfonyl)phenyl)amino)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 328) [1929] Step 1. Synthesis of 1,2-difluoro-3-(methylsulfonyl)benzenete [1930] A mixture of 1,2-difluoro-3-iodo-benzene (4.5 g, 18.8 mmol), sodium;methanesulfinate (2.3 g, 22.5mmol), cuprous iodide (357 mg, 1.88 mmol), (2S)- pyrrolidine-2-carboxylic acid (432 mg, 3.75 mmol) in dimethylsulfoxide (30 mL) was degassed and purged with nitrogen(3x), and then the mixture was stirred at 100 °C for 12 hr under nitrogen for atmosphere. On completion, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL x 2), filtered and the combined organiclayers were washed with brine (5 mL x 2), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 5/1) to give 1,2-difluoro-3- methylsulfonyl-benzene (0.6 g, 3.12 mmol, 17%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 - 7.68 (m, 1H), 7.54 - 7.45 (m, 1H), 7.32 (dt, J = 4.0, 8.0 Hz, 1H), 3.26 (s, 3H). [1931] Step 2. Synthesis of (R)-8-(1-((2-fluoro-6-(methylsulfonyl)phenyl)amino)ethyl)-3, 6- dimethyl-2-morpholinoquinazolin-4(3H)-one [1932] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (50 mg, 165 μmol), 1,2-difluoro-3-methylsulfonyl-benzene (127 mg, 661 μmol) and cesium carbonate (162 mg, 496 μmol) in dimethyl acetamide (0.2 mL) was stirred at 140 °C for 12 hr under nitrogen atmosphere. The reaction mixture was cooled to 20 ^o C, filtered under reduced pressure to get the filtrate. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile]; B%: 49%-79%, 10 min) to give (R)-8-(1-((2-fluoro-6-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl-2- morpholinoquinazolin-4(3H)-one (54.8 mg, 114 μmol, 69%) as a white solid. ¹ H NMR (400 MHz, acetonitrile-d3) δ 7.82 (d, J = 1.2 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.29 – 7.24 (m, 1H), 6.83 – 6.79 (m, 1H), 6.62 (br. d, J = 8.8 Hz, 1H), 5.67 – 5.60 (m, 1H), 3.83 - 3.79 (m, 4H), 3.52 (s, 3H), 3.30 – 3.26 (m, 2H), 3.18 - 3.11 (m, 2H), 2.79 (s, 3H), 2.40 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 429.1. Example 188. Preparation of 8-[(1R)-1-(4-Chloro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2- morpholino-quinazolin-4-one (Compound 390) [1933] Step 1. Synthesis of 1,4-dichloro-2-methylsulfanyl-benzene [1934] A solution of 2,5-dichlorobenzenethiol (2.60 g, 14.5 mmol) in ethanol (10 mL) and water (0.7 mL) at -15 °C was added sodium hydroxide (598 mg, 14.9 mmol) under nitrogen atmosphere, and then methyl iodide (8.24 g, 58.1 mmol) was added, the mixture was stirred at -15 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) filtered and concentrated under reduced pressure to give 1,4-dichloro-2-methylsulfanyl- benzene (1.60 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.23 – 7.21 (m, 1H), 2.52 (s, 3H). [1935] Step 2. Synthesis of 1,4-dichloro-2-methylsulfonyl-benzene [1936] To a solution of 1,4-dichloro-2-methylsulfanyl-benzene (1.00 g, 5.18 mmol) in dichloromethane (30 mL) was added 3-chloroperoxybenzoic acid (3.15 g, 15.54 mmol, 85% purity). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was quenched by sodium sulphite solution (50 mL), and then diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 3/1) to give 1,4-dichloro-2-methylsulfonyl-benzene (850 mg, 3.78 mmol, 73 %) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 2.4 Hz, 1H), 7.58 - 7.48 (m, 2H), 3.29 (s, 3H). [1937] Step 3. Synthesis of 8-[(1R)-1-(4-chloro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2- morpholino-quinazolin-4-one [1938] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (220 mg, 727 μmol) and 1,4-dichloro-2-methylsulfonyl-benzene (819 mg, 3.64 mmol) in dimethyl acetamide (3 mL) was added cesium carbonate (948 mg, 2.91 mmol). The mixture was stirred at 140 °C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%: 50%-80%, 8 min) and purified by pre-TLC (petroleum ether : ethyl acetate =1/1) to give 8- [(1R)-1-(4-chloro-2-methylsulfonyl-anilino)ethyl]-3,6-dimeth yl-2-morpholino-quinazolin-4- one (6.27 mg, 12.3 μmol, 2%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.17 (dd, J= 2.4, 8.8 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 6.51 (d, J = 9.2 Hz, 1H), 5.43 - 5.34 (m, 1H), 3.94 - 3.86 (m, 4H), 3.62 (s, 3H), 3.34 - 3.24 (m, 4H), 3.11 (s, 3H), 2.38 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 491.1. Example 189. Preparation of (R)-8-(1-((5-fluoro-3-(methylsulfonyl)pyridin-2- yl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-on e (Compound 338) [1939] Step 1. Synthesis of (R)-8-(1-((3-bromo-5-fluoropyridin-2-yl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one [1940] To a solution of 3-bromo-2,5-difluoro-pyridine (192 mg, 992 μmol) and 8-[(1R)-1- aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4-one (100 mg, 330 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (323 mg, 992 μmol). The mixture was stirred at 140 °C for 16 hr. On completion, the mixture was poured in water (10 mL), then extracted with ethyl acetate (15 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 8/1 to 5/1) to give 8-[(1R)-1-[(3-bro-mo-5-fluoro-2-pyridyl)amino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one (80.0 mg, 118 μmol, 35%) as a yellow solid. m/z ES+ [M+H] ⁺ 476.1. [1941] Step 2. Synthesis of (R)-8-(1-((5-fluoro-3-(methylsulfonyl)pyridin-2-yl)amino)eth yl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [1942] To a solution of 8-[(1R)-1-[(3-bromo-5-fluoro-2-pyridyl)amino]ethyl]-3,6-dime thyl- 2-morpholino-quinazolin-4-one (55.0 mg, 115 μmol) in dimethylsulfoxide (0.5 mL) was added copper iodide (21.9 mg, 115 μmol) and sodium;methanesulfinate (23.5 mg, 230 μmol) and L- proline (13.2 mg, 115 μmol) and sodium hydroxide (4.62 mg, 115 μmol). The mixture was stirred at 100 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C1875 x 30mm,3um; mobile phase: [water(formic acid)-acetonitrile]; B%: 45%-75%, 7 min) to give (R)-8-(1-((5-fluoro-3- (methylsulfonyl)pyridin-2-yl)amino)ethyl)-3,6-dimethyl-2-mor pholinoquinazolin-4(3H)-one (19.3 mg, 40.3 μmol, 34%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.75 (dd, J = 2.8, 7.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 5.85 - 5.71 (m, 1H), 3.95 - 3.82 (m, 4H), 3.61 (s, 3H), 3.45 - 3.34 (m, 2H), 3.30 - 3.17 (m, 2H), 2.99 (s, 3H), 2.42 (s, 3H), 1.74 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 476.2. Example 190. Preparation of 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]pyridazine-4-carboxylic acid (Compound 436) [1943] Step 1. Synthesis of methyl 6-chloro-3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]amino] pyridazine-4-carboxylate [1944] To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (274 mg, 1.32 mmol) in dimethyl acetamide (3 mL) was added diisopropylethylamine (256 mg, 1.98 mmol) and 8- [(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4-o ne (200 mg, 661 μmol). The mixture was stirred at 80 °C for 4 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate =1/1) to give methyl 6-chloro-3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazo lin-8- yl)ethyl]amino]pyridazine-4-carboxylate (200 mg, 423 μmol, 64%) as a white solid. m/z ES+ [M+H] ⁺ 473.2. [1945] Step 2. Synthesis of 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]pyridazine-4-carboxylate [1946] A mixture of methyl 6-chloro-3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]amino]pyridazine-4-carboxylate (85 mg, 180 μmol), ammonium formate (33.5 mg, 532 μmol), triethylamine (92.0 mg, 909 μmol) and palladium triphenylphosphane (41.5 mg, 36.0 μmol) in dioxane (2 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified was purified by pre-TLC (petroleum ether/ethyl acetate=1/1) to give methyl 3-[[(1R)-1-(3,6- dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)ethyl]amino]pyri dazine-4-carboxylate (60 mg, 82.1 μmol, 45%) as a white solid. m/z ES+ [M+H] ⁺ 439.3. [1947] Step 3. Synthesis of 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]pyridazine-4-carboxylic acid [1948] A mixture of methyl 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino] pyridazine-4-carboxylate (60 mg, 137 μmol), lithium hydroxide (23 mg, 547 μmol) in tetrahydrofuran (0.3 mL) methanol (0.3 mL) and water (0.3 mL) was stirred at 40 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purificated by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(formic acid)- acetonitrile];B%: 15%-45%,9 min) to give 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl) ethyl]amino]pyridazine- 4-carboxylic acid (7.28 mg, 17.1 μmol, 12 %) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.87 (d, J = 6.0 Hz, 1H), 8.39 (d, J = 4.4 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.46 (s, 1H), 6.03 – 5.95 (m, 1H), 3.82 – 3.70 (m, 4H), 3.50 (s, 3H), 3.26 – 3.23 (m, 4H), 2.32 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 425.2. Example 191. Preparation of 4-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]pyrimidine-5-carboxylic acid (Compound 373) [1949] Step 1. Synthesis of ethyl 4-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin- 8-yl)ethyl] amino]pyrimidine-5-carboxylate [1950] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (100 mg, 331 μmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (137 mg, 992 μmol) and ethyl 4-chloropyrimidine-5-carboxylate (67.9 mg, 364 μmol). The mixture was stirred at 50 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 3/1) to give ethyl 4-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]amino]pyrimidine-5-carboxylate (80 mg, 177 μmol, 53%) as a white solid. m/z ES+ [M+H] ⁺ 453.2. [1951] Step 2. Synthesis of 4-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]pyrimidine-5-carboxylic acid [1952] To a solution of ethyl 4-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]pyri- midine-5-carboxylate (70 mg, 155 μmol) in anhydrous tetrahydrofuran (1 mL), methanol (0.5 mL) and water (0.5 mL) was added lithium hydroxide (37.1 mg, 1.55 mmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was diluted with water 10 mL and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C1875 x 30mm, 3um; mobile phase: [water (formic acid)- acetonitrile]; B%: 18%-48%, 7 min) to give 4-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8- yl)ethyl]amino]pyrimidine-5-carboxylic acid (42.9 mg, 101 μmol, 65%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.0 (d, J = 8.8 Hz, 1H), 8.87 - 8.62 (m, 2H), 7.92 (s, 1H), 7.45 (s, 1H), 6.03 - 5.89 (m, 1H), 3.85 (s, 4H), 3.59 (s, 3H), 3.45 - 3.37 (m, 2H), 3.27 - 3.18 (m, 2H), 2.41 (s, 3H), 1.77 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 425.2. Example 192. Preparation of 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino] pyrazine-2-carboxylic acid (Compound 375) [1953] Step 1. Synthesis of methyl 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin- 8-yl)ethyl]amino]pyrazine-2-carboxylate [1954] To a solution of methyl 3-chloropyrazine-2-carboxylate (285 mg, 1.65 mmol) and 8- [(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4-o ne (100 mg, 331 μmol) in dimethylsulfoxide (2 mL) was added triethylamine (167 mg, 1.65 mmol). The mixture was stirred at 60 °C for 12 hr. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=1/2) to give methyl 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]pyrazine-2-carboxylate (75 mg, 171 μmol, 51%) as a white solid. m/z ES+ [M+H] ⁺ 439.2. [1955] Step 2. Synthesis of 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]pyrazine-2-carboxylic acid [1956] To a solution of methyl 3-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino] pyrazine-2-carboxylate (55 mg, 125 μmol) in water (0.5 mL), anhydrous tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added lithium hydroxide monohydrate (26.3 mg, 627 μmol). The mixture was stirred at 40 °C for 1 hr. The reaction mixture was diluted with water 15 mL and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 34%-64%, 10 min) to give 3-[[(1R)-1-(3,6-dimethyl-2- morpholino-4-oxo-quinazolin-8-yl)ethyl]amino]pyrazine-2-carb oxylic acid (24.0 mg , 54.8 μmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 9.2 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 5.96 - 5.77 (m, 1H), 3.96 - 3.80 (m, 4H), 3.62 (s, 3H), 3.44 - 3.28 (m, 4H), 2.42 (s, 3H), 1.76 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 425.2. Example 193. Preparation of N-[2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8- yl)ethyl]amino] phenyl]methanesulfonamide (Compound 385) [1957] Step 1. Synthesis of 3,6-dimethyl-2-morpholino-8-[(1R)-1-(2-nitroanilino)ethyl]- quinazolin-4-one [1958] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (200 mg, 661 μmol) and 1-fluoro-2-nitro-benzene (140 mg, 992 μmol) in dimethyl acetamide (3 mL) was added cesium carbonate (646 mg, 1.98 mmol). The mixture was stirred at 140 °C for 12 hr. The mixture was stirred at 60 °C for 1 hr. The reaction mixture was filtered and the filtrate was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 3,6-dimethyl-2-morpholino-8-[(1R)-1-(2-nitroanilino)ethyl]qu inazolin-4-one (210 mg, 496 μmol, 75%) as a yellow oil. m/z ES+ [M+H] ⁺ 424.2. [1959] Step 2. Synthesis of 8-[(1R)-1-(2-aminoanilino)ethyl]-3,6-dimethyl-2-morpholino- quinazolin-4-one [1960] To a solution of 3,6-dimethyl-2-morpholino-8-[(1R)-1-(2- nitroanilino)ethyl]quinazolin-4-one (60 mg, 142 μmol ) in ethanol (1 mL) and water (1 mL) was added iron powder (39.6 mg, 708 μmol) and ammonium chloride (75.8 mg, 1.42 mmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was filtered and the filtered liquor was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-[(1R)-1-(2- aminoanilino)ethyl]-3,6-dimethyl-2-morpholino-quinazolin-4-o ne (50 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 394.2. [1961] Step 3. Synthesis of N-[2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]phenyl] methanesulfonamide [1962] To a solution of 8-[(1R)-1-(2-aminoanilino)ethyl]-3,6-dimethyl-2-morpholino- quinazolin-4-one (40 mg, 102 μmol) in dichloromethane (1 mL) was added methylsulfonyl methanesulfonate (35.4 mg, 203 μmol) and triethylamine (30.9 mg, 305 μmol) at 0 °C. The mixture was stirred at 0-25 °C for 0.5 hr. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 38%-68%, 10 min) to give N-[2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin- 8-yl)ethyl]amino]phenyl]-methanesulfonamide (9.38 mg, 19.3 μmol, 19%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 0.8 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.12 - 7.06 (m, 1H), 7.02 (s, 1H), 6.62 (s, 1H), 6.48 (d, J = 7.6 Hz, 1H), 5.96 (s, 1H), 5.38 - 5.27 (m, 1H), 3.94 - 3.88 (m, 4H), 3.62 (s, 3H), 3.33 - 3.25 (m, 4H), 3.08 (s, 3H), 2.37 (s, 3H), 1.61 (s, 3H); m/z ES+ [M+H] ⁺ 472.2. Example 194. Preparation of (R)-3,6-dimethyl-8-(1-((7-methyl-8-oxo-7,8-dihydro-1,7- naphthyridin-3-yl)amino)ethyl)-2-morpholinoquinazolin-4(3H)- one (Compound 443) [1963] Step 1. Synthesis of 3-bromo-7-methyl-1,7-naphthyridin-8(7H)-one [1964] To a solution of 3-bromo-1,7-naphthyridin-8-ol (100 mg, 444 μmol) and methyl iodide (94.6 mg, 667 μmol) in acetonitrile (1 mL) was added silver carbonate (245 mg, 889 μmol). The mixture was stirred at 60 °C for 3 hr. The reaction mixture was quenched by addition water (10 mL), then was filtered and washed with ethyl acetate (10 mL), the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-bromo-7-methyl-1,7-naphthyridin-8-one (90 mg, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 3.53 (s, 3H); m/z ES+ [M+H] ⁺ 239.0. [1965] Step 2. Synthesis of (R)-3,6-dimethyl-8-(1-((7-methyl-8-oxo-7,8-dihydro-1,7- naphthyridin-3-yl)amino)ethyl)-2-morpholinoquinazolin-4(3H)- one [1966] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (28 mg, 92.6 μmol) and 3-bromo-7-methyl-1,7-naphthyridin-8-one (88.6 mg, 370 μmol) in toluene (1.5 mL) was added tris(dibenzylideneacetone)dipalladium (8.48 mg, 9.26 μmol) and cesium carbonate (90.5 mg, 278 μmol), dicyclohexyl-[2-[2,6-di(propan-2- yloxy)phenyl]phenyl]phosphane (4.32 mg, 9.26 μmol). The mixture was stirred at 60 °C for 3 hr. The reaction mixture was quenched by water (10 mL), then filtered and washed with ethyl acetate (10 mL), the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filteredcand concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (formic acid)- acetonitrile]; B%: 19%-49%, 9 min) to give 3,6-dimethyl-8-[(1R)-1-[(7-methyl-8-oxo-1,7- naphthyridin-3-yl)amino]ethyl]-2-morpholino-quinazolin-4-one (9.93 mg, 21.5 μmol, 23%) as a pink solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 7.94 - 7.89 (m, 1H), 7.47 (s, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.55 (s, 1H), 6.13 (d, J = 7.2 Hz, 1H), 5.34 (s, 2H), 3.95 - 3.85 (m, 4H), 3.62 (s, 3H), 3.57 (s, 3H), 3.28 (d, J = 3.2 Hz, 4H), 2.38 (s, 3H), 1.66 (d, J = 5.6 Hz, 3H); m/z ES+ [M+H] ⁺ 461.2. Example 195. Preparation of 8-[(1R)-1-[2-(difluoromethyl)-4-fluoro-anilino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one (Compound 450) [1967] Step 1. Synthesis of 8-[(1R)-1-[2-(difluoromethyl)-4-fluoro-anilino]ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one [1968] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (200 mg, 661 μmol), 1-bromo-2-(difluoromethyl)-4-fluoro-benzene (446 mg, 1.98 mmol), tris(dibenzylideneacetone)dipalladium (60.6 mg, 66.1 μmol), 2-dicyclohexylphosphino-2,6-di- i-propoxy-1,1-biphenyl (30.9 mg, 66.1 μmol) and cesium carbonate (647 mg, 1.98 mmol) in toluene (2 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 5/1 to 1/1). Then, the crude product was purified by prep-HPLC (column: YMC Triart C18150 x 25mm x 5um; mobile phase: [water(formic acid)- acetonitrile]; B%: 66%-96%, 8.5 min) to give 8-[(1R)-1-[2- (difluoromethyl)-4-fluoro-anilino]ethyl]-3,6-dimethyl-2-morp holino-quinazolin-4-one (104 mg, 231 μmol, 35%) as a off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 3.2, 8.4 Hz, 1H), 6.90 - 6.83 (m, 1H), 6.81 - 6.50 (m, 1H), 6.47 (dd, J = 4.4, 9.2 Hz, 1H), 5.24 (d, J = 6.0 Hz, 1H), 4.95 (s, 1H), 3.95 - 3.85 (m, 4H), 3.62 (s, 3H), 3.32 - 3.20 (m, 4H), 2.39 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+1] ⁺ 447.2. Example 196. Preparation of 2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]-5-fluoro-N-methoxy-benzamide (Compound 458) [1969] Step 1. Synthesis of 2-[[(1R)-1-(3, 6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]-5-fluoro-benzoic acid [1970] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (500 mg, 1.65 mmol), 5-fluoro-2-iodo-benzoic acid (2.20 g, 8.27 mmol), copper power (105 mg, 1.65 mmol), triethylamine (3.35 g, 33.0 mmol) in dimethyl acetamide (8 mL) was degassed and purged with under nitrogen atmosphere (3x), and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere atmosphere. On completion, the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 1/1) to give 2-[[(1R)-1-(3,6-dimethyl-2- morpholino-4- oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-benzoic acid (300 mg, 681 μmol, 41%) as a white solid. m/z ES+ [M+H] ⁺ 441.2. [1971] Step 2. Synthesis of 2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]-5-fluoro-N-methoxy-benzamide [1972] To a solution of 2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]-5-fluoro-benzoic acid (40 mg, 90.8 μmol) and O-methylhydroxylamine (22.7 mg, 272 μmol, hydrogen chloride) in dichloromethane (0.4 mL) was added dimethylamino(triazolo[4,5-b]pyridin-3-yloxymethylene]-di-me thyl- ammonium;hexafluorophosphate (69.0 mg, 181 μmol) and diisopropylethylamine (58.6 mg, 454 μmol). The mixture was stirred at 20 °C for 3 hr. The reaction mixture was extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with water (1.5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water (formic acid)-acetonitrile];B%: 46%-76%, 10 min) to give 2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl) ethyl]amino]-5-fluoro- N-methoxy-benzamide(4.45 mg, 9.48 μmol, 10%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 - 8.55 (m, 1H), 7.88 (s, 1H), 7.49 (s, 1H), 7.38 - 7.35 (m, 1H), 7.04 – 7.01 (m, 1H), 6.88 – 6.84 (m, 1H), 6.40 - 6.37 (m, 1H), 5.38 - 5.32 (m, 1H), 3.96 – 3.84 (m, 7H), 3.62 (s, 3H), 3.33 – 3.25 (m, 4H), 2.37 (s, 3H), 1.57 (s, 3H); m/z ES+ [M+H] ⁺ 470.2. Example 197. Preparation of 8-((R)-1-((2-((R)-3-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (Compound 537) [1973] Step 1. Synthesis of (R)-1-(2-bromophenyl)piperidin-3-ol [1974] To a solution of (3R) -piperidin-3-ol; hydrochloride (2 g, 14.5 mmol) in isopropyl alcohol (20 mL) was added sodium hydroxide (2.33 g, 58.1 mmol) and stirred at 25 °C for 0.5 hr, then 1-bromo-2-iodo-benzene (4.52 g, 16.0 mmol) and copper iodide (83.0 mg, 436 μmol) was added to the mixture and stirred at 95 °C for 16 hr under nitrogen atmosphere. On completion, ammonium hydroxide (10 mL) was poured into the reaction mixture, then the mixture was diluted with ethyl acetate (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% ethyl acetate/petroleum ethergradient @ 40 mL/min) to give (R)-1-(2- bromophenyl)piperidin-3-ol (1.3 g, 4.82 mmol, 33%) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.31 - 7.28 (m, 1H), 7.08 (d, J = 7.2 Hz, 1H), 7.00 - 6.90 (m, 1H), 4.01 (s, 1H), 3.07 (s, 3H), 2.94 - 2.70 (m, 2H), 2.14 - 1.94 (m, 1H), 1.80 - 1.66 (m, 3H); m/z ES+ [M+H] ⁺ 256.0. [1975] Step 2. Synthesis of (R)-1-(2-bromophenyl)-3-((tert- butyldimethylsilyl)oxy)piperidine [1976] To a solution of (3R) -1-(2-bromophenyl) piperidin-3-ol (1.3 g, 5.08 mmol), imidazole (691 mg, 10.2 mmol) in N,N-dimethylformamide (10 mL) was added tert- butylchlorodimethylsilane (1.15 g, 7.61 mmol), the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~5% ethyl acetate/petroleum ethergradient @ 20 mL/min) to give (R)-1-(2-bromophenyl)-3-((tert-butyldimethylsilyl)oxy)piperi dine (1.8 g, 4.86 mmol, 96%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (dd, J = 1.2, 8.0 Hz, 1H), 7.29 (d, J = 1.2 Hz, 1H), 7.25 (d, J = 1.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.94 - 6.86 (m, 1H), 3.98 - 3.84 (m, 1H), 3.45 - 3.33 (m, 1H), 3.22 (d, J = 11.2 Hz, 1H), 2.63 - 2.51 (m, 1H), 2.49 - 2.38 (m, 1H), 2.08 - 1.95 (m, 1H), 1.84 - 1.69 (m, 2H), 1.40 - 1.24 (m, 1H), 0.90 (s, 9H), 0.10 (d, J = 6.8 Hz, 6H); m/z ES+ [M+H] ⁺ 370.1. [1977] Step 3. Synthesis of 8-((R)-1-((2-((R)-3-((tert-butyldimethylsilyl)oxy)piperidin- 1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [1978] To a solution of [(3R)-1-(2-bromophenyl)-3-piperidyl]oxy-tert-butyl-dimethyl- silane (130 mg, 351 μmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (66.3 mg, 219 μmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (13.7 mg, 21.9 μmol), sodium t-butanolate (63.2 mg, 658 μmol) in dioxane (3 mL) was added palladium diacetate (4.92 mg, 21.9 μmol) and stirred at 90 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to givea residue, the residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/1) to give 8-[(1R)-1-[2-[(3R)-3-[tert-butyl (dimethyl) silyl]oxy- 1-piperidyl]anilino]ethyl]-3,6-dimethyl-2-morpholino-quinazo lin-4-one (50 mg, 73.5 μmol, 48%) as a yellow oil. m/z ES+ [M+H] + 592.4. [1979] Step 4. Synthesis of 8-((R)-1-((2-((R)-3-((tert-butyldimethylsilyl)oxy)piperidin- 1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [1980] To a solution of 8-[(1R)-1-[2-[(3R)-3-[tert-butyl(dimethyl)silyl]oxy-1- piperidyl]anilino]ethyl]-3,6-dimethyl-2-morpholino-quinazoli n-4-one (50 mg, 84.5 μmol) in dichloromethane (0.5 mL) was added hydrochloric acid/dioxane (4 M, 0.5 mL). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10um; mobile phase: [water (formic acid)- acetonitrile];gradient: 44%-74% B over 10 min) followed by lyophilization to give 8-((R)-1- ((2-((R)-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)phen yl)amino)ethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (23.5 mg, 49.2 μmol, 58%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.60 - 7.48 (m, 1H), 7.04 - 6.94 (m, 1H), 6.90 - 6.74 (m, 1H), 6.66 - 6.59 (m, 1H), 6.34 (d, J = 2.8 Hz, 1H), 5.42 - 5.28 (m, 1H), 4.11 - 3.93 (m, 1H), 3.91 - 3.87 (m, 4H), 3.62 (s, 3H), 3.36 - 2.42 (m, 9H), 2.38 (s, 3H), 2.10 - 1.87 (m, 2H), 1.83 - 1.68 (m, 2H), 1.57 (s, 3H); m/z ES+ [M+H] ⁺ 478.3. Example 198. Preparation of 8-((R)-1-((2-((S)-3-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (Compound 535) [1981] Step 1. Synthesis of (S)-1-(2-bromophenyl)piperidin-3-ol [1982] To a solution of (3S)-piperidin-3-ol (500 mg, 4.94 mmol) and 1-bromo-2-iodo-benzene (1.54 g, 5.44 mmol, 698 ^L) in isopropanol (10 mL) was added sodium hydroxide (395 mg, 9.89 mmol) and copper iodide (30 mg, 158 μmol). The mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (25 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/1) to give (S)-1-(2- bromophenyl)piperidin-3-ol (420 mg, 1.62 mmol, 33%) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (dd, J = 1.2, 8.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.11 - 7.05 (m, 1H), 6.95 (dt, J = 1.2, 7.6 Hz, 1H), 4.00 (br. s, 1H), 3.14 - 2.99 (m, 3H), 2.91 - 2.77 (m, 2H), 2.11 - 2.00 (m, 1H), 1.78 - 1.64 (m, 3H); m/z ES+ [M+H] ⁺ 256.1. [1983] Step 2. Synthesis of (S)-1-(2-bromophenyl)-3-((tert- butyldimethylsilyl)oxy)piperidine [1984] To a solution of (3S)-1-(2-bromophenyl)piperidin-3-ol (320 mg, 1.25 mmol) in N,N- dimethylformamide (6 mL) was added tert-butylchlorodimethylsilane (282 mg, 1.87 mmol, 231 ^L) and imidazole (170 mg, 2.50 mmol). The mixture was stirred at 20 °C for 2 hr. The mixture was quenched with ammonium chloride (20 mL) and extracted with petroleum ether (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, ethyl acetate/petroleum ether= 0/1 to 5/95) to give (S)-1-(2-bromophenyl)-3- ((tert-butyldimethylsilyl)oxy)piperidine (400 mg, 1.07 mmol, 86%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (dd, J = 1.2, 8.0 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.07 (br. d, J = 6.4 Hz, 1H), 6.94 - 6.87 (m, 1H), 3.91 (td, J = 5.2, 9.6 Hz, 1H), 3.44 - 3.35 (m, 1H), 3.23 (br. d, J = 11.2 Hz, 1H), 2.56 (br. s, 1H), 2.44 (br. t, J = 10.2 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.79 (br. d, J = 8.4 Hz, 2H), 1.42 - 1.28 (m, 1H), 0.90 (s, 9H), 0.10 (d, J = 6.8 Hz, 6H); m/z ES+ [M+H] ⁺ 370.1. [1985] Step 3. Synthesis of 8-((R)-1-((2-((S)-3-((tert-butyldimethylsilyl)oxy)piperidin- 1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [1986] A mixture of [(3S)-1-(2-bromophenyl)-3-piperidyl]oxy-tert-butyl-dimethyl- silane (300 mg, 810 μmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (150 mg, 496 μmol), palladium(II) acetate (12 mg, 53.4 μmol), (R)-(+)-2,2'- Bis(diphenylphosphino)-1,1'-binaphthyl (31 mg, 49.8 μmol) and sodium tert-butoxide (143 mg, 1.49 mmol) in dioxane (6 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 90 °C for 3 hr under nitrogen atmosphere. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (ethyl acetate, petroleum ether/ethyl acetate=100/1 to 3/1) to give 8-((R)-1-((2-((S)-3-((tert-butyldimethylsilyl)oxy)piperidin- 1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (240 mg, 365 μmol, 74%) as light yellow oil. m/z ES+ [M+H] ⁺ 592.5. [1987] Step 4. Synthesis of 8-((R)-1-((2-((S)-3-hydroxypiperidin-1-yl)phenyl)amino)ethyl )- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [1988] To a solution of 8-[(1R)-1-[2-[(3S)-3-[tert-butyl(dimethyl)silyl]oxy-1- piperidyl]anilino]ethyl]-3,6-dimethyl-2-morpholino-quinazoli n-4-one (120 mg, 203 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 1 mL). The mixture was stirred at 20 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Welch ultimate C18150*25 mm* 7 um; mobile phase: [water (formic acid- acetonitrile)];B%: 39%- 69%,15min) to give 8-[(1R)-1-[2-[(3S)-3-hydroxy-1-piperidyl]anilino]ethyl]-3,6- dimethyl-2- morpholino-quinazolin-4-one (56.5 mg, 118 μmol, 58%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 1.2 Hz, 1H), 7.53 (s, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.67 - 6.58 (m, 1H), 6.34 (br. d, J = 8.0 Hz, 1H), 5.34 (br. d, J = 6.4 Hz, 1H), 4.09 - 3.98 (m, 1H), 3.92 - 3.87 (m, 4H), 3.62 (s, 3H), 3.38 - 2.67 (m, 9H), 2.38 (s, 3H), 2.15 - 1.93 (m, 2H), 1.80 - 1.70 (m, 2H), 1.59 (br. d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 478.4. Example 199. Preparation of (R)-8-(1-((4-fluoro-2-(4-hydroxy-4-methylpiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (Compound 562) [1989] Step 1. Synthesis of 1-(5-fluoro-2-nitrophenyl)-4-methylpiperidin-4-ol [1990] To a solution of 2,4-difluoro-1-nitro-benzene (2.00 g, 12.5 mmol) and 4- methylpiperidin-4-ol (1.45 g, 12.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (3.47 g, 25.1 mmol). The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 3/1) to give 1-(5-fluoro-2-nitro-phenyl)-4-methyl-piperidin-4-ol (2.40 g, 9.34 mmol, 74%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (dd, J = 6.0, 9.2 Hz, 1H), 6.80 (dd, J = 2.8, 10.8 Hz, 1H), 6.65 (ddd, J = 2.8, 6.8, 9.2 Hz, 1H), 3.27 - 3.16 (m, 2H), 3.06 (td, J = 3.2, 12.8 Hz, 2H), 1.94 - 1.82 (m, 2H), 1.69 (d, J = 12.8 Hz, 2H), 1.34 (s, 3H); m/z ES+ [M+H] ⁺ 255.1. [1991] Step 2. Synthesis of 1-(2-amino-5-fluorophenyl)-4-methylpiperidin-4-ol [1992] To a solution of 1-(5-fluoro-2-nitro-phenyl)-4-methyl-piperidin-4-ol (2.40 g, 9.44 mmol) in ethanol (20 mL) and water (4 mL) was added iron power (2.64 g, 47.2 mmol) and ammonium chloride (2.52 g, 47.2 mmol). The mixture was stirred at 80 °C for 3 hr. On completion, the reaction mixture was filtered and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 1-(2-amino-5-fluoro-phenyl)-4-methyl-piperidin-4-ol (1.50 g, 6.69 mmol, 70%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 10.0 Hz, 1H), 6.65 (d, J = 6.8 Hz, 2H), 4.06 - 3.66 (m, 1H), 3.02 - 2.84 (m, 4H), 1.89 - 1.69 (m, 4H), 1.34 (s, 3H); m/z ES+ [M+H] ⁺ 225.2. [1993] Step 3. Synthesis of 1-(2-bromo-5-fluorophenyl)-4-methylpiperidin-4-ol [1994] Concentrated sulfuric acid (245 mg, 2.45 mmol) was dropped slowly into stirred water (3 mL) at 0 ° C.1-(2-amino-5-fluoro-phenyl)-4-methyl-piperidin-4-ol (0.50 g, 2.23 mmol) was added slowly into the system and stirred. A solution of sodium nitrite (169 mg, 2.45 mmol) in water (1 mL) was slowly dropped into the raw material system while controlling the temperature to 0 to 10 °C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 1.5 hr to form a diazonium salt system. Then a mixture of sodium bromide (917 mg, 8.92 mmol) and copper(I) bromide (319 mg, 2.23 mmol) in water (1 mL) was added to the diazonium salt system at 0 °C slowly and stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition ammonium hydroxide (10 mL) at 0 °C, and then diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 1-(2-bromo-5-fluoro-phenyl)-4-methyl-piperidin-4-ol (420 mg, 1.43 mmol, 64%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 6.0, 8.8 Hz, 1H), 6.82 (dd, J = 2.4, 10.4 Hz, 1H), 6.64 (ddd, J = 2.8, 7.6, 8.8 Hz, 1H), 3.16 - 2.96 (m, 4H), 1.96 - 1.83 (m, 2H), 1.73 (d, J = 12.8 Hz, 2H), 1.34 (s, 3H); m/z ES+ [M+H] ⁺ 288.0. [1995] Step 4. Synthesis of (R)-8-(1-((4-fluoro-2-(4-hydroxy-4-methylpiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [1996] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (50.0 mg, 165 μmol) and 1-(2-bromo-5-fluoro-phenyl)-4-methyl-piperidin-4-ol (71.4 mg, 248 μmol) in dioxane (1 mL) was added cesium carbonate (161 mg, 496 μmol) and 1,3-bis[2,6- bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-i de;3- chloropyridine;dichloropalladium (16.0 mg, 16.5 μmol). The mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( ammoniumformate)-acetonitrile];gradient:40%-70% B over 10 min) to give 8-[(1R)-1- [4-fluoro-2-(4-hydroxy-4-methyl-1-piperidyl)anilino]ethyl]-3 ,6-dimethyl-2-morpholino- quinazolin-4-one (21.8 mg, 42.4 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.47 (s, 1H), 6.84 - 6.74 (m, 1H), 6.58 - 6.46 (m, 1H), 6.29 - 6.18 (m, 1H), 5.31 - 5.20 (m, 1H), 5.01 - 4.88 (m, 1H), 3.90 (t, J = 4.4 Hz, 4H), 3.62 (s, 3H), 3.28 (d, J = 2.8 Hz, 4H), 3.15 - 2.83 (m, 4H), 2.38 (s, 3H), 1.83 (m, 2H), 1.59 (d, J = 6.8 Hz, 3H), 1.35 - 1.22 (m, 2H); m/z ES+ [M+H] ⁺ 510.3. Example 200. Preparation of 8-((R)-1-((4-fluoro-2-((S)-3-hydroxypiperidin-1- yl)phenyl)amino) ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 583) [1997] Step 1. Synthesis of (S)-1-(5-fluoro-2-nitrophenyl)piperidin-3-ol [1998] To a solution of (3S)-piperidin-3-ol (1.73 g, 12.5 mmol, hydrochloric acid salt) and 2,4-difluoro-1-nitro-benzene (2.00 g, 12.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (5.21 g, 37.7 mmol). The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was partitioned between water (200 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give (S)-1-(5-fluoro-2-nitrophenyl)piperidin-3-ol (2.20 g, 9.16 mmol, 72%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 6.0, 9.2 Hz, 1H), 6.81 (dd, J = 2.8, 10.4 Hz, 1H), 6.72 (ddd, J = 2.8, 6.4, 9.2 Hz, 1H), 4.06 - 3.91 (m, 1H), 3.19 (dd, J = 2.8, 11.6 Hz, 1H), 3.08 - 2.93 (m, 3H), 2.04 - 1.93 (m, 1H), 1.88 - 1.76 (m, 1H), 1.75 - 1.62 (m, 2H); m/z ES+ [M+H]+ 241.1. [1999] Step 2. Synthesis of (S)-1-(2-amino-5-fluorophenyl)piperidin-3-ol [2000] To a solution of (3S)-1-(5-fluoro-2-nitro-phenyl)piperidin-3-ol (2.20 g, 9.16 mmol) in ethanol (20 mL) and water (4 mL) was added iron (2.56 g, 45.7 mmol) and ammonium chloride (2.45 g, 45.7 mmol). The mixture was stirred at 80 °C for 3 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give (S)-1-(2-amino-5-fluorophenyl)piperidin-3-ol (1.40 g, 6.59 mmol, 71%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.71 (d, J = 10.0 Hz, 1H), 6.68 - 6.63 (m, 2H), 4.01 - 3.90 (m, 1H), 3.02 (d, J = 10.0 Hz, 1H), 2.82 (s, 3H), 2.01 - 1.79 (m, 2H), 1.75 - 1.56 (m, 2H); m/z ES+ [M+H] ⁺ 211.1. [2001] Step 3. Synthesis of (S)-1-(2-bromo-5-fluorophenyl)piperidin-3-ol [2002] Concentrated sulfuric acid (261 mg, 2.62 mmol) was dropped slowly into water (3 mL) stirred and cooled to 0 ° C. (3S)-1-(2-amino-5-fluoro-phenyl)piperidin-3-ol (0.50 g, 2.38 mmol) was added slowly into the system and stirred. A solution of sodium nitrite (180 mg, 2.62 mmol) in water (1 mL) was slowly dropped into the raw material system while controlling the temperature at 0 to 10 °C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 0.5 hr to form a diazonium salt system. Then a mixture of sodium bromide (978 mg, 9.51 mmol) and copper(I) bromide (341 mg, 2.38 mmol) in water (1 mL) was added to the diazonium salt system at 0 °C and stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition ammonium hydroxide (20 mL) at 0 °C, and then diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give (S)-1-(2-bromo-5-fluorophenyl)piperidin-3-ol (460 mg, 1.64 mmol, 69%) as a brown solid. m/z ES+ [M+H] ⁺ 276.0. [2003] Step 4. Synthesis of (S)-1-(2-bromo-5-fluorophenyl)-3-((tert- butyldimethylsilyl)oxy)piperidine [2004] To a solution of (3S)-1-(2-bromo-5-fluoro-phenyl)piperidin-3-ol (460 mg, 1.68 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (342. mg, 5.03 mmol) and tert- butylchlorodimethylsilane (505 mg, 3.36 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, washed with saturated sodium bicarbonate (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 10/1) to give (S)-1-(2-bromo-5-fluorophenyl)-3-((tert- butyldimethylsilyl)oxy)piperidine (600 mg, 1.53 mmol, 91%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (dd, J = 6.4, 8.8 Hz, 1H), 6.81 - 6.73 (m, 1H), 6.67 - 6.60 (m, 1H), 3.89 (td, J = 5.2, 9.6 Hz, 1H), 3.44 - 3.34 (m, 1H), 3.27 - 3.16 (m, 1H), 2.59 - 2.48 (m, 1H), 2.41 (t, J = 10.0 Hz, 1H), 2.02 (dd, J = 4.0, 12.4 Hz, 1H), 1.86 - 1.69 (m, 2H), 1.38 - 1.31 (m, 1H), 0.94 - 0.81 (m, 9H), 0.10 (d, J = 6.0 Hz, 6H); m/z ES+ [M+H] ⁺ 389.8. [2005] Step 5. Synthesis of 8-((R)-1-((2-((S)-3-((tert-butyldimethylsilyl)oxy)piperidin- 1-yl)- 4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazo lin-4(3H)-one [2006] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (100 mg, 330 μmol) and [(3S)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl - dimethyl-silane (128 mg, 330 μmol) in dioxane (2 mL) was added cesium carbonate (323 mg, 992 μmol) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidaz ol-1-ium-2- ide;3-chloropyridine;dichloropalladium (32.1 mg, 33.0 μmol). The mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 8-[(1R)- 1-[2-[(3S)-3-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-4-f luoro-anilino]ethyl]-3,6-dimethyl- 2-morpholino-quinazolin-4-one (60.0 mg, 98.3 μmol, 29%) as a brown solid. m/z ES+ [M+H] ⁺ 610.4. [2007] Step 6. Synthesis of 8-((R)-1-((4-fluoro-2-((S)-3-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [2008] To a solution of 8-[(1R)-1-[2-[(3S)-3-[tert-butyl(dimethyl)silyl]oxy-1-piperi dyl]-4- fluoro-anilino]ethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (60.0 mg, 98.3 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 1.23 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:59%-83% B over 8 min) to give 8-[(1R)-1-[4-fluoro-2-[(3S)-3-hydroxy- 1-piperidyl]anilino]ethyl]-3,6-dimethyl-2-morpholino-quinazo lin-4-one (23.4 mg, 47.3 μmol, 48%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 6.72 (dd, J = 2.8, 10.0 Hz, 1H), 6.52 (dt, J = 2.8, 8.4 Hz, 1H), 6.31 - 6.20 (m, 1H), 5.31 (d, J = 6.0 Hz, 1H), 4.03 (s, 1H), 3.94 - 3.84 (m, 4H), 3.61 (s, 3H), 3.33 - 3.22 (m, 4H), 3.19 - 3.03 (m, 1H), 2.98 - 2.70 (m, 3H), 2.38 (s, 3H), 2.09 - 1.85 (m, 2H), 1.81 - 1.66 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 496.3. Example 201. Preparation of 8-((R)-1-((4-fluoro-2-((R)-3-hydroxypiperidin-1- yl)phenyl)amino) ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 580) [2009] Step 1. Synthesis of (R)-1-(5-fluoro-2-nitrophenyl)piperidin-3-ol [2010] To a solution of (3R)-piperidin-3-ol (3.00 g, 21.8 mmol) and 2,4-difluoro-1-nitro- benzene (3.47 g, 21.8 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (9.04 g, 65.4 mmol). The mixture was stirred at 80 °C for 3 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 4/1) to give (R)-1-(5-fluoro-2-nitrophenyl)piperidin-3-ol (3.50 g, 14.4 mmol, 66%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (dd, J = 6.0, 9.2 Hz, 1H), 6.73 (dd, J = 2.4, 10.4 Hz, 1H), 6.64 (ddd, J = 2.4, 6.8, 9.2 Hz, 1H), 3.96 - 3.86 (m, 1H), 3.11 (dd, J = 2.4, 11.6 Hz, 1H), 2.98 - 2.87 (m, 3H), 1.96 - 1.87 (m, 1H), 1.79 - 1.70 (m, 1H), 1.65 - 1.58 (m, 2H). m/z ES+ [M+H] ⁺ 241.0. [2011] Step 2. Synthesis of (R)-1-(2-amino-5-fluorophenyl)piperidin-3-ol [2012] To a solution of (3R)-1-(5-fluoro-2-nitro-phenyl)piperidin-3-ol (3.50 g, 14.5 mmol) in ethanol (35 mL) was added ammonium chloride (8 M, 18.2 mL) and iron (4.07 g, 72.8 mmol), the mixture was stirred at 60 °C for 3 hr. On completion, the mixture was filtered and washed with ethyl acetate (30 mL x 3), the filtrate was added saturated potassium carbonate solution to adjust pH = 8. The organic phase was separated, washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give (R)-1-(2-amino-5-fluorophenyl)piperidin-3-ol (2.00 g, 9.51 mmol, 65%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 6.73 (br. d, J = 10.4 Hz, 1H), 6.68 (br. d, J = 6.4 Hz, 2H), 3.98 (br. s, 1H), 3.04 (br. d, J = 9.2 Hz, 1H), 2.91 - 2.76 (m, 3H), 2.00 - 1.83 (m, 2H), 1.75 - 1.59 (m, 2H). m/z ES+ [M+H] ⁺ 211.1. [2013] Step 3. Synthesis of (R)-1-(2-bromo-5-fluorophenyl)piperidin-3-ol [2014] Concentrated sulfuric acid (523 mg, 5.23 mmol) was dropped slowly into water (5 mL) at 0 °C. (3R)-1-(2-amino-5-fluoro-phenyl)piperidin-3-ol (1.00 g, 4.76 mmol) was added slowly into the system and stirred. A solution of sodium nitrite (360 mg, 5.23 mmol) in water (5 mL) was slowly dropped into the raw material system while controlling the temperature at 0 to 10 ° C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 1.5 hr to form a diazonium salt system. A mixture of sodium bromide (1.96 g, 19.0 mmol) and cuprous bromide (682 mg, 4.76 mmol) in water (2.5 mL) was added at 25 °C, the mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition ammonium hydroxide to pH = 7, and then diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/1) to give (R)-1-(2-bromo-5- fluorophenyl)piperidin-3-ol (900 mg, 3.28 mmol, 69%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (dd, J = 6.0, 8.8 Hz, 1H), 6.82 (dd, J = 2.4, 10.0 Hz, 1H), 6.71 (ddd, J = 2.8, 7.6, 8.8 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.16 - 2.96 (m, 3H), 2.91 - 2.80 (m, 1H), 2.09 - 2.02 (m, 1H), 1.78 - 1.67 (m, 3H). m/z ES+ [M+H] ⁺ 274.0. [2015] Step 4. Synthesis of (R)-1-(2-bromo-5-fluorophenyl)-3-((tert- butyldimethylsilyl)oxy)piperidine [2016] To a solution of (3R)-1-(2-bromo-5-fluoro-phenyl)piperidin-3-ol (500 mg, 1.82 mmol) in N,N-dimethylformamide (5 mL) was added tert-butylchlorodimethylsilane (412 mg, 2.74 mmol) and imidazole (310 mg, 4.56 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), the combined organic layers were washed with sodium bicarbonate (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, ethyl acetate/petroleum ether =0/1 to 1/99) to give [(3R)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl - dimethyl-silane (600 mg, 1.54 mmol, 84%) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 6.0, 8.8 Hz, 1H), 6.79 (dd, J = 2.8, 10.4 Hz, 1H), 6.65 (ddd, J = 2.8, 7.6, 8.8 Hz, 1H), 3.98 - 3.85 (m, 1H), 3.46 - 3.37 (m, 1H), 3.29 - 3.18 (m, 1H), 2.55 (dt, J = 3.6, 11.2 Hz, 1H), 2.42 (t, J = 10.0 Hz, 1H), 2.10 - 1.99 (m, 1H), 1.88 - 1.72 (m, 2H), 1.42 - 1.32 (m, 1H), 0.92 (s, 9H), 0.11 (d, J = 6.0 Hz, 6H); m/z ES+ [M+H] ⁺ 390.1. [2017] Step 5. Synthesis of 8-((R)-1-((2-((R)-3-((tert-butyldimethylsilyl)oxy)piperidin- 1-yl)- 4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazo lin-4(3H)-one [2018] A mixture of [(3R)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl -dimethyl- silane (192 mg, 496 μmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 - one (100 mg, 330 μmol), cesium carbonate (323 mg, 992 μmol), 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (32.1 mg, 33.0 μmol) in dioxane (1 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-((R)-1-((2-((R)-3-((tert- butyldimethylsilyl)oxy)piperidin-1-yl)-4-fluorophenyl)amino) ethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (100 mg, 162 μmol, 49%) as green oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.49 - 7.34 (m, 1H), 6.73 - 6.58 (m, 1H), 6.52 - 6.36 (m, 1H), 6.29 - 6.07 (m, 1H), 5.27 - 5.13 (m, 1H), 3.79 - 3.73 (m, 4H), 3.48 (s, 3H), 3.20 - 3.06 (m, 5H), 2.54 - 2.43 (m, 1H), 2.23 (s, 3H), 1.84 - 1.79 (m, 1H), 1.47 (br. d, J = 6.4 Hz, 3H), 1.41 (s, 6H), 1.36 - 1.25 (m, 1H), 0.79 (s, 9H), 0.00 (d, J = 3.6 Hz, 6H) m/z ES+ [M+H] ⁺ 610.4. [2019] Step 6. Synthesis of 8-((R)-1-((4-fluoro-2-((R)-3-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [2020] To a solution of 8-[(1R)-1-[2-[(3R)-3-[tert-butyl(dimethyl)silyl]oxy-1-piperi dyl]-4- fluoro-anilino]ethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (100 mg, 163 μmol) in dichloromethane (1 mL) was added hydrochloric acid /dioxane (4 M, 1 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(formic acid)-acetonitrile];gradient:52%-82% B over 10 min) to give 8-((R)-1-((4-fluoro-2-((R)-3-hydroxypiperidin-1-yl)phenyl)am ino)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (52.5 mg, 106 μmol, 64%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.42 (s, 1H), 6.73 - 6.61 (m, 1H), 6.50 - 6.40 (m, 1H), 6.25 - 6.09 (m, 1H), 5.21 (q, J = 6.0 Hz, 1H), 4.05 - 3.91 (m, 1H), 3.85 - 3.78 (m, 4H), 3.54 (s, 3H), 3.24 - 3.16 (m, 4H), 3.10 - 2.80 (m, 3H), 2.79 - 2.58 (m, 1H), 2.30 (s, 3H), 1.98 - 1.81 (m, 2H), 1.74 - 1.62 (m, 2H), 1.51 (br. d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 496.3. Example 202. Preparation of (R)-8-(1-((4-fluoro-2-(hydroxymethyl)phenyl)amino)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 664) [2021] Step 1. Synthesis of ((2-bromo-5-fluorobenzyl)oxy)(tert-butyl)dimethylsilane [2022] To a solution of (2-bromo-5-fluoro-phenyl)methanol (1.00 g, 4.88 mmol) in N,N- dimethylformamide (10 mL) was added imidazole (830 mg, 12.1 mmol) and tert-butyl-chloro- dimethyl-silane (1.10 g, 7.32 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 5/1) to give (2-bromo-5-fluoro-phenyl)methoxy-tert-butyl-dimethyl-silane (1.50 g, 4.70 mmol, 96%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 5.2, 8.8 Hz, 1H), 7.25 (dd, J = 2.8, 9.6 Hz, 1H), 7.11 (dt, J = 2.8, 8.4 Hz, 1H), 4.66 (s, 2H), 0.92 (s, 9H), 0.12 (s, 6H). [2023] Step 2. Synthesis of (R)-8-(1-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazoli n-4(3H)-one [2024] To a solution of (2-bromo-5-fluoro-phenyl)methoxy-tert-butyl-dimethyl-silane (316 mg, 992 μmol) and 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (150 mg, 496 μmol) in dioxane (2 mL) was added cesium carbonate (484 mg, 1.49 mmol) and 1,3- bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1 -ium-2-ide;3- chloropyridine;dichloropalladium (96.1 mg, 99.2 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give (R)-8-(1-((2-(((tert- butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)amino)ethyl)-3 ,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (110 mg, 203 μmol, 41%) as a colourless oil. m/z ES+ [M+H] ⁺ 541.5. [2025] Step 3. Synthesis of (R)-8-(1-((4-fluoro-2-(hydroxymethyl)phenyl)amino)ethyl)-3,6 - dimethyl-2-morpholinoquinazolin-4(3H)-one [2026] To a solution of (R)-8-(1-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazoli n-4(3H)-one (110 mg, 203 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 254 ^L). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:35%-65% B over 10 min) to give (R)-8-(1-((4-fluoro-2- (hydroxymethyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholino quinazolin-4(3H)-one (29.5 mg, 69.3 μmol, 34%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 6.83 (dd, J = 2.8, 8.8 Hz, 1H), 6.72 (dt, J = 3.2, 8.8 Hz, 1H), 6.36 (dd, J = 4.8, 8.8 Hz, 1H), 5.31 (q, J = 6.8 Hz, 1H), 4.72 (s, 2H), 3.90 (t, J = 4.8 Hz, 4H), 3.62 (s, 3H), 3.29 (br. d, J = 2.8 Hz, 4H), 2.38 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 427.4. Example 203. Preparation of (R)-8-(1-((3-fluoro-2-(hydroxymethyl)phenyl)amino)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 665) [2027] Step 1. Synthesis of ((2-bromo-6-fluorobenzyl)oxy)(tert-butyl)dimethylsilane [2028] To a solution of (2-bromo-6-fluoro-phenyl)methanol (0.50 g, 2.44 mmol) in N,N- dimethylformamide (5 mL) was added imidazole (415 mg, 6.10 mmol) and tert-butyl-chloro- dimethyl-silane (551 mg, 3.66 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2-bromo-6-fluoro- phenyl)methoxy-tert-butyl-dimethyl-silane (0.60 g, 1.88 mmol, 77%) as a colourless oil. ¹ H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 7.6 Hz, 1H), 7.33 (dt, J = 6.0, 8.0 Hz, 1H), 7.29 - 7.23 (m, 1H), 4.77 (d, J = 2.0 Hz, 2H), 0.86 (s, 8H), 0.08 (s, 6H). [2029] Step 2. Synthesis of (R)-8-(1-((2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazoli n-4(3H)-one [2030] To a solution of (2-bromo-6-fluoro-phenyl)methoxy-tert-butyl-dimethyl-silane (316 mg, 992 μmol) and 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (0.15 g, 496 μmol) in dioxane (2 mL) was added cesium carbonate (484 mg, 1.49 mmol) and 1,3- bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1 -ium-2-ide;3- chloropyridine;dichloropalladium (96.5 mg, 99.2 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen. On completion, the reaction mixture was diluted with water 30 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give (R)-8-(1-((2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)amino)ethyl)-3 ,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (0.20 g, 351 μmol, 71%) as a colourless oil. m/z ES+ [M+H] ⁺ 541.4. [2031] Step 3. Synthesis of (R)-8-(1-((3-Fluoro-2-(hydroxymethyl)phenyl)amino)ethyl)-3,6 - dimethyl-2-morpholinoquinazolin-4(3H)-one [2032] To a solution of (R)-8-(1-((2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazoli n-4(3H)-one (0.20 g, 370 μmol) in dichloromethane (2 mL) was added hydrochloric acid/dioxane (4 M, 460 ^L). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate C18 150*25mm*5um;mobile phase: [water(formic acid)- acetonitrile];gradient:42%-72% B over 11 min) to give (R)-8-(1-((3-fluoro-2- (hydroxymethyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholino quinazolin-4(3H)-one (6.13 mg, 14.2 μmol, 4%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.49 (s, 1H), 7.00 - 6.88 (m, 1H), 6.37 (br. t, J = 8.8 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 5.36 (q, J = 6.4 Hz, 1H), 4.87 (s, 2H), 3.90 (t, J = 4.4 Hz, 4H), 3.62 (s, 3H), 3.33 - 3.25 (m, 4H), 2.38 (s, 3H), 1.63 (br. d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 427.3. Example 204. Preparation of (R)-8-(1-((4-fluoro-2-(1H-indazol-6-yl)phenyl)amino)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 690) [2033] Step 1. Synthesis of (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2- morpholinoquinazolin-4(3H)-one [2034] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (300 mg, 992 μmol), (2-bromo-4-fluoro-phenyl)boronic acid (2.17 g, 9.92 mmol), copper acetate (360 mg, 1.98 mmol), triethylamine (1.00 g, 9.92 mmol) and 4Å molecular sieves (100 mg, 992 μmol) in dichloromethane (20 mL) was degassed and purged with oxygen (3x), and then the mixture was stirred at 25 °C for 12 hr under oxygen atmosphere (15 psi). The reaction mixture was partitioned between saturated ammonium chloride (30 mL) and dichloromethane (20 mL). The organic phase was separated and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5/1 to 1/1) to give (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one (180 mg, 379 μmol, 38%) as a yellow oil. m/z ES+ [M+H] ⁺ 477.1. [2035] Step 2. Synthesis of (R)-8-(1-((4-fluoro-2-(1H-indazol-6-yl)phenyl)amino)ethyl)-3 ,6- dimethyl-2-morpholinoquinazolin-4(3H)-one [2036] A mixture of 8-[(1R)-1-(2-bromo-4-fluoro-anilino)ethyl]-3,6-dimethyl-2-mo rpholino- quinazolin-4-one (130 mg, 273 μmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole (80.1 mg, 328 μmol), tetratriphenylphosphopalladium (31.6 mg, 27.3 μmol), potassium carbonate (75.6 mg, 547 μmol) in water (0.2 mL) and dioxane (2 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase was separated and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(formic acid)- acetonitrile];gradient:51%-81% B over 10 min) to give (R)-8-(1-((4-fluoro-2-(1H-indazol-6-yl)phenyl)amino)ethyl)-3 ,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (83.2 mg, 160 μmol, 59%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (br. s, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.25 (s, 1H), 6.89 - 6.80 (m, 2H), 6.54 (br dd, J = 4.4, 8.8 Hz, 1H), 5.08 (q, J = 6.4 Hz, 1H), 3.71 (t, J = 4.4 Hz, 4H), 3.54 (s, 3H), 2.98 - 2.78 (m, 3H), 2.79 - 2.78 (m, 1H), 2.40 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 513.3. Example 205. Preparation of (R)-8-(1-((3,4-difluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (Compound 715) [2037] Step 1. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-3,4- difluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazo lin-4(3H)-one [2038] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (100 mg, 330 μmol) in dioxane (5 mL) was added [1-(6-bromo-2,3-difluoro-phenyl)-4- piperidyl]oxy-tert-butyl-dimethyl-silane (268 mg, 661 μmol), 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (64.3 mg, 66.1 μmol) and cesium carbonate (323 mg, 992 μmol). The mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 3/1) to give 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1- piperidyl]-3,4-difluoro-anilino]ethyl]-3,6-dimethyl-2-morpho lino-quinazolin-4-one (200 mg, 305 μmol, 92%) as a yellow solid. m/z ES+ [M+H] ⁺ 628.5. [2039] Step 2. Synthesis of (R)-8-(1-((3,4-difluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [2040] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 3,4- difluoro-anilino]ethyl]-3,6-dimethyl-2-morpholino-quinazolin -4-one (200 mg, 318 μmol) in dichloromethane (2 mL) was added hydrochloric acid/dioxane (4 M, 1 mL), the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC [column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:50%-80% B over 11 min] to give (R)-8-(1-((3,4-difluoro-2-(4-hydroxypiperidin-1-yl)phenyl)am ino)ethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (59.7 mg, 116 μmol, 36%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 0.8 Hz, 1H), 7.40 (s, 1H), 6.65 (q, J = 9.2 Hz, 1H), 6.00 (dd, J = 1.6, 3.2 Hz, 1H), 5.38 - 5.26 (m, 1H), 3.95 - 3.78 (m, 5H), 3.61 (s, 3H), 3.33 - 3.26 (m, 4H), 3.26 - 3.14 (m, 2H), 3.11 - 2.81 (m, 2H), 2.38 (s, 3H), 2.17 - 2.01 (m, 2H), 1.78 - 1.66 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 514.0. Example 206. Preparation of (R)-8-(1-((4-chloro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (Compound 684) [2041] Step 1. Synthesis of 1-(5-chloro-2-nitro-phenyl)piperidin-4-ol [2042] To a solution of 4-chloro-2-fluoro-1-nitro-benzene (5 g, 28.5 mmol) in N,N- dimethylformamide (50 mL) was added cesium carbonate (27.8 g, 85.45 mmol) and piperidin- 4-ol (2.8 g, 28.5 mmol) at 25 °C, The mixture was stirred at 80 °C for 2 hr. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (250 mL). The combined organic layers were dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 3/1) to give 1-(5-chloro-2-nitro- phenyl) piperidin-4-ol (6.9 g, 26.8 mmol, 94%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d6) δ 7.83 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 2.0, 8.8 Hz, 1H), 4.73 (d, J = 4.4 Hz, 1H), 3.64 (qt, J = 4.0, 8.4 Hz, 1H), 3.21 - 3.10 (m, 2H), 2.87 (ddd, J = 3.2, 9.6, 12.4 Hz, 2H), 1.86 - 1.74 (m, 2H), 1.55 - 1.43 (m, 2H); m/z ES+ [M+H] ⁺ 257.2. [2043] Step 2. Synthesis of 1-(2-amino-5-chloro-phenyl)piperidin-4-ol [2044] To a solution of ammonium chloride (2.08 g, 39.0 mmol) in ethanol (20 mL) and water (8 mL) was added 1-(5-chloro-2-nitrophenyl) piperidin-4-ol (2 g, 7.79 mmol) and iron power (2.18 g, 39.0 mmol), the mixture was stirred at 60 °C for 2 hours under nitrogen. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (300 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 1-(2-amino-5-chloro-phenyl) piperidin-4-ol (1.68 g, 7.41 mmol, 95%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.84 - 6.77 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 4.81 (s, 2H), 4.66 (d, J = 4.0 Hz, 1H), 3.59 (dt, J = 4.4, 8.8 Hz, 1H), 3.01 - 2.92 (m, 2H), 2.60 - 2.52 (m, 2H), 1.89 - 1.77 (m, 2H), 1.56 (dtd, J = 3.6, 9.6, 12.4 Hz, 2H); m/z ES+ [M+H] ⁺ 227.0. [2045] Step 3. Synthesis of 1-(2-amino-5-chloro-phenyl)piperidin-4-ol [2046] To a solution of 1-(2-amino-5-chloro-phenyl) piperidin-4-ol (1.68 g, 7.41 mmol,) in water (12 mL) was added sulfuric acid (816 mg, 8.15 mmol) and a solution of sodium nitrite (562 mg, 8.15 mmol) in water (5 mL) at 0 °C, The mixture was stirred at 20 °C for 1.5 hr, then a solution of sodium bromide (3.05 g, 29.6 mmol) and copper bromide (1.06 g, 7.41 mmol) in water (5 mL) was added at 20 °C, The mixture was stirred at 80 °C for 1.5 hr. The reaction was adjusted to pH = 7 with aqueous sodium bicarbonate solution (100 mL) and extracted with ethylacetate (250 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(2-bromo-5-chloro-phenyl) piperidin-4-ol (2.12 g, crude) as brown oil. m/z ES+ [M+H] ⁺ 292.1. [2047] Step 4. Synthesis of [1-(2-bromo-5-chloro-phenyl)-4-piperidyl]oxy-tert-butyl- dimethyl-silane [2048] To a solution of 1-(2-bromo-5-chloro-phenyl) piperidin-4-ol (2.12 g, 7.30 mmol) in N,N-dimethylformamide (21 mL) was added imidazole (1.24 g, 18.3 mmol) and tert- butylchlorodimethylsilane (1.65 g, 10.9 mmol), The mixture was stirred at 25 °C for 2 hours. The reaction was adjusted to pH = 7 with Saturated ammonium chloride solution (25 mL) and extracted with ethylacetate (200 mL x 2). The combined organic layers were washed with brine (150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, ethyl acetate/petroleum ether = 0/1 to 1/10) to give [1-(2- bromo-5-chloro-phenyl)-4-piperidyl]oxy-tert-butyl-dimethyl-s ilane (1.86 g, 4.59 mmol, 63%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (d, J = 8.4 Hz, 1H), 7.02 (br. s, 1H), 6.93 - 6.83 (m, 1H), 3.90 (br. s, 1H), 3.21 (br. s, 2H), 2.85 (br. t, J = 8.0 Hz, 2H), 1.93 (br. s, 2H), 1.82 - 1.69 (m, 2H), 0.92 (s, 9H), 0.09 (s, 6H). m/z ES+ [M+H] ⁺ 405.8. [2049] [2050] Step 5. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- chlorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazoli n-4(3H)-one [2051] To a solution of [1-(2-bromo-5-chloro-phenyl)-4-piperidyl]oxy-tert-butyl-dime thyl- silane (268 mg, 661 μmol) in dioxane (2 mL) was added 8-[(1R)-1-aminoethyl]-3,6-dimethyl- 2-morpholino-quinazolin-4-one (100 mg, 331 μmol), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]- 4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichlo ropalladium (96.5 mg, 99.2 μmol) and cesium carbonate (323 mg, 992 μmol). The mixture was stirred at 110 °C for 16 hr under nitrogen. On completion, the mixture was diluted with brine (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 2/3) to give (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- chlorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazoli n-4(3H)-one (60.0 mg, 81.4 μmol, 25%) as a yellow oil. m/z ES+ [M+H] ⁺ 626.4. [2052] Step 6. Synthesis of (R)-8-(1-((4-chloro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [2053] To a solution of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- chlorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazoli n-4(3H)-one (60.0 mg, 81.4 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 850 ^L). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo. The residue was purfied by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(formic acid)- acetonitrile]; gradient:50%-80% B over 10 min) to give (R)-8-(1-((4-chloro-2-(4-hydroxypiperidin-1-yl)phenyl)amino) ethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (17.8 mg, 34.7 μmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.44 (s, 1H), 6.94 (br. s, 1H), 6.76 (br. d, J = 8.4 Hz, 1H), 6.25 (br. d, J = 8.0 Hz, 1H), 5.43 - 4.94 (m, 2H), 3.90 (br. t, J = 4.0 Hz, 5H), 3.62 (s, 3H), 3.28 (br. d, J = 4.8 Hz, 4H), 3.22 - 3.12 (m, 2H), 2.83 - 2.62 (m, 2H), 2.38 (s, 3H), 2.10 (br. d, J = 8.4 Hz, 2H), 1.85 - 1.74 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 512.4. Example 207. Preparation of (R)-8-(1-((4-Fluoro-2-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (Compound 745) [2054] Step 1. Synthesis of (R)-8-(1-((2-(4-(2-((tert-butyldimethylsilyl)oxy)acetyl)pipe razin- 1-yl)-4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoq uinazolin-4(3H)-one [2055] A mixture of 1-[4-(2-bromo-5-fluoro-phenyl)piperazin-1-yl]-2-[tert- butyl(dimethyl)silyl]oxy-ethanone (285 mg, 661 μmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl- 2-morpholino-quinazolin-4-one (100 mg, 330 μmol), cesium carbonate (323 mg, 992 μmol) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidaz ol-1-ium-2-ide;3- chloropyridine;dichloropalladium (32.1 mg, 33.0 μmol) in dioxane (1 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water 10 mL and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 0/1) to give (R)-8-(1-((2-(4-(2-((tert- butyldimethylsilyl)oxy)acetyl)piperazin-1-yl)-4-fluorophenyl )amino)ethyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (140 mg, 203 μmol, 62%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 6.72 (dd, J = 2.8, 9.6 Hz, 1H), 6.65 - 6.52 (m, 1H), 6.38 - 6.25 (m, 1H), 5.38 - 5.24 (m, 1H), 4.38 (s, 2H), 3.91 (t, J = 4.4 Hz, 4H), 3.86 - 3.76 (m, 2H), 3.63 (s, 3H), 3.36 - 3.25 (m, 4H), 3.07 - 2.96 (m, 2H), 2.96 - 2.85 (m, 2H), 2.40 (s, 3H), 1.62 (br. d, J = 6.4 Hz, 3H), 0.96 (s, 9H), 0.16 (s, 6H); m/z ES+ [M+H] ⁺ 653.4. [2056] Step 2. Synthesis of (R)-8-(1-((4-Fluoro-2-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [2057] To a solution of (R)-8-(1-((2-(4-(2-((tert-butyldimethylsilyl)oxy)acetyl)pipe razin-1- yl)-4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoqui nazolin-4(3H)-one (120 mg, 183 μmol) in anhydrous tetrahydrofuran (1.2 mL) was added tetrabutylammonium;fluoride (1 M in tetrahydrofuran, 551 ^L). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was diluted with water 30 mL and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/1 to 0/1) to give (R)-8-(1-((4-fluoro-2-(4-(2-hydroxyacetyl)piperazin-1-yl)phe nyl)amino)ethyl)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one (83.5 mg, 153 μmol, 84%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 3.2, 10.4 Hz, 1H), 6.67 - 6.58 (m, 1H), 6.40 - 6.30 (m, 1H), 5.34 - 5.28 (m, 1H), 5.27 - 5.18 (m, 1H), 4.67 (t, J = 5.6 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H), 3.79 (t, J = 4.4 Hz, 4H), 3.75 - 3.52 (m, 4H), 3.50 (s, 3H), 3.30 - 3.19 (m, 4H), 2.84 (br. s, 4H), 2.35 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 539.3. Example 208. Preparation of (R)-8-(1-((4-fluoro-2-(4-propionylpiperazin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (Compound 742) [2058] Step 1. Synthesis of (R)-8-(1-((4-Fluoro-2-(4-propionylpiperazin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one [2059] To a suspension of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 - one (60.2 mg, 199 μmol), 1-[4-(2-bromo-5-fluoro-phenyl)piperazin-1-yl]propan-1-one (125 mg, 398 μmol), cesium carbonate (195 mg, 597 μmol) in dioxane (2 mL) was added 1,3- bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1 -ium-2-ide;3- chloropyridine;dichloropalladium (13.6 mg, 13.9 μmol), the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. On completion, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(formic acid)- acetonitrile];gradient:47%-77% B over 10 min) and then re-purified by prep-TLC (silicon dioxide, ethyl acetate) to give (R)-8-(1-((4- fluoro-2-(4-propionylpiperazin-1-yl)phenyl)amino)ethyl)-3,6- dimethyl-2- morpholinoquinazolin-4(3H)-one (31.7 mg, 59.07 μmol, 30%) as a light purple solid. ¹ H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.45 (s, 1H), 6.74 - 6.66 (m, 1H), 6.60 - 6.51 (m, 1H), 6.32 - 6.23 (m, 1H), 5.28 (q, J = 6.8 Hz, 1H), 3.89 (t, J = 4.4 Hz, 4H), 3.86 - 3.65 (m, 3H), 3.62 (s, 4H), 3.32 - 3.23 (m, 4H), 3.06 - 2.83 (m, 4H), 2.43 (q, J = 6.8 Hz, 2H), 2.38 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 537.4. Example 209. Preparation of (R)-8-(1-((2,4-difluoro-3- (hydroxymethyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholino quinazolin-4(3H)-one (Compound 725) [2060] Step 1. Synthesis of (3-bromo-2,6-difluorophenyl)methanol [2061] To a mixture of 3-bromo-2,6-difluoro-benzaldehyde (2.00 g, 9.05 mmol) in methanol (45 mL) was added sodium borohydride (342 mg, 9.05 mmol) portionwise at 0 °C under nitrogen. The mixture was stirred at 25 °C for 1 hr. The reaction was quenched by 30 mL ammonium chloride slowly and then extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (3-bromo-2, 6-difluoro-phenyl)methanol (1.94 g, 8.70 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 - 7.47 (m, 1H), 6.86 (dt, J = 1.6, 8.8 Hz, 1H), 4.82 (s, 2H). [2062] Step 2. Synthesis of ((3-bromo-2,6-difluorobenzyl)oxy)(tert-butyl)dimethylsilane [2063] To a mixture of (3-bromo-2,6-difluoro-phenyl)methanol (1.94 g, 8.70 mmol) in N,N- dimethylformamide (20 mL) was added tert-butylchlorodimethylsilane (1.97 g, 13.1 mmol) and imidazole (1.48 g, 21.8 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into ethyl acetate (100 mL) and water (100 mL), then the mixture was separated. The organic phase was washed with brine (50 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 10/1) to give (3-bromo-2,6-difluoro-phenyl)methoxy-tert-butyl-dimethyl- silane (2.74 g, 8.12 mmol, 93%) as a colourless oil. ¹ H NMR (400 MHz, CDCl3) δ 7.49 - 7.43 (m, 1H), 6.82 (dt, J = 1.6, 8.8 Hz, 1H), 4.78 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H). [2064] Step 3. Synthesis of (R)-8-(1-((3-(((tert-butyldimethylsilyl)oxy)methyl)-2,4- difluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazo lin-4(3H)-one [2065] To a mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-morpholino-quinazolin-4 -one (100 mg, 331 μmol) and (3-bromo-2,6-difluoro-phenyl)methoxy-tert-butyl-dimethyl-sil ane (223 mg, 661 μmol) in dioxane (2 mL) was added cesium carbonate (323 mg, 992 μmol). Then 1,3-bis[2, 6-bis (1-propylbutyl) phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (64.3 mg, 66.1 μmol) was added into the mixture under nitrogen. The mixture was stirred at 110 °C for 16 hr under nitrogen. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 5/1) to give (R)-8- (1-((3-(((tert-butyldimethylsilyl)oxy)methyl)-2,4-difluoroph enyl)amino)ethyl)-3,6-dimethyl- 2-morpholinoquinazolin-4(3H)-one (120 mg, 208 μmol, 63%) as a yellow oil. m/z ES+ [M+H] ⁺ 559.2. [2066] Step 4. Synthesis of (R)-8-(1-((2,4-difluoro-3-(hydroxymethyl)phenyl)amino)ethyl) - 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [2067] To a mixture of (R)-8-(1-((3-(((tert-butyldimethylsilyl)oxy)methyl)-2,4- difluorophenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazo lin-4(3H)-one (120 mg, 215 μmol) in dichloromethane (5 mL) was added hydrochloric acid/dioxane (4 M, 53.7 ^L). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (formic acid) -acetonitrile]; gradient: 35%-65% B over 10 min) followed by lyophlization to give (R)-8-(1-((2,4-difluoro-3- (hydroxymethyl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholino quinazolin-4(3H)-one (63.2 mg, 142 μmol, 66%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 6.62 (dt, J = 1.6, 8.8 Hz, 1H), 6.43 (dt, J = 5.6, 9.2 Hz, 1H), 5.12 (q, J = 6.4 Hz, 1H), 4.76 (s, 2H), 3.93 - 3.89 (m, 4H), 3.61 (s, 3H), 3.29 - 3.25 (m, 4H), 2.40 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 444.9. Example 210. Preparation of 3,6-dimethyl-2-morpholino-8-[(1R)-1-[2-(1,2,4-triazol-4- yl)anilino] ethyl]quinazolin-4-one and 3,6-dimethyl-2-morpholino-8-[(1S)-1-[2-(1,2,4- triazol-4-yl) anilino]ethyl]quinazolin-4-one (Compounds 303 and 304) (stereochemistry arbitrarily assigned) [2068] Step 1. Synthesis of 4-(2-nitrophenyl)-1,2,4-triazole [2069] To a solution of 2-nitroaniline (1 g, 7.24 mmol) and N-formamidoformamide (2.55 g, 29.0 mmol) in a 100 mL round-bottomed flask. The reaction mixture was stirred at 150 °C for 12 hr. The reaction mixture was diluted with methanol (10 mL), then concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 4-(2-nitrophenyl)-1,2,4-triazole (300 mg, 1.58 mmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 2H), 8.22 - 8.15 (m, 1H), 7.88 - 7.73 (m, 2H), 7.54 - 7.46 (m, 1H). [2070] Step 2. Synthesis of 2-(1,2,4-triazol-4-yl)aniline [2071] To a solution of 4-(2-nitrophenyl)-1,2,4-triazole (280 mg, 1.47 mmol) in anhydrous tetrahydrofuran (10 mL) was added platinum vanadium carbon (1.92 g, 7.36 mmol). The mixture was stirred at 25 °C for 2 hr under hydrogen atmosphere at 15 Psi. The reaction mixture was filtered and diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(1,2,4-triazol-4-yl)aniline (200 mg, 812 μmol, 55%) as a white solid. m/z ES+ [M+H] ⁺ 161.1. [2072] Step 3. Synthesis of 3,6-dimethyl-2-morpholino-8-[1-[2-(1,2,4-triazol-4- yl)anilino]ethyl] quinazolin-4-one [2073] To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (286 mg, 780 μmol), 2-(1,2,4-triazol-4-yl)aniline (150 mg, 937 μmol) in N,N-dimethylformamide (2 mL) was added diisopropylethylamine (504 mg, 3.90 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)- acetonitrile];B%: 29%- 59%, 9 min) to give 3,6-dimethyl-2-morpholino-8- [1-[2-(1,2,4-triazol-4- yl)anilino]ethyl]quinazolin-4-one (20 mg, 44.9 μmol, 6%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 2H), 7.91 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.08 - 7.00 (m, 1H), 6.78 - 6.70 (m, 2H), 5.18 (t, J = 7.2 Hz, 1H), 4.51 (br. d, J = 7.6 Hz, 1H), 3.91 - 3.85 (m, 4H), 3.60 (s, 3H), 3.23 - 3.00 (m, 4H), 2.40 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). [2074] Step 4. Chiral purification [2075] The crude product was purified by reversed-phase SFC( column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [0.1% ammonium hydroxide methanol];B%: 35%-35%,2.4min) to give 3,6-dimethyl-2-morpholino-8-[(1S)-1-[2-(1,2,4- triazol-4-yl)anilino]ethyl]quinazolin-4-one (3.67 mg, 7.48 μmol, 16%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.35 (s, 2H), 7.91 (d, J = 1.2 Hz, 1H), 7.36 - 7.34 (m, 1H), 7.25 - 7.20 (m, 1H), 7.06 - 7.02 (m, 1H), 6.77 - 6.70 (m, 2H), 5.23 - 5.13 (m, 1H), 4.51 (br. d, J = 7.2 Hz, 1H), 3.92 - 3.83 (m, 4H), 3.60 (s, 3H), 3.24 - 2.99 (m, 4H), 2.42 - 2.39 (m, 3H), 1.54 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 446.2. And 3,6-dimethyl-2-morpholino-8-[(1R)-1-[2-(1,2,4- triazol- 4-yl)anilino]ethyl]quinazolin-4-one (3.67 mg, 7.48 μmol, 16%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.35 (s, 2H), 7.91 (d, J = 1.2 Hz, 1H), 7.36 - 7.34 (m, 1H), 7.25 - 7.20 (m, 1H), 7.06 - 7.02 (m, 1H), 6.79 - 6.68 (m, 2H), 5.24 - 5.13 (m, 1H), 4.52 (br. d, J = 7.2 Hz, 1H), 3.93 - 3.81 (m, 4H), 3.60 (s, 3H), 3.24 - 2.99 (m, 4H), 2.42 - 2.39 (m, 3H), 1.54 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 446.2. Example 211. Preparation of (R)-8-(1-((2-(1H-tetrazol-1-yl)phenyl)amino)ethyl)-3,6- dimethyl-2-morpholin-oquinazolin-4(3H)-one and (S)-8-(1-((2-(1H-tetrazol-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (Compounds 348 and 349) (stereochemistry arbitrarily assigned)

[2076] Step 1. Synthesis of 1-(2-nitrophenyl)-1H-tetrazole [2077] To a solution of 1-fluoro-2-nitro-benzene (500 mg, 3.54 mmol) and tetrazole (297 mg, 4.25 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (587 mg, 4.25 mmol). The mixture was stirred at 80 °C for 1.5 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 0/1) to give 1-(2- nitrophenyl)tetrazole (500 mg, 2.43 mmol, 68%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.97 (s, 1H), 8.25 (dd, J = 1.6, 8.0 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.86 - 7.81 (m, 1H), 7.64 (dd, J = 1.6, 8.0 Hz, 1H); m/z ES+ [M+H] ⁺ 192.0. [2078] Step 2. Synthesis of 2-(1H-tetrazol-1-yl)aniline [2079] To a solution of palladium/carbon (40.0 mg, 10% purity) in methanol (5 mL) was added 1-(2-nitrophenyl)tetrazole (420 mg, 2.20 mmol) under hydrogen atmosphere. The mixture was stirred at 25 °C for 12 hr under hydrogen atmosphere at 15 Psi. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2-(1H- tetrazol-1-yl)aniline (360 mg, 2.19 mmol, 99%) as brown oil. ¹ H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.37 - 7.30 (m, 1H), 7.22 (dd, J = 1.2, 8.0 Hz, 1H), 6.98 - 6.85 (m, 2H), 4.34 (s, 2H); m/z ES+ [M+H] ⁺ 162.1. [2080] Step 3. Synthesis of 8-(1-((2-(1H-tetrazol-1-yl)phenyl)amino)ethyl)-3,6-dimethyl- 2- morpholinoquinazolin-4(3H)-one [2081] To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (362 mg, 988 μmol) in N,N-dimethylformamide (4 mL) was added 2,6-lutidine (317 mg, 2.97 mmol) and 2-(tetrazol-1-yl)aniline (238 mg, 1.48 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate 60 mL (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) and then was purified by reversed-phase HPLC (column: Phenomenex C1875 x 30mm,3um; mobile phase: [water(formic acid)-acetonitrile];B%: 38%- 68%, 7 min) to give 8-(1-((2-(1H-tetrazol-1-yl)phenyl)amino)ethyl)-3,6-dimethyl- 2- morpholinoquinazolin-4(3H)-one (60.0 mg, 134 μmol, 13%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.90 (s, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.19 - 7.13 (m, 1H), 6.82 - 6.69 (m, 2H), 5.54 (d, J = 7.2 Hz, 1H), 5.34-5.24 (m, 1H), 4.00 - 3.82 (m, 4H), 3.61 (s, 3H), 3.36 - 3.15 (m,4H), 2.39 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 447.2. [2082] Step 4. Chiral purification [2083] 8-(1-((2-(1H-tetrazol-1-yl)phenyl)amino)ethyl)-3,6-dimethyl- 2- morpholinoquinazolin-4(3H)-one (60.0 mg, 134 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mm x 30mm,10um);mobile phase: [0.1% ammonium hydroxide ethanol];B%: 45%-45%,2.7 min) to give (R)-8-(1-((2-(1H-tetrazol-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholin-oquinazolin- 4(3H)-one (24.4 mg, 54.1 μmol, 40%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.90 (s, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.81 - 6.69 (m, 2H), 5.66 - 5.44 (m, 1H), 5.34-5.24 (m, 1H), 4.00 - 3.83 (m, 4H), 3.61 (s, 3H), 3.33 - 3.16 (m, 4H), 2.39 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 447.2; and (S)-8-(1-((2-(1H-tetrazol-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (24.9 mg, 55.9 μmol, 41%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.90 (s, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.80 - 6.69 (m, 2H), 5.66 - 5.44 (m, 1H), 5.34-5.24 (m, 1H), 3.97 - 3.84 (m, 4H), 3.61 (s, 3H), 3.34 - 3.16 (m, 4H), 2.39 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 447.2. Example 212. Preparation of 3,6-dimethyl-8-[1-[(1-methylsulfonylpyrazol-3- yl)amino]ethyl]-2-morpholino-quinazolin-4-one (Compound 262)

[2084] Step 1. Synthesis of 2-methylsulfonylpyrazol-3-amine [2085] To a mixture of 1H-pyrazol-5-amine (1 g, 12.0 mmol) in dioxane (15 mL) was added methylsulfonyl methanesulfonate (1.68 g, 9.63 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 35/65) to give 1-methylsulfonylpyrazol-3-amine (170 mg, 1.05 mmol, 9%) as a colorless oil. [2086] Step 2. Synthesis of 3,6-dimethyl-8-[1-[(1-methylsulfonylpyrazol-3-yl)amino]ethyl ]- 2-morpholino-quinazolin-4-one [2087] To a mixture of 8-(1-bromoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (30 mg, 81.9 μmol) in N,N-dimethylformamide (2 mL) was added diisopropylethylamine (52.9 mg, 409 μmol) and 1-methylsulfonylpyrazol-3-amine (15.8 mg, 98.3 μmol), the reaction mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];B%: 30%-60%,2min) to give 3,6-dimethyl-8-[1-[(1-methylsulfonylpyrazol-3- yl)amino]ethyl]-2-morpholino-quinazolin-4-one (3.67 mg, 8.22 μmol, 10%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 2.8 Hz, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.90 (d, J = 3.2 Hz, 1H), 5.42 - 5.36 (m, 1H), 3.79 - 3.76 (m, 4H), 3.48 (s, 3H), 3.24 - 3.20 (m, 1H), 3.12 (s, 3H), 2.35 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 477.2. Example 213. Preparation of 4-[[(1R)-1-(3, 6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]thiophene-3-carboxylic acid and 4-[[(1S)-1-(3, 6-dimethyl-2-morpholino- 4-oxo-quinazolin-8-yl)ethyl]amino]thiophene-3-carboxylic acid (Compounds 253 and [2088] Step 1. Synthesis of methyl 4-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl)amino)phene-3-carboxylate [2089] To a solution of 8-(1-bromoethyl)-3, 6-dimethyl-2-morpholino-quinazolin-4-one (120 mg, 328 μmol) in N,N-dimethylformamide (3 mL) was added diisopropylethylamine (212 mg, 1.64 mmol) and methyl 4-aminothiophene-3-carboxylate (61.8 mg, 393 μmol). The mixture was stirred at 80 °C for 3 hr. On completion. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, dichloromethane/methanol =10/1) to give methyl 4-[1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl)amino)phene-3-carboxylate (120 mg, 138 μmol, 42%) as a yellow oil; m/z ES+ [M+H] ⁺ 443.2. [2090] Step 2. Synthesis of 4-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl)amino)thiophene-3-carboxylic acid [2091] To a solution of methyl 4-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino] thiophene-3-carboxylate (110 mg, 249 μmol) in methanol (0.6 mL), water (0.6 mL) and anhydrous tetrahydrofuran (1.1 mL) was added lithium hydroxide (23.8 mg, 994 μmol). The mixture was stirred at 60 °C for 0.5 hr. On completion. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: PhenomenexSynergiC18 150 x 25mm, 10 um; mobile phase: [water(formic acid)- acetonitrile];B%: 39%-69%,10 min) to give 4-[1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl)amino)thiophene-3-carboxylic acid (15.6 mg, 36.1 μmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (d, J = 3.6 Hz, 1H), 7.72 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 5.83 (d, J = 2.8 Hz, 1H), 5.07 - 4.97 (m, 1H), 3.84 - 3.75 (m, 4H), 3.50 (s, 3H), 3.30 - 3.19 (m, 4H), 2.36 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 429.2. [2092] Step 3. Chiral purification [2093] The racemic 4-[1-(3, 6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]thiophene-3-carboxylic acid(18.0 mg, 42.0 μmol) was purified by SFC (column: DAICEL CHIRALPAK IG (250mm x 30mm,10 um); mobile phase: [0.1% ammonium hydroxide isopropanol]; B%: 40%-40%, 3.5 min) to give 4-[[(1R)-1-(3,6-dimethyl-2- morpholino-4-oxo-quinazolin-8-yl)ethyl]amino]thiophene-3-car boxylic acid (8.63 mg, 19.5 μmol) as brown gum. ¹ H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 5.77 (s, 1H), 5.10 - 4.99 (m, 1H), 3.85 - 3.70 (m, 4H), 3.50 (s, 3H), 3.27 - 3.18 (m, 4H), 2.35 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 429.2. And 4-[[(1S)-1-(3,6-dimethyl-2- morpholino-4-oxo-quinazolin-8-yl)ethyl]amino]thiophene-3-car boxylic acid (10.5 mg, 23.0 μmol) as brown gum. ¹ H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 5.68 (s, 1H), 5.10 - 4.97 (m, 1H), 3.79 - 3.74 (m, 4H), 3.49 (s, 3H), 3.26 - 3.18 (m, 4H), 2.35 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 429.1. Example 214. Preparation of 8-(1-((2-(Dimethylphosphoryl)phenyl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one (Compound 250) [2094] Step 1. Synthesis of 8-(1-((2-(dimethylphosphoryl)phenyl)amino)ethyl)-3,6-dimethy l- 2-mor-pholinoquinazolin-4(3H)-one [2095] To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (350 mg, 956 μmol) in N,N-dimethylformamide (6 mL) was added diisopropylethylamine (618 mg, 4.78 mmol) and 2-dimethylphosphorylaniline (194 mg, 1.15 mmol). The mixture was stirred at 80 °C for 3 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40mm, 15um; mobile phase: [water(formic acid)-acetonitrile];B%: 35%-65%, 9 min) to give 8-(1-((2- (dimethylphosphoryl)phenyl)amino)ethyl)-3,6-dimethyl-2-mor-p holinoquinazolin-4(3H)-one (60 mg, 21.1 μmol, 14%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.83 - 7.73 (m, 2H), 7.53 - 7.21 (m, 1H), 7.03 - 6.94 (m, 2H), 6.48 (t, J = 1.6 Hz, 1H), 6.32 - 6.26 (m, 1H), 5.38 - 5.33 (m, 1H), 3.86 - 3.80 (m, 4H), 3.54 (s, 3H), 3.27-3.15 (m, 4H), 2.93 (s, 3H), 1.78 - 1.73 (m, 6H), 1.50 - 1.47(m, 3H); m/z ES+ [M+H] ⁺ 455.2. Example 215. Preparation of 8-[(1R)-1-(2-dimethylphosphorylanilino)ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one & 8-[(1S)-1-(2- dimethylphosphorylanilino)ethyl]-3,6-dimethyl-2-morpholino-q uinazolin-4-one (Compounds 301 and 302) (stereochemistry arbitrarily assigned) [2096] Step 1. Chiral purification [2097] 8-(1-((2-(dimethylphosphoryl)phenyl)amino)ethyl)-3,6-dimethy l-2- morpholinoquinazolin-4(3H)-one was separated by SFC (column: DAICEL CHIRALPAK AD(250mm x 30mm,10um);mobile phase: [0.1% ammonium hydroxide isopropanol];B%: 30%-30%,2.2min) to give 8-[(1R)-1-(2-dimethylphosphorylanilino)ethyl]-3,6-dimethyl-2 - morpholino-quinazolin-4-one (26 mg, 57 μmol, 43%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82 (s, 1H), 7.63 (s, 1H), 7.31 - 7.23 (m, 1H), 7.17 - 7.07 (m, 1H), 6.69 - 6.58 (m, 1H), 6.49 - 6.38 (m, 1H), 5.58 - 5.46 (m, 1H), 4.62 (s, 1H), 3.95 - 3.84 (m, 4H), 3.64 (s, 3H), 3.32 (s, 4H), 2.39 (s, 3H), 1.87 (dd, J = 4.4, 13.2 Hz, 6H), 1.58 (d, J = 6.8 Hz, 3H); ES+ [M+H] ⁺ 455.2; and 8-[(1S)-1-(2-dimethylphosphorylanilino)ethyl]-3,6-dimethyl-2 -morpholino- quinazolin-4-one (28.4 mg, 62.5 μmol, 47 %) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82 (s, 1H), 7.63 (s, 1H), 7.31 - 7.21 (m, 1H), 7.15 - 7.07 (m, 1H), 6.68 - 6.58 (m, 1H), 6.45 - 6.40 (m, 1H), 5.56 - 5.45 (m, 1H), 4.61 (s, 1H), 3.95 - 3.84 (m, 4H), 3.64 (s, 3H), 3.33 (s, 4H), 2.38 (s, 3H), 1.87 (dd, J = 4.8, 13.2 Hz, 6H), 1.58 (d, J = 6.8 Hz, 3H); ES+ [M+H] ⁺ 455.2. Example 216. Preparation of 8-[(1R)-1-(2,4-difluoro-6-methylsulfonyl-anilino)ethyl]-3,6- dimethyl -2-morpholino-quinazolin-4-one and 8-[(1S)-1-(2,4-difluoro-6-methylsulfonyl- anilino)ethyl]-3,6-dimethyl-2-morpholino-quinazolin-4-one (Compounds 429 and 430) (stereochemistry arbitrarily assigned)

[2098] Step 1. Synthesis of 2-amino-3,5-difluoro-benzenethiol [2099] To a solution of 4,6-difluoro-1,3-benzothiazol-2-amine (5.00 g, 26.8 mmol) in water (40 mL) was added potassium hydroxide (32.2 g, 574 mmol). The mixture was stirred at 100 °C for 12 hr. On completion, the mixture was cooled down to give 2-amino-3,5-difluoro- benzenethiol (4.33 g, crude) as a yellow oil. [2100] Step 2. Synthesis of 2,4-difluoro-6-methylsulfanyl-aniline [2101] To a solution of 2-amino-3,5-difluoro-benzenethiol (4.33 g, 26.8 mmol) in water (100 mL) was added methyl iodide (3.81 g, 26.8 mmol).The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether: ethyl acetate = 10:1) to give 2,4- difluoro-6-methylsulfanyl-aniline (2.90 g, 16.5 mmol, 61%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.91 - 6.80 (m, 1H), 6.77 - 6.63 (m, 1H), 2.42 (s, 3H). [2102] Step 3. Synthesis of 8-[1-(2,4-difluoro-6-methylsulfanyl-anilino)ethyl]-3,6-dimet hyl- 2-mor-pholino-quinazolin-4-one [2103] To a solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-on e (404 mg, 1.33 mmol) in dichloromethane (20 mL) was added phosphorus tribromide (541 mg, 2.00 mmol) dropwise under 0 °C. The mixture was stirred at 40 °C for 7 hr under nitrogen atmosphere. Then added 2,4-difluoro-6-methylsulfanyl-aniline (700 mg, 4.00 mmol) and potassium tert-butoxide (1 M, 13.3 mL) to the mixture under nitrogen. The mixture was stirred at 80 °C for 13 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched with saturated sodium bicarbonate solution 50 mL and extracted with dichloromethane (25 mL x 3). The combined organic layers were washed with brine (45 mL), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8-[1-(2,4-difluoro-6-methylsulfanyl-anilino)ethyl]-3,6-dimet hyl-2-mor- pholino-quinazolin-4-one (150 mg, 325 μmol, 24%) as white solid. m/z ES+ [M+H] ⁺ 461.2. [2104] Step 4. Synthesis of 8-[1-(2,4-difluoro-6-methylsulfonyl-anilino)ethyl]-3,6-dimet hyl- 2-morpholino-quinazolin-4-one [2105] To a solution of 8-[1-(2,4-difluoro-6-methylsulfanyl-anilino)ethyl]-3,6-dimet hyl-2- morpholino-quinazolin-4-one (60.0 mg, 130 μmol) in tetrahydrofuran (6 mL) was added oxone (160 mg, 260 μmol) in water (1.5 mL). The mixture was stirred at 0 °C for 6 hr. On completion, the reaction mixture was quenched by saturated sodium thiosulfate solution (10 mL) and saturated sodium carbonate solution 10 mL at 0°C, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 X 25mm, 5um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 50%-80%, 8 min) to give 8-[1-(2,4-difluoro-6- methylsulfonyl-anilino)ethyl]-3,6-dimethyl-2-morpholino-quin azolin-4-one (60.0 mg, 110 μmol, 85%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.00 - 6.91 (m, 1H), 6.52 (d, J = 7.6 Hz, 1H), 5.51 - 5.40 (m, 1H), 3.89 (t, J = 4.8 Hz, 4H), 3.61 (s, 3H), 3.37 - 3.17 (m, 4H), 2.78 (s, 3H), 2.41 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 493.2 [2106] Step 5. Chiral purification [2107] 8-[1-(2,4-difluoro-6-methylsulfonyl-anilino)ethyl]-3,6-dimet hyl-2-morpholino- quinazolin-4-one (0.06 g, 122 μmol) was for SFC (column: DAICEL CHIRALCEL OD(250mm X 30 mm,10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 30%-30%, 4.6min) to give 8-[(1R)-1-(2,4-difluoro-6-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2-morpholino-quinazolin-4-one (25.0 mg, 50.7 μmol, 41%) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.38 - 7.33 (m, 1H), 6.99 - 6.91 (m, 1H), 6.51 (d, J = 8.8 Hz, 1H), 5.45 (t, J = 7.2 Hz, 1H), 3.88 (t, J = 4.4 Hz, 4H), 3.60 (s, 3H), 3.37 - 3.19 (m, 4H), 2.77 (s, 3H), 2.40 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 493.2; and 8-[(1S)-1-(2,4-difluoro-6-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2- morpholino-quinazolin-4-one (25.0 mg, 50.7 μmol, 41%) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.00 - 6.91 (m, 1H), 6.51 (d, J = 8.8 Hz, 1H), 5.45 (t, J = 7.2 Hz, 1H), 3.88 (t, J = 4.4 Hz, 4H), 3.60 (s, 3H), 3.36 - 3.17 (m, 4H), 2.77 (s, 3H), 2.40 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 493.1. Example 217. Preparation of 8-[(1R)-1-(3,4-difluoro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl -2-morpholino-quinazolin-4-one & 8-[(1S)-1-(3,4-difluoro-2-methylsulfonyl- anilino)ethyl]-3,6-dimethyl-2-morpholino-quinazolin-4-one (Compounds 398 and 399) [2108] Step 1. Synthesis of 8-[1-(2-bromo-3,4-difluoro-anilino)ethyl]-3,6-dimethyl-2- morpholino-quinazolin-4-one [2109] To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (1 g, 2.73 mmol) in dimethyl acetamide (10 mL) was added 2-bromo-3,4-difluoro-aniline (1.70 g, 8.19 mmol) and diisopropyl ethylamine (1.06 g, 8.19 mmol), the mixture was stirred at 80 °C for 2 hr. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reversed-phase HPLC [water(0.1% formic acid)- acetonitrile, 70%]; 30 min to give 8-[1-(2-bromo-3,4-difluoro- anilino)ethyl]-3,6-dimethyl-2-morpholino-quinazolin-4-one (560 mg, 1.14 mmol, 41%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.18 (q, J = 9.2 Hz, 1H), 6.45 - 6.33 (m, 1H), 5.80 (d, J = 8.4 Hz, 1H), 5.32 - 5.19 (m, 1H), 3.85 -3.72 (m, 4H), 3.51 (s, 3H), 3.29 - 3.18 (m, 4H), 2.35 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); m /z ES+ [M+H] ⁺ 493.1. [2110] Step 2. Synthesis of 8-[1-(3,4-difluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimet hyl- 2-morpholino-quinazolin-4-one [2111] A solution of 8-[1-(2-bromo-3,4-difluoro-anilino)ethyl]-3,6-dimethyl-2-mor pholino- quinazolin-4-one (460 mg, 932 μmol), sodium methanesulfinate (475 mg, 4.66 mmol), copper iodide (35.5 mg, 186 μmol), (2S)-pyrrolidine-2-carboxylic acid (42.9 mg, 372 μmol) in dimethylsulfoxide (6 mL) was stirred at 100 °C for 20 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 4/1) to give 8-[1-(3,4-difluoro-2- methylsulfonyl-anilino)ethyl]-3,6-dimethyl-2-morpholino-quin azolin-4-one (120 mg, 233 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 0.8, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.49 - 7.38 (m, 1H), 6.47 - 6.30 (m, 1H), 5.38 - 5.24 (m, 1H), 3.81- 3.72 (m, 4H), 3.51 (s, 3H), 3.42 (s, 3H), 3.30 - 3.19 (m, 4H), 2.37 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 493.2. [2112] Step 3. Chiral purification [2113] Compound 8-[1-(3,4-difluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimet hyl-2- morpholino-quinazolin-4-one (120 mg, 243 μmol) was separated by SFC [column: DAICEL CHIRALPAK AD (250mm x 30mm,10um); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 20%-20%,A3;30min] to give 8-[(1R)-1-(3,4-difluoro-2-methylsulfonyl- anilino)ethyl]-3,6-dimethyl-2-morpholino-quinazolin-4-one (44.0 mg, 88.2 μmol, 36%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.72 - 7.48 (m, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.06 - 6.95 (m, 1H), 6.19 - 6.12 (m, 1H), 5.35 (q, J = 6.0 Hz, 1H), 3.96 - 3.85 (m, 4H), 3.62 (s, 3H), 3.32 (s, 3H), 3.30 - 3.24 (m, 4H), 2.40 (s, 3H), 1.59 (s, 3H); m/z ES+ [M+H] ⁺ 493.2; and 8-[(1S)-1-(3,4-difluoro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2- morpholino-quinazolin-4-one (48.7 mg, 97.3 μmol, 40%) as a grey gum. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.62 - 7.48 (m, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.06 - 6.95 (m, 1H), 6.21 - 6.13 (m, 1H), 5.35 (q, J = 6.8 Hz, 1H), 3.95 - 3.85 (m, 4H), 3.62 (s, 3H), 3.32 (s, 3H), 3.30 - 3.22 (m, 4H), 2.40 (s, 3H), 1.59 (s, 3H); m/z ES+ [M+H] ⁺ 493.2. Example 218. Preparation of (R)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one & (S)-8-(1-((4- fluoro-2-(4-hydroxypiperidin-1-yl)phenyl)amino)ethyl)-3,6-di methyl-2- morpholinoquinazolin-4(3H)-one (Compounds 512 and 513) (stereochemistry arbitrarily assigned) [2114] Step 1. Synthesis of 8-(1-((4-fluoro-2-(4-hydroxypiperidin-1-yl)phenyl)amino)ethy l)- 3,6-dimethyl-2-morpholinoquinazolin-4(3H)-one [2115] To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (120 mg, 327 μmol) in dichloromethane (1 mL) was added 1-(2-amino-5-fluoro-phenyl)piperidin- 4-ol (137 mg, 655 μmol) and diisopropylethylamine (84.6 mg, 655 μmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18150 x 25mm,10um; mobile phase: [water(formic acid)- acetonitrile];B%: 48%-78%, 10 min) to give 8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (70.0 mg, 141 μmol, 43%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 1.2 Hz, 1H), 7.47 (s, 1H), 6.73 (dd, J = 2.8, 10.0 Hz, 1H), 6.56 - 6.46 (m, 1H), 6.29 - 6.16 (m, 1H), 5.24 (d, J = 7.2 Hz, 1H), 5.13 - 4.88 (m, 1H), 3.93 - 3.80 (m, 5H), 3.62 (s, 3H), 3.36 - 3.09 (m, 6H), 2.86 - 2.61 (m, 2H), 2.38 (s, 3H), 2.17 - 2.05 (m, 2H), 1.80 (d, J = 10.0 Hz, 2H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 496.3. [2116] Step 2. Chiral purification [2117] 8-[1-[4-fluoro-2-(4-hydroxy-1-piperidyl)anilino]ethyl]-3,6-d imethyl-2-morpholino- quinazolin-4-one (60.0 mg, 121 μmol) was separated by SFC (column: DAICEL CHIRALCEL OX (250mm x 30mm,10 μm); mobile phase: [0.1% ammonium hydroxide methanol];B%: 40%-40%,5.8 min) to give (R)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (22.0 mg, 44.4 μmol, 36%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 2.8, 10.0 Hz, 1H), 6.55 - 6.45 (m, 1H), 6.26 - 6.17 (m, 1H), 5.29 - 5.19 (m, 1H), 4.95 (s, 1H), 3.95 - 3.75 (m, 5H), 3.62 (s, 3H), 3.32 - 3.26 (m, 4H), 3.25 - 3.07 (m, 2H), 2.84 - 2.59 (m, 2H), 2.38 (s, 3H), 2.15 - 2.02 (m, 2H), 1.86 - 1.73 (m, 2H), 1.59 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 496.3; and (S)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-morpholinoquinazolin-4 (3H)-one (22.7 mg, 45.0 μmol, 37%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 2.8, 10.0 Hz, 1H), 6.55 - 6.45 (m, 1H), 6.26 - 6.19 (m, 1H), 5.29 - 5.19 (m, 1H), 4.95 (s, 1H), 3.95 - 3.80 (m, 5H), 3.62 (s, 3H), 3.35 - 3.26 (m, 4H), 3.24 - 3.07 (m, 2H), 2.83 - 2.61 (m, 2H), 2.38 (s, 3H), 2.15 - 2.06 (m, 2H), 1.86 - 1.78 (m, 2H), 1.59 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 496.3. Example 219. Preparation of (R)-2-((1-(3-cyclopropyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 256) [2118] Step 1. Synthesis of (R)-2-((1-(3-cyclopropyl-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2119] To a solution of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-methyl-2-morpholino- quinazolin-4-one (150 mg, 457 μmol) and 2-iodobenzoic acid (566 mg, 2.28 mmol) in dimethylacetamide (2 mL) was added copper (58.1 mg, 914 μmol) and triethylamine (231 mg, 2.28 mmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150x25mm 10um;mobile phase: [water(ammonium bicarbonate)- acetonitrile];B%: 14%-44%, min) to give (R)-2-((1-(3-cyclopropyl-6-methyl-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (46.8 mg, 102 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.39 (m, 1H), 7.83 - 7.70 (m, 1H), 7.68 - 7.60 (m, 1H), 7.42 (s, 1H), 7.19 - 7.11 (m, 1H), 6.58 - 6.31 (m, 2H), 5.50 - 5.13 (m, 1H), 3.83 - 3.70 (m, 4H), 3.45 (s, 4H), 2.35 - 2.32 (m, 1H), 2.29 (s, 3H), 1.60 - 1.44 (m, 3H), 1.22 - 1.11 (m, 2H), 0.86 - 0.69 (m, 2H); m/z ES+ [M+H] ⁺ 449.2. Example 220. Preparation of 3-cyclopropyl-6-methyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (Compound 255) [2120] Step 1. Synthesis of 3-cyclopropyl-6-methyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one [2121] To a solution of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-methyl-2-morpholino- quinazolin-4-one (150 mg, 457 μmol) and 1-fluoro-2-methylsulfonyl-benzene (159 mg, 914 μmol) in N,N-dimethylformamide (1.5 mL) was added cesium carbonate (446 mg, 1.37 mmol). The mixture was stirred at 140 °C for 12 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150x25mmx5um;mobile phase: [water(ammonium bicarbonate)-acetonitrile];B%: 36%- 66%,2min) to give 3-cyclopropyl-6-methyl-8-[(1R)-1-(2-methylsulfonylanilino)et hyl]-2- morpholino-quinazolin-4-one (77.5 mg, 161 μmol, 35%) as a off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.38 - 7.31 (m, 1H), 6.75 - 6.68 (m, 3H), 5.40 - 5.20 (m, 1H), 3.77 (t, J = 4.4 Hz, 4H), 3.45 (d, J = 4.8 Hz, 4H), 3.13 (s, 3H), 2.31 (s, 4H), 1.59 (d, J = 6.4Hz, 3H), 1.21 - 1.14 (m, 2H), 0.83 - 0.70 (m, 2H); m/z ES+ [M+H] ⁺ 483.1. Example 221. Preparation of (R)-2-((1-(3,6-dimethyl-2-(morpholino-d ₈ )-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound D2) [2122] Step 1. Synthesis of (R)-2-((1-(3,6-dimethyl-2-(morpholino-d8)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2123] A solution of 2-(((1R)-1-(3,6-dimethyl-2-(methylsulfinyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (400 mg, 1.00 mmol) and morpholine- 2,2,3,3,5,5,6,6-d ₈ (198 mg, 1.50 mmol, hydrogen chloride salt) in diisopropylethylamine (4 mL) was stirred at 60 °C for 12 hr. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)- acetonitrile];gradient:7%-37% B over 10 min) to give (R)-2-((1-(3,6-dimethyl-2-(morpholino- d ₈ )-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (116 mg, 269 μmol, 27%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.60 (br. s, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.52 (s, 1H), 7.22 - 7.11 (m, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 5.57 - 5.39 (m, 1H), 3.63 (s, 3H), 2.38 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 431.3. Example 222. Preparation of (R)-2-((1-(6-methyl-3-(methyl-d ₃ )-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic-3,4,5,6-d ₄ acid (Compound D3) [2124] Step 1. Synthesis of methyl 2-bromobenzoate-3,4,5,6-d4 [2125] To a solution of 2-bromobenzoic-3,4,5,6-d ₄ acid (200 mg, 975.41 μmol), cesium carbonate (636 mg, 1.95 mmol) in N,N-dimethylformamide (2 mL) was added methyl iodide (277 mg, 1.95 mmol) at 15 °C. The mixture was stirred at 15 °C for 2 hr. On completion, the mixture was adjusted to pH = 4~5 with aqueous citric acid and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give methyl 2-bromobenzoate- 3,4,5,6-d ₄ (190 mg, 867 μmol, 89%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.94 (s, 3H). [2126] Step 2. Synthesis of methyl (R)-2-((1-(6-methyl-3-(methyl-d3)-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate-d ₄ [2127] To a solution of 8-[(1R)-1-aminoethyl]-6-methyl-2-morpholino-3- (trideuteriomethyl)quinazolin-4-one (100 mg, 327 μmol), methyl 2-bromobenzoate-3,4,5,6-d4 (143 mg, 655 μmol), dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (30.6 mg, 65.5 μmol) and cesium carbonate (213 mg, 655 μmol) in toluene (3 mL) was added tris(dibenzylideneacetone)dipalladium (30.0 mg, 32.8 μmol), the mixture was stirred at 100 °C for 2 hr under nitrogen atmosphere. On completion, the mixture was quenched with 30 mL water and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid- acetonitrile) to give methyl (R)-2-((1-(6-methyl-3-(methyl-d ₃ )-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate-d4 (120 mg, 219 μmol, 67%) as an off-white solid. m/z ES+ [M+H] ⁺ 444.2. [2128] Step 3. Synthesis of (R)-2-((1-(6-Methyl-3-(methyl-d ₃ )-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic-3,4,5,6-d4 acid [2129] To a solution of methyl (R)-2-((1-(6-methyl-3-(methyl-d3)-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate-d4 (120 mg, 271 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (56.8 mg, 1.35 mmol), the mixture was stirred at 15 °C for 1 hr. On completion, the mixture was adjusted to pH = 4~5 with citric acid and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid-acetonitrile) to give (R)-2-((1-(6-methyl-3-(methyl-d3)-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic-3,4,5,6-d ₄ acid (97.1 mg, 226 μmol, 84%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.62 (br. s, 1H), 8.47 (br. s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.45 – 5.35 (m, 1H), 3.79 (t, J = 4.4 Hz, 4H), 3.29 - 3.23 (m, 4H), 2.33 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 430.3. Example 223. Preparation of (R)-2-((1-(6-methyl-3-(methyl-d ₃ )-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound D4) [2130] Step 1. Synthesis of (R)-2-((1-(6-methyl-3-(methyl-d3)-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2131] To a solution of 8-[(1R)-1-aminoethyl]-6-methyl-2-morpholino-3- (trideuteriomethyl)quinazolin-4-one (130 mg, 426 μmol), 2-iodobenzoic acid (211 mg, 851 μmol), cesium carbonate (416 mg, 1.28 mmol) in dioxane (2 mL) was added [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl -[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (16.9 mg, 21.3 μmol), the mixture was stirred at 90 °C for 12 hr under nitrogen protection. On completion, the mixture was quenched with 30 mL water and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with 30 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid- acetonitrile conditions) to give (R)-2-((1-(6-methyl-3-(methyl-d ₃ )-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (42 mg, 98.7 μmol, 23%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.98 (br. d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.50 (s, 1H), 7.20 (br. t, J = 7.6 Hz, 1H), 6.56 (br. t, J = 7.6 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 5.43 - 5.53 (m, 1H), 3.95 - 3.88 (m, 4H), 3.36 - 3.27 (m, 4H), 2.38 (s, 3H), 1.65 (br. d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 426.2. Example 224. Preparation of 3,6-dimethyl-8-[(1R)-1-(2-methylsulfonylphenoxy)ethyl]-2- morpholino-quinazolin-4-one and 3,6-dimethyl-8-[(1S)-1-(2- methylsulfonylphenoxy)ethyl]-2-morpholino-quinazolin-4-one (Compounds 342 and 343) (stereochemistry arbitrarily assigned) [2132] Step 1. Synthesis of 3,6-dimethyl-8-[1-(2-methylsulfonylphenoxy)ethyl]-2- morpholino-quinazolin-4-one [2133] To a mixture of 8-(1-hydroxyethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-on e (50.0 mg, 164 μmol) and 1-fluoro-2-methylsulfonyl-benzene (114 mg, 659 μmol) in dimethylsulfoxide (2 mL) was added potassium tert-butoxide (55.4 mg, 494 μmol), the reaction mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1:1) to give 3,6-dimethyl-8-[1-(2- methylsulfonylphenoxy)ethyl]-2-morpholino-quinazolin-4-one (45.0 mg, 98.3 μmol, 59%) as a white solid. m/z ES+ [M+H] ⁺ 458.2. [2134] Step 2. Chiral purification [2135] The crude product was purified by SFC (column: DAICEL CHIRALPAK IG (250mm x 30mm,10um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 35%-35%,5.9 min) to give 3,6-dimethyl-8-[(1R)-1-(2-methylsulfonylphenoxy)ethyl]-2-mor pholino-quinaz olin-4-one (15.0 mg, 32.8 μmol, 33%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (dd, J = 1.6, 7.6 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.39 - 7.31 (m, 1H), 7.03 - 6.95 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.46 (q, J = 6.4 Hz, 1H), 3.94 - 3.84 (m, 4H), 3.62 (s, 3H), 3.35 (s, 3H), 3.33 - 3.24 (m, 4H), 2.39 (s, 3H), 1.77 (d, J = 6.4 Hz, 3H); m/z ES+ 458.2. And 3,6-dimethyl-8-[(1S)-1-(2-methylsulfonylphen-oxy)ethyl]-2- morpholino-quinazolin-4-one (11.9 mg, 26.0 μmol, 26%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 1.6, 7.6 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.41 - 7.31 (m, 1H), 7.03 - 6.95 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.46 (q, J = 6.4 Hz, 1H), 3.95 - 3.82 (m, 4H), 3.63 (s, 3H), 3.35 (s, 3H), 3.32 - 3.23 (m, 4H), 2.39 (s, 3H), 1.77 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 458.2. Example 225. Preparation of N-[2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethoxy]phenyl] methanesulfonamide (Compound 386) [2136] Step 1. Synthesis of 3,6-dimethyl-2-morpholino-8-[1-(2- nitrophenoxy)ethyl]quinazolin-4-one [2137] To a solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-on e (150 mg, 494 μmol) and 1-fluoro-2-nitro-benzene (83.7 mg, 593 μmol) in anhydrous tetrahydrofuran (3 mL) was added potassium bis(trimethylsilyl)amide (1 M, 593 ^L). The mixture was stirred at 0 °C for 4 hr. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL), then was slowly warmed to 25°C, then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 3/1) to give 3,6-dimethyl-2-morpholino-8-[1-(2-nitrophenoxy)ethyl]quinazo lin-4-one (180 mg, 424 μmol, 86%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 1.2 Hz, 1 H), 7.78 (dd, J = 1.6, 8.0 Hz, 1 H), 7.68 (d, J = 2.0 Hz, 1 H), 7.33 - 7.27 (m, 1 H), 6.96 - 6.89 (m, 2 H), 6.37 (d, J = 6.4 Hz, 1 H), 3.92 (s, 4 H), 3.62 (s, 3 H), 3.34 - 3.23 (m, 4 H), 2.40 (s, 3 H), 1.70 (d, J = 6.4 Hz, 3 H); m/z ES+ [M+H] ⁺ 425.2. [2138] Step 2. Synthesis of 8-[1-(2-aminophenoxy)ethyl]-3,6-dimethyl-2-morpholino- quinazolin-4-one [2139] To a solution of 3,6-dimethyl-2-morpholino-8-[1-(2-nitrophenoxy)ethyl]quinazo lin-4- one (180 mg, 424 μmol) in ethanol (1.5 mL) and water (0.5 mL) was added iron powder (118 mg, 2.12 mmol) and ammonium chloride (227 mg, 4.24 mmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-[1- (2-aminophenoxy)ethyl]-3,6-dimethyl-2-morpholino- quinazolin-4-one (150 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 395.2. [2140] Step 3. Synthesis of N-[2-[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethoxy]phenyl] methanesulfonamide [2141] To a solution of 8-[1-(2-aminophenoxy)ethyl]-3,6-dimethyl-2-morpholino- quinazolin-4-one (150 mg, 380 μmol) in dichloromethane (2 mL) was added diisopropylethylamine (147 mg, 1.14 mmol), then was added methylsulfonyl methanesulfonate (132 mg, 760 μmol) at 0 °C. The mixture was stirred 0 -25 °C for 0.5 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 30%-60%, 10 min) to give N-[2-[1-(3,6-dimethyl-2- morpholino-4-oxo-quinazolin-8-yl)ethoxy]phenyl]methanesulfon amide (45.0 mg, 95.2 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 6.8 (s, 1H), 6.78 - 6.69 (m, 2H), 6.65 - 6.59 (m, 1H), 6.10 - 6.01 (m, 1H), 3.71 (d, J = 3.6 Hz, 4H), 3.43 (s, 3H), 3.09 (d, J = 3.6 Hz, 4H), 2.76 (s, 3H), 2.20 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 473.2. Example 226. Preparation of 2-[[(1R)-1-(3,6,7-trimethyl-2-morpholino-4-oxo-quinazolin- 8-yl)ethyl]amino]benzoic acid and 2-[[(1S)-1-(3,6,7-trimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]amino]benzoic acid (Compounds 346 and 347) (stereochemistry arbitrarily assigned) [2142] Step 1. Synthesis of 2-[1-(3,6,7-trimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethylamino]benzoic acid [2143] A mixture of 8-(1-aminoethyl)-3,6,7-trimethyl-2-morpholino-quinazolin-4-o ne (50.0 mg, 158 μmol), 2-iodobenzoic acid (117 mg, 474 μmol), N,N-diethylethanamine (319 mg, 3.16 mmol), copper (10.0 mg, 15.0 μmol) in dimethyl acetamide (1 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x 25mm, 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 40%-70%, 10 min) to give 2-[1-(3,6,7-trimethyl-2-morpholino-4-oxo-quinazolin-8-yl)eth ylamino]benzoic acid (15.0 mg, 34.4 μmol,21%) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 8.01 - 7.88 (m, 2H), 7.28 - 7.23 (m, 2H), 6.74 - 6.55 (m, 2H), 3.92 (t, J = 4.4 Hz, 4H), 3.63 (s, 3H), 3.48 - 3.27 (m, 4H), 2.47 (s, 3H), 2.39 (s, 3H), 1.81 - 1.78 (m, 3H). m/z ES+ [M+H] ⁺ 437.3. [2144] Step 2. Chiral purification [2145] 2-[1-(3,6,7-trimethyl-2-morpholino-4-oxo-quinazolin-8-yl)eth ylamino]benzoic acid ((30.0 mg, 68.7 μmol) was purified by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [0.1% ammonium hydroxide methanol];B%: 30%- 30%,3.65min) to give 2-[[(1R)-1-(3,6,7-trimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]benzoic acid (6.93 mg, 15.9 μmol, 23%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.03 - 7.86 (m, 2H), 7.26 (br. s, 1H), 6.71 - 6.49 (m, 2H), 6.12 - 5.20 (m, 1H), 3.92 (t, J = 4.4 Hz, 4H), 3.63 (s, 3H), 3.46 - 3.21 (m, 4H), 2.50 (s, 3H), 2.38 (s, 3H), 1.78 (br. d, J = 6.4 Hz, 3H). m/z ES+ [M+H] ⁺ 437.2; and 2-[[(1S)-1-(3,6,7-trimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]amino]benzoic acid (7.46 mg, 16.9 μmol, 24%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.07 - 7.82 (m, 2H), 7.26 (br. s, 1H), 6.71 - 6.48 (m, 2H), 6.21 - 5.15 (m, 1H), 3.92 (t, J = 4.4 Hz, 4H), 3.63 (s, 3H), 3.43 - 3.26 (m, 4H), 2.50 (s, 3H), 2.38 (s, 3H), 1.78 (br. d, J = 6.4 Hz, 3H). m/z ES+ [M+H] ⁺ 437.2. Example 227. Preparation of 3,6,7-Trimethyl-8-[(1R)-1-(2-methylsulfonylanilino)ethyl]- 2-morpholino-quinazolin-4-one and 3,6,7-Trimethyl-8-[(1S)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (Compounds 336 and 337) (stereochemistry arbitrarily assigned) [2146] Step 1. Synthesis of 3,6,7-trimethyl-8-[1-(2-methylsulfonylanilino)ethyl]-2- morpholino-quinazolin-4-one [2147] To a solution of 8-(1-aminoethyl)-3,6,7-trimethyl-2-morpholino-quinazolin-4-o ne (70.0 mg, 221 μmol) and 1-fluoro-2-methylsulfonyl-benzene (192 mg, 1.11 mmol) in dimethyl acetamide (1.5 mL) was added cesium carbonate (216 mg, 663 μmol) and potassium fluoride (19.2 mg, 331 μmol). The mixture was stirred at 140 °C for 2 hr. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mLx 3), the combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40mm, 15um; mobile phase: [water (formic acid)- acetonitrile]; B%: 48%-78%, 9 min) to give 3,6,7-trimethyl-8-[1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (30.0 mg, 63.7 μmol, 28%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.76 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.47 - 7.31 (m, 1H), 7.00 - 6.82 (m, 1H), 6.75 - 6.65 (m, 1H), 5.52 – 5.32 (m ,1H), 3.79 (s, 4H), 3.50 (s, 3H), 3.22 (s, 3H), 2.96 - 2.85 (m, 2H), 2.74 (s, 2H), 2.48 (s, 3H), 2.34 (s, 3H), 1.74 (s, 3H); m/z ES+ [M+H] ⁺ 471.2. [2148] Step 2. Chiral purification [2149] The residue was purified by SFC (column: DAICEL CHIRALPAK AD (250mm x 30mm,10um);mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 30%-30%,3.3min) to give 3,6,7-trimethyl-8-[(1R)-1-(2-methylsulfonylanilino)ethyl]-2- morpholino-quinazolin-4- one (13.3 mg, 28.3 μmol, 44%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.73 (dd, J = 1.6, 8.0 Hz, 1H), 7.39 - 7.27 (m, 1H), 6.79 - 6.63 (m, 2H), 5.80 - 4.91 (m, 1H), 3.95 -3.81 (m, 4H), 3.60 (s, 3H), 3.38 (s, 2H), 3.33 - 3.24 (m, 2H), 3.08 - 2.82 (m, 3H), 2.49 (s, 3H), 2.37 (s, 3H), 1.77 (d, J = 3.2 Hz, 3H); m/z ES+ [M+H-100] ⁺ 471.2; and 3,6,7-trimethyl-8- [(1S)-1-(2-methylsulfonylanilino)ethyl]-2-morpholino-quinazo lin-4-one (13.8 mg, 29.4 μmol, 46%) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.73 (dd, J = 1.6, 8.0 Hz, 1H), 7.39 - 7.27 (m, 1H), 6.80 - 6.61 (m, 2H), 5.67 - 5.11 (m, 1H), 3.95 -3.80 (m, 4H), 3.60 (s, 3H), 3.38 (s, 2H), 3.33 - 3.24 (m, 2H), 3.06 - 2.84 (m, 3H), 2.49 (s, 3H), 2.37 (s, 3H), 1.77 (d, J = 3.2 Hz, 3H); m/z ES+ [M+H-100] ⁺ 471.2. Example 228. Preparation of 5-fluoro-3,6-dimethyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2- morpholino-quinazolin-4-one (Compound 368) [2150] Step 1. Synthesis of 5-fluoro-3,6-dimethyl-8-[(1R)-1-(2-methylsulfonylanilino)eth yl]- 2- morpholino-quinazolin-4-one [2151] To a solution of 8-[(1R)-1-aminoethyl]-5-fluoro-3,6-dimethyl-2-morpholino- quinazolin-4-one (50 mg, 156 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (153 mg, 468 μmol) and 1-fluoro-2-methylsulfonyl-benzene (81.6 mg, 468 μmol). The mixture was stirred at 140 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C18 75 x 30mm, 3um; mobile phase: [water(formic acid)- acetonitrile];B%: 40%-70%, 7 min) to give 5-fluoro-3,6-dimethyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (30.0 mg, 61.7 μmol, 39%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.82 - 7.73 (m, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.27 - 7.22 (m, 1H), 6.80 - 6.70 (m, 2H), 6.52 (d, J = 8.4 Hz, 1H), 5.46 - 5.31 (m, 1H), 3.96 - 3.87 (m, 4H), 3.61 (s, 3H), 3.36 - 3.28 (m, 4H), 3.12 (s, 3H), 2.28 (d, J = 2.4 Hz, 3H), 1.63 (s, 3H); m/z ES+ [M+H] ⁺ 475.2. Example 229. Preparation of 2-[[(1R)-1-(5-fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl] amino]benzoic acid (Compound 371) [2152] Step 1. Synthesis of 2-[[(1R)-1-(5-fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl] amino]benzoic acid [2153] To a solution of 8-[(1R)-1-aminoethyl]-5-fluoro-3,6-dimethyl-2-morpholino- quinazolin-4-one (125 mg, 390 μmol) and 2-iodobenzoic acid (290 mg, 1.17 mmol) in dimethyl acetamide (1.5 mL) was added triethylamine (237 mg, 2.34 mmol) and copper (24.8 mg, 390 μmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex C1875 x 30mm, 3um; mobile phase: [water(formic acid)- acetonitrile]; B%: 35%-65%, 7 min) to give 2-[[(1R)-1-(5-fluoro- 3,6- dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)ethyl]amino]benz oic acid (23.9 mg, 54.3 μmol, 14%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 - 7.93 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.24 - 7.17 (m, 1H), 6.62-6.52 (m, 1H), 6.42 (d, J = 8.8 Hz, 1H), 5.45 - 5.35 (m, 1H), 3.93 - 3.83 (m, 4H), 3.59 (s, 3H), 3.36 - 3.24 (m, 4H), 2.27 (d, J = 2.0 Hz, 3H), 1.61 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 441.2. Example 230. Preparation of (R)-2-((1-(2-(3,6-dihydro-2H-pyran-4-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (Compound 476) [2154] Step 1. Synthesis of (3,6-dihydro-2H-pyran-4-yl)boronic acid [2155] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (500 mg, 2.38 mmol) in acetone (10 mL) and water (10 mL) was added ammonium acetate (550 mg, 7.14 mmol) and sodium periodate (1.53 g, 7.14 mmol). The mixture was stirred at 25 °C for 12 hr. The mixture was filtered, organic phase was diluted with ethyl acetate (100 mL) and extracted with water (100 mL). The organic layer was then dried with brine (100 mL), dried over with anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 0/1) to give 3,6-dihydro-2H-pyran-4-ylboronic acid (220 mg, 1.72 mmol, 72%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 6.91 (s, 1H), 4.31- 4.25 (m, 2H), 3.82 - 3.76 (m,, 2H), 2.37 - 2.27 (m, 2H); m/z ES+ [M+H] ⁺ 129.1. [2156] Step 2. Synthesis of (R)-2-((1-(2-(3,6-dihydro-2H-pyran-4-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid [2157] To a solution of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]-5-fluoro-benzoic acid (100 mg, 249 μmol) and 3,6-dihydro-2H-pyran-4- ylboronic acid (47.8 mg, 373 μmol) in anhydrous tetrahydrofuran (10 mL) was added palladium triphenylphosphane (28.7 mg, 24.9 μmol) and thiophene-2-carbonyloxycopper (61.7 mg, 323 μmol) was added at 25 °C. The mixture was stirred at 60 °C for 12 hr. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 45%-65%, 10 min) to give (R)-2-((1-(2-(3,6-dihydro-2H-pyran-4-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (49.3 mg, 111 μmol, 45% yield) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.66 ( dd, J = 2.4, 9.6 Hz, 1H), 7.53 (s, 1H), 7.02 - 6.87 (m, 1H), 6.41 (dd, J = 4.4, 9.2 Hz, 1H), 6.16 ( s, 1H), 5.54 (q, J = 6.0 Hz, 1H), 4.41 ( d, J = 2.8 Hz, 2H), 4.09 - 3.92 (m, 2H), 3.66 (s, 3H), 2.68 - 2.58 (m, 2H), 2.42 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 438.2. Example 231. Preparation of N-(1-cyano-1-methyl-ethyl)-2-[[(1R)-1-[2-(4,4-difluoro-1- piperidyl)-3,6-dimethyl-4-oxo-quinazolin-8-yl]ethyl]amino]-5 -fluoro-benzamide (Compound 444) [2158] Step 1. Synthesis of N-(1-cyano-1-methyl-ethyl)-2-[[(1R)-1-(3,6-dimethyl-2- methylsulfanyl-4-oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-b enzamide [2159] To a solution of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]-5-fluoro-benzoic acid (200 mg, 498 μmol), 2-amino-2-methyl- propanenitrile;hydrochloride (72.1 mg, 598 μmol) and 1-methylimidazole (143 mg, 1.74 mmol) in acetonitrile (2 mL) was added [chloro(dimethyla-(dimethylamino)methylene]- dimethyl-ammonium; hexafluorophosphate (168 mg, 598 μmol) at 25 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give N-(1-cyano-1-methyl-ethyl)-2-[[(1R)-1-(3,6-dimethyl-2- methylsulfanyl-4-oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-b enzamide (135 mg, 234 μmol, 47%) as a yellow solid. m/z ES+ [M+H] ⁺ 468.2. [2160] Step 2. Synthesis of N-(1-cyano-1-methyl-ethyl)-2-[[(1R)-1-(3,6-dimethyl-2- methylsulfinyl-4-oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-b enzamide [2161] To a solution of N-(1-cyano-1-methyl-ethyl)-2-[[(1R)-1-(3,6-dimethyl-2- methylsulfanyl-4-oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-b enzamide (135 mg, 289 μmol) in anhydrous tetrahydrofuran (2 mL) was added a solution of oxone (568 mg, 924 μmol) in water (1.7 mL) at 0 °C, the mixture was stirred at 0 °C for 2.5 hr. On completion, the reaction mixture was diluted with dichloromethane (60 mL) at 0 °C, extracted with ice cold saturated sodium sulfite solution (20 mL x 5) and ice cold water (20 mL x 5). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-(1-cyano-1-methyl-ethyl)-2-[[(1R)-1-(3,6- dimethyl-2-methylsulfinyl-4-oxo-quinazolin-8-yl)ethyl]amino] -5-fluoro-benzamide (120 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 484.2. [2162] Step 3. Synthesis of N-(1-cyano-1-methyl-ethyl)-2-[[(1R)-1-[2-(4,4-difluoro-1- piperidyl)-3,6-dimethyl-4-oxo-quinazolin-8-yl]ethyl]amino]-5 -fluoro-benzamide [2163] A mixture of N-(1-cyano-1-methyl-ethyl)-2-[[(1R)-1-(3,6-dimethyl-2-methyl sulfinyl- 4-oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-benzamide (120 mg, 248 μmol), diisopropylethylamine (128 mg, 993 μmol) and 4A molecular sieve in N,N-dimethylformamide (1.2 mL) was stirred at 25 °C for 0.25 hr. Then 4,4-difluoropiperidine hydrochloride (78.2 mg, 496 μmol) was added, the mixture reaction was stirred at 100 °C for 12 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (16 mL x 3). The combined organic layers were washed with brine (16 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water(ammonium bicarbonate)- acetonitrile];B%: 49%-79%, 10 min) to give N-(1-cyano-1- methyl-ethyl)-2-[[(1R)-1-[2-(4,4-difluoro-1-piperidyl)-3,6-d imethyl-4-oxo-quinazolin-8- yl]ethyl]ami-no]-5-fluoro-benzamide (23.8 mg, 44.0 μmol, 18%) as a pink solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.03 (dd, J = 2.8, 9.2 Hz, 1H), 6.91 - 6.83 (m, 1H), 6.38 (dd, J = 4.4, 9.2 Hz, 1H), 6.17 (s, 1H), 5.29 (q, J = 6.4 Hz, 1H), 3.61 (s, 3H), 3.45 - 3.35 (m, 4H), 2.38 (s, 3H), 2.26 - 2.16 (m, 4H), 1.84 (s, 6H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 541.2. Example 232. Preparation of N-(1-Cyanocyclopropyl)-2-[[(1R)-1-[2-(4,4-difluoro-1- piperidyl)-3,6-dimethyl-4-oxo-quinazolin-8-yl]ethyl]amino]-5 -fluoro-benzamide (Compound 445) [2164] Step 1. Synthesis of N-(1-cyanocyclopropyl)-2-[[(1R)-1-(3,6-dimethyl-2- methylsulfanyl-4-oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-b enzamide [2165] To a solution of 2-[[(1R)-1-(3,6-dimethyl-2-methylsulfanyl-4-oxo-quinazolin-8 - yl)ethyl]amino]-5-fluoro-benzoic acid (100 mg, 249 μmol), 1- aminocyclopropanecarbonitrilehydrochloride (35.4 mg, 299 μmol) and 1-methylimidazole (71.6 mg, 872 μmol) in acetonitrile (1 mL) was added [chloro(dimethyla-mino)methylene]- dimethyl-ammonium;hexafluorophosphate (83.9 mg, 299 μmol) at 25 °C. The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give N-(1-cyanocyclopropyl)-2-[[(1R)-1-(3,6-dimethyl-2- methylsulfanyl-4-oxo-quinazolin-8-yl)ethyl]ami-no]-5-fluoro- benzamide (95.0 mg, 204 μmol, 82%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 5.6 Hz, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 2.8, 9.2 Hz, 1H), 6.90 - 6.82 (m, 1H), 6.69 (s, 1H), 6.33 (dd, J = 4.4, 9.2 Hz, 1H), 5.49 - 5.37 (m, 1H), 3.65 (s, 3H), 2.69 (s, 3H), 2.38 (s, 3H), 1.71 - 1.68 (m, 2H), 1.63 (s, 3H), 1.41 - 1.35 (m, 2H); m/z ES+ [M+H] ⁺ 466.2. [2166] Step 2. Synthesis of N-(1-cyanocyclopropyl)-2-[[(1R)-1-(3,6-dimethyl-2- methylsulfinyl-4-oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-b enzamide [2167] To a solution of N-(1-cyanocyclopropyl)-2-[[(1R)-1-(3,6-dimethyl-2-methylsulf anyl- 4-oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-benzamide (52.0 mg, 112 μmol) in anhydrous tetrahydrofuran (1.1 mL) was added a solution of oxone (220 mg, 357 μmol) in water (0.66 mL) at 0 °C, the mixture was stirred at 0 °C for 2.5 hr. The reaction mixture was diluted with dichloromethane 30 mL at 0 °C, extracted with ice saturated sodium sulfite solution (10 mL x 5) and ice water (10 mL x 5). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-(1-cyanocyclopropyl)-2-[[(1R)-1-(3,6-dimethyl-2-methylsulf inyl-4-oxo-quinazolin-8- yl)ethyl]amino]-5-fluoro-benzamide (45.0 mg, 77.6 μmol, 69%) as a yellow solid. m/z ES+ [M+H] ⁺ 482.2. [2168] Step 3. Synthesis of N-(1-Cyanocyclopropyl)-2-[[(1R)-1-[2-(4,4-difluoro-1- piperidyl)-3,6-dimethyl-4-oxo-quinazolin-8-yl]ethyl]amino]-5 -fluoro-benzamide [2169] A mixture of N-(1-cyanocyclopropyl)-2-[[(1R)-1-(3,6-dimethyl-2-methylsulf inyl-4- oxo-quinazolin-8-yl)ethyl]amino]-5-fluoro-benzamide (45.0 mg, 93.5 μmol), diisopropylethylamine (48.3 mg, 374 μmol) and 4A molecular sieve in N,N- dimethylformamide (0.4 mL) was stirred at 25°C for 0.25 hr. Then 4,4- difluoropiperidine;hydrochloride (29.5 mg, 187 μmol) was added, the mixture reaction was stirred at 100 °C for 12 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150 x 50mm, 10um;mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%: 55%-85%,9 min) to give N-(1-cyanocy-clopropyl)-2-[[(1R)-1-[2-(4,4-difluoro-1-piperi dyl)- 3,6-dimethyl-4-oxo-quinazolin-8-yl]ethyl]amino]-5-fluoro-ben zamide (11.8 mg, 21.9 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.51 (s, 1H), 6.98 (dd, J = 2.8, 9.2 Hz, 1H), 6.93 - 6.82 (m, 1H), 6.65 (s, 1H), 6.39 (dd, J = 4.4, 9.2 Hz, 1H), 5.33 (q, J = 6.4 Hz, 1H), 3.61 (s, 3H), 3.50 - 3.35 (m, 4H), 2.38 (s, 3H), 2.28 - 2.16 (m, 4H), 1.69 - 1.66 (m, 2H), 1.61 (d, J = 6.4 Hz, 3H), 1.41 - 1.35 (m, 2H); m/z ES+ [M+H] ⁺ 539.2. Example 233. Preparation of 2-[[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)- 2,2-difluoro-ethyl]amino]-5-fluoro-benzoic acid and (S)-2-((1-(3,6-dimethyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)-2,2-difluoroeth yl)amino)-5-fluorobenzoic acid (Compounds 407 and 453) (stereochemistry arbitrarily assigned) [2170] Step 1. Synthesis of N-[2-(benzenesulfonyl)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)-2,2-difluoro-ethyl]-2-methyl-propane-2-sulf inamide [2171] To a solution of N-[(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)methylen e]-2- methyl-propane-2-sulfinamide (2.2 g, 5.63 mmol) and difluoromethylsulfonylbenzene (2.17 g, 11.2 mmol) in anhydrous tetrahydrofuran (100 mL) was added double trimethylsilaminolithium (1 M, 16.9 mL) at -78 °C, the mixture was stirred at -78 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition saturated ammonium chloride (300 mL) at 0 °C, and then extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 0/1) to give N-[2-(benzenesulfonyl)-1-(3,6-dimethyl-2-morpholino-4-oxo-qu inazolin-8-yl)- 2,2-difluoro-ethyl]-2-methyl-propane-2-sulfinamide (2.7 g, 4.17 mmol, 37%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.92 ( d, J = 7.2 Hz, 2H), 7.76 - 7.68 (m, 1H), 7.61- 7.46 (m, 2H), 6.99 - 6.72 (m, 1H), 5.50 - 5.34 (m, 1H), 3.90 ( d, J = 4.0 Hz, 4H), 3.57 (s, 3H), 3.35 - 3.06 (m, 4H), 2.44 (s, 3H), 1.36 - 1.28 (m, 9H); m/z ES+ [M+H] ⁺ 583.2. [2172] Step 2. Synthesis of 8-(1-amino-2,2-difluoro-ethyl)-3,6-dimethyl-2-morpholino- quinazolin-4-one [2173] To a solution of N-[2-(benzenesulfonyl)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)-2,2-difluoro-ethyl]-2-methyl-propane-2-sulf inamide (2.5 g, 4.29 mmol) in N,N-dimethylformamide (100 mL) was added a solution of sodium acetate (3.52 g, 42.9 mmol) and acetic acid (2.58 g, 42.9 mmol) dissolved in water (25 mL) and stirred for 15 min, then magnesium (1.56 g, 64.3 mmol) powder was added portiowise below at 25 ~ 45 °C under nitrogen atmosphere. The mixture was stirred at 60 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition water (300 mL) at 0 °C, and then extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC[water(0.1% formic acid)- acetonitrile]; 30min to give 8-(1-amino-2,2-difluoro-ethyl)-3,6-dimethyl-2- morpholino-quinazolin-4-one (970 mg, 2.75 mmol, 64%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (s, 1H), 7.74 (s, 1H), 6.68 - 6.33 (m, 1H), 5.30 - 5.13 (m, 1H), 3.87 - 3.72 (m, 4H), 3.49 (s, 3H), 3.28 - 3.18 (m, 4H), 2.43 (s, 3H); m/z ES+ [M+H] ⁺ 339.2. [2174] Step 3. Synthesis of 2-[[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)-2,2- difluoro-ethyl]amino]-5-fluoro-benzoic acid [2175] To a solution of 8-(1-amino-2,2-difluoro-ethyl)-3,6-dimethyl-2-morpholino- quinazolin-4-one (100 mg, 295 μmol) in dimethyl acetamide (2 mL) was added 5-fluoro-2- iodo-benzoic acid (393 mg, 1.48 mmol), copper (18.7 mg, 295 μmol) and tethyl acetate (89.7 mg, 886 μmol), the mixture was stirred at 100 °C for 2 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purificated by reversed-phase HPLC[column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 42%-72%,58min] to give 2-[[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)-2,2- difluoro-ethyl]amino]-5-fluoro-benzoic acid (33 mg, 69.2 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.95 - 8.76 (m, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 3.2, 9.6 Hz, 1H), 7.26 - 7.3.16 (m, 1H), 6.85 (dd, J = 4.0, 9.2 Hz, 1H), 6.81 - 6.50 (m, 1H), 5.79 - 5.58 (m, 1H), 3.84-3.69 (m, 4H), 3.51 (s, 3H), 3.29 - 3.26 (m, 4H), 2.37 (s, 3H); m/z ES+ [M+H] ⁺ 477.2. [2176] Step 4. Chiral purification [2177] 2-[[1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)-2,2- difluoro-ethyl]amino]- 5-fluoro-benzoic acid was separated by SFC (column: DAICEL CHIRALPAK AD(250mm x 30mm,10um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 25%-25%,3.3min) to give (S)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8-yl)-2,2- difluoroethyl)amino)-5-fluorobenzoic acid (11.4 mg, 23.9 μmol, 57%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.69 - 8.55 (m, 1H), 8.00 (s, 1H), 7.68 ( d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.10 - 7.00 (m, 1H), 6.58 ( dd, J = 3.2, 7.6 Hz, 1H), 6.51 - 6.18 (m, 1H), 5.71 - 5.56 (m, 1H), 3.96 - 3.85 (m, 4H), 3.63 (s, 3H), 3.36 - 3.28 (m, 4H), 2.41 (s, 3H); m/z ES+ [M+H] ⁺ 477.2. Example 234. Preparation of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)propyl)amino)-5-fluorobenzoic acid (Compound 756) [2178] Step 1. Synthesis of (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)propyl)-2-methylpropane-2-sulfinamide [2179] A mixture of dimethylzinc (1 M in toluene, 12.2 mL) and bromo(ethyl)magnesium (3 M in tetrahydrofuran, 12.2 mL) was stirred at 25 °C for 0.1 hr under nitrogen. After cooling to −78 ºC, a solution of (R)-N-((3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinazoli n-8- yl)methylene)-2-methylpropane-2-sulfinamide (1.90 g, 4.87 mmol) in anhydrous tetrahydrofuran (28.5 mL) was added dropwise into the above solution. The mixture was stirred at -78 °C for 0.4 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched with saturated ammonium chloride solution (100 mL) at -78 °C. Then, the cooling bath was removed and the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250*80mm*10um;mobile phase: [water(ammonium hydroxide)-acetonitrile];gradient:25%-55% B over 20 min) to give (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)propyl)-2-methylpropane-2-sulfinamide (1.40 g, 3.20 mmol, 66%) as a white solid. m/z ES+ [M+H] ⁺ 421.3 [2180] Step 2. Synthesis of (R)-8-(1-aminopropyl)-3,6-dimethyl-2-morpholinoquinazolin- 4(3H)-one [2181] To a solution of (R)-N-((R)-1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)propyl)-2-methylpropane-2-sulfinamide (400 mg, 951 μmol) in dichloromethane (4 mL) was added hydrochloric acid/dioxane (4 M, 4.00 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 10 with aqueous ammonium hydroxide and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-8-(1-aminopropyl)-3,6-dimethyl-2- morpholinoquinazolin-4(3H)-one (300 mg, 939 μmol, 99%) as a white solid. m/z ES+ [M+H] ⁺ 317.2. [2182] Step 3. Synthesis of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)propyl)amino)-5-fluorobenzoic acid [2183] To a solution of (R)-8-(1-aminopropyl)-3,6-dimethyl-2-morpholinoquinazolin-4( 3H)- one (100 mg, 316 μmol) and 5-fluoro-2-iodo-benzoic acid (126 mg, 474 μmol) in dioxane (2 mL) was added cesium carbonate (309 mg, 948 μmol) and [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6-triisopro pylphenyl)phenyl]phosphane (7.53 mg, 9.48 μmol). The mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 0/1) and then re-purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:50%-80% B over 10 min) to give (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8- yl)propyl)amino)-5-fluorobenzoic acid (85.5 mg, 188 μmol, 60%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.67 (dd, J = 3.2, 9.6 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 6.95 (dt, J = 3.2, 8.4 Hz, 1H), 6.43 (dd, J = 4.4, 9.2 Hz, 1H), 5.27 (br. t, J = 6.4 Hz, 1H), 3.92 (t, J = 4.4 Hz, 4H), 3.64 (s, 3H), 3.31 (br. d, J = 3.2 Hz, 4H), 2.39 (s, 3H), 2.05 - 1.91 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 455.2. Example 235. Preparation of (R)-2-((1-(3-(Difluoromethyl)-6-fluoro-2-morpholino-4-oxo- 3,4-dihydroquina-zolin-8-yl)ethyl)amino)benzoic acid (Compound 362) [2184] Step 1. Synthesis of (R)-2-((1-(3-(difluoromethyl)-6-fluoro-2-morpholino-4-oxo-3, 4- dihydroquina-zolin-8-yl)ethyl)amino)benzoic acid [2185] To a mixture of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-fluoro-2-morpholi no- quinazolin-4-one (15 mg, 43.8 μmol) and 2-iodobenzoic acid (54.3 mg, 219 μmol) in dimethyl acetamide (2.4 mL) was added triethylamine (88.7 mg, 876 μmol) and copper powder (27.9 mg, 438 μmol). The mixture was stirred at 110 °C for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water(ammonium bicarbonate)- acetonitrile];B%:27%-57%, 8 min) to give (R)-2-((1-(3- (difluoromethyl)-6-fluoro-2-morpholino-4-oxo-3,4-dihydroquin azolin-8- yl)ethyl)amino)benzoic acid (3.88 mg, 7.96 μmol, 18%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.29 – 8.10 (m, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.80 – 7.44 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.35 (d, J = 4.8 Hz, 1H), 5.55 - 5.52 (m, 1H), 3.90 (d, J = 2.4 Hz, 4 H), 3.86 (d, J = 2.4 Hz, 4 H), 1.68 (d, J = 3.2 Hz, 3H); m/z ES+ [M+H] ⁺ 463.2. Example 236. Preparation of (R)-2-((1-(3-(Difluoromethyl)-6-fluoro-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (Compound 504) [2186] Step 1. Synthesis of (R)-2-((1-(3-(difluoromethyl)-6-fluoro-2-morpholino-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid [2187] To a solution of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-fluoro-2-morpholi no- quinazolin-4-one (100 mg, 292 μmol) and 5-fluoro-2-iodo-benzoic acid (233 mg, 876 μmol) in dimethyl acetamide (1 mL) was added copper (18.6 mg, 292 μmol), 4A MS and triethylamine (296 mg, 2.92 mmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150×25mm, 10um;mobile phase: [water(FA)-acetonitrile];B%: 66%-96%, 10 min) to give 2-[[(1R)-1-[3- (difluoromethyl)-6-fluoro-2-morpholino-4-oxo-quinazolin-8-yl ]ethyl]amino]-5-fluoro- benzoic acid (28.1 mg, 57.6 μmol, 20%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.20 - 7.89 (m, 1H), 7.80 - 7.43 (m, 4H), 7.00 - 6.89 (m, 1H), 6.27 (dd, J = 4.4, 9.2 Hz, 1H), 5.54 - 5.43 (m, 1H), 3.89 (d, J = 5.2 Hz, 4H), 3.87 - 3.80 (m, 4H), 1.67 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 481.1. Example 237. Preparation of (R)-5-chloro-2-((1-(3-(difluoromethyl)-6-fluoro-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (Compound 510)

[2188] Step 1. Synthesis of (R)-5-Chloro-2-((1-(3-(difluoromethyl)-6-fluoro-2-morpholino - 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2189] To a solution of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-fluoro-2-morpholi no- quinazolin-4-one (50 mg, 146 μmol) in dimethyl acetamide (0.5 mL) was added 5-chloro-2- iodo-benzoic acid (124 mg, 438 μmol), copper (9.28 mg, 146 μmol), 4A MS and triethylamine (148 mg, 1.46 mmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 150 x 25mm,5um;mobile phase: [water(hydrochloric acid)-acetonitrile];B%: 68%-98%,8.5min) to give 5-chloro-2-[[(1R)-1-[3- (difluoromethyl)-6-fluoro-2-morpholino-4-oxo-quinazolin-8-yl ]ethyl]amino] benzoic acid (12.5 mg, 25.0 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.96 - 7.42 (m, 4H), 7.11 (dd, J = 2.8, 9.2 Hz, 1H), 6.29 (d, J = 9.2 Hz, 1H), 5.56 - 5.42 (m, 1H), 3.93 - 3.87 (m, 4H), 3.85 (d, J = 4.4 Hz, 4H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 497.1. Example 238. Preparation of (R)-3-(Difluoromethyl)-6-fluoro-8-(1-((2- (methylsulfonyl)phenyl) amino)ethyl)-2-morpholinoquinazolin-4(3H)-one (Compound 420)

[2190] Step 1. Synthesis of (R,Z)-N-(1-(6-fluoro-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylid-ene)-2-methylpropane-2-sulfin amide [2191] A mixture of 8-acetyl-6-fluoro-2-morpholino-3H-quinazolin-4-one (620 mg, 2.13 mmol), (R)-2-methylpropane-2-sulfinamide (1.03 g, 8.51 mmol), tetraethoxytitanium (2.43 g, 10.64 mmol) in tetrahydrofuran (6 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 75 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (60 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by triturated with (petroleum ether/ethyl acetate= 1/1, 100 mL) at 20 ^o C for 0.5 hr to give (NZ, R)-N-[1-(6-fluoro-2-morpholino-4-oxo-3H-quinazolin-8-yl)ethy lidene]- 2-methyl-propane-2-sulfinamide (540 mg, 1.33 mmol, 63%) as a yellow solid. m/z ES+ [M+H] ⁺ 395.1. [2192] Step 2. Synthesis of (R)-N-((R)-1-(6-Fluoro-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [2193] To a solution of (NZ,R)-N-[1-(6-fluoro-2-morpholino-4-oxo-3H-quinazolin-8- yl)ethylidene]-2-methyl-propane-2-sulfinamide (440 mg, 1.12 mmol) in tetrahydrofuran (18 mL) was added borane dimethyl sulfide (10 M, 1.12 mL) at -70 °C. The mixture was stirred at -30 °C for 2 hr. On completion, the reaction mixture was quenched by methanol (60 mL) at 0 °C, and then stirred at 0 - 20 °C for 0.5 hr. At last, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water (ammonia hydroxide v/v)- acetonitrile]; B%: 14%-44%, 9 min) to give (R)-N-[(1R)-1-(6-fluoro-2-morpholino-4-oxo-3H-quinazolin-8- yl)ethyl]-2-methyl-propane-2-sulfinamide (270 mg, 678 μmol, 61%) as a white solid. m/z ES+ [M+H] ⁺ 397.2. [2194] Step 3. Synthesis of (R)-8-(1-aminoethyl)-6-fluoro-2-morpholinoquinazolin-4(3H)- one [2195] To a solution of (R)-N-[(1R)-1-(6-fluoro-2-morpholino-4-oxo-3H-quinazolin-8- yl)ethyl]-2-methyl-pr-opane-2-sulfinamide (170 mg, 429 μmol) in dichloromethane (4 mL) was added hydrochloric acid /dioxane (4 M, 6.80 mL). The mixture was stirred at 0 - 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 8-[(1R)-1- aminoethyl]-6-fluoro-2-morpholino-3H-quinazolin-4-one (70 mg, crude, hydrochloride salt) as a white solid. m/z ES+ [M+H] ⁺ 293.1. [2196] Step 4. Synthesis of (R)-6-fluoro-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2- morpholinoquin-azolin-4(3H)-one [2197] To a solution of 8-[(1R)-1-aminoethyl]-6-fluoro-2-morpholino-3H-quinazolin-4- one (70 mg, 213 μmol, hydrochloride) and 1-fluoro-2-methylsulfonyl-benzene (148 mg, 852 μmol) in dimethyl acetamide (2.8 mL) was added cesium carbonate (208 mg, 639 μmol). The mixture was stirred at 120 °C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=1/1) to give 6-fluoro-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-3H-quinazolin-4-on e (33 mg, 69.5 μmol, 33%) as a white solid. m/z ES+ [M+H] ⁺ 447.1. [2198] Step 5. Synthesis of (R)-3-(difluoromethyl)-6-fluoro-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-morpholinoquinazolin-4 (3H)-one [2199] To a solution of 6-fluoro-8-[(1R)-1-(2-methylsulfonylanilino) ethyl]-2-morpholino- 3H-quinazolin-4-one (30 mg, 67.2 μmol) and sodium difluorochloroacetate (15.4 mg, 101 μmol) in N,N-dimethylformamide (0.6 mL) was added sodium carbonate (33.5 mg, 316 μmol). The mixture was stirred at 100 °C for 3 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water(formic acid)-acetonitrile]; B%: 59%-89%, 10 min) to give 3-(difluoromethyl)-6-fluoro-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (8 mg, 16.1 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 - 7.34 (m, 4H), 7.17 - 7.12 (m, 1H), 6.74 - 6.63 (m, 2H), 6.34 (d, J = 8.4 Hz, 1H), 5.37 (q, J = 6.4 Hz, 1H), 3.82 - 3.74 (m, 8H), 3.05 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 497.2. Example 239. Preparation of (R)-3-(difluoromethyl)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-6-methyl-2-morpholinoqui nazolin-4(3H)-one (Compound 496) [2200] Step 1. Synthesis of (R,Z)-2-methyl-N-(1-(6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)propane-2-sulfinamide [2201] To a solution of 8-acetyl-6-methyl-2-morpholino-3H-quinazolin-4-one (3.98 g, 13.85 mmol) and (R)-2-methylpropane-2-sulfinamide (8.39 g, 69.3 mmol) in anhydrous tetrahydrofuran (30 mL) was added titanium tetraethoxy (15.8 g, 69.3 mmol). The mixture was stirred at 75 °C for 48 hr. On completion, the reaction mixture was poured into water (100 mL) and filtered. The liquid was extracted with ethyl acetate (30 mL x 3). The combined organic layers dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5/1 to 2/1) to give (NZ,R)-2-methyl-N-[1-(6-methyl-2- morpholino-4-oxo-3H-quinazolin-8-yl)ethylidene]propane-2-sul finamide (1.83 g, 784 μmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.6 - 11.3 (m, 1H), 7.93 - 7.73 (m, 1H), 7.21 - 7.13 (m, 1H), 3.78 - 3.60 (m, 4H), 3.59 - 3.48 (m, 4H), 2.36 (s, 3H), 1.20 (s, 3H), 1.08 - 1.04 (m, 9H); m/z ES+ [M+H] ⁺ 291.2. [2202] Step 2. Synthesis of (R)-2-methyl-N-((R)-1-(6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)propane-2-sulfinamide [2203] To a solution of (NZ,R)-2-methyl-N-[1-(6-methyl-2-morpholino-4-oxo-3H- quinazolin-8-yl)ethylidene]propane-2-sulfinamide (1.63 g, 4.17 mmol) in anhydrous tetrahydrofuran (17 mL) was added borane; methylsulfanylmethane (10 M, 4.17 mL) dropwise at -70 - -60 °C. Then the resulting mixture was stirred at -30 - 20°C for 1 hr. On completion, the reaction mixture was quenched by addition of methanol (30 mL) and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 250 x 50mm,10 um; mobile phase: [water(ammonium bicarbonate)- acetonitrile];B%: 26%-56%, 9 min) to give (R)-2-methyl-N-[(1R)-1-(6-methyl-2-morpholino- 4-oxo-3H-quinazolin-8-yl)ethyl]propane-2-sulfinamide(0.612 g, 1.39 mmol, 33%) as a yellow solid. [2204] Step 3. Synthesis of (R)-8-(1-aminoethyl)-6-methyl-2-morpholinoquinazolin-4(3H)- one [2205] To a solution of (R)-2-methyl-N-[(1R)-1-(6-methyl-2-morpholino-4-oxo-3H- quinazolin-8-yl)ethyl]propane-2-sulfinamide (0.3 g, 764 μmol) in dichloromethane (3 mL) was added hydrochloric acid/dioxane (4 M, 4.97 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated under reduced pressure to give 8-[(1R)-1- aminoethyl]-6-methyl-2-morpholino-3H-quinazolin-4-one (0.287 g, crude) as off-white solid. m/z ES+ [M+H] ⁺ 289.2. [2206] Step 4. Synthesis of (R)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-6- methyl-2-morpholinoquinazolin-4(3H)-one [2207] To a solution of 8-[(1R)-1-aminoethyl]-6-methyl-2-morpholino-3H-quinazolin-4- one (0.277 g, 961 μmol) and 1,4-difluoro-2-methylsulfonyl-benzene (554 mg, 2.88 mmol) in dimethyl acetamide (3 mL) was added cesium carbonate (939 mg, 2.88 mmol). The mixture was stirred at 140 °C for 16 hr. On completion, the reaction mixture was filtered, and then filter liquid was diluted with water (10 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5/1 to 2/1) to give (R)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-6-methyl-2-morpholinoqui nazolin-4(3H)-one (300 mg, 651 μmol, 67.8%) as brown oil. m/z ES+ [M+H] ⁺ 461.2. [2208] Step 5. Synthesis of (R)-3-(difluoromethyl)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-6-methyl-2-morpholinoqui nazolin-4(3H)-one [2209] To a solution of 8-[(1R)-1-(4-fluoro-2-methylsulfonyl-anilino)ethyl]-6-methyl -2- morpholino-3H-quinazolin-4-one(150 mg, 326 μmol) and sodium;2-chloro-2,2-difluoro- acetate (149 mg, 977 μmol) in N,N-dimethylformamide (3 mL) was added sodium carbonate (104 mg, 977 μmol), then the reaction mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25mm, 10um; mobile phase: [water (formic acid)-acetonitrile];B%: 58%-88%,10 min) to give (R)-3- (difluoromethyl)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)am ino)ethyl)-6-methyl-2- morpholinoquinazolin-4(3H)-one (52 mg, 102 μmol, 31%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.81 - 7.42 (m, 4H), 7.01 - 6.92 (m, 1H), 6.60 (s, 1H), 6.47 (dd, J = 4.4, 9.2 Hz, 1H), 5.44 - 5.34 (m, 1H), 3.91 - 3.79 (m, 8H), 3.12 (s, 3H), 2.38 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 511.2. Example 240. Preparation of (R)-5-chloro-2-((1-(3-(difluoromethyl)-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (Compound 539) [2210] Step 1. Synthesis of 8-acetyl-3-(difluoromethyl)-6-methyl-2-morpholinoquinazolin- 4(3H)-one [2211] To a solution of 8-acetyl-6-methyl-2-morpholino-3H-quinazolin-4-one (1.00 g, 3.48 mmol) in N,N-dimethylformamide (5.00 mL) was added sodium carbonate (2.21 g, 20.9 mmol) and sodium;2-chloro-2,2-difluoro-acetate (796 mg, 5.22 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was diluted with water (250 mL) then filtered and the cake was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 1/1) to give 8-acetyl-3-(difluoromethyl)-6-methyl-2-morpholino-quinazolin -4-one (550 mg, 1.14 mmol, 33%) as a white solid. m/z ES+ [M+H] ⁺ 338.1. [2212] Step 2. Synthesis of (R,Z)-N-(1-(3-(difluoromethyl)-6-methyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide [2213] To a solution of 8-acetyl-3-(difluoromethyl)-6-methyl-2-morpholino-quinazolin -4- one (550 mg, 1.63 mmol) in anhydrous tetrahydrofuran (6.00 mL) was added tetraethoxytitanium (1.86 g, 8.15 mmol) and (R)-2-methylpropane-2-sulfinamide (988 mg, 8.15 mmol). The mixture was stirred at 75 °C for 3 hr. On completion, the reaction mixture was diluted with anhydrous tetrahydrofuran (50 mL) and poured into water (80 mL), filtered and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5/1 to 2/1) to give (NZ,R)-N-[1-[3-(difluoromethyl)-6-methyl-2- morpholino-4-oxo-quinazolin-8-yl]ethylidene]-2-methyl-propan e-2-sulfinamide (500 mg, 1.02 mmol, 63%) as a white solid. m/z ES+ [M+H] ⁺ 441.2. [2214] Step 3. Synthesis of (R)-N-((R)-1-(3-(difluoromethyl)-6-methyl-2-morpholino-4-oxo - 3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinam ide [2215] To a solution of (NZ,R)-N-[1-[3-(difluoromethyl)-6-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylidene]-2-methyl-propane-2-sulfinamide (500 mg, 1.14 mmol) in anhydrous tetrahydrofuran (10.0 mL) was added borane-methyl sulfide complex (10 M, 568 ^L). The mixture was stirred at -78 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was quenched by methanol (25 mL) at -78 °C. The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 1/1) to give (R)-N-[(1R)-1-[3-(difluoromethyl)-6-methyl- 2-morpholino-4-oxo-quinazolin-8-yl]ethyl]-2-methyl-propane-2 -sulfinamide (250 mg, 508 μmol, 45%) as a white solid. m/z ES+ [M+H] ⁺ 443.2. [2216] Step 4. Synthesis of (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-methyl-2- morpholinoquinazolin-4(3H)-one [2217] To a solution of (R)-N-[(1R)-1-[3-(difluoromethyl)-6-methyl-2-morpholino-4-ox o- quinazolin-8-yl]ethyl]-2-methyl-propane-2-sulfinamide (250 mg, 565 μmol) in dioxane (0.30 mL) was added hydrogen chloride/dioxane (4 M, 141 ^L). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide condition) to give 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-methyl-2-morpholi no- quinazolin-4-one (130 mg, 346 μmol, 61%) as a white solid. m/z ES+ [M+H] ⁺ 339.2. [2218] Step 5. Synthesis of (R)-5-chloro-2-((1-(3-(difluoromethyl)-6-methyl-2-morpholino - 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2219] To a solution of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-methyl-2-morpholi no- quinazolin-4-one (120 mg, 355 μmol) and 5-chloro-2-iodo-benzoic acid (301 mg, 1.06 mmol) in dimethyl acetamide (1.20 mL) was added copper (22.5 mg, 355 μmol), 4A molecular sieve and triethylamine (359 mg, 3.55 mmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered, diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 1/1), then purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm x 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:73%-100% B over 10 min) to give (R)-5-chloro-2-((1-(3- (difluoromethyl)-6-methyl-2-morpholino-4-oxo-3,4-dihydroquin azolin-8- yl)ethyl)amino)benzoic acid (10.8 mg, 21.9 μmol, 6.2%) as a white solid. (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 2.8 Hz, 1H), 7.81 - 7.43 (m, 3H), 7.10 (dd, J = 2.8, 9.2 Hz, 1H), 6.37 (d, J = 9.2 Hz, 1H), 5.46 (q, J = 6.4 Hz, 1H), 3.91 - 3.85 (m, 4H), 3.85 - 3.81 (m, 4H), 2.37 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 493.2. Example 241. Preparation of 2-[1-[6-(Difluoromethyl)-3-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid (Compound 377) [2220] Step 1. Synthesis of 2-[1-[6-(difluoromethyl)-3-methyl-2-morpholino-4-oxo- quinazolin-8-yl]ethylamino]benzoic acid [2221] To a solution of 8-(1-aminoethyl)-6-(difluoromethyl)-3-methyl-2-morpholino- quinazolin-4-one (20.0 mg, 59.1 μmol) and 2-iodobenzoic acid (73.3 mg, 295 μmol) in dimethyl acetamide (10 mL) was added copper powder (3.76 mg, 59.1 μmol) and triethylamine (119 mg, 1.18 mmol). The mixture was stirred at 110 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Shim-pack C18 150 x 25, 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 35%-65%, 10 min) to give 2-[1-[6- (difluoromethyl)-3-methyl-2-morpholino-4-oxo-quinazolin-8-yl ]ethylamino]benzoic acid (3.2 mg, 6.63 μmol, 11%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.22-7.14 (m, 1H), 6.80 - 6.49 (m, 2H), 6.39 (d, J = 8.8 Hz, 1H), 5.51 - 5.43 (m, 1H), 3.96 - 3.88 (m, 4H), 3.64 (s, 3H), 3.40 - 3.32 (m, 4H), 1.67 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 459.2. Example 242. Preparation of (R)-6-(difluoromethyl)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3-methyl-2-morpholinoqui nazolin-4(3H)-one and (S)-6-(difluoromethyl)-8-(1-((4-fluoro-2-(methylsulfonyl)phe nyl)amino)ethyl)-3-methyl- 2-morpholinoquinazolin-4(3H)-one (Compounds 548 and 549) (stereochemistry arbitrarily assigned) [2222] Step 1. Synthesis of 6-(difluoromethyl)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3-methyl-2-morpholinoqui nazolin-4(3H)-one [2223] To a solution of 8-(1-aminoethyl)-6-(difluoromethyl)-3-methyl-2-morpholino- quinazolin-4-one (35 mg, 103 μmol) and 1,4-difluoro-2-methylsulfonyl-benzene (99.4 mg, 517 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (169 mg, 517 μmol). The mixture was stirred at 140 °C for 16 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=1/1) to give yellow oil. Then the yellow oil was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (formic acid)- acetonitrile]; gradient: 46%-76% B over 10 min) to give 6-(difluoromethyl)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3-methyl-2-morpholinoqui nazolin-4(3H)-one (10 mg, 19.4 μmol, 19%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.76 (s, 1H), 7.52 (dd, J = 3.2, 8.0 Hz, 1H), 7.03 - 6.95 (m,1H), 6.81 - 6.51 (m, 2H), 6.45 (dd, J = 4.0, 9.2 Hz, 1H), 5.42 - 5.32 (m, 1H), 3.94 - 3.89 (m, 4H), 3.64 (s, 3H), 3.39 - 3.33 (m, 4H), 3.14 (s, 3H), 1.66 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 511.2. [2224] Step 2. Chiral purification [2225] Compound 6-(difluoromethyl)-8-[1-(4-fluoro-2-methylsulfonyl-anilino)e thyl]-3- methyl-2-morpholino-quinazolin-4-one (10 mg, 19.6 μmol) was resolution by prep-SFC (column: DAICEL CHIRALCEL OJ (250mm x 30mm, 10um); mobile phase: [CO2-methanol]; 25% B isocratic elution mode) followed by lyophilization to give (R)-6-(difluoromethyl)-8-(1- ((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3-methyl-2- morpholinoquinazolin-4(3H)- one (2.41 mg, 4.63 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.52 (dd, J = 3.2, 8.0 Hz, 1H), 7.03 - 6.95 (m, 1H), 6.83 - 6.51 (m, 2H), 6.45 (dd, J = 4.0, 9.2 Hz, 1H), 5.40 - 5.34 (m, 1H), 3.95 - 3.87 (m, 4H), 3.64 (s, 3H), 3.39 - 3.33 (m, 4H), 3.14 (s, 3H), 1.66 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 511.3. And (S)-6- (difluoromethyl)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)am ino)ethyl)-3-methyl-2- morpholinoquinazolin-4(3H)-one (2.52 mg, 4.89 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.52 (dd, J = 3.2, 8.0 Hz, 1H), 7.02 - 6.96 (m, 1H), 6.81 - 6.52 (m, 2H), 6.45 (dd, J = 4.0, 9.2 Hz, 1H), 5.41 - 5.30 (m, 1H), 3.93 - 3.89 (m, 4H), 3.64 (s, 3H), 3.38 - 3.34 (m, 4H), 3.14 (s, 3H), 1.66 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 511.3. Example 243. Preparation of 2-((6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazoline)-8-sulfonamido)benzoic acid (Compound 532) [2226] Step 1. Synthesis of methyl 3-((6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)sulfonyl)propanoate [2227] A mixture of (3-methoxy-3-oxo-propyl)sulfinyloxysodium (2.04 g, 11.6 mmol), 8- bromo-6-fluoro-3-methyl-2-morpholino-quinazolin-4-one (800 mg, 2.34 mmol) and cuprous iodide (2.23 g, 11.6 mmol) in dimethylsulfoxide (8 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 5 hr under nitrogen atmosphere. The mixture was filtered, diluted with ethyl acetate (100 mL) and extracted with water (50 mL). The organic layer was then dried with brine (50 mL), dried over with anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=1/1, 20 mL) at 25 ^o C for 30 min to give methyl 3- (6-fluoro-3-methyl-2-morpholino-4-oxo-quinazolin-8-yl)sulfon ylpropanoate (570 mg, 813 μmol, 35%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 - 8.09 (m, 2H), 4.10 - 4.01 (m, 2H), 3.92 - 3.83 (m, 4H), 3.66 (s, 3H), 3.59 (s, 3H), 3.42 - 3.37 (m, 4H), 2.83 - 2.74 (m, 2H); m/z ES+ [M+H] ⁺ 414.1. [2228] Step 2. Synthesis of sodium 6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazoline-8-sulfinate [2229] To a solution of methyl 3-(6-fluoro-3-methyl-2-morpholino-4-oxo-quinazolin-8- yl)sulfonylpropanoate (300 mg, 725 μmol) in dimethylsulfoxide (3 mL) was added sodium methylate (118 mg, 2.18 mmol) at 25 °C and the mixture was stirred at 25 °C for 0.5 hr. sodium 6-fluoro-3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazoline- 8-sulfinate (253 mg, crude) as a yellow liquid. The mixture was not work up and go straight to the next step. m/z ES+ [M+H] ⁺ 350.1. [2230] Step 3. Synthesis of 6-fluoro-3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazoline- 8-sulfonamide [2231] To a solution of (6-fluoro-3-methyl-2-morpholino-4-oxo-quinazolin-8- yl)sulfinyloxysodium (253 mg, 724 μmol) in dimethylsulfoxide (3 mL) was added sodium acetate (237 mg, 2.90 mmol) and amino hydrogen sulfate (409 mg, 3.62 mmol) in water (6 mL) at 0 °C. Then the mixture was stirred at 25 °C for 12 hr. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (40 mL). The organic phase was separated, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC ( 0.1% formic acid condition) to give 6-fluoro-3-methyl-2-morpholino-4-oxo-quinazoline-8- sulfonamide(80 mg, 231 μmol, 32%) as an off-white solid. m/z ES+ [M+H] ⁺ 343.1. [2232] Step 4. Synthesis of 2-((6-fluoro-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazoline)-8-sulfonamido)benzoic acid [2233] To a solution of 6-fluoro-3-methyl-2-morpholino-4-oxo-quinazoline-8-sulfonami de (65 mg, 189 μmol) and 2-iodobenzoic acid (141 mg, 569 μmol) in dimethyl acetamide (1 mL) was added copper powder (12.0 mg, 189 μmol) and trifluoroacetic acid (76.8 mg, 759 μmol). The mixture was stirred at 100 °C for 1.5 hr under nitrogen. The reaction mixture was partitioned between ammonium chloride (5 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (formic acid)- acetonitrile];B%: 41%-71%, 10 min) to give 2-[(6-fluoro-3-methyl-2-morpholino-4-oxo- quinazolin-8-yl)sulfonylamino]benzoic acid (56.7 mg, 120 μmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 11.4 - 11.1 (m, 1H), 8.25 (dd, J = 3.2, 8.0 Hz, 1H), 8.03 (dd, J = 3.2, 7.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.02 - 6.98 (m, 1H), 3.98 - 3.90 (m, 4H), 3.57 (s, 3H), 3.44 - 3.40 (m, 4H); m/z ES+ [M+H] ⁺ 463.1. Example 244. Preparation of (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 274) [2234] Step 1. Synthesis of (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2235] To a solution of 8-[(1R)-1-aminoethyl]-6-fluoro-3-methyl-2-morpholino-quinazo lin- 4-one (50 mg, 163 μmol) and 5-fluoro-2-iodo-benzoic acid (130 mg, 490 μmol) in dimethyl acetamide (0.5 mL) was added copper powder (10.4 mg, 163 μmol) and triethylamine (49.6 mg, 490 μmol). The mixture was stirred at 110 °C for 1 hr. The mixture was poured in water (5 mL) then extracted with ethyl acetate (10 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40 mm, 15 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 53%-83%, 9 min) to give (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-2-morpholino-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (12.08 mg, 27.2 μmol, 17%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.4 - 12.8 (m, 1H), 8.60 - 8.27 (m, 1H), 7.58 (dd, J = 3.2, 8.4 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.17 - 7.00 (m, 1H), 6.49 - 6.34 (m, 1H), 5.43 - 5.29 (m, 1H), 3.82 - 3.72 (m, 4H), 3.50 (s, 3H), 3.28 (s, 4H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 445.2. Example 245. Preparation of (R)-6-fluoro-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3-methyl-2-morpholinoquinazolin-4(3H) -one (Compound 604) [2236] Step 1. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- fluorophenyl)amino)ethyl)-6-fluoro-3-methyl-2-morpholinoquin azolin-4(3H)-one [2237] To a solution of 8-[(1R)-1-aminoethyl]-6-fluoro-3-methyl-2-morpholino-quinazo lin- 4-one (200 mg, 653 μmol) in dioxane (5 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]- 4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichlo ropalladium (63.5 mg, 65.3 μmol), [1-(2-bromo-5-fluoro-phenyl)-4-piperidyl]oxy-tert-butyl-dime thyl-silane (304 mg, 784 μmol) and cesium carbonate (638 mg, 1.96 mmol). The mixture was stirred at 105 °C for 4 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 2/1) to give 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4- fluoro-anilino]ethyl]-6-fluoro-3-methyl-2-morpholino-quinazo lin-4-one (170 mg, 277 μmol, 43%) as a brown solid. m/z ES+ [M+H] ⁺ 614.3. [2238] Step 2. Synthesis of (R)-6-fluoro-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3-methyl-2-morpholinoquinazolin-4(3H) -one [2239] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4-fluoro- anilino]ethyl]-6-fluoro-3-methyl-2-morpholino-quinazolin-4-o ne (150 mg, 244 μmol) in dichloromethane (1.5 mL) was added hydrochloric acid /dioxane (4 M, 3.00 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:50%-80% B over 10 min) to give 6-fluoro-8-[(1R)-1-[4-fluoro-2-(4- hydroxy-1-piperidyl)anilino]ethyl]-3-methyl-2-morpholino-qui nazolin-4-one (84.8 mg, 168 μmol, 69%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.77 - 7.67 (m, 1H), 7.42 (br. d, J = 7.6 Hz, 1H), 6.76 (br. d, J = 8.4 Hz, 1H), 6.59 - 6.44 (m, 1H), 6.21 - 6.03 (m, 1H), 5.35 - 5.14 (m, 1H), 5.04 - 4.76 (m, 1H), 3.99 - 3.81 (m, 5H), 3.63 (s, 3H), 3.35 - 3.22 (m, 5H), 3.19 - 3.07 (m, 1H), 2.89 - 2.77 (m, 1H), 2.75 - 2.61 (m, 1H), 2.23 - 2.03 (m, 2H), 1.81 (br. d, J = 2.0 Hz, 2H), 1.60 (br. d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 500.2. Example 246. Preparation of (R)-2-(3,6-dihydro-2H-pyran-4-yl)-8-(1-((4-fluoro-2- (methylsulfonyl) phenyl)amino)ethyl)-3,6-dimethylquinazolin-4(3H)-one (Compound 469)

[2240] Step 1. Synthesis of (R)-2-(3,6-dihydro-2H-pyran-4-yl)-8-(1-((4-fluoro-2- (methylsulfonyl)phenyl)amino) ethyl)-3,6-dimethylquinazolin-4(3H)-one [2241] To a solution of 8-[(1R)-1-(4-fluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dime thyl-2- methylsulfanyl-quinazolin-4-one (60 mg, 137 μmol) and 3,6-dihydro-2H-pyran-4-ylboronic acid (52.8 mg, 413 μmol) in anhydrous tetrahydrofuran (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (15.9 mg, 13.7 μmol) at 25 °C for 10 min. Then thiophene-2-carbonyloxycopper (34.1 mg, 179 μmol) was added at 25 °C. The mixture was stirred at 60 °C for 12 hr. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (7 mL x 3) mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water (formic acid)- acetonitrile];B%: 49%-71%, 11 min) to give (R)-2-(3,6-dihydro-2H- pyran-4-yl)-8-(1-((4-fluoro-2-(methylsulfonyl)phenyl)amino) ethyl)-3,6-dimethylquinazolin- 4(3H)-one (8.11 mg, 17.2 μmol, 13%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 1.2 Hz, 1 H), 7.46 - 7.52 (m, 2 H), 7.00 - 6.93 (m, 1 H), 6.62 (d, J = 6.8 Hz, 1 H), 6.56 - 6.49 (m, 1 H), 6.15 (d, J = 1.6 Hz, 1 H), 5.47 - 5.38 (m, 1 H), 4.41 - 4.35 (m, 1 H), 4.02 - 3.95 (m, 2 H), 3.65 (s, 3 H), 3.13 (s, 3 H), 2.56 - 2.65 (m, 2 H), 2.42 (s, 3 H), 1.63 (s, 3 H); m/z ES+ [M+H] ⁺ 472.2. Example 247. Preparation of N-(cyanomethyl)-2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4- oxo-quinazolin-8-yl)ethyl]amino]benzamide (Compound 367) [2242] Step 1. Synthesis of N-(cyanomethyl)-2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]amino]benzamide [2243] To a solution of 2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8- yl)ethyl]amino]benzoic acid (90 mg, 213 μmol), 2-aminoacetonitrile (29.6 mg, 320 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) was added triethylamine (86.2 mg, 852 μmol) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (122 mg, 320 μmol) at 0 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875 x 30mm, 3um; mobile phase: [water(formic acid)- acetonitrile]; B%: 46%-66%, 8 min) to give N- (cyanomethyl)-2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo-qu inazolin-8- yl)ethyl]amino]benzamide (50 mg, 108 μmol, 51%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1 H), 7.51 (d, J = 1.6 Hz, 1 H), 7.36 (d, J = 7.2 Hz, 1 H), 7.17 - 7.09 (m, 1 H), 6.70 - 6.41 (m, 1 H), 6.37 - 6.63 (m, 2 H), 5.45 - 5.35 (m, 1 H), 4.40 - 4.32 (m, 2 H), 3.83 - 3.99 (m, 4 H), 3.62 (s, 3 H), 3.22 - 3.39 (m, 4 H), 2.37 (s, 3 H), 1.62 (d, J = 6.4 Hz, 3 H); m/z ES+ [M+H] ⁺ 461.2. Example 248. Preparation of (2S,3S,4S,5R,6S)-6-((2-(((R)-1-(3,6-dimethyl-2-morpholino- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoyl)oxy)-3, 4,5-trihydroxytetrahydro- 2H-pyran-2-carboxylic acid (Compound 652) [2244] Step 1. Synthesis of benzyl (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxytetrahydro-2H- pyran-2-carboxylate [2245] To a solution of (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxytetrahydropyran-2-carbo xylic acid (1.00 g, 5.15 mmol) in N,N-dimethylformamide (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 5.67 mL) and then dropwise addition of (bromomethyl)benzene (925 mg, 5.41 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (50 mL) and then lyophilized to give a residue. The residue was purified by column chromatography (silicon dioxide, dichloromethane/isopropanol = 100/1 to 5/1). The impure product was further triturated in dichloromethane (20 mL), and then filtered. The filtered cake was collected to give benzyl (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxytetrahydropyran-2- carboxylate (0.90 g, 3.17 mmol, 61%) as a white solid. ¹ H NMR (400 MHz, acetone-d ₆ and D2O) δ 7.43 - 7.21 (m, 5H), 5.15 (d, J = 2.8 Hz, 2H), 5.12 (d, J = 3.2 Hz, 0.5H), 4.55 (d, J = 7.6 Hz, 0.5H), 4.31 - 4.24 (m, 0.5H), 3.85 - 3.80 (m, 0.5H), 3.75 - 3.64 (m, 0.5H), 3.61 - 3.50 (m, 1H), 3.48 - 3.37 (m, 1H), 3.26 - 3.14 (m, 0.5H). [2246] Step 2. Synthesis of benzyl (2S,3S,4S,5R,6S)-6-((2-(((R)-1-(3,6-dimethyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oyl)oxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2carboxylate [2247] To a solution of benzyl (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxytetrahydropyran-2- carboxylate (100 mg, 355 μmol) and 2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]amino]benzoic acid (150 mg, 355 μmol) in acetonitrile (3 mL) was added N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (99.6 mg, 355 μmol) and 1-methyl-1H-imidazole (58.3 mg, 710 μmol) at 0 °C. The mixture was stirred at 20 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated (below 30 °C) under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:49%-79% B over 10 min) to give benzyl (2S,3S,4S,5R,6S)-6-[2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4- oxo-quinazolin-8- yl)ethyl]amino]benzoyl]oxy-3,4,5-trihydroxy-tetrahydropyran- 2-carboxylate (100 mg, 108 μmol, 30%) as a white solid. m/z ES+ [M+H] ⁺ 689.3. [2248] Step 3. Synthesis of (2S,3S,4S,5R,6S)-6-((2-(((R)-1-(3,6-dimethyl-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoyl)oxy)-3,4, 5-trihydroxytetrahydro-2H- pyran-2-carboxylic acid [2249] To a solution of palladium on activated carbon (10.0 mg, 10% loading) in isopropanol (5 mL) and anhydrous tetrahydrofuran (5 mL) was added benzyl (2S,3S,4S,5R,6S)-6-[2-[[(1R)- 1-(3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)ethyl]ami no]benzoyl]oxy-3,4,5- trihydroxy-tetrahydropyran-2-carboxylate (100 mg, 145 μmol). The mixture was stirred at 60 °C for 1.5 hr under hydrogen (15 psi) atmosphere. On completion, the reaction mixture was filtered and concentrated (below 30 °C) under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(formic acid)-acetonitrile];gradient:38%-68% B over 9 min) to give (2S,3S,4S,5R,6S)-6-[2-[[(1R)-1-(3,6-dimethyl-2-morpholino-4- oxo-quinazolin- 8-yl)ethyl]amino]benzoyl]oxy-3,4,5-trihydroxy-tetrahydropyra n-2-carboxylic acid (59.9 mg, 100 μmol, 68%) as a white solid. ¹ H NMR (400 MHz, acetone-d6/D2O) δ 7.97 (dd, J = 1.6, 8.0 Hz, 1H), 7.79 (s, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.20 (ddd, J = 1.6, 7.2, 8.4 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 6.52 (t, J = 7.2 Hz, 1H), 5.83 - 5.75 (m, 1H), 5.52 (d, J = 6.8 Hz, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.92 - 3.82 (m, 4H), 3.73 - 3.62 (m, 3H), 3.61 - 3.59 (m, 3H), 3.39 - 3.29 (m, 4H), 2.34 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 599.2. Example 249. Preparation of 7-Fluoro-3,6-dimethyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholi-noquinazolin-4-one (Compound 391) [2250] Step 1. Synthesis of 2-bromo-3-fluoro-4-iodo-aniline [2251] To a solution of 2-bromo-3-fluoro-aniline (10 g, 52.6 mmol) in dimethylsulfoxide (400 mL) was added N-iodosuccinimide (11.8 g, 52.6 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hr. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- bromo-3-fluoro-4-iodo-aniline (12 g, crude) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 - 7.35 (m, 1H), 6.42 - 6.34 (m, 1H), 4.30 (s, 2H); m/z ES+ [M+H] ⁺ 315.9. [2252] Step 2. Synthesis of 2-bromo-3-fluoro-4-methyl-aniline [2253] To a solution of 2-bromo-3-fluoro-4-iodo-aniline (11 g, 34.8 mmol) and methylboronic acid (10.4 g, 174 mmol) in dioxane (110 mL) was added cesium fluoride (15.9 g, 104 mmol) and palladium triphenylphosphane (4.02 g, 3.48 mmol). The mixture was stirred at 80 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 4/1) to give 2-bromo-3-fluoro-4-methyl-aniline (7 g, 31.2 mmol, 89%) as a brown oil. m/z ES+ [M+H] ⁺ 204.0. [2254] Step 3. Synthesis of N-(2-bromo-3-fluoro-4-methyl-phenyl)-2-hydroxyimino- acetamide [2255] To a solution of 2-bromo-3-fluoro-4-methyl-aniline (7 g, 34.3 mmol) and 2,2,2- trichloroethane-1,1-diol (6.81 g, 41.2 mmol) in water (200 mL) was added hydroxylamine hydrochloride (8.58 g, 124 mmol), hydrogen chloride (2 M, 8.40 mL) and anhydrous sodium sulfate (39.0 g, 275 mmol). The mixture was stirred at 70 °C for 12 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=4/1, 20 mL) at 25 °C for 30 min to give N-(2- bromo-3-fluoro-4-methyl-phenyl)-2-hydroxyimino-acetamide (5 g, 16.5 mmol, 47%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.87 (d, J = 2.0 Hz, 1H), 8.15 - 8.09 (m, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.20 - 7.10 (m, 1H), 2.31 (d, J = 2.0 Hz, 3H); m/z ES+ [M+H] ⁺ 275.0. [2256] Step 4. Synthesis of 7-bromo-6-fluoro-5-methyl-indoline-2,3-dione [2257] To a solution of N-(2-bromo-3-fluoro-4-methyl-phenyl)-2-hydroxyimino-acetamid e (5 g, 18.2 mmol) in sulfuric acid (18 mL) was stirred at 80 °C for 0.5 hr. Then the reaction mixture was added to water (100 mL) slowly at 0 °C and adjust to pH = 9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7-bromo-6-fluoro-5- methyl- indoline-2,3-dione (4.5 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.48 (d, J = 6.8 Hz, 1H), 2.31 (d, J = 2.4 Hz, 3H); m/z ES+ [M+H] ⁺ 257.9. [2258] Step 5. Synthesis of 2-amino-3-bromo-4-fluoro-5-methyl-benzoic acid [2259] To a solution of 7-bromo-6-fluoro-5-methyl-indoline-2,3-dione (4.5 g, 17.4 mmol) in sodium hydroxide (2 M, 43.6 mL) was added hydrogen peroxide (12.8 g, 132 mmol, 35% purity). The mixture was stirred at 25 °C for 12 hr. The pH of the mixture was adjusted to pH = 2 by hydrochloric acid (4N), then the mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-3-bromo-4-fluoro-5-methyl-benzoic acid (4 g, 15.2 mmol, 87%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 - 7.75 (m, 1H), 2.23 (s, 3H); m/z ES+ [M+H] ⁺ 248.0. [2260] Step 6. Synthesis of 2-amino-3-bromo-4-fluoro-N,5-dimethyl-benzamide [2261] To a solution of 2-amino-3-bromo-4-fluoro-5-methyl-benzoic acid (4 g, 16.1 mmol) and methanamine;hydrochloride (1.63 g, 24.2 mmol) in N,N-dimethylformamide (40 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethylammonium;hexafluorophosphate (9.20 g, 24.2 mmol) and diisopropylethylamine (10.4 g, 80.6 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-3-bromo-4-fluoro-N,5-dimethyl- benzamide (4 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.13 (d, J = 8.0 Hz, 1H), 6.17 (s, 1H), 5.91 - 4.59 (m, 2H), 2.96 (d, J = 1.2 Hz, 3H), 2.18 (d, J = 1.6 Hz, 3H); m/z ES+ [M+H] ⁺ 261.0. [2262] Step 7. Synthesis of 8-bromo-2-chloro-7-fluoro-3,6-dimethyl-quinazolin-4-one [2263] To a solution of 2-amino-3-bromo-4-fluoro-N,5-dimethyl-benzamide (6 g, 23.0 mmol) in dioxane (65 mL) was added thiocarbonyl dichloride (5.55 g, 48.3 mmol) dropwised at 25 °C. The mixture was stirred at 25 °C for 1 hr, then stirred at 105 °C for 0.5 hr under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give 8-bromo- 2-chloro-7-fluoro-3,6-dim-ethyl-quinazolin-4-one (6.5 g, crude) as a yellow soild. m/z ES+ [M+H] ⁺ 304.9. [2264] Step 8. Synthesis of 8-bromo-7-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one [2265] To a solution of 8-bromo-2-chloro-7-fluoro-3,6-dimethyl-quinazolin-4-one (6 g, 19.6 mmol) in dichloromethane (60 mL) was added morpholine (5.13 g, 58.9 mmol). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (30 mL) at 25 °C for 30 min to give 8-bromo-7-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one (5 g, 10.1 mmol, 51%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 8.0 Hz, 1H), 3.94 - 3.83 (m, 4H), 3.57 (s, 3H), 3.42 - 3.28 (m, 4H), 2.41 (d, J = 1.6 Hz, 3H); m/z ES+ [M+H] ⁺ 356.0. [2266] Step 9. Synthesis of 8-acetyl-7-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one [2267] To a solution of 8-bromo-7-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one (4.8 g, 13.5 mmol) and 1-vinyloxybutane (4.05 g, 40.4 mmol) in n-butyl alcohol (48 mL) was added palladium acetate (303 mg, 1.35 mmol), diisopropylethylamine (5.23 g, 40.4 mmol) and [2-(2- diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (726 mg, 1.35 mmol). The mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere. Then formic acid (647 mg, 13.5 mmol) and water (20 mL) was added to the mixture and stirred at 25 °C for 0.5 hr. The reaction mixture was adjusted to pH = 9 with saturated sodium bicarbonate solution and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-acetyl-7-fluoro-3,6-dimethyl-2-morpholino- quinazolin-4-one (3.1 g, 8.93 mmol, 66%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 - 8.03 (m, 1H), 3.88 - 3.82 (m, 4H), 3.56 (s, 3H), 3.27 - 3.21 (m, 4H), 2.68 (s, 3H), 2.36 (d, J = 1.2 Hz, 3H); m/z ES+ [M+H] ⁺ 320.1. [2268] Step 10. Synthesis of (NE,R)-N-[1-(7-fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl) ethylidene]-2-methyl-propane-2-sulfinamide [2269] To a solution of 8-acetyl-7-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one (1.5 g, 4.70 mmol) and (R)-2-methylpropane-2-sulfinamide (2.85 g, 23.5 mmol) in toluene (20 mL) was added tetraethoxytitanium (5.36 g, 23.5 mmol). The mixture was stirred at 110 °C for 12 hr. The reaction mixture was diluted with anhydrous tetrahydrofuran (30 mL) and poured to water (100 mL), filtered and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (NE,R)-N-[1-(7-fluoro-3,6-dimethyl-2- morpholino-4-oxo-quinazolin-8-yl)ethylidene]-2-methyl-propan e-2-sulfinamide (700 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 423.1. [2270] Step 11. Synthesis of (R)-N-[(1R)-1-(7-fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin- 8-yl)ethyl]-2-methyl-propane-2-sulfinamide [2271] To a mixture of (NE,R)-N-[1-(7-fluoro-3,6-dimethyl-2-morpholino-4-oxo-quinaz olin- 8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (500 mg, 1.18 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere at -78 °C, was added borane dimethyl sulfide complex (10 M, 592 ^L) slowly, the mixture was stirred at -78 °C for 0.5 hr. The mixture was quenched by water (50 mL) at -10 °C. The mixture was stirred at 25 °C for 0.5 hr. Then the mixture was poured in water (50 mL) then extracted with ethyl acetate (60 mL x 2). The organic phase was concentrated in vacuo to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge C18 150 x 50mm, 10um; mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%: 33%-63%, 10 min) to give (R)-N-[(1R)-1- (7-fluoro-3,6-dimethyl-2-morpholino-4-oxo-quinazolin-8-yl)et hyl]-2-methyl-propane-2- sulfinamide (150 mg, 336 μmol, 28%) as a white solid. m/z ES+ [M+H] ⁺ 425.2. [2272] Step 12. Synthesis of 8-[(1R)-1-aminoethyl]-7-fluoro-3,6-dimethyl-2-morpholino- quinazolin-4-one [2273] To a solution of (R)-N-[(1R)-1-(7-fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethyl]-2- methyl-propane-2-sulfinamide (140 mg, 330 μmol) in dioxane (1 mL) was added hydrochloric acid /dioxane (4 M, 1 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give 8- [(1R)-1-aminoethyl]-7-fluoro-3,6-di-methyl-2-morpholino-quin azolin-4-one (80 mg, 250 μmol, 75%) as a white solid. m/z ES+ [M+H] ⁺ 321.2. [2274] Step 13. Synthesis of 7-Fluoro-3,6-dimethyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholi-noquinazolin-4-one [2275] To a solution of 8-[(1R)-1-aminoethyl]-7-fluoro-3,6-dimethyl-2-morpholino- quinazolin-4-one (80 mg, 250 μmol) in dimethyl acetamide (2 mL) was added cesium carbonate (244 mg, 749 μmol) and 1-fluoro-2-methylsulfonyl-benzene (131 mg, 749 μmol). The mixture was stirred at 140 °C for 12 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 48%-78%, 8 min) to give 7-fluoro-3,6-dimethyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-morpholino-quinazolin-4-one (15.7 mg, 33.0 μmol, 13%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.33-7.28 (m, 1H), 7.20 - 6.99 (m, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.72-6.64 (m, 1H), 5.64 - 5.48 (m, 1H), 3.95-3.82 (m, 4H), 3.60 (s, 3H), 3.43 - 3.28 (m, 4H), 3.04 (s, 3H), 2.35 (s, 3H), 1.78 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 475.2. Example 250. Preparation of (R)-2-((1-(6-Methoxy-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 755)

[2276] Step 1. Synthesis of 2-amino-3-bromo-5-methoxybenzoic acid [2277] To a solution of 2-amino-5-methoxy-benzoic acid (20.0 g, 119 mmol) in N,N- dimethylformamide (400 mL) was added N-bromosuccinimide (21.2 g, 119 mmol) portionwise at 0 °C. The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (2000 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 2-amino-3-bromo-5- methoxy-benzoic acid (11.0 g, 44.7 mmol, 37%) as a yellow solid. m/z ES+ [M+H] ⁺ 245.9/247.9 [2278] Step 2. Synthesis of 2-amino-3-bromo-5-methoxy-N-methylbenzamide [2279] To a solution of 2-amino-3-bromo-5-methoxy-benzoic acid (5.50 g, 22.3 mmol) and methanamine (3.08 g, 44.70 mmol, hydrogen chloride salt) in N,N-dimethylformamide (60 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl-ammonium hexafluorophosphate (10.3 g, 26.8 mmol) and diisopropylethylamine (11.5 g, 89.41 mmol, 15.5 mL). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 2-amino-3-bromo-5- methoxy-N-methyl-benzamide (6.00 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 259.0/261.0 [2280] Step 3. Synthesis of 8-bromo-2-chloro-6-methoxy-3-methylquinazolin-4(3H)-one [2281] To a solution of 2-amino-3-bromo-5-methoxy-N-methyl-benzamide (5.50 g, 21.2 mmol) in dioxane (55 mL) was added thiocarbonyl dichloride (5.13 g, 44.5 mmol) dropwise at 25 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 1 hr and then stirred at 105 °C for 0.5 hr under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give 8-bromo-2-chloro-6-methoxy-3-methyl-quinazolin-4-one (7.00 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 302.9/304.9. [2282] Step 4. Synthesis of 8-bromo-6-methoxy-3-methyl-2-morpholinoquinazolin-4(3H)- one [2283] To a solution of 8-bromo-2-chloro-6-methoxy-3-methyl-quinazolin-4-one (7.00 g, 23.0 mmol) in dichloromethane (70 mL) was added morpholine (6.03 g, 69.1 mmol, 6.09 mL). The mixture was stirred at 40 °C for 12 hr. The reaction mixture was diluted with aqueous hydrochloric acid (0.5 M, 100 mL) and extracted with dichloromethane (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-6-methoxy-3-methyl-2- morpholino-quinazolin-4-one (6.50 g, 18.3 mmol, 80%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 3.95 – 3.85 (m, 7H), 3.59 (s, 3H), 3.31 (t, J = 4.8 Hz, 4H); m/z ES+ [M+H] ⁺ 354.0/356.0 [2284] Step 5. Synthesis of 8-acetyl-6-methoxy-3-methyl-2-morpholinoquinazolin-4(3H)- one [2285] To a solution of 8-bromo-6-methoxy-3-methyl-2-morpholino-quinazolin-4-one (4.00 g, 11.2 mmol) in toluene (40 mL) was added dichloropalladium triphenylphosphane (396 mg, 564 μmol) and tributyl(1-ethoxyvinyl)stannane (10.2 g, 28.2 mmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction was quenched with saturated potassium fluoride solution (400 mL) at 25 °C and stirred at 25 °C for 2 hr. The mixture was then filtered and the filtrate was extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in dichloromethane (20 mL), and hydrochloric acid (1 M, 40 mL) was added. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was neutralized to pH = 9 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (petroleum ether/ethyl acetate=4/1, 30 mL) at 25 °C for 30 min to give 8-acetyl-6-methoxy-3-methyl-2-morpholino-quinazolin-4-one (2.90 g, 9.14 mmol, 81%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 3.2 Hz, 1H), 7.63 (d, J = 3.2 Hz, 1H), 3.95 - 3.85 (m, 7H), 3.61 (s, 3H), 3.23 (t, J = 4.8 Hz, 4H). 2.84 (s, 3H); m/z ES+ [M+H] ⁺ 318.1. [2286] Step 6. Synthesis of (R)-N-(1-(6-methoxy-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide [2287] To a solution of 8-acetyl-6-methoxy-3-methyl-2-morpholino-quinazolin-4-one (2.90 g, 9.14 mmol) and (R)-2-methylpropane-2-sulfinamide (3.32 g, 27.4 mmol) in anhydrous tetrahydrofuran (29 mL) was added tetraethoxytitanium (8.34 g, 36.5 mmol). The mixture was stirred at 75 °C for 12 hr under nitrogen atmosphere. The reaction mixture was poured into water (200 mL), then stirred at 25 °C for 0.5 hr and filtered. The filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (150 mL x 3), then washed with brine (150 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-N-(1-(6-methoxy-3-methyl-2-morpholino-4- oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2 -sulfinamide (3.20 g, 7.61 mmol, 83%) as a yellow solid. m/z ES+ [M+H] ⁺ 421.2. [2288] Step 7. Synthesis of (R)-N-((R)-1-(6-methoxy-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [2289] To a solution of (R)-N-(1-(6-methoxy-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (3.00 g, 7.13 mmol) in anhydrous tetrahydrofuran (30 mL) was added borane dimethyl sulfide complex (10 M in tetrahydrofuran, 3.57 mL) dropwise at -78 °C and the mixture was stirred at -78 °C for 0.5 hr under nitrogen atmosphere. Then the mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched by methanol (60 mL) dropwise at -20 °C for 0.5 hr. Then the mixture was stirred at 25 °C for 0.5 h and concentrated in vacuo to give a residue. The crude product was purified by prep-HPLC (column: Kromasil Eternity XT 250*80mm*10um;mobile phase: [water(ammonium hydroxide)- acetonitrile];gradient:29%-59% B over 20 min) to give (R)-N- ((R)-1-(6-methoxy-3-methyl-2-morpholino-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (1.30 g, 3.08 mmol, 43%) as a yellow solid. m/z ES+ [M+H] ⁺ 423.3. [2290] Step 8. Synthesis of (R)-8-(1-aminoethyl)-6-methoxy-3-methyl-2- morpholinoquinazolin-4(3H)-one [2291] To a solution of (R)-N-((R)-1-(6-methoxy-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 3.08 mmol) in dichloromethane (5 mL) was added hydrochloric acid/dioxane (4 M, 10 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was then diluted with water (50 mL) and neutralized to pH = 9 with aqueous sodium bicarbonate solution. Which was further extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)- 6-methoxy-3-methyl-2-morpholinoquinazolin-4(3H)-one (900 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 319.3. [2292] Step 9. Synthesis of (R)-2-((1-(6-methoxy-3-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2293] To a solution of (R)-8-(1-aminoethyl)-6-methoxy-3-methyl-2-morpholinoquinazol in- 4(3H)-one (200 mg, 628 μmol) and 2-iodobenzoic acid (311 mg, 1.26 mmol) in dioxane (4 mL) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert -butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (24.9 mg, 31.4 μmol) and cesium carbonate (614 mg, 1.88 mmol). The mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:45%-65% B over 10 min ) to give (R)-2-((1-(6- methoxy-3-methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (115 mg, 264 μmol, 42% ) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.17 (br. s, 1H), 8.01 - 7.95 (m, 1H), 7.49 (d, J = 2.8 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.24 - 7.16 (m, 1H), 6.56 (t, J = 7.2 Hz, 1H), 6.43 (d, J = 8.8 Hz, 1H), 5.46 (q, J = 6.4 Hz, 1H), 3.95 - 3.89 (m, 4H), 3.84 (s, 3H), 3.65 (s, 3H), 3.33 - 3.26 (m, 4H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 439.2. Example 251. Preparation of (R)-2-((1-(3-methyl-2-morpholino-4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoic acid (Compound 760)

[2294] Step 1. Synthesis of 2-amino-N-methyl-5-(trifluoromethyl)benzamide [2295] To a mixture of 2-amino-5-(trifluoromethyl)benzoic acid (10.0 g, 48.8 mmol) and methanamine (4.54 g, 67.3 mmol, hydrogen chloride salt) in N,N-dimethylformamide (100 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl ammonium;hexafluorophosphate (29.7 g, 78.0 mmol) and diisopropylethylamine (25.2 g, 195 mmol), then the mixture was stirred at 20 °C for 1 hr. On completion, the reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (30 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 2-amino-N-methyl-5-(trifluoromethyl)benzamide (10.0 g, 45.8 mmol, 94%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 6.09 (s, 1H), 5.39 (br. s, 2H), 2.67 (d, J = 4.8 Hz, 3H). [2296] Step 2. Synthesis of 2-amino-3-bromo-N-methyl-5-(trifluoromethyl)benzamide [2297] To a mixture of 2-amino-N-methyl-5-(trifluoromethyl)benzamide (10.0 g, 45.8 mmol) in dichloromethane (50 mL) was added bromine (14.7 g, 91.7 mmol) portionwise at 0 °C, then the mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was slowly quenched with ice-cold saturated sodium thiosulfate aqueous solution (100 mL) and extracted with petroleum ether (30 mL x 3). The combined extracts were washed with water (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 2-amino-3-bromo-N-methyl-5- (trifluoromethyl)benzamide (9.00 g, 30.3 mmol, 66%) as a yellow solid; m/z ES+ [M+H] ⁺ 296.9/298.9. [2298] Step 3. Synthesis of 8-bromo-2-chloro-3-methyl-6-(trifluoromethyl)quinazolin- 4(3H)-one [2299] To a mixture of 2-amino-3-bromo-N-methyl-5-(trifluoromethyl)benzamide (9.00 g, 30.3 mmol) in dioxane (90 mL) was added thiocarbonyl dichloride (6.97 g, 60.6 mmol) dropwise at 0 °C. The mixture was then stirred at 0 °C for 0.5 hr. Then the mixture was stirred at 105 °C for 0.5 hr under nitrogen atmosphere. On completion, the mixture was cooled down and then concentrated in vacuo to give 8-bromo-2-chloro-3-methyl-6- (trifluoromethyl)quinazolin-4-one (8.00 g, 23.4 mmol, 77%) as a white solid; m/z ES+ [M+H] ⁺ 342.8. [2300] Step 4. Synthesis of 8-bromo-3-methyl-2-morpholino-6-(trifluoromethyl)quinazolin- 4(3H)-one [2301] To a mixture of 8-bromo-2-chloro-3-methyl-6-(trifluoromethyl)quinazolin-4-on e (8.00 g, 23.4 mmol) in dichloromethane (40 mL) was added morpholine (10.2 g, 117 mmol), then the mixture was stirred at 40 °C for 16 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,15 um);mobile phase: [water(formic acid)- acetonitrile];gradient:45%-75% B over 18 min) to give 8-bromo-3-methyl-2- morpholino-6-(trifluoromethyl)quinazolin-4-one (7.00 g, 17.9 mmol, 76%) as a white solid. m/z ES+ [M+H] ⁺ 392.0/394.0. [2302] Step 5. Synthesis of 8-acetyl-3-methyl-2-morpholino-6-(trifluoromethyl)quinazolin - 4(3H)-one [2303] To a mixture of 8-bromo-3-methyl-2-morpholino-6-(trifluoromethyl)quinazolin- 4-one (3.00 g, 7.65 mmol) and 1-vinyloxybutane (2.30 g, 23.0 mmol) in n-butanol (40 mL) was added [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (412 mg, 765 μmol), diacetoxypalladium (172 mg, 765 μmol) and N-ethyl-N-isopropyl-propan-2-amine (2.97 g, 23.0 mmol). Then the mixture was stirred at 95 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was re-dissolved in n-butanol (40 mL) and then hydrochloric acid (1 M, 7.29 mL) was added. The mixture was stirred at 20 °C for 1 hr. On completion, the reaction mixture was neutralized with saturated sodium bicarbonate solution to pH = 8, then washed with water (100 mL) and petroleum ether (60 mL). The mixture was filtered and the filtered cake was collected and dried in vacuo to give 8-acetyl-3-methyl-2-morpholino-6-(trifluoromethyl)quinazolin -4- one (0.70 g, 1.97 mmol, 27%) as a white solid; m/z ES+ [M+H] ⁺ 356.2. [2304] Step 6. Synthesis of (R)-2-methyl-N-(1-(3-methyl-2-morpholino-4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethylidene)prop ane-2-sulfinamide [2305] To a mixture of 8-acetyl-3-methyl-2-morpholino-6-(trifluoromethyl)quinazolin -4-one (0.70 g, 1.97 mmol) and (R)-2-methylpropane-2-sulfinamide (1.19 g, 9.85 mmol) in anhydrous tetrahydrofuran (10 mL) was added tetraethoxytitanium (2.25 g, 9.85 mmol), then the mixture was stirred at 75 °C for 16 hr. On completion, the reaction mixture was quenched with water 50 mL and extracted with ethyl acetate (30 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give (R)-2- methyl-N-(1-(3-methyl-2-morpholino-4-oxo-6-(trifluoromethyl) -3,4-dihydroquinazolin-8- yl)ethylidene)propane-2-sulfinamide (0.50 g, 1.09 mmol, 55%) as a yellow solid. m/z ES+ [M+H] ⁺ 459.1. [2306] Step 7. Synthesis of (R)-2-methyl-N-((R)-1-(3-methyl-2-morpholino-4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)propane-2 -sulfinamide [2307] To a mixture of (R)-2-methyl-N-(1-(3-methyl-2-morpholino-4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethylidene)prop ane-2-sulfinamide (0.50 g, 1.09 mmol) in anhydrous tetrahydrofuran (10 mL) was added borane dimethyl sulfide complex (10 M in tetrahydrofuran, 545 ^L) dropwise at -78 °C, then the mixture was stirred at -78 ~ -30 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was carefully quenched by methanol (20 mL) at -10 °C and then concentrated in vacuo to give a residue. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18 150*25mm*5um;mobile phase: [water(ammonium bicarbonate)- acetonitrile];gradient:43%-63% B over 10 min) to give (R)-2-methyl-N-((R)-1-(3-methyl-2-morpholino-4-oxo-6-(triflu oromethyl)-3,4- dihydroquinazolin-8-yl)ethyl)propane-2-sulfinamide (300 mg, 647 μmol, 59%) as a white solid. m/z ES+ [M+H] ⁺ 461.1. [2308] Step 8. Synthesis of (R)-8-(1-aminoethyl)-3-methyl-2-morpholino-6- (trifluoromethyl)quinazolin-4(3H)-one [2309] To a mixture of (R)-2-methyl-N-((R)-1-(3-methyl-2-morpholino-4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)propane-2 -sulfinamide (300 mg, 651 μmol) in dichloromethane (2 mL) was added hydrochloric acid/dioxane (4 M, 163 ^L), then the mixture was stirred at 20 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give (R)-8-(1-aminoethyl)-3-methyl-2-morpholino-6- (trifluoromethyl)quinazolin-4(3H)-one (100 mg, 281 μmol, 43%) as a yellow solid. m/z ES+ [M+H] ⁺ 357.1. [2310] Step 9. Synthesis of (R)-2-((1-(3-methyl-2-morpholino-4-oxo-6-(trifluoromethyl)-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2311] To a mixture of (R)-8-(1-aminoethyl)-3-methyl-2-morpholino-6- (trifluoromethyl)quinazolin-4(3H)-one (90.0 mg, 253 μmol) and 2-iodobenzoic acid (313 mg, 1.26 mmol) in dimethyl acetamide (1 mL) was added copper powder (48.2 mg, 758 μmol) and triethylamine (511 mg, 5.05 mmol), then the mixture was stirred at 110 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched with water 50 mL and extracted with ethyl acetate (30 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give (R)-2-((1-(3-methyl-2-morpholino-4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoic acid (33.6 mg, 70.0 μmol, 28%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.22 (br. s, 1H), 8.01 - 7.96 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.24 - 7.19 (m, 1H), 6.61 - 6.58 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.49 - 5.40 (m, 1H), 3.95 - 3.89 (m, 4H), 3.64 (s, 3H), 3.40 - 3.34 (m, 4H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 476.8. Example 252. Preparation of (R)-2-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquin-nazolin-8-yl)ethyl)amino)-N-methylbenzenesulfona mide (Compound 268) [2312] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one [2313] To a solution of 2-amino-3-bromo-N,5-dimethyl-benzamide (3 g, 12.3 mmol) in dimethylsulfoxide (40 mL) was added pyridine-4-carbaldehyde (1.45 g, 13.6 mmol, 1.28 mL). Then the mixture was stirred at 140 °C for 12 hr. On completion, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried with anhydrous anhydrous sodium sulfate, filtered and concentrated in vacuo to give 8-bromo-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one (2 g, crude) as a black solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.85 - 7.81 (m, 1H), 7.57 - 7.54 (m, 2H), 3.51 (s, 3H), 2.50 (s, 3H); m/z ES+ [M+H] ⁺ 331.7. [2314] Step 2. Synthesis of 8-(1-butoxyvinyl)-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one [2315] A solution of 8-bromo-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one (2 g, 6.06 mmol) and 1-vinyloxybutane (1.82 g, 18.1 mmol, 2.34 mL) in n-butyl alcohol (20 mL) was added palladium acetate (136 mg, 606 μmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl- phosphane (326 mg, 606 μmol) and N-ethyl-N-isopropyl-propan-2-amine (2.35 g, 18.2 mmol), then the mixture was stirred at 100 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was concentrated in vacuo to give a residue which was dissolved in n-butyl alcohol (10 mL) was added formic acid (275 mg, 5.72 mmol), then the mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give 8-acetyl-3,6-dimethyl-2- (4-pyridyl)quinazolin-4-one (2.7 g, crude) as a brown solid. m/z ES+ [M+H] ⁺ 294.0. [2316] Step 3. Synthesis of (NZ,R)-N-[1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethylidene]-2-methyl-propane-2-sulfinamide [2317] To a solution of 8-acetyl-3,6-dimethyl-2-(4-pyridyl)quinazolin-4-one (2.7 g, 9.20 mmol) and (R)-2-methylpropane-2-sulfinamide (5.58 g, 46.0 mmol) in anhydrous tetrahydrofuran (30 mL) was added Tetraethyl titanium oxide (10.5 g, 46.0 mmol) then the mixture was stirred at 85 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried with anhydrous anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give (NZ,R)-N-[1-[3,6-dimethyl-4-oxo-2-(4- pyridyl)quinazolin-8-yl]ethylidene]-2-methyl-propane-2-sulfi namide (3.65 g, 8.09 mmol) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 - 8.76 (m, 2H), 8.22 - 8.09 (m, 1H), 7.67 (s, 1H), 7.54 - 7.43 (m, 2H), 3.53 - 3.49 (m, 3H), 2.52 (s, 3H), 1.94 (s, 3H), 1.27 - 1.25 (m, 9H); m/z ES+ [M+H] ⁺ 397.1. [2318] Step 4. Synthesis of (R)-N-[(1R)-1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethyl]-2-methyl-propane-2-sulfinamide [2319] To a solution of (NZ,R)-N-[1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethylidene]-2-methyl-propane-2-sulfinamide (3.65 g, 9.21 mmol) in anhydrous tetrahydrofuran (40 mL) was added sodium borohydride (696 mg, 18.4 mmol) , the mixture was stirred at -40 °C for 3 hr, then the mixture was stirred at 15 °C for 12 hr. On completion, the mixture was quenched by water (200 mL). Then the mixture was poured into water (80 mL) slowly, extracted with ethyl acetate (100 mL x 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250x70mm,10 um);mobile phase: [water( ammonium bicarbonate)-acetonitrile]; B%: 19%-49%, 20 min) to give (R)-N-[(1R)-1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethyl]-2-methyl- propane-2-sulfinamide (3 g, 6.70 mmol, 89%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, J = 4.4 Hz, 2H), 7.58 (d, J = 6.8 Hz, 2H), 7.18 (dd, J = 1.6, 9.6 Hz, 2H), 6.80 (d, J = 6.4 Hz, 1H), 6.41 (d, J = 2.8 Hz, 1H), 5.79 - 5.77 (m, 1H), 4.37 - 4.33 (m, 1H), 3.18 (s, 3H), 3.10 - 3.07 (m, 1H), 2.30 (s, 6H), 2.02 (s, 2H), 1.51 (d, J = 6.8 Hz, 3H), 1.08 (s, 9H); m/z ES+ [M+H] ⁺ 399.3. [2320] Step 5. Synthesis of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-4-yl)quinazolin - 4(3H)-one [2321] To a solution of (R)-N-[(1R)-1-[3,6-dimethyl-4-oxo-2-(4-pyridyl)quinazolin-8- yl]ethyl]-2-methyl-propane-2-sulfinamide (20 mg, 50.2 μmol) in hydrochloric acid/dioxane (0.5 mL) then the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was adjusted to pH = 9 with aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried with anhydrous anhydrous sodium sulfate, filtered and concentrated in vacuo to give (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-4- yl)quinazolin-4(3H)-one (20 mg, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.47 (dt, J = 1.6, 4.0 Hz, 2H), 7.25 - 7.18 (m, 2H), 7.08 - 6.98 (m, 1H), 5.84 (d, J = 2.4 Hz, 1H), 4.04 - 3.95 (m, 1H), 2.96 (d, J = 8.4 Hz, 3H), 2.11 (d, J = 3.2 Hz, 3H), 1.10 (dd, J = 6.4, 18.4 Hz, 3H); m/z ES+ [M+H] ⁺ 280.4. [2322] Step 6. Synthesis of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-4-yl)quinazolin - 4(3H)-one [2323] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(4-pyridyl)quinazolin-4 -one (70 mg, 238 μmol) and 1-fluoro-2-methylsulfonyl-benzene (82.9 mg, 476 μmol) in N,N- dimethylformamide (1 mL) was added cesium carbonate (232 mg, 713 μmol), then the mixture was stirred at 140 °C for 12 hr. On completion, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried with anhydrous anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];B%: 31%-61%,min) to give 3,6-dimethyl-8-[(1R)-1-(2- methylsulfonylanilino)ethyl]-2-(4-pyridyl)quinazolin-4-one (44.50 mg, 99.21 μmol, 42%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 5.6 Hz, 2H), 8.04 (s, 1H), 7.76 - 7.72 (m, 1H), 7.58 - 7.55 (m, 3H), 7.24 - 7.18 (m, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 5.54 - 5.45 (m, 1H), 3.55 (s, 3H), 3.07 (s, 3H), 2.45 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 449.2. Example 253. Preparation of 2-(((R)-1-(3,6-dimethyl-4-oxo-2-((S)-tetrahydrofuran-3-yl)- 3,4-dihydroquinazazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid and 2-(((R)-1-(3,6- dimethyl-4-oxo-2-((R)-tetrahydrofuran-3-yl)-3,4-dihydroquina zolin-8-yl)ethyl)amino)-5- fluorobenzoic acid (Compounds 447 and 448) (single enantiomer with one stereochemistry known and the other arbitrarily assigned) [2324] Step 1. Synthesis of 8-bromo-3,6-dimethyl-2-(tetrahydrofuran-3-yl)quinazolin-4(3H )- one [2325] To a solution of 2-amino-3-bromo-N,5-dimethyl-benzamide (3 g, 12.3 mmol) in ethanol (20 mL) was added tetrahydrofuran-3-carbaldehyde (1.48 g, 14.8 mmol) and iodine (3.13 g, 12.3 mmol), the mixture was degassed and purged with nitrogen (3x), and then the mixture was stirred at 80 °C for 17 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched with saturated sodium sulfite solution (80 mL) and extracted with ethyl acetate (100 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-bromo- 3,6-dimethyl-2-tetrahydrofuran-3-yl-quinazolin-4-one (3.4 g, 9.31 mmol, 75%) as a brown solid. m/z ES+ [M+H] ⁺ 323.0. [2326] Step 2. Synthesis of 8-acetyl-3,6-dimethyl-2-(tetrahydrofuran-3-yl)quinazolin-4(3 H)- one [2327] A mixture of 8-bromo-3,6-dimethyl-2-tetrahydrofuran-3-yl-quinazolin-4-one (3.4 g, 10.5 mmol), 1-vinyloxybutane (10.5 g, 105 mmol), diisopropylethylamine (13.6 g, 105 mmol), palladium acetate (472 mg, 2.1 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]- diphenyl-phosphane (1.13 g, 2.1 mmol) in n-butyl alcohol (34 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was added formic acid (10 mL) stirred at 25 °C for 1 hr, then adjust to pH = 8 by saturated sodium bicarbonate solution, then diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/2) to give 8-acetyl-3,6-dimethyl-2-tetrahydrofuran-3-yl-quinazolin-4-on e (2 g, 5.72 mmol, 54%) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 4.25 - 4.17 (m, 2H), 4.04 - 3.98 (m, 2H), 3.70 - 3.64 (m, 4H), 2.86 (s, 3H), 2.50 - 2.47 (m, 3H), 2.45 - 2.36 (m, 2H); m/z ES+ [M+H] ⁺ 287.1 [2328] Step 3. Synthesis of (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2-tetrahydrofuran-3-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide [2329] A mixture of 8-acetyl-3,6-dimethyl-2-tetrahydrofuran-3-yl-quinazolin-4-on e (1 g, 3.49 mmol), (R)-2-methylpropane-2-sulfinamide (1.69 g, 14 mmol), tetraethoxytitanium (3.98 g, 17.5 mmol) in tetrahydrofuran (12 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by water (40 mL), then filtered and washed with ethyl acetate (40 mL), the filtrate was extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (60 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 0/1) to give (NZ,R)-N-[1-(3,6- dimethyl-4-oxo-2-tetrahydrofuran-3-yl-quinazolin-8-yl)ethyli dene]-2-methyl-propane-2- sulfinamide (1 g, 2.50 mmol, 72%) as brown oil. m/z ES+ [M+H] ⁺ 390.2. [2330] Step 4. Synthesis of (R)-N-((1R)-1-(3,6-dimethyl-4-oxo-2-(tetrahydrofuran-3-yl)-3 ,4- dihydroquin-azolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide [2331] To a mixture of (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2-tetrahydrofuran-3-yl-quina zolin- 8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (540 mg) in tetrahydrofuran (5 mL) was added borane-methyl sulfide complex (10 M, 1.39 mL) at -70 °C, and then the mixture was stirred at -30 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by methanol (50 mL) at 0 °C, and then stirred at 0-20 °C for 0.5 hr. At last, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150 x 50mm, 10um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 28%-58%, 10 min) to give (R)-N-[(1R)-1- (3,6-dimethyl-4-oxo-2-tetrahydrofuran-3-yl-quinazolin-8-yl)e thyl]-2-methyl-propane-2- sulfinamide (90 mg, 227 μmol, 16%) as a white solid. m/z ES+ [M+H]+ 392.2. [2332] Step 5. Synthesis of 8-((R)-1-aminoethyl)-3,6-dimethyl-2-(tetrahydrofuran-3- yl)quinazolin-4(3H)-one [2333] A mixture of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydrofuran-3-yl-qui nazolin-8- yl)ethyl]-2-met-hyl-propane-2-sulfinamide (90 mg, 230 μmol), hydrochloric acid/dioxane (4 M, 3.58 mL) in dichloromethane (3 mL) was stirred at 0 - 20 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25mm, 10um; mobile phase: [water (formic acid)- acetonitrile]; B%: 1%-30%, 9 min) to give 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydrofuran-3-yl-qu inazolin-4-one (45 mg, 154 μmol, 66%) as a white solid. m/z ES+ [M+H]+ 288.2. [2334] Step 6. Synthesis of 2-(((1R)-1-(3,6-dimethyl-4-oxo-2-(tetrahydrofuran-3-yl)-3,4- dihydroquinzolin-8-yl)ethyl)amino)-5-fluorobenzoic acid [2335] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydrofuran-3-yl- quinazolin-4-one (40 mg, 139 μmol) and 5-fluoro-2-iodo-benzoic acid (111 mg, 418 μmol) in dimethyl acetamide (2 mL) was added copper power (8.85 mg, 139 μmol) and triethylamine (282 mg, 2.78 mmol). The mixture was stirred at 110 °C for 2 hr. On completion, the reaction mixture was partitioned between water (15 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with saturated ammonium chloride solution (10 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875 x 30mm, 3um; mobile phase: [water (formic acid)- acetonitrile]; B%: 45%-75%, 7 min) to give 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2- tetrahydrofuran-3-yl-quinazolin-8-yl)ethyl]amino]-5-fluoro-b enzoic acid (33.4 mg, 78.3 μmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.69 - 7.63 (m, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.99 - 6.90 (m, 1H), 6.40 - 6.34 (m, 1H), 5.58 - 5.51 (m, 1H), 4.34 - 4.25 (m, 2H), 4.16 - 4.04 (m, 2H), 3.79 - 3.73 (m, 1H), 3.71 (s, 3H), 2.62 - 2.53 (m, 1H), 2.48 - 2.36 (m, 4H), 1.65 (dd, J = 2.8, 6.8 Hz, 3H); m/z ES+ [M+H]+ 426.2. [2336] Step 7. Chiral purification [2337] 2-(((1R)-1-(3,6-dimethyl-4-oxo-2-(tetrahydrofuran-3-yl)-3,4- dihydroquinazolin-8- yl)ethyl)amino)-5-fluorobenzoic acid (16 mg, 37.6 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mm x 30mm,10um); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 35%-35%,2.3min) to give 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[(3S)- tetrahydrofuran-3-yl]quinazolin-8-yl]ethyl]amino]-5-fluoro-b enzoic acid (5.67 mg, 13.3 μmol, 35%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.57 (dd, J = 3.2, 9.6 Hz, 1H), 7.45 (d, J = 1.2 Hz, 1H), 6.85 - 6.77 (m, 1H), 6.25 (dd, J = 4.4, 9.2 Hz, 1H), 5.44 (q, J = 6.4 Hz, 1H), 4.34 - 4.25 (m, 2H), 4.06 - 3.93 (m, 2H), 3.69 - 3.63 (m, 1H), 3.61 (s, 3H), 2.53 - 2.45 (m, 1H), 2.37 - 2.28 (m, 4H), 1.53 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 426.2; and 2- [[(1R)-1-[3,6-dimethyl-4-oxo-2-[(3R)-tetrahydrofuran-3-yl]qu inazolin-8-yl]ethyl]amino]-5- fluoro-benzoic acid (3.67 mg, 8.63 μmol, 23 %) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.67 (dd, J = 3.2, 9.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.36 (dd, J = 4.2, 9.4 Hz, 1H), 5.54 (q, J = 6.4 Hz, 1H), 4.34 - 4.25 (m, 2H), 4.16 - 4.03 (m, 2H), 3.80 - 3.74 (m, 1H), 3.71 (s, 3H), 2.60 - 2.50 (m, 1H), 2.47 - 2.39 (m, 4H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 426.2. Example 254. Preparation of 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[(3R)-tetrahydropyran-3- yl]quinazolin-8-yl]ethyl]amino]-5-fluoro-benzoic acid and 2-[[(1R)-1-[3,6-dimethyl-4- oxo-2-[(3S)-tetrahydropyran-3-yl]quinazolin-8-yl]ethyl]amino ]-5-fluoro-benzoic acid (Compounds 439 and 440) (single enantiomer with stereochemistry arbitrarily assigned for the other chiral center) [2338] Step 1. Synthesis of tetrahydropyran-3-carbaldehyde [2339] To a solution of tetrahydropyran-3-ylmethanol (4.3 g, 37.0 mmol) in dichloromethane (100 mL) was added Dess-Martin (17.3 g, 40.7 mmol) at 0 °C. The mixture was stirred 0-25 °C for 1 hr. The reaction mixture was quenched by sodium hydroxide (1M, 30 mL), and then diluted with water (30 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 3/1) to give tetrahydropyran-3-carbaldehyde (3.4 g, 29.8 mmol, 80%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 3.95 (dd, J = 3.2, 12.0 Hz, 1H), 3.82 - 3.72 (m, 1H), 3.71 - 3.62 (m, 1H), 3.59 - 3.49 (m, 1H), 2.49 - 2.38 (m, 1H), 2.05 (s, 1H), 1.97 - 1.79 (m, 2H), 1.72- 1.59 (m, 1H). [2340] Step 2. Synthesis of 8-bromo-3,6-dimethyl-2-tetrahydropyran-3-yl-quinazolin-4-one [2341] To a solution of tetrahydropyran-3-carbaldehyde (3.10 g, 27.2 mmol) in ethanol (40 mL) was added iodine (5.74 g, 22.6 mmol) and 2-amino-3-bromo-N,5-dimethyl-benzamide (5.5 g, 22.6 mmol). The mixture was stirred at 80 °C for 12 hr. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25mm, 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 40%-88%, 10min) to give 8-bromo-3,6-dimethyl-2-tetrahydropyran-3-yl- quinazolin-4-one (0.8 g, 2.37 mmol, 10%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.82 (s, 1H), 4.18 (d, J = 11.6 Hz, 1H), 4.05 (d, J = 9.6 Hz, 1H), 3.89 - 3.84 (m, 1H), 3.67 (s, 3H), 3.59-3.54 (m, 1H), 3.15-3.12 (m, 1H), 2.45 (s, 3H), 2.21 - 2.13 (m, 1H), 2.11 - 1.97 (m, 1H), 1.89 - 1.76 (m, 2H); m/z ES+ [M+H] ⁺ 337.0. [2342] Step 3. Synthesis of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-3-yl-quinazolin-4-on e [2343] A mixture of 8-bromo-3,6-dimethyl-2-tetrahydropyran-3-yl-quinazolin-4-one (800 mg, 2.37 mmol), 1-vinyloxybutane (713 mg, 7.12 mmol), palladium acetate (53.3 mg, 237 μmol), [2-(2-diphenylphosphanylphen-oxy)phenyl]-diphenyl-phosphane (128mg, 237 μmol) and diisopropylethylamine (920 mg, 7.12 mmol) in n-butyl alcohol (8 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere. The reaction mixture was added hydrogen chloride (1 M, 5 mL), then the mixture was stirred at 25 °C for 0.5 hr, and then diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 1/1) to give 8-acetyl-3,6-dimethyl-2-tetrahydropyran-3-yl- quinazolin-4-one (460 mg, 1.53 mmol, 64%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 4.22 - 4.11 (m, 1H), 4.10 - 4.02 (m, 1H), 3.78 - 3.70 (m, 2H), 3.69 (s, 3H), 2.86 (s, 3H), 2.48 (s, 3H), 2.03 - 1.67 (m, 5H); m/z ES+ [M+H] ⁺ 301.1. [2344] Step 4. Synthesis of (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl- quinazolin-8-yl)ethylidene]-2-methyl-prop-ane-2-sulfinamide [2345] To a solution of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-3-yl-quinazolin-4-on e (460 mg, 1.53 mmol) in anhydrous tetrahydrofuran (5 mL) was added tetraethoxytitanium (1.75 g, 7.66 mmol) and (R)-2-methylpropane-2-sulfinamide (928 mg, 7.66 mmol). The mixture was stirred at 75 °C for 12 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 1/1) to give (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2- tetrahydropyran-3-yl-quinazolin-8-yl)ethylidene]-2-methyl-pr op-ane-2-sulfinamide (480 mg, 1.19 mmol, 78%) as a white solid. m/z ES+ [M+H] ⁺ 404.2. [2346] Step 5. Synthesis of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide [2347] To a solution of (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl-quina zolin- 8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (430 mg, 1.07 mmol) in anhydrous tetrahydrofuran (25 mL) was added borane-methyl sulfide complex (10 M, 1.07 mL) slowly at -70 °C under nitrogen atmosphere. The mixture was stirred at -60 °C for 1.5 hr. Then was stirred at -30 °C for 0.5 hr. The reaction mixture was quenched by methanol (50 mL) at 0 °C, and then stirred at 0 - 20 °C for 0.5 hr. At last, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was added manganese dioxide (853 mg, 9.81 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 × 25 mm, 5um; mobile phase: [water (ammonia hydroxide v/v)- acetonitrile]; B%: 35%-65%, 9 min) to give (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2- tetrahydropyran-3-yl-quinazolin-8-yl)ethyl]-2-methyl-propane -2-sulfinamide (110 mg, 271 μmol, 27%) as a white solid. m/z ES+ [M+H] ⁺ 406.2. [2348] Step 6. Synthesis of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-3-yl- quinazolin-4-one [2349] To a solution of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (110 mg, 271 μmol) in dioxane (2 mL) was added hydrochloric acid /dioxane (4 M, 2 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was added saturated sodium bicarbonate solution (10 mL), then diluted with water (10 mL) and extracted with dichloromethane (10 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-3-yl- quinazolin-4-one (80 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 302.2. [2350] Step 7. Synthesis of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl- quinazolin-8-yl)ethyl]amino]-5-fluoro-benzoic acid [2351] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-3-yl- quinazolin-4-one (75 mg, 249 μmol) in dimethyl acetamide (2 mL) was added 5-fluoro-2-iodo- benzoic acid (331 mg, 1.24 mmol), copper power (15.8 mg, 249 μmol) and triethylamine (504 mg, 4.98 mmol). The mixture was stirred at 110 °C for 4 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge 150 × 25mm, 5um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 15%-45%, 8 min). to give 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2- tetrahydropyran-3-yl-quinazolin-8-yl)ethyl]amino]-5-fluoro-b enzoic acid (23.1 mg, 49.9 μmol, 20%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.70 - 7.3 (m, 2H), 6.93 (s, 1H), 6.83 - 6.39 (m, 1H), 5.52 (d, J = 6.4 Hz, 1H), 4.30 - 4.17 (m, 1H), 4.08 (dd, J = 3.6, 6.8 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.71 (s, 3H), 3.59 - 3.52 (m, 1H), 3.24 - 3.17 (m, 1H), 2.39 (s, 3H), 2.25 - 2.19 (m, 1H), 2.05 - 1.97 (m, 1H), 1.88 - 1.79 (m, 2H), 1.64 (s, 3H). m/z ES+ [M+H] ⁺ 440.2. [2352] Step 8. Chiral purification [2353] 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl-quinaz olin-8- yl)ethyl]amino]-5-fluoro-benzoic acid (23.1 mg, 49.9 μmol) was purificated by SFC (column: DAICEL CHIRALPAK IC(250mmx30mm,10um);mobile phase: [0.1% ammonium hydroxide ethanol];B%: 35%-35%,4.5min to give 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[(3R)- tetrahydropyran-3-yl]quinazolin-8-yl]ethyl]amino]-5-fluoro-b enzoic acid (4.81 mg, 10.7 μmol, 60%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.51 (s, 1H), 6.98 - 6.85 (m, 1H), 6.42 - 6.31 (m, 1H), 5.55 - 5.42 (m, 1H), 4.23 (d, J = 11.2 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.88 - 3.77 (m, 1H), 3.71 (s, 3H), 3.60 - 3.49 (m, 1H), 3.26 - 3.15 (m, 1H), 2.39 (s, 3H), 2.24 - 2.19 (m, 1H), 2.03 - 1.97 (m, 1H), 1.87 - 1.77 (m, 2H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 440.2; and 2-[[(1R)-1-[3,6-dimethyl-4-oxo-2-[(3S)- tetrahydropyran-3-yl]quinazolin-8-yl]ethyl]amino]-5-fluoro-b enzoic acid (7.79 mg, 16.9 μmol, 95%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.66 (d, J = 6.4 Hz, 1H), 7.51 (s, 1H), 6.97 - 6.85 (m, 1H), 6.42 - 6.31 (m, 1H), 5.57 - 5.41 (m, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.87 - 3.77 (m, 1H), 3.70 (s, 3H), 3.59 - 3.50 (m, 1H), 3.24 - 3.14 (m, 1H), 2.38 (s, 3H), 2.27 - 2.26 (m, 1H), 2.03 - 1.98 (m, 1H), 1.88 - 1.78 (m, 2H), 1.61 (d, J = 5.6 Hz, 3H); m/z ES+ [M+H] ⁺ 440.2. Example 255. Preparation of 8-((R)-1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)- 3,6-dimethyl-2-((R)-tetrahydro-2H-pyran-3-yl)quinazolin-4(3H )-one & 8-((R)-1-((4- fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2- ((S)-tetrahydro-2H- pyran-3-yl)quinazolin-4(3H)-one (Compounds 497 and 498) (one enantiomer with stereochemistry arbitrarily assigned for the other chiral center) [2354] Step 1. Synthesis of tetrahydro-2H-pyran-3-carboxylic acid [2355] To a solution of methyl tetrahydropyran-3-carboxylate (7.70 g, 53.4 mmol) in ethanol (20 mL) was added lithium hydroxide hydrate (8.96 g, 214 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was adjusted to PH = 5 with hydrochloric acid (1M), and then diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tetrahydropyran-3- carboxylic acid (6.6 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 131.1. [2356] Step 2. Synthesis of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)tetrahydro- 2H-pyran-3-carboxamide [2357] To a solution of tetrahydropyran-3-carboxylic acid (1.00 g, 7.68 mmol) in pyridine (10 mL) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (14.7 g, 23.1 mmol, 50% purity) at 0 °C. After addition, the mixture was stirred at this temperature for 0.1 hr, and then 2-amino-3-bromo-N, 5-dimethyl-benzamide (2.24 g, 9.22 mmol) was added at 0 °C. The resulting mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-[2-bromo-4-methyl-6- (methylcarbamoyl)phenyl]tetrahydropyran-3-carboxamide (1.40 g, 3.78 mmol, 49%) as a white solid. m/z ES+ [M+H] ⁺ 355.1. [2358] Step 3. Synthesis of 8-bromo-3,6-dimethyl-2-(tetrahydro-2H-pyran-3-yl)quinazolin- 4(3H)-one [2359] A mixture of N-[2-bromo-4-methyl-6-(methylcarbamoyl)phenyl]tetrahydropyra n-3- carboxamide (1.56 g, 4.39 mmol) and sodium;methanolate (5 M, 2.63 mL) in methanol (15 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 80 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (30 mL) and filtered to give 8-bromo-3,6-dimethyl-2-tetrahydropyran-3-yl- quinazolin-4-one (1.40 g, 4.15 mmol, 95%) as a white solid. m/z ES+ [M+H] ⁺ 337.0. [2360] Step 4. Synthesis of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-3-yl-quinazolin-4-on e [2361] To a solution of 8-bromo-3,6-dimethyl-2-tetrahydropyran-3-yl-quinazolin-4-one (1.10 g, 3.26 mmol), 1-vinyloxybutane (980 mg, 9.79 mmol) in butan-1-ol (11 mL) was added [2- (2-diphenylphosphenylphe-noxy)phenyl]-diphenyl-phosphane (176 mg, 326 μmol), diisopropylethylamine (1.26 g, 9.79 mmol) and palladium(ii) acetate (73.2 mg, 326 μmol). The mixture was stirred at 100 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue which was dissolved in dichloromethane (8 mL), water (8 mL) and methanoic acid (148 mg, 3.09 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was quenched by saturated sodium bicarbonate solution (40 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 1/1) to give 8- acetyl-3,6-dimethyl-2-tetrahydropyran-3-yl-quinazolin-4-one (860 mg, 2.83 mmol, 92%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 4.20 - 4.12 (m, 1H), 4.11 - 3.99 (m, 1H), 3.74 (d, J = 10.4 Hz, 1H), 3.70 (s, 3H), 3.55 - 3.43 (m, 1H), 3.22 - 3.11 (m, 1H), 2.85 (s, 3H), 2.47 (s, 3H), 2.18 (d, J = 12.4 Hz, 1H), 1.93 - 1.71 (m, 3H); m/z ES+ [M+H] ⁺ 301.1. [2362] Step 5. Synthesis of (R)-N-((Z)-1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-3-yl )- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide [2363] To a solution of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-3-yl-quinazolin-4-on e (850 mg, 2.83 mmol) in anhydrous tetrahydrofuran (8.50 mL) was added tetraethoxytitanium (3.23 g, 14.2 mmol) and (R)-2-methylpropane-2-sulfinamide (1.71 g, 14.2 mmol). The mixture was stirred at 75 °C for 3 hr. On completion, the reaction mixture was diluted with anhydrous tetrahydrofuran (30 mL) and poured to water (100 mL), filtered and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide condition) to give (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl-quina zolin-8- yl)ethylidene]-2-methyl-propane-2-sulfinamide (900 mg, 2.09 mmol, 74%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.63 (s, 1H), 4.17 - 4.08 (m, 1H), 4.06 (d, J = 1.2 Hz, 1H), 3.72 - 3.69 (m, 1H), 3.68 (s, 3H), 3.50 - 3.44 (m, 1H), 3.22 - 3.05 (m, 1H), 2.92 - 2.85 (m, 3H), 2.49 (s, 3H), 2.13 (s, 1H), 1.99 - 1.82 (m, 3H), 1.78 (s, 2H), 1.39 - 1.30 (m, 1H), 1.34 (s, 9H); m/z ES+ [M+H] ⁺ 404.2. [2364] Step 6. Synthesis of (R)-N-((1R)-1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-3- yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide [2365] To a solution of (NZ,R)-N-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl-quina zolin- 8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (800 mg, 1.98 mmol) in anhydrous tetrahydrofuran (8 mL) was added borane;tetrahydrofuran (1 M, 9.91 mL). The mixture was stirred at -78 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was quenched by methanol (40 mL) at -78 °C. The organic phase was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water (ammonia hydroxide v/v)- acetonitrile]; B%: 38%-68%,9 min) to give (R)-N- [(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl-quinazoli n-8-yl)ethyl]-2-methyl- propane-2-sulfinamide (210 mg, 518 μmol, 26%) as a white solid. m/z ES+ [M+H] ⁺ 406.2. [2366] Step 7. Synthesis of 8-((R)-1-aminoethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-3- yl)quinazolin-4(3H)-one [2367] To a solution of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-3-yl- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (180 mg, 444 μmol) in dioxane (2 mL) was added hydrochloric acid/dioxane (4 M, 2 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide condition) to give 8-((R)-1-aminoethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-3- yl)quinazolin-4(3H)-one (120 mg, 398 μmol, 90%) as a white solid. m/z ES+ [M+H] ⁺ 302.2. [2368] Step 8. Synthesis of 8-((R)-1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(tetrahydro-2H-pyran-3-yl)quinazolin-4(3H)-one [2369] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-3-yl-qu inazolin- 4-one (110 mg, 365 μmol), 1,4-difluoro-2-methylsulfonyl-benzene (210 mg, 1.09 mmol) and cesium carbonate (297 mg, 912 μmol) in dimethyl acetamide (1 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 140 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water(ammonium bicarbonate)-acetonitrile]; B%: 50%-80%, 10 min) to give 8-((R)-1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl-2- (tetrahydro-2H-pyran-3-yl)quinazolin-4(3H)-one (88.8 mg, 187 μmol, 51%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.57 - 7.43 (m, 2H), 7.05 - 6.92 (m, 1H), 6.71 - 6.41 (m, 2H), 5.57 - 5.32 (m, 1H), 4.20 (d, J = 11.2 Hz, 1H), 4.06 (dd, J = 2.0, 11.6 Hz, 1H), 3.94 - 3.76 (m, 1H), 3.70 (d, J = 2.8 Hz, 3H), 3.62 - 3.46 (m, 1H), 3.15 (d, J = 2.0 Hz, 4H), 3.24 - 3.11 (m, 1H), 2.41 (d, J = 2.4 Hz, 3H), 2.27 - 2.15 (m, 1H), 2.08 - 1.93 (m, 1H), 1.93 - 1.74 (m, 2H), 1.67 - 1.61 (m, 3H); m/z ES+ [M+H] ⁺ 474.2. [2370] Step 9. Chiral purification [2371] The crude product was purified by SFC (column: DAICEL CHIRALCEL OD(250mm x 30mm,10um); mobile phase: [0.1% ammonium hydroxide, IPA];B%: 35%-35%,2.4min) to give 8-((R)-1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl-2-((R)- tetrahydro-2H-pyran-3-yl)quinazolin-4(3H)-one (29.8 mg, 62.8 μmol, 37%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.57 - 7.43 (m, 2H), 7.05 - 6.92 (m, 1H), 6.60 - 6.48 (m, 2H), 5.57 - 5.32 (m, 1H), 4.23 - 4.14 (m, 1H), 4.10 - 4.03 (m, 1H), 3.94 - 3.76 (m, 1H), 3.70 (s, 3H), 3.60 - 3.50 (m, 1H), 3.24 - 3.12 (m, 4H), 2.41 (s, 3H), 2.27 - 2.15 (m, 1H), 2.08 - 1.93 (m, 1H), 1.93 - 1.74 (m, 2H), 1.67 - 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 474.2; and 8-((R)-1-((4-fluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl-2-((S)- tetrahydro-2H-pyran-3-yl)quinazolin-4(3H)-one (29.47 mg, 62.2 μmol, 37%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.56 - 7.43 (m, 2H), 7.03 - 6.91 (m, 1H), 6.56 - 6.44 (m, 2H), 5.50 - 5.40 (m, 1H), 4.23 - 4.14 (m, 1H), 4.10 - 4.03 (m, 1H), 3.84 - 3.75 (m, 1H), 3.71 (s, 3H), 3.56 - 3.45 (m, 1H), 3.24 - 3.12 (m, 4H), 2.40 (s, 3H), 2.27 - 2.15 (m, 1H), 2.09 - 1.97 (m, 1H), 1.89 - 1.74 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 474.2. Example 256. Preparation of (R)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(4-methyltetrahydro-2H -pyran-4-yl)quinazolin- 4(3H)-one (Compound 704) [2372] Step 1. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(4-methyltetrahydro -2H-pyran-4-yl)quinazolin- 4(3H)-one [2373] To a mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-(4-methyltetrahydropyra n-4- yl)quinazolin-4-one (50 mg, 159 μmol) and [1-(2-bromo-5-fluoro-phenyl)-4-piperidyl]oxy- tert-butyl-dimethyl-silane (123 mg, 317 μmol) in dioxane (1 mL) was added 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide3-ch loropyridine dichloropalladium (15.4 mg, 15.9 μmol) and cesium carbonate (155 mg, 476 μmol), then the mixture was stirred at 100 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched with water 30 mL and extracted with ethyl acetate (30 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4- fluoro-anilino]ethyl]-3,6-dimethyl-2-(4-methyltetrahydropyra n-4-yl)quinazolin-4-one (45.0 mg, 72.2 μmol, 46%) as a yellow oil. m/z ES+ [M+H] ⁺ 623.3. [2374] Step 2. Synthesis of (R)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(4-methyltetrahydro-2H -pyran-4-yl)quinazolin- 4(3H)-one [2375] A solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4-fluoro- anilino]ethyl]-3,6-dimethyl-2-(4-methyltetrahydropyran-4-yl) quinazolin-4-one (40.0 mg, 64.2 μmol) in hydrochloric acid/dioxane (1 mL) was stirred at 20 °C for 10 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide conditions) to give (R)-8- (1-((4-fluoro-2-(4-hydroxypiperidin-1-yl)phenyl)amino)ethyl) -3,6-dimethyl-2-(4- methyltetrahydro-2H-pyran-4-yl) [2376] quinazolin-4(3H)-one (14.9 mg, 29.3 μmol, 46%) as a yellow gum. ¹ H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 6.75 (dd, J = 2.8, 10.2 Hz, 1H), 6.55 - 6.50 (m, 1H), 6.19 (dd, J = 8.8, 5.2 Hz, 1H), 5.34 - 5.26 (m, 1H), 4.92 (s, 1H), 4.01 - 3.88 (m, 1H), 3.85 - 3.80 (m, 4H), 3.75 (s, 3H), 3.30 - 3.23 (m, 1H), 3.21 - 3.12 (m, 1H), 2.86 - 2.65 (m, 2H), 2.64 - 2.58 (m, 1H), 2.56 - 2.50 (m, 1H), 2.43 (s, 3H), 2.17 - 2.06 (m, 2H), 1.98 - 1.89 (m, 2H), 1.86 - 1.77 (m, 2H), 1.61 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 509.5. Example 257. Preparation of (R)-8-(1-((4-Fluoro-2-(1-propionylpiperidin-4- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(4-methyltetrahydro-2H -pyran-4-yl)quinazolin- 4(3H)-one (Compound 780) [2377] Step 1. Synthesis of (R)-8-(1-((4-fluoro-2-(1-propionylpiperidin-4- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(4-methyltetrahydro-2H -pyran-4-yl)quinazolin- 4(3H)-one [2378] To a solution of (R)-8-(1-((4-fluoro-2-(piperidin-4-yl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(4-methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H )-one (20.0 mg, 40.6 μmol) and diisopropylethylamine (15.7 mg, 121 μmol) in dichloromethane (1 mL) was added propanoyl chloride (4.88 mg, 52.8 μmol) at 0 °C, the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150x25mmx10um;mobile phase: [water(formic aced)-acetonitrile];gradient:48%-78% B over 10 min) to give (R)-8-(1-((4-fluoro-2-(1-propionylpiperidin-4-yl)phenyl)amin o)ethyl)-3,6- dimethyl-2-(4-methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H )-one (11.0 mg, 20.1 μmol, 49%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.52 (s, 1H), 6.83 - 6.73 (m, 1H), 6.69 - 6.57 (m, 1H), 6.37 - 6.22 (m, 1H), 5.40 - 5.24 (m, 1H), 4.95 - 4.82 (m, 1H), 4.13 - 4.00 (m, 1H), 3.86 - 3.79 (m, 4H), 3.75 (s, 3H), 3.28 - 3.15 (m, 1H), 2.91 - 2.78 (m, 1H), 2.77 - 2.66 (m, 1H), 2.58 - 2.47 (m, 2H), 2.46 - 2.40 (m, 5H), 2.06 - 1.87 (m, 10H), 1.62 (br. s, 3H), 1.20 (t, J = 7.6 Hz, 3H); m/z ES+ [M+H] ⁺ 549.4. Example 258. Preparation of (R)-8-(1-((4-Fluoro-2-(1-(2-hydroxyacetyl)piperidin-4- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(4-methyltetrahydro-2H -pyran-4-yl)quinazolin- 4(3H)-one (Compound 781) [2379] Step 1. Synthesis of (R)-8-(1-((4-fluoro-2-(1-(2-hydroxyacetyl)piperidin-4- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(4-methyltetrahydro-2H -pyran-4-yl)quinazolin- 4(3H)-one [2380] A mixture of (R)-8-(1-((4-fluoro-2-(piperidin-4-yl)phenyl)amino)ethyl)-3, 6-dimethyl- 2-(4-methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (44.0 mg, 89.3 μmol), 2- hydroxyacetic acid (8.15 mg, 107 μmol), [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (50.9 mg, 133 μmol) and diisopropylethylamine (34.6 mg, 267 μmol) in N,N-dimethylformamide (1 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(fomic acid) - acetonitrile];gradient:43%-73% B over 10 min) to give (R)-8-(1-((4- fluoro-2-(1-(2-hydroxyacetyl)piperidin-4-yl)phenyl)amino)eth yl)-3,6-dimethyl-2-(4- methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (39.0 mg, 70.8 μmol, 79%) as an off- white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.52 (m, 1H), 6.85 - 6.73 (m, 1H), 6.65 (br. t, J = 7.2 Hz, 1H), 6.42 - 6.21 (m, 1H), 5.42 - 5.23 (m, 1H), 4.89 - 4.75 (m, 1H), 4.29 - 4.18 (m, 2H), 3.88 - 3.76 (m, 5H), 3.75 (s, 3H), 3.72 - 3.64 (m, 2H), 3.21 (br. t, J = 12.4 Hz, 1H), 2.94 - 2.81 (m, 2H), 2.50 (br. s, 2H), 2.42 (s, 3H), 2.13 - 1.75 (m, 6H), 1.74 - 1.61 (m, 6H); m/z ES+ [M+1] ⁺ 551.4. Example 259. Preparation of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)- tetrahydrofuran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino )benzoic acid (Compound 634)

[2381] Step 1. Synthesis of (R)-N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydrofuran-2-carboxamide [2382] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (3.50 g, 12.8 mmol) and (2R)-tetrahydrofuran-2-carboxylic acid (1.64 g, 14.1 mmol) in pyridine (35 mL) was added 2,4,6-tributyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (27.7 g, 38.4 mmol, 50% purity). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL× 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2R)-N-[2-bromo-6- (cyclopropylcarbamoyl)-4-fluoro-phenyl]tetrahydrofuran-2-car boxamide (5.50 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 371.0/373.0. [2383] Step 2. Synthesis of (R)-8-bromo-3-cyclopropyl-6-fluoro-2-(tetrahydrofuran-2- yl)quinazolin-4(3H)-one [2384] To a solution of (2R)-N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro- phenyl]tetrahydrofuran-2-carboxamide (5.00 g, 13.4 mmol) in acetonitrile (50 mL) was added dichlorozinc (5.51 g, 40.4 mmol) and [dimethyl-(trimethylsilylamino)silyl]methane (5.43 g, 33.6 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL× 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-3-cyclopropyl-6-fluoro-2- [(2R)-tetrahydrofuran-2-yl]quinazolin-4-one (4.20 g, crude) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 2.8, 8.0 Hz, 1H), 7.66 (dd, J = 2.8, 8.0 Hz, 1H), 5.57 (dd, J = 4.0, 7.6 Hz, 1H), 4.08 - 3.99 (m, 1H), 3.96 - 3.86 (m, 1H), 3.15 - 3.00 (m, 1H), 2.71 - 2.56 (m, 1H), 2.28 - 2.13 (m, 2H), 2.02 - 1.93 (m, 1H), 1.33 - 1.22 (m, 2H), 1.12 - 0.98 (m, 1H), 0.79 - 0.72 (m, 1H). [2385] Step 3. Synthesis of (R)-8-acetyl-3-cyclopropyl-6-fluoro-2-(tetrahydrofuran-2- yl)quinazolin-4(3H)-one [2386] A mixture of 8-bromo-3-cyclopropyl-6-fluoro-2-[(2R)-tetrahydrofuran-2- yl]quinazolin-4-one (2.00 g, 5.66 mmol), tributyl(1-ethoxyvinyl)stannane (6.14 g, 16.9 mmol), dichloropalladium triphenylphosphane (397 mg, 566 μmol) in toluene (20 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 130 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by saturated potassium fluoride solution (40 mL) at 25 °C, and stirred at 25 °C for 2 hr. Then the mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (40 mL× 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which dissolved in dichloromethane (20 mL) was added hydrochloric acid (1 M, 20 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was quenched by saturated sodium bicarbonate solution until pH ~ 7 and then extracted with dichloromethane (40 mL× 3). The combined organic layers were washed with brine (40 mL× 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 4/1) to give 8-acetyl-3-cyclopropyl-6- fluoro-2-[(2R)-tetrahydrofuran-2-yl]quinazolin-4-one (1.30 g, 4.00 mmol, 70%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (dd, J = 3.2, 7.6 Hz, 1H), 7.67 (dd, J = 3.2, 8.6 Hz, 1H), 5.55 (dd, J = 4.8, 7.6 Hz, 1H), 3.90 (t, J = 6.9 Hz, 2H), 3.13 - 3.01 (m, 1H), 2.80 (s, 3H), 2.58 - 2.47 (m, 1H), 2.26 - 2.16 (m, 1H), 2.10 - 1.93 (m, 2H), 1.31 - 1.24 (m, 2H), 1.10 - 0.99 (m, 1H), 0.82 - 0.75 (m, 1H); m/z ES+ [M+H] ⁺ 317.0. [2387] Step 4. Synthesis of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydrofura n- 2-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane -2-sulfinamide [2388] A mixture of 8-acetyl-3-cyclopropyl-6-fluoro-2-[(2R)-tetrahydrofuran-2- yl]quinazolin-4-one (1.30 g, 4.11 mmol), (R)-2-methylpropane-2-sulfinamide (1.49 g, 12.3 mmol), tetraethoxytitanium (4.69 g, 20.5 mmol) in anhydrous tetrahydrofuran (13 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 75 °C for 12 hr under nitrogen atmosphere. On completion, the mixture was poured in water (25 mL) and then filtered. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL× 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-N-(1-(3- cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydrofuran-2-yl)-3,4- dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.5 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 420.2. [2389] Step 5. Synthesis of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)- tetrahydrofuran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-me thylpropane-2-sulfinamide [2390] To a solution of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydrofura n-2-yl)- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide (1.30 g, 3.10 mmol) in anhydrous tetrahydrofuran (13 mL) was slowly added borane-dimethyl sulfide complex (10 M in tetrahydrofuran, 929 ^L) under nitrogen atmosphere at -78 °C. The mixture was stirred at -78 °C ~ -30 °C for 1 hr. On completion, the mixture was carefully quenched by methanol (50 mL) at -10 °C, then stirred at 25 °C for 0.5 hr and further concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250x80mmx10um;mobile phase: [water (ammonia hydroxide v/v)-ACN];gradient:32%-62% B over 20 min) to give (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro furan-2- yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide (300 mg, 711 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 2.8, 8.4 Hz, 1H), 7.41 (dd, J = 2.8, 8.8 Hz, 1H), 5.61 (dd, J = 5.4, 7.2 Hz, 1H), 5.03 (q, J = 6.8 Hz, 1H), 4.68 (br. d, J = 6.8 Hz, 1H), 4.09 - 3.93 (m, 2H), 3.20 - 3.08 (m, 1H), 2.70 - 2.57 (m, 1H), 2.35 - 2.16 (m, 2H), 2.12 - 2.02 (m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.40 - 1.30 (m, 2H), 1.24 (s, 9H), 1.18 - 1.11 (m, 1H), 0.93 - 0.82 (m, 1H). [2391] Step 6. Synthesis of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((R)- tetrahydrofuran-2-yl)quinazolin-4(3H)-one [2392] To a solution of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro furan- 2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-su lfinamide (300 mg, 711 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 3.00 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide conditions) to give 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro- 2-((R)-tetrahydrofuran-2-yl)quinazolin-4(3H)-one (200 mg, 623 μmol, 87%) as a white solid. NMR (400 MHz, CDCl ₃ ) δ 7.75 (dd, J = 2.8, 8.4 Hz, 1H), 7.52 (dd, J = 2.8, 9.6 Hz, 1H), 5.66 (dd, J = 4.4, 7.6 Hz, 1H), 4.87 (q, J = 6.8 Hz, 1H), 4.14 - 3.92 (m, 2H), 3.18 - 3.07 (m, 1H), 2.69 - 2.55 (m, 1H), 2.35 - 2.16 (m, 2H), 2.13 - 2.02 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.41 - 1.28 (m, 2H), 1.19 - 1.09 (m, 1H), 0.92 - 0.82 (m, 1H); m/z ES+ [M+H] ⁺ 318.1. [2393] Step 7. Synthesis of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydrofur an- 2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2394] A mixture of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((R)-tetrahydr ofuran-2- yl)quinazolin-4(3H)-one (80.0 mg, 252 μmol), 2-iodobenzoic acid (312 mg, 1.26 mmol), copper (37.3 mg, 587 μmol), triethylamine (510 mg, 5.04 mmol) in dimethyl acetamide (1.5 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL× 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:51%-71% B over 10 min) to give 2-[[(1R)-1-[3-cyclopropyl-6-fluoro-4- oxo-2-[(2R)-tetrahydrofuran-2-yl]quinazolin-8-yl]ethyl]amino ]benzoic acid (21.5 mg, 48.9 μmol, 19%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (br. s, 1H), 8.00 (dd, J = 1.6, 8.0 Hz, 1H), 7.82 - 7.71 (m, 1H), 7.52 - 7.41 (m, 1H), 7.23 - 7.18 (m, 1H), 6.67 - 6.57 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.75 – 5.70 (m, 1H), 5.63 - 5.51 (m, 1H), 4.14 - 3.97 (m, 2H), 3.24 - 3.13 (m, 1H), 2.83 - 2.69 (m, 1H), 2.36 - 2.19 (m, 2H), 2.14 - 2.04 (m, 1H), 1.66 (d, J = 6.6 Hz, 3H), 1.42 - 1.35 (m, 2H), 1.23 - 1.17 (m, 1H), 0.91 (dt, J = 3.6, 7.2 Hz, 1H); m/z ES+ [M+H] ⁺ 438.2. Example 260. Preparation of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)- tetrahydrofuran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino )benzoic acid (Compound 640) [2395] Step 1. Synthesis of (S)-N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydrofuran-2-carboxamide [2396] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (6.00 g, 21.9 mmol) and (2S)-tetrahydrofuran-2-carboxylic acid (3.06 g, 26.3 mmol) in pyridine (60 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (41.9 g, 65.9 mmol, 50% purity) dropwise. The mixture was stirred at 25 °C for 12 hr. On completion, the reaction solution was slowly poured into water (100 mL), resulting in a large amount of precipitate. The precipitate was collected via filtration and dried in vacuo to give (2S)-N-[2-bromo-6- (cyclopropylcarbamoyl)-4-fluoro-phenyl]tetrahydrofuran-2-car boxamide (7.20 g, 17.1 mmol, 78%) as a yellow solid. m/z ES+ [M+H] ⁺ 372.8. [2397] Step 2. Synthesis of (S)-8-bromo-3-cyclopropyl-6-fluoro-2-(tetrahydrofuran-2- yl)quinazolin-4(3H)-one [2398] To a solution of (2S)-N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro- phenyl]tetrahydrofuran-2-carboxamide (7.20 g, 19.4 mmol) in dimethyl acetamide (72 mL) was added [dimethyl-(trimethylsilylamino)silyl]methane (7.83 g, 48.4 mmol) and dichlorozinc (7.93 g, 58.1 mmol) The mixture was stirred at 120 °C for 2 hr. On completion, the reaction mixture was slowly poured into water (300 mL), resulting in a large amount of precipitate. The precipitate was filtered and collected, which was re-dissolved in dichloromethane (300 mL) and stirred at 25 °C for 15 min. The resulting suspension was filtered to remove the residual dichlorozinc and the filtrate was concentrated under reduced pressure to give 8-bromo-3- cyclopropyl-6-fluoro-2-[(2S)-tetrahydrofuran-2-yl]quinazolin -4-one (5.00 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 2.8, 8.0 Hz, 1H), 7.66 (dd, J = 2.8, 8.0 Hz, 1H), 5.57 (dd, J = 3.6, 7.6 Hz, 1H), 4.09 - 3.97 (m, 1H), 3.96 - 3.86 (m, 1H), 3.11 - 3.00 (m, 1H), 2.69 - 2.55 (m, 1H), 2.31 - 2.09 (m, 2H), 2.03 - 1.91 (m, 1H), 1.29 - 1.23 (m, 2H), 1.09 - 0.96 (m, 1H), 0.77 - 0.71 (m, 1H); m/z ES+ [M+H] ⁺ 354.9. [2399] Step 3. Synthesis of (S)-8-acetyl-3-cyclopropyl-6-fluoro-2-(tetrahydrofuran-2- yl)quinazolin-4(3H)-one [2400] To a solution of 8-bromo-3-cyclopropyl-6-fluoro-2-[(2S)-tetrahydrofuran-2- yl]quinazolin-4-one (4.00 g, 11.33 mmol) and tributyl(1-ethoxyvinyl)stannane (6.14 g, 16.99 mmol) in toluene (40 mL) was added dichloropalladium triphenylphosphane (1.59 g, 2.27 mmol). The mixture was stirred at 100 °C for 16 hr under nitrogen. On completion, the reaction mixture was quenched by saturated potassium fluoride solution 200 mL at 25 °C and then stirred at 25 °C for 3 hr, which was further extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was dissolved in dichloromethane (50 mL) was added formic acid (12 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was basified to pH 7~9 with saturated sodium bicarbonate solution (50 mL), and extracted with dichlormethane (100 mL x 3). The combined organic layers were washed with brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give 8- acetyl-3-cyclopropyl-6-fluoro-2-[(2S)-tetrahydrofuran-2-yl]q uinazolin-4-one (4.00 g, 12.4 mmol, 95%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 3.2, 7.6 Hz, 1H), 7.74 (dd, J = 3.2, 8.8 Hz, 1H), 5.63 (dd, J = 5.2, 7.6 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 3.19 - 3.10 (m, 1H), 2.88 (s, 3H), 2.65 - 2.53 (m, 1H), 2.34 - 2.24 (m, 1H), 2.20 - 2.10 (m, 1H), 2.09 - 1.99 (m, 1H), 1.39 - 1.32 (m, 2H), 1.17 - 1.08 (m, 1H), 0.94 - 0.82 (m, 1H); m/z ES+ [M+H] ⁺ 317.2. [2401] Step 4. Synthesis of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydrofura n- 2-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane -2-sulfinamide [2402] To a solution of 8-acetyl-3-cyclopropyl-6-fluoro-2-[(2S)-tetrahydrofuran-2- yl]quinazolin-4-one (4.00 g, 12.6 mmol) and (R)-2-methylpropane-2-sulfinamide (7.66 g, 63.2 mmol) in 2-methyltetrahydrofuran (40 mL) was added tetraethoxytitanium (14.4 g, 63.2 mmol). The mixture was stirred at 85 °C for 12 hr. On completion, the reaction mixture was diluted with water (200 mL) and then filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give (R)-N-(1- (3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydrofuran-2-yl)-3 ,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (5.00 g, 11.7 mmol, 93%) as a yellow solid. m/z ES+ [M+H] ⁺ 420.4. [2403] Step 5. Synthesis of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)- tetrahydrofuran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-me thylpropane-2-sulfinamide [2404] To a solution of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydrofura n-2-yl)- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide (2.00 g, 4.77 mmol) in anhydrous tetrahydrofuran (20 mL) was added borane-dimethyl sulfide complex (10 M in tetrahydrofuran, 2.38 mL) dropwise at -75 °C under nitrogen. After addition, the mixture was warmed to 0 °C and stirred at 0 °C for 2 hr. On completion, the mixture was quenched with methanol (40 mL) slowly and then concentrated in vacuo to give a residue. The residue was purificated by prep-HPLC (column: Waters Xbridge BEH C18 250x50mmx10um;mobile phase: [water(ammonium bicarbonate)-acetonitrile];gradient:35%-65% B over 10 min) to give (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro furan-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (0.64 g, 1.52 mmol, 32%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 2.8, 8.3 Hz, 1H), 7.31 (dd, J = 2.8, 8.8 Hz, 1H), 5.55 (dd, J = 4.8, 7.6 Hz, 1H), 4.98 - 4.82 (m, 2H), 4.03 (q, J = 7.2 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.01 - 2.87 (m, 1H), 2.47 - 2.33 (m, 1H), 2.31 - 2.20 (m, 1H), 2.08 (br dd, J = 6.4, 13.2 Hz, 1H), 2.03 - 1.93 (m, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.30 - 1.23 (m, 2H), 1.16 (s, 9H), 1.04 - 0.98 (m, 1H), 0.89 - 0.81 (m, 1H); m/z ES+ [M+H] ⁺ 422.2. [2405] Step 6. Synthesis of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((S)- tetrahydrofuran-2-yl)quinazolin-4(3H)-one [2406] To a solution of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro furan- 2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-su lfinamide (0.64 g, 1.52 mmol) in dichloromethane (2 mL) was added hydrochloric acid/dioxane (4 M, 1.90 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condidtions) to give 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((S)- tetrahydrofuran-2-yl)quinazolin-4(3H)-one (0.40 g, 1.26 mmol, 83%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.81 (dd, J = 2.8, 8.1 Hz, 1H), 7.55 (dd, J = 2.8, 8.8 Hz, 1H), 5.62 - 5.58 (m, 1H), 4.97 (q, J = 6.8 Hz, 1H), 4.14 - 3.91 (m, 2H), 3.10 - 2.96 (m, 1H), 2.49 - 2.29 (m, 2H), 2.21 - 1.98 (m, 2H), 1.74 (d, J = 6.8 Hz, 3H), 1.41 - 1.29 (m, 2H), 1.12 - 1.04 (m, 1H), 0.99 - 0.92 (m, 1H); m/z ES+ [M+H] ⁺ 318.4. [2407] Step 7. Synthesis of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydrofur an- 2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2408] To a solution of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((S)-tetrahydr ofuran- 2-yl)quinazolin-4(3H)-one (150 mg, 472 μmol) and 2-iodobenzoic acid (586 mg, 2.36 mmol) in dimethyl acetamide (1 mL) was added triethylamine (956 mg, 9.45 mmol, 1.32 mL) and copper powder (90.1 mg, 1.42 mmol). The mixture was stirred at 100 °C for 2 hr under nitrogen. On completion, the reaction mixture was diluted with water 30 mL and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purificated by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:45%-75% B over 11 min) to give 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydrofur an-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (31.4 mg, 71.8 μmol, 15.2%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (br. s, 1H), 7.98 (br. d, J = 7.6 Hz, 1H), 7.75 (dd, J = 2.4, 7.6 Hz, 1H), 7.50 - 7.40 (m, 1H), 7.18 (br. t, J = 8.0 Hz, 1H), 6.59 (t, J = 7.2 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.70 (dd, J = 4.0, 6.8 Hz, 1H), 5.62 - 5.52 (m, 1H), 4.08 - 3.97 (m, 2H), 3.20 - 3.08 (m, 1H), 2.80 – 2.70 (m, 1H), 2.31 - 2.20 (m, 2H), 2.12 - 2.03 (m, 1H), 1.65 (br. d, J = 6.6 Hz, 3H), 1.37 (br. d, J = 5.2 Hz, 2H), 1.26 - 1.20 (m, 1H), 0.93 - 0.88 (m, 1H); m/z ES+ [M+H] ⁺ 438.3. Example 261. Preparation of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)- tetrahydrofuran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino )benzoic acid & 2-(((S)-1- (3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydrofuran-3-yl)-3 ,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Compounds 632 and 633) (single enantiomer with one stereochemistry known and the other arbitrarily assigned) [2409] Step 1. Synthesis of (R)-N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydrofuran-3-carboxamide [2410] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (2.35 g, 8.61 mmol) in pyridine (10 mL) was added 2,4,6-tributyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide (18.6 g, 25.8 mmol) and (3R)-tetrahydrofuran-3-carboxylic acid (1.00 g, 8.61 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was poured into water (200 mL), then stirred at 25 °C for 1 hr and filtered. The filtered cake was concentrated under reduced pressure to give (R)-N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydrofuran-3-carboxamide (1.20 g, 3.23 mmol, 38%) as a white solid. m/z ES+ [M+H] ⁺ 371.0. [2411] Step 2. Synthesis of (S)-8-bromo-3-cyclopropyl-6-fluoro-2-(tetrahydrofuran-3- yl)quinazolin-4(3H)-one [2412] To a solution of (3R)-N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro- phenyl]tetrahydrofuran-3-carboxamide (1.20 g, 3.23 mmol) in acetonitrile (24 mL) was added dichlorozinc (1.32 g, 9.70 mmol) and [dimethyl-(trimethylsilylamino)silyl]methane (1.30 g, 8.08 mmol). The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was poured into water (40 mL), then stirred at 25 °C for 1 hr and filtered. The filtered cake was concentrated under reduced pressure to give 8-bromo-3-cyclopropyl-6-fluoro-2-[(3S)- tetrahydrofuran-3-yl]quinazolin-4-one (1.10 g, 3.11 mmol, 96%) as a white solid. m/z ES+ [M+H] ⁺ 353.0. [2413] Step 3. Synthesis of (S)-8-acetyl-3-cyclopropyl-6-fluoro-2-(tetrahydrofuran-3- yl)quinazolin-4(3H)-one [2414] To a solution of 8-bromo-3-cyclopropyl-6-fluoro-2-[(3S)-tetrahydrofuran-3- yl]quinazolin-4-one (1.10 g, 3.11 mmol) in toluene (11 mL) was added dichloropalladium;triphenylphosphane (219 mg, 311 μmol) and tributyl(1- ethoxyvinyl)stannane (3.37 g, 9.34 mmol) under nitrogen atmosphere. The mixture was stirred at 125 °C for 12 hr. On completion, the reaction mixture was quenched by saturated potassium fluoride solution (100 mL), and then diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL) and then concentrated under reduced pressure to give a residue. The residue was dissolved in dichloromethane (5 mL) was added formic acid (149 mg, 3.11 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was adjusted to pH ~10 with saturated sodium bicarbonate solution. Then it was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 1/1) to give 8-acetyl-3-cyclopropyl-6-fluoro-2-[(3S)-tetrahydrofuran-3- yl]quinazolin-4-one (250 mg, 782 μmol, 25%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 3.2, 7.6 Hz, 1H), 7.75 (dd, J = 3.2, 8.8 Hz, 1H), 4.31 - 4.19 (m, 2H), 4.10 - 3.98 (m, 3H), 3.03 - 2.94 (m, 1H), 2.86 (s, 3H), 2.47 - 2.32 (m, 2H), 1.44 - 1.36 (m, 2H), 0.97 - 0.89 (m, 2H); m/z ES+ [M+H] ⁺ 317.1. [2415] Step 4. Synthesis of 8-(1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((S)-tetrahydrofur an- 3-yl)quinazolin-4(3H)-one [2416] To a solution of 8-acetyl-3-cyclopropyl-6-fluoro-2-[(3S)-tetrahydrofuran-3- yl]quinazolin-4-one (220 mg, 695 μmol) in dichloromethane (15 mL) and methanol (15 mL) was added sodium cyanoboranuide (65.6 mg, 1.04 mmol) and ammonium acetate (804 mg, 10.4 mmol). The mixture was stirred at 60 °C for 1.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give 8-(1-aminoethyl)-3-cyclopropyl- 6-fluoro-2-[(3S)-tetrahydrofuran-3-yl]quinazolin-4-one (170 mg, 504 μmol, 72%) as a white solid. m/z ES+ [M+H] ⁺ 318.2. [2417] Step 5. Synthesis of 2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydrofuran-3 - yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2418] To a solution of 8-(1-aminoethyl)-3-cyclopropyl-6-fluoro-2-[(3S)-tetrahydrofu ran-3- yl]quinazolin-4-one (150 mg, 473 μmol) in dioxane (3 mL) was added 2-iodobenzoic acid (117 mg, 473 μmol), cesium carbonate (462 mg, 1.42 mmol) and [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6-triisopro pylphenyl)phenyl]phosphane (11.3 mg, 14.2 μmol). The mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 3/1 to 0/1) and then re-purified by reversed-phase HPLC (0.1% formic acid condition) to give 2-[1-[3-cyclopropyl-6-fluoro-4-oxo-2-[(3S)-tetrahydrofuran-3 -yl]quinazolin-8- yl]ethylamino]benzoic acid (65.0 mg, 135 μmol, 29%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.75 (br. s, 1H), 8.49 - 8.31 (m, 1H), 7.80 (br. d, J = 7.6 Hz, 1H), 7.61 (br dd, J = 2.8, 8.4 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.22 - 7.10 (m, 1H), 6.52 (br. t, J = 7.2 Hz, 1H), 6.38 (br. d, J = 8.4 Hz, 1H), 5.51 - 5.37 (m, 1H), 4.21 (br. d, J = 4.4 Hz, 2H), 4.06 - 4.00 (m, 1H), 3.99 - 3.87 (m, 2H), 3.05 (br. s, 1H), 2.42 - 2.30 (m, 2H), 1.60 - 1.51 (m, 3H), 1.24 (br. d, J = 6.8 Hz, 2H), 0.92 (br. s, 2H); m/z ES+ [M+H] ⁺ 438.2. [2419] Step 6. Chiral purification [2420] 2-[1-[3-cyclopropyl-6-fluoro-4-oxo-2-[(3S)-tetrahydrofuran-3 -yl]quinazolin-8- yl]ethylamino]benzoic acid (65.0 mg, 135 μmol) was separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm,10um);mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:50%, isocratic elution mode) to give 2-[[(1R)-1-[3-cyclopropyl- 6-fluoro-4-oxo-2-[(3S)-tetrahydrofuran-3-yl]quinazolin-8-yl] ethyl]amino]benzoic acid (21.8 mg, 49.3 μmol, 33%) as a white solid, 1 ^st peak, R.T. 1.72 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (br. s, 1H), 8.00 (br. d, J = 7.6 Hz, 1H), 7.73 (br dd, J = 2.4, 8.0 Hz, 1H), 7.48 - 7.38 (m, 1H), 7.17 (br. t, J = 7.6 Hz, 1H), 6.68 - 6.48 (m, 1H), 6.31 (br. d, J = 8.8 Hz, 1H), 5.50 (br. d, J = 4.8 Hz, 1H), 4.38 - 4.31 (m, 1H), 4.30 - 4.23 (m, 1H), 4.13 (td, J = 7.2, 14.0 Hz, 2H), 4.09 - 4.01 (m, 1H), 3.02 - 2.94 (m, 1H), 2.53 - 2.36 (m, 2H), 1.64 (br. d, J = 6.4 Hz, 3H), 1.43 - 1.35 (m, 2H), 1.01 - 0.92 (m, 2H); m/z ES+ [M+H] ⁺ 438.2; and 2-[[(1S)-1-[3-cyclopropyl-6- fluoro-4-oxo-2-[(3S)-tetrahydrofuran-3-yl]quinazolin-8-yl]et hyl]amino]benzoic acid (27.2 mg, 62.1 μmol, 41%) as a white solid, 2 ^nd peak, R.T. 2.25 min. ¹ H NMR (400 MHz, CDCl3) δ 8.17 (br. s, 1H), 8.00 (dd, J = 1.6, 8.0 Hz, 1H), 7.74 (dd, J = 3.2, 8.4 Hz, 1H), 7.46 (dd, J = 2.8, 9.2 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.54 (br. d, J = 5.2 Hz, 1H), 4.37 - 4.22 (m, 2H), 4.17 - 4.03 (m, 3H), 3.04 - 2.95 (m, 1H), 2.51 - 2.39 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.41 (br. d, J = 6.0 Hz, 2H), 1.05 - 0.94 (m, 2H); m/z ES+ [M+H] ⁺ 438.2. Example 262. Preparation of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro- 2H-pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (Compound 636) [2421] Step 1. Synthesis of (R)-N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydro-2H-pyran-2-carboxamide [2422] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (1.72 g, 6.29 mmol) and (2R)-tetrahydropyran-2-carboxylic acid (900 mg, 6.92 mmol) in pyridine (9 mL) was added 2,4,6-tributyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (13.5 g, 18.8 mmol). The mixture was stirred at 25 °C for 5 hr. On completion, the reaction mixture was slowly poured into water (100 mL) and much solid precipitated. The precipitate was filtered and the solid was collected, concentrated under reduced pressure to give (2R)-N-[2-bromo-6- (cyclopropylcarbamoyl)-4-fluoro-phenyl]tetrahydropyran-2-car boxamide (2.1 g, 5.45 mmol, 86%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.42 (dd, J = 2.8, 7.6 Hz, 1H), 7.20 (dd, J = 2.8, 8.0 Hz, 1H), 6.59 (s, 1H), 4.15 (d, J = 11.0 Hz, 1H), 3.99 - 3.89 (m, 1H), 3.67 - 3.49 (m, 1H), 2.82 (dt, J = 3.6, 7.2 Hz, 1H), 2.12 (d, J = 8.4 Hz, 1H), 1.97 (s, 1H), 1.65 - 1.55 (m, 4H), 0.87 - 0.79 (m, 2H), 0.63 - 0.53 (m, 2H). [2423] Step 2. Synthesis of (R)-8-bromo-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-2- yl)quinazolin-4(3H)-one [2424] To a solution of (2R)-N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro- phenyl]tetrahydropyran-2-carboxamide (1.90 g, 4.93 mmol) in acetonitrile (19 mL) was added dichlorozinc (2.02 g, 14.8 mmol) and [dimethyl-(trimethylsilylamino)silyl]methane (1.99 g, 12.3 mmol). The mixture was stirred at 80 °C for 12 hr. The reaction mixture was partitioned between ethyl acetate (300 mL) and water (100 mL). The organic phase was separated and then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=40/1 to 1 /1) to give 8-bromo-3-cyclopropyl-6- fluoro-2-[(2R)-tetrahydropyran-2-yl]quinazolin-4-one (1.80 g, 4.85 mmol, 98%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (dd, J = 2.8, 8.0 Hz, 1H), 7.73 (dd, J = 2.8, 8.0 Hz, 1H), 4.93 (dd, J = 2.4, 10.4 Hz, 1H), 4.09 (dd, J = 2.0, 11.2 Hz, 1H), 3.63 (dt, J = 2.4, 11.2 Hz, 1H), 3.27 - 3.13 (m, 1H), 2.42 - 2.24 (m, 1H), 2.15 - 2.06 (m, 1H), 2.00 (dd, J = 2.4, 14.0 Hz, 1H), 1.78 - 1.61 (m, 3H), 1.37 - 1.22 (m, 2H), 1.15 - 1.05 (m, 1H), 0.84 - 0.75 (m, 1H). [2425] Step 3. Synthesis of (R)-8-acetyl-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-2 - yl)quinazolin-4(3H)-one [2426] A mixture of 8-bromo-3-cyclopropyl-6-fluoro-2-[(2R)-tetrahydropyran-2- yl]quinazolin-4-one (1.6 g, 4.36 mmol), tributyl(1-ethoxyvinyl)stannane (4.72 g, 13.07 mmol) and dichloropalladium triphenylphosphane (305 mg, 435 μmol) in toluene (16 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 125 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched by saturated potassium fluoride solution (50 mL), and then diluted with water (20 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure to give a residue which was dissolved in dichloromethane (15 mL) was added hydrochloric acid (1 M, 15 mL). The mixture was stirred at 25 °C for 0.5 hr. The mixture was quenched by saturated sodium bicarbonate solution until pH ~ 7. Then the reaction mixture was extracted with dichloromethane (40 mL× 3). The combined organic layers were washed with brine (40 mL× 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=40/1 to 1/1) to give 8-acetyl-3-cyclopropyl-6- fluoro-2-[(2R)-tetrahydropyran-2-yl]quinazolin-4-one (1.40 g, 4.20 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 3.2, 8.0 Hz, 1H), 7.77 (dd, J = 3.2, 8.8 Hz, 1H), 4.94 (dd, J = 2.0, 10.4 Hz, 1H), 4.20 - 4.05 (m, 1H), 3.70 - 3.59 (m, 1H), 3.28 - 3.17 (m, 1H), 2.90 (s, 3H), 2.26 - 2.06 (m, 2H), 1.96 (d, J = 13.6 Hz, 1H), 1.74 - 1.62 (m, 3H), 1.35 - 1.26 (m, 2H), 1.18 - 1.04 (m, 1H), 0.88 - 0.76 (m, 1H). [2427] Step 4. Synthesis of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro-2H- pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylp ropane-2-sulfinamide [2428] To a solution of 8-acetyl-3-cyclopropyl-6-fluoro-2-[(2R)-tetrahydropyran-2- yl]quinazolin-4-one (1.40 g, 4.24 mmol) in anhydrous tetrahydrofuran (15 mL) was added tetraethoxytitanium (4.83 g, 21.1 mmol) and (R)-2-methylpropane-2-sulfinamide (1.54 g, 12.7 mmol). The mixture was stirred at 75 °C for 12 hr. The reaction mixture was quenched by addition water (100 mL) at 25 °C and then filtered. The organic layer in the filtrate was separated and the aqueous layer was further extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (150 mL x 2), dried over sodium sulphate, filtered and concentrated under reduced pressure to give (R)-N-(1-(3-cyclopropyl-6-fluoro-4- oxo-2-((R)-tetrahydro-2H-pyran-2-yl)-3,4-dihydroquinazolin-8 -yl)ethylidene)-2- methylpropane-2-sulfinamide (1.70 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 434.1. [2429] Step 5. Synthesis of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro - 2H-pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide [2430] To a solution of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro-2H- pyran- 2-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane -2-sulfinamide (1.5 g, 3.46 mmol) in anhydrous tetrahydrofuran (15 mL) was added borane-dimethyl sulfide complex (10 M in tetrahydrofuran, 692 ^L) at -78 °C. The mixture was stirred at -78 °C ~ -30 °C for 2 hr under nitrogen atmosphere. The mixture was carefully quenched by methanol (10 mL) at - 10 °C and further stirred at 25 °C for 0.5 hr. Then the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250*80mmx10um;mobile phase: [water(ammonium hydroxide)- acetonitrile];gradient:40%-70% B over 20 min) to give (R)-N-((R)-1-(3-cyclopropyl-6-fluoro- 4-oxo-2-((R)-tetrahydro-2H-pyran-2-yl)-3,4-dihydroquinazolin -8-yl)ethyl)-2-methylpropane- 2-sulfinamide (700 mg, 1.53 mmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 2.8, 8.4 Hz, 1H), 7.38 (dd, J = 2.8, 8.8 Hz, 1H), 4.96 - 4.86 (m, 3H), 4.10 (d, J = 10.8 Hz, 1H), 3.68 - 3.58 (m, 1H), 3.18 - 3.10 (m, 1H), 2.27 - 2.15 (m, 1H), 2.13 - 2.04 (m, 1H), 1.93 (d, J = 13.2 Hz, 1H), 1.76 - 1.67 (m, 3H), 1.65 (d, J = 6.8 Hz, 3H), 1.37 - 1.30 (m, 2H), 1.23 (s, 9H), 1.14 - 1.10 (m, 1H), 0.88 - 0.82 (m, 1H). [2431] Step 6. Synthesis of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((R)-tetrahydr o- 2H-pyran-2-yl)quinazolin-4(3H)-one [2432] To a solution of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro -2H- pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide (700 mg, 1.61 mmol) in dichloromethane (7 mL) was added hydrochloric acid/dioxane (4 M, 7 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was diluted with water (20 mL), ammonium hydroxide (4 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((R)-tetrahydr o-2H-pyran-2- yl)quinazolin-4(3H)-one (400 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.73 (dd, = 2.8, 8.4 Hz, 1H), 7.49 (dd, J = 2.8, 9.6 Hz, 1H), 4.98 - 4.77 (m, 2H), 4.15 - 4.06 (m, 2H), 3.69 - 3.58 (m, 1H), 3.24 - 3.10 (m, 1H), 2.29 - 2.16 (m, 1H), 2.11 - 2.05 (m, 1H), 2.00 - 1.93 (m, 3H), 1.77 - 1.61 (m, 3H), 1.49 (d, J = 6.8 Hz, 3H), 1.38 - 1.29 (m, 1H), 1.16 - 1.06 (m, 1H), 0.86 - 0.74 (m, 1H). [2433] Step 7. Synthesis of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro-2H - pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2434] To a solution of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((R)-tetrahydr o-2H- pyran-2-yl)quinazolin-4(3H)-one (100 mg, 301 μmol) and 2-iodobenzoic acid (149 mg, 603 μmol) in dioxane (2 mL) was added cesium carbonate (294 mg, 905 μmol) and [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl -[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (23.9 mg, 30.1 μmol). The mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was separated, then washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=40/1 to 1 /1) to give 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2- ((R)-tetrahydro-2H-pyran-2-yl)-3,4-dihydroquinazolin-8-yl)et hyl)amino)benzoic acid (35.5 mg, 78.7 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 11.28 (br. s, 1H), 8.15 (br. s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 2.4, 8.0 Hz, 1H), 7.44 (dd, J = 2.4, 8.8 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 8.8 Hz, 1H), 5.57 (d, J = 5.6 Hz, 1H), 4.96 (d, J = 9.6 Hz, 1H), 4.15 (d, J = 9.2 Hz, 1H), 3.68 (t, J = 11.2 Hz, 1H), 3.25 (d, J = 3.6 Hz, 1H), 2.35 - 2.22 (m, 1H), 2.13 - 2.01 (m, 2H), 1.78 - 1.62 (m, 6H), 1.36 - 1.26 (m, 2H), 1.13 (dt, J = 6.0, 10.4 Hz, 1H), 0.87 (dd, J = 5.2, 9.2 Hz, 1H); m/z ES+ [M+H] ⁺ 452.2. Example 263. Preparation of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro- 2H-pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (Compound 655)

[2435] Step 1. Synthesis of (S)-N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydro-2H-pyran-2-carboxamide [2436] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (5.00 g, 18.3 mmol) in pyridine (50 mL) was added (2S)-tetrahydropyran-2-carboxylic acid (2.86 g, 21.9 mmol) and 2,4,6-tributyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (39.5 g, 54.9 mmol, 50% purity). The mixture was stirred at 25 °C for 12 hr. On completion, the mixture was poured into water (200 mL) and filtered. The filtered cake was concentrated to give (S)-N-(2-bromo-6- (cyclopropylcarbamoyl)-4-fluorophenyl)tetrahydro-2H-pyran-2- carboxamide (4.70 g, 11.9 mmol, 65%) as a white solid. m/z ES+ [M+H] ⁺ 384.9/386.8. [2437] Step 2. Synthesis of (S)-8-bromo-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-2- yl)quinazolin-4(3H)-one [2438] To a solution of (S)-N-(2-bromo-6-(cyclopropylcarbamoyl)-4- fluorophenyl)tetrahydro-2H-pyran-2-carboxamide (4.70 g, 12.2 mmol) in dimethyl acetamide (50 mL) was added [dimethyl-(trimethylsilylamino)silyl]methane (4.92 g, 30.5 mmol) and zinc chloride (4.99 g, 36.6 mmol), the mixture was stirred at 120 °C for 2 hr. On completion, the mixture was diluted with water (200 mL) and filtered. The filtered cake was collected, which was further triturated in dichloromethane (300 mL) for 15 min. The mixture was then filtered and the filtrated was concentrated to give 8-bromo-3-cyclopropyl-6-fluoro-2-[(2S)- tetrahydropyran-2-yl]quinazolin-4-one (3.80 g, 10.1 mmol, 83%) as a yellow solid. m/z ES+ [M+H] ⁺ 367.2/369.2. [2439] Step 3. Synthesis of (S)-8-acetyl-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H-pyran-2 - yl)quinazolin-4(3H)-one [2440] To a solution of 8-bromo-3-cyclopropyl-6-fluoro-2-[(2S)-tetrahydropyran-2- yl]quinazolin-4-one (3.80 g, 10.3 mmol) in toluene (50 mL) was added dichloropalladium triphenylphosphane (726 mg, 1.03 mmol) and tributyl(1-ethoxyvinyl)stannane (7.47 g, 20.7 mmol) at 25 °C, the mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by saturated potassium fluoride solution (400 mL) at 25 °C and then stirred at 25 °C for 3 hr, which was further diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-cyclopropyl-8-(1-ethoxyvinyl)-6-fluoro-2-[(2S)-tetrahydrop yran-2-yl]quinazolin-4- one (3.80 g, crude) as a yellow solid. To the above crude material in dichloromethane (40 mL) was added formic acid (4.88 g, 106 mmol), the mixture was stirred at 25 °C for 2 hr. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 4/1) to give 8-acetyl-3-cyclopropyl-6-fluoro-2- [(2S)-tetrahydropyran-2-yl]quinazolin-4-one (2.90 g, 8.67 mmol, 82%) as a yellow solid. m/z ES+ [M+H] ⁺ 331.0. [2441] Step 4. Synthesis of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H- pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylp ropane-2-sulfinamide [2442] To a solution of 8-acetyl-3-cyclopropyl-6-fluoro-2-[(2S)-tetrahydropyran-2- yl]quinazolin-4-one (2.90 g, 8.78 mmol) in anhydrous tetrahydrofuran (50 mL) was added (R)- 2-methylpropane-2-sulfinamide (5.32 g, 43.8 mmol) and tetraethoxytitanium (10.0 g, 43.8 mmol), the mixture was stirred at 85 °C for 16 hr. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 3/1) to give (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H- pyran-2-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (3.10 g, 7.01 mmol, 80%) as a yellow solid. m/z ES+ [M+H] ⁺ 434.2. [2443] Step 5. Synthesis of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro - 2H-pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide [2444] To a solution of (R)-N-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H- pyran- 2-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane -2-sulfinamide (2.80 g, 6.46 mmol) in anhydrous tetrahydrofuran (30 mL) was added borane-dimethyl sulfide complex (10 M in tetrahydrofuran, 3.23 mL) dropwise at -75 °C. After addition completed, the mixture was stirred at 0 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was carefully quenched with methanol (50 mL) and then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC [column: Phenomenex luna C18 (250x70mm,10 um);mobile phase: [water(ammonium bicarbonate)-acetonitirle];gradient:50%-80% B over 20 min] to give (R)-N- ((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H-py ran-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 3.31 mmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (dd, J = 2.8, 8.0 Hz, 1H), 7.31 (dd, J = 2.8, 8.4 Hz, 1H), 4.85 (d, J = 9.6 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.55 - 3.48 (m, 1H), 3.10 - 3.00 (m, 1H), 2.15 - 1.95 (m, 2H), 1.90 - 1.80 (m, 1H), 1.70 - 1.55 (m, 5H), 1.25 - 1.15 (m, 2H), 1.13 (s, 9H), 1.10 - 1.05 (m, 1H), 0.80 - 0.74 (m, 1H); m/z ES+ [M+H] ⁺ 436.2. [2445] Step 6. Synthesis of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((S)-tetrahydr o- 2H-pyran-2-yl)quinazolin-4(3H)-one [2446] To a solution of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro -2H- pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide (1.50 g, 3.44 mmol) in dichloromethane (20 mL) was added hydrochloric acid/dioxane (4 M, 4.30 mL), the mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by reversed-phase HPLC ([water(0.1% formic acid)- acetonitrile; gradient:15%-20%], 30 min) to give 8-((R)-1-aminoethyl)-3-cyclopropyl-6- fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)quinazolin-4(3H)-one (1.10 g, 2.89 mmol, 84%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (dd, J = 2.8, 8.0 Hz, 1H), 7.50 (dd, J = 2.8, 8.8 Hz, 1H), 5.00 – 4.85 (m, 2H), 4.10 (d, J = 10.8 Hz, 1H), 3.62 (t, J = 11.2 Hz, 1H), 3.20 - 3.10 (m, 1H), 2.15 - 1.90 (m, 3H), 1.80 - 1.57 (m, 6H), 1.36 - 1.22 (m, 2H), 1.13 - 1.05 (m, 1H), 0.90 - 0.80 (m, 1H); m/z ES+ [M+H] ⁺ 332.1 [2447] Step 7. Synthesis of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H - pyran-2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2448] A mixture of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-((S)-tetrahydr o-2H- pyran-2-yl)quinazolin-4(3H)-one (100 mg, 301 μmol), 2-iodobenzoic acid (134 mg, 543 μmol), methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl -1,1'-biphenyl)(2'-amino-1,1'- biphenyl-2-yl)palladium(II) (tBuXPhos Pd G3) (23.9 mg, 30.1 μmol) and cesium carbonate (294 mg, 905 μmol) in dioxane (3 mL) was stirred at 90 °C for 16 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC [column: Welch Ultimate C18150*25mmx5um;mobile phase: [water(formic acid)-acetonitrile];gradient:54%- 84% B over 11 min] and then re-purified by prep-HPLC [column: Waters xbridge 150*25mm 10um;mobile phase: [water(ammonium bicarbonate)-acetonitrile];gradient:14%-44% B over 10 min] to give 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H -pyran-2-yl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (27.7 mg, 60.8 μmol, 20%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.18 (br. s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 2.8, 8.0 Hz, 1H), 7.46 (dd, J = 2.8, 9.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.61 (d, J = 5.2 Hz, 1H), 4.98 (dd, J = 10.4, 2.0 Hz, 1H), 4.14 (d, J = 10.4 Hz, 1H), 3.68 (t, J = 10.8 Hz, 1H), 3.30 - 3.20 (m, 1H), 2.35 - 2.25 (m, 1H), 2.15 – 2.00 (m, 2H), 1.85 – 1.60 (m, 6H), 1.40 – 1.25 (m, 2H), 1.24 – 1.15 (m, 1H), 0.95 – 0.85 (m, 1H); m/z ES+ [M+H] ⁺ 452.4. Example 264. Preparation of 2-(2-(3-cyclopropyl-6-fluoro-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)cyclopropyl)benzoic acid (Compound 764) [2449] Step 1. Synthesis of 8-bromo-2-chloro-3-cyclopropyl-6-fluoro-quinazolin-4-one [2450] To a solution of 2-amino-3-bromo-N-cyclopropyl-5-fluoro-benzamide (45.6 g, 166 mmol) in dioxane (450 mL) was added thiocarbonyl dichloride (40.3 g, 350 mmol) at 25 °C under nitrogen atmosphere, and stirred at 25 °C for 0.5 hr, then the mixture was stirred at 105 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether/ethyl acetate=5/1 (200 mL) at 25 °C for 30 min to give 8-bromo-2-chloro-3-cyclopropyl-6-fluoro-quinazolin-4-one (47.3 g, 148 mmol, 89%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 2.8, 8.0 Hz, 1H), 7.76 (dd, J = 2.8, 7.6 Hz, 1H), 3.10 - 2.96 (m, 1H), 1.43 - 1.35 (m, 2H), 1.04 - 0.96 (m, 2H). [2451] Step 2. Synthesis of 8-bromo-3-cyclopropyl-6-fluoro-2-morpholinoquinazolin-4(3H)- one [2452] To a solution of 8-bromo-2-chloro-3-cyclopropyl-6-fluoro-quinazolin-4-one (2.60 g, 8.19 mmol) in dichloromethane (52 mL) was added morpholine (3.57 g, 40.9 mmol), then the reaction mixture was stirred at 40 °C for 12 hr. The reaction mixture was partitioned between ethyl acetate 200 mL and water 50 mL. The organic phase was separated, washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether/ethyl acetate=5/1 (20 mL) at 25 °C for 30 min to give 8-bromo-3-cyclopropyl-6-fluoro-2- morpholino-quinazolin-4-one (2.30 g, 5.81 mmol, 70%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (dd, J = 2.8, 8.4 Hz, 1H), 7.67 (dd, J = 2.8, 8.0 Hz, 1H), 3.97 - 3.83 (m, 4H), 3.61 - 3.52 (m, 4H), 3.13 - 3.03 (m, 1H), 1.32 - 1.25 (m, 2H), 0.92 - 0.83 (m, 2H). [2453] Step 3. Synthesis of methyl (E)-2-(2-(3-cyclopropyl-6-fluoro-2-morpholino-4-oxo- 3,4-dihydroquinazolin-8-yl)vinyl)benzoate [2454] To a solution of 8-bromo-3-cyclopropyl-6-fluoro-2-morpholino-quinazolin-4-one (756 mg, 2.06 mmol) and methyl 2-vinylbenzoate (500 mg, 3.08 mmol) in N,N- dimethylformamide (7 mL) was added palladium acetate (46.1 mg, 205 μmol), diisopropylethylamine (796 mg, 6.17 mmol) and tris-o-tolylphosphane (125 mg, 411 μmol) under nitrogen atmosphere. Then the mixture was stirred at 120 °C for 12 hr. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was separated, washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 1/1) and then re- purified by prep-HPLC (column: Phenomenex luna C18 150x40mmx 15um;mobile phase: [water (formic acid)- acetonitrile];gradient:55%-85% B over 15 min) to give methyl (E)-2-(2- (3-cyclopropyl-6-fluoro-2-morpholino-4-oxo-3,4-dihydroquinaz olin-8-yl)vinyl)benzoate (530 mg, 1.12 mmol, 54%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 16.4 Hz, 1H), 7.97 (dd, J = 1.2, 8.0 Hz, 1H), 7.83 - 7.68 (m, 4H), 7.60 - 7.53 (m, 1H), 7.40 - 7.33 (m, 1H), 3.94 (s, 3H), 3.92 - 3.86 (m, 4H), 3.54 - 3.46 (m, 4H), 3.12 - 3.01 (m, 1H), 1.36 - 1.28 (m, 2H), 0.96 - 0.87 (m, 2H). [2455] Step 4. Synthesis of methyl 2-(2-(3-cyclopropyl-6-fluoro-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)cyclopropyl)benzoate [2456] To an 15 mL vial equipped with a stir bar was added methyl (E)-2-(2-(3-cyclopropyl- 6-fluoro-2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)vinyl )benzoate (200 mg, 444 μmol), 8-(iodomethyl)-8,8'-spirobi[7,9-dioxa-8-silanuidabicyclo[4.3 .0]nona-1(6),2,4-triene] (865 mg, 1.78 mmol), 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN, 17.5 mg, 22.2 μmol) in dimethylsulfoxide (6 mL). The vial was sealed and placed under nitrogen was added. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr. On completion, the reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was separated, washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water(formic acid)- acetonitrile];gradient:59%-81% B over 11 min) to give methyl 2-[2-(3-cyclopropyl-6-fluoro- 2-morpholino-4-oxo-quinazolin-8-yl)cyclopropyl]benzoate (60.0 mg, 121 μmol, 27%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.85 (dd, J = 1.2, 8.0 Hz, 1H), 7.62 (dd, J = 2.8, 8.4 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.34 - 7.29 (m, 1H), 7.05 (dd, J = 2.8, 9.6 Hz, 1H), 3.79 (t, J = 4.8 Hz, 4H), 3.65 (s, 3H), 3.44 - 3.28 (m, 4H), 3.07 - 2.91 (m, 3H), 1.63 - 1.54 (m, 1H), 1.53 - 1.43 (m, 1H), 1.32 - 1.27 (m, 2H), 0.92 - 0.85 (m, 2H). [2457] Step 5. Synthesis of 2-(2-(3-cyclopropyl-6-fluoro-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)cyclopropyl)benzoic acid [2458] To a solution of methyl 2-[2-(3-cyclopropyl-6-fluoro-2-morpholino-4-oxo-quinazolin- 8-yl)cyclopropyl]benzoate (50.0 mg, 107 μmol) in water (0.2 mL), tetrahydrofuran (0.2 mL) and methanol (0.2 mL) was added lithium hydroxide monohydrate (27.1 mg, 647 μmol). The mixture was stirred at 45 °C for 5 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with water (2 mL) and then adjusted to pH ~ 5 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine 20 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [n- Heptane- isopropanol (0.1% formic acid)];gradient:44%-74% B over 10 min) to give 2-[2-(3- cyclopropyl-6-fluoro-2-morpholino-4-oxo-quinazolin-8-yl)cycl opropyl]benzoic acid (25.5 mg, 56.9 μmol, 52%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (dd, J = 1.2, 8.0 Hz, 1H), 7.60 (dd, J = 2.8, 8.4 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.37 - 7.28 (m, 2H), 7.06 (dd, J = 2.8, 9.6 Hz, 1H), 3.77 (t, J = 4.7 Hz, 4H), 3.38 - 3.24 (m, 4H), 3.01 - 2.92 (m, 3H), 1.66 - 1.55 (m, 1H), 1.53 - 1.46 (m, 1H), 1.28 - 1.17 (m, 2H), 0.89 - 0.79 (m, 2H); m/z ES+ [M+H] ⁺ 450.2 [2459] Step 6. Synthesis of (iodomethyl)trimethoxysilane [2460] To a solution of chloromethyl(trimethoxy)silane (5.00 g, 29.3 mmol) in acetonitrile (50 mL) was added sodium iodide (8.78 g, 58.5 mmol). The mixture was stirred at 60 °C for 12 hr. The resulting mixture was diluted with petroleum ether (60 mL). The heterogeneous solution was stirred at 25 °C for 5 min and then quickly filtered. The filtered cake was washed with additional petroleum ether (100 mL) and the filtrate was then collected, which was further concentrated in vacuo by careful evaporation at 23 °C. After most of the solvent was removed, further purification was accomplished by vacuum distillation to give iodomethyl(trimethoxy)silane (5.70 g, crude) as a light-pink oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.64 (s, 9H), 1.96 (s, 2H). [2461] Step 7. Synthesis of 8-(iodomethyl)-8,8'-spirobi[7,9-dioxa-8- silanuidabicyclo[4.3.0]nona-1(6),2,4-triene] [2462] To a solution of benzene-1,2-diol (1.64 g, 14.8 mmol) in triethylamine (3.28 g, 32.4 mmol) was added iodomethyl(trimethoxy)silane (2.00 g, 7.63 mmol) at 40 °C. The mixture was sitrred at 40 °C for 0.5 hr. On completion, the mixture was cooled to 25 °C and a mixed solvent of methyl tert-butyl ether/pentane (1/1, 50 mL) was added. The resulting suspension was filtered, and the filtered cake was washed with pentane (50 mL), followed by methyl tert- butyl ether (3 × 50 mL) to give 8-(iodomethyl)-8,8'-spirobi[7,9-dioxa-8- silanuidabicyclo[4.3.0]nona-1(6),2,4-triene] (3.00 g, crude, triethylamine) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.81 (br. s, 1H), 6.68 - 6.41 (m, 8H), 3.08 (q, J = 7.2 Hz, 6H), 1.90 (s, 2H), 1.16 (t, J = 7.2 Hz, 9H). Example 265. Preparation of (R)-2-((1-(3-cyclopropyl-6-fluoro-2-(4-methyltetrahydro- 2H-pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) -5-fluorobenzoic acid (Compound 718) [2463] Step 1. Synthesis of N-(2-bromo-6-(cyclopropylcarbamoyl)-4-fluorophenyl)-4- methyltetrahydro-2H-pyran-4-carboxamide [2464] To a solution of N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (6.08 g, 21.6 mmol), 1-methylimidazole (3.56 g, 45.3 mmol) and 4- methyltetrahydropyran-4-carboxylic acid (2.50 g, 17.3 mmol) in acetonitrile (50 mL) was added 2-amino-3-bromo-5-fluoro-N-methyl-benzamide (3.95 g, 14.4 mmol), the mixture was stirred at 60 °C for 12 hr. The reaction solution was added to water (200 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure to give N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro-phenyl]-4-methy l- tetrahydropyran-4-carboxamide (5 g, crude) was obtained as a white solid. m/z ES+ [M+H] ⁺ 401.1. [2465] Step 2. Synthesis of 8-bromo-3-cyclopropyl-6-fluoro-2-(4-methyltetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2466] To a solution of N-[2-bromo-6-(cyclopropylcarbamoyl)-4-fluoro-phenyl]-4-methy l- tetrahydropyran-4-carboxamide (1.50 g, 3.76 mmol) and dichlorozinc (1.54 g, 11.2 mmol) in dimethyl acetamide (15.0 mL) was added min[dimethyl-(trimethylsilylamino)silyl]methane (1.52 g, 9.39 mmol) , the mixture was stirred at 125 °C for 36 hr. The reaction solution was added to water (60 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure to give 8-bromo-3-cyclopropyl-6-fluoro-2-(4- methyltetrahydropyran-4-yl)quinazolin-4-one (1.00 g, crude) was obtained as a white solid. m/z ES+ [M+H] ⁺ 381.0. [2467] Step 3. Synthesis of 8-acetyl-3-cyclopropyl-6-fluoro-2-(4-methyltetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2468] A mixture of 8-bromo-3-cyclopropyl-6-fluoro-2-(4-methyltetrahydropyran-4- yl)quinazolin-4-one (1.00 g, 2.62 mmol), tributyl(1-ethoxyvinyl)stannane (2.84 g, 7.87 mmol) and dichloroditribenthyl phosphorus palladium (92.0 mg, 131 μmol) in toluene (10 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 125 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched by addition potassium fluoride 30 mL at 25 °C, and then extracted with ethyl acetate (10 mL), then added hydrochloric acid (2 M, 20.0 mL), the mixture was stirred at 25 °C for 0.5 hr. The mixture was treated with potassium carbonate to pH=8, and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, Petroleum ether/Ethyl acetate=5/1 to 1/1) to give 8-acetyl-3-cyclopropyl-6- fluoro-2-(4-methyltetrahydropyran-4-yl)quinazolin-4-one (700 mg, 2.03 mmol, 76%) was obtained as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (dd, J = 3.2, 7.6 Hz, 1H), 7.74 (dd, J = 3.2, 8.8 Hz, 1H), 3.79 (ddd, J = 2.8, 8.4, 11.6 Hz, 2H), 3.69 - 3.59 (m, 2H), 3.22 - 3.14 (m, 1H), 2.82 (s, 3H), 2.62 - 2.49 (m, 2H), 2.08 - 2.00 (m, 2H), 1.38 - 1.30 (m, 2H), 0.96 - 0.89 (m, 2H). [2469] Step 4. Synthesis of (R,E)-N-(1-(3-cyclopropyl-6-fluoro-2-(4-methyltetrahydro-2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-m ethylpropane-2-sulfinamide [2470] To a solution of 8-acetyl-3-cyclopropyl-6-fluoro-2-(4-methyltetrahydropyran-4 - yl)quinazolin-4-one (700 mg, 2.03 mmol) and (R)-2-methylpropane-2-sulfinamide (985 mg, 8.13 mmol) in anhydrous tetrahydrofuran (10 mL) was added tetraethoxytitanium (2.32 g, 10.1 mmol), the mixture was stirred at 75 °C for 12 hr. The reaction mixture was quenched with water (30 mL), filtered and extracted with ethyl acetate (30 mL x 3). The combined organic layers were and concentrated under reduced pressure to give (NE,R)-N-[1-[3-cyclopropyl-6- fluoro-2-(4-methyltetrahydropyran-4-yl)-4-oxo-quinazolin-8-y l]ethylidene]-2-methyl- propane-2-sulfinamide (700 mg, crude) was obtained as a yellow oil. [2471] Step 5. Synthesis of (R)-N-((R)-1-(3-cyclopropyl-6-fluoro-2-(4-methyltetrahydro-2 H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methyl propane-2-sulfinamide [2472] To a solution of (NE,R)-N-[1-[3-cyclopropyl-6-fluoro-2-(4-methyltetrahydropyr an-4- yl)-4-oxo-quinazolin-8-yl]ethylidene]-2-methyl-propane-2-sul finamide (500 mg, 1.12 mmol) inanhydrous tetrahydrofuran (5 mL) was added borane-methyl sulfide complex (10 M, 1.12 mL) at -50 °C under nitrogen, the mixture was stirred at -10 °C for 1 hr. The mixture was added methanol (20 mL) dropwised at -30 °C the mixture was stirred at 25 °C for 0.5 hr. Then the mixture wasconcentrated in vacuo to give a residue. The residue was purified by pre-HPLC (column: Kromasil Eternity XT 250*80mm*10um;mobile phase: [water(ammonium hydoxide)-acetonitrile];gradient:40%-60% B over 20 min) to give (R)-N-[(1R)-1-[3- cyclopropyl-6-fluoro-2-(4-methyltetrahydropyran-4-yl)-4-oxo- quinazolin-8-yl]ethyl]-2- methyl-propane-2-sulfinamide (350 mg, 738 μmol, 66.1%) was obtained as a white solid. m/z ES+ [M+H] ⁺ 450.3. [2473] Step 6. Synthesis of (R)-8-(1-aminoethyl)-3-cyclopropyl-6-fluoro-2-(4- methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2474] To a solution of (R)-N-[(1R)-1-[3-cyclopropyl-6-fluoro-2-(4-methyltetrahydrop yran- 4-yl)-4-oxo-quinazolin-8-yl]ethyl]-2-methyl-propane-2-sulfin amide (350 mg, 778 μmol) in dichloromethane (3.5 mL) was added hydrochloric acid/dioxane (4 M, 3.5 mL) , the mixture was stirred at 25 °C for 0.5 hr. The mixture was treated with ammonium hydroxide to pH=8, then diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-(4- methyltetrahydropyran-4-yl)quinazolin-4-one (250 mg, crude) was obtained as a white solid. m/z ES+ [M+H] ⁺ 346.2. [2475] Step 7. Synthesis of (R)-2-((1-(3-cyclopropyl-6-fluoro-2-(4-methyltetrahydro-2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5- fluorobenzoic acid [2476] A mixture of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-(4- methyltetrahydropyran-4-yl)quinazolin-4-one (100 mg, 289 μmol), 5-fluoro-2-iodo-benzoic acid (154 mg, 579 μmol), cesium carbonate (283 mg, 868 μmol) and [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl -[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (23.0 mg, 28.9 μmol) in dioxane (2 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. The mixture was poured into saturated ammonium chloride (30 mL), and extracted with ethyl acetate (30 mL x 5). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1/1, Rf = 0.40) to give (R)-2-((1-(3-cyclopropyl-6-fluoro-2-(4- methyltetrahydro-2H-pyran-4-yl)-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)-5- fluorobenzoic acid (83.77 mg, 171 μmol, 59%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (br. s, 1H), 7.73 - 7.65 (m, 2H), 7.43 (dd, J = 2.8, 9.2 Hz, 1H), 6.96 (ddd, J = 3.2, 7.6, 9.2 Hz, 1H), 6.26 (dd, J = 4.4, 9.2 Hz, 1H), 5.45 (q, J = 6.4 Hz, 1H), 3.89 - 3.81 (m, 2H), 3.75 - 3.66 (m, 2H), 3.23 - 3.14 (m, 1H), 2.75 - 2.62 (m, 2H), 2.14 - 2.03 (m, 2H), 1.67 (s, 3H), 1.62 (d, J = 6.7 Hz, 3H), 1.41 - 1.25 (m, 2H), 1.06 - 0.92 (m, 2H); m/z ES+ [M+H] ⁺ 484.2. Example 266. Preparation of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro- 2H-pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid & 2-(((R)-1-(3- cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H-pyran-3-yl)- 3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Compounds 638 and 639) (single enantiomer with one stereochemistry known and the other arbitrarily assigned) [2477] Step 1. Synthesis of 2-(((1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2478] To a solution of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H - pyran-3-yl)quinazolin-4(3H)-one (100 mg, 302 μmol) and 2-iodobenzoic acid (135 mg, 543 μmol) in dioxane (1.5 mL) was added cesium carbonate (295 mg, 905 μmol) and [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium ditert-butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (7.19 mg, 9.05 μmol). The mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:47%-77% B over 10 min) to give 2-(((1R)-1-(3-cyclopropyl-6-fluoro-4- oxo-2-(tetrahydro-2H-pyran-3-yl)-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoic acid (100 mg, 219 μmol, 73%) as a white solid. m/z ES+ [M+H] ⁺ 452.2. [2479] Step 2. Chiral purification [2480] 2-(((1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-py ran-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (100 mg, 219 μmol) was separated by SFC (column: DAICEL CHIRALPAK IG 250mmx30mmx5um;mobile phase: [carbon dioxide- isopropanol (0.1% ammonium hydroxide)];B%:30%, isocratic elution mode) to give 2-(((R)- 1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro-2H-pyran-3 -yl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (35.0 mg, 73.7 μmol, 33%) as a white solid. 1 ^st peak, R.T. 1.72 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 - 8.07 (m, 1H), 8.06 - 7.94 (m, 1H), 7.78 - 7.68 (m, 1H), 7.47 - 7.43 (m, 1H), 7.24 - 7.14 (m, 1H), 6.60 (t J = 7.2 Hz, 1H), 6.34 (d, J = 8.8 Hz, 1H), 5.62 - 5.45 (m, 1H), 4.21 (br. d, J = 10.8 Hz, 1H), 4.13 - 4.02 (m, 1H), 3.89 - 3.67 (m, 2H), 3.60 - 3.50 (m, 1H), 3.04 - 2.98 (m, 1H), 2.24 - 2.14 (m, 1H), 2.11 - 1.98 (m, 1H), 1.96 - 1.74 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H), 1.46 - 1.36 (m, 2H), 1.02 - 0.92 (m, 2H); m/z ES+ [M+H] ⁺ 452.2; and 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H -pyran-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (36.4 mg, 78.1 μmol, 35%) as a white solid, [2481] 2 ^nd peak, R.T.1.85 min. ¹ H NMR (400 MHz, CDCl3) δ 8.19 (br. s, 1H), 8.04 - 7.97 (m, 1H), 7.76 - 7.69 (m, 1H), 7.49 - 7.38 (m, 1H), 7.24 - 7.15 (m, 1H), 6.60 (t J = 7.6 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.62 - 5.47 (m, 1H), 4.22 - 4.16 (m, 1H), 4.10 - 4.05 (m, 1H), 3.85 - 3.78 (m, 2H), 3.59 - 3.51 (m, 1H), 3.03 - 2.98 (m, 1H), 2.23 (br. d, J = 14.0 Hz, 1H), 2.08 - 1.94 (m, 1H), 1.93 - 1.73 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.47 - 1.38 (m, 2H), 1.04 - 0.93 (m, 2H); m/z ES+ [M+H] ⁺ 452.3. Example 267. Preparation of 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((R)-tetrahydro- 2H-pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-flu orobenzoic acid & 2-(((R)- 1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H-pyran-3 -yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (Compounds 676 and 677) (single enantiomer with one stereochemistry known and the other arbitrarily assigned) [2482] Step 1. Synthesis of 2-(((1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro benzoic acid [2483] To a solution of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-tetrahydropyr an-3- yl-quinazolin-4-one (150 mg, 453 μmol), 5-fluoro-2-iodo-benzoic acid (120 mg, 453 μmol) in dioxane (3 mL) was added cesium carbonate (442 mg, 1.36 mmol) and [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl -[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (10.8 mg, 13.6 μmol). The mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 0/1) to give 2-[[(1R)-1-(3-cyclopropyl-6- fluoro-4-oxo-2-tetrahydropyran-3-yl-quinazolin-8-yl)ethyl]am ino]-5-fluoro-benzoic acid (200 mg, 409 μmol, 90%) as a light yellow solid. m/z ES+ [M+H] ⁺ 470.2. [2484] Step 2. Chiral purification [2485] 2-[[(1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyran-3 -yl-quinazolin-8- yl)ethyl]amino]-5-fluoro-benzoic acid (80 mg, 170 μmol) was separated by SFC (column: DAICEL CHIRALPAK IK(250mmx30mm,10um);mobile phase: [carbon dioxide- isopropanol];B%:30%, isocratic elution mode) to give 2-(((R)-1-(3-cyclopropyl-6-fluoro-4- oxo-2-((R)-tetrahydro-2H-pyran-3-yl)-3,4-dihydroquinazolin-8 -yl)ethyl)amino)-5- fluorobenzoic acid (21.0 mg, 44.8 μmol, 26%) as an off-white solid, 1 ^st peak, R.T. 1.76 min. ¹ H NMR (400 MHz, CDCl3) δ 7.98 (br. s, 1H), 7.72 (ddd, J = 3.0, 8.8, 17.0 Hz, 2H), 7.42 (dd, J = 2.8, 9.2 Hz, 1H), 6.97 (ddd, J = 3.2, 7.6, 9.2 Hz, 1H), 6.31 (dd, J = 4.4, 9.6 Hz, 1H), 5.51 (q, J = 6.8 Hz, 1H), 4.19 (br. d, J = 7.6 Hz, 1H), 4.13 - 4.03 (m, 1H), 3.88 - 3.76 (m, 2H), 3.55 (dt, J = 2.8, 11.6 Hz, 1H), 3.06 - 2.97 (m, 1H), 2.24 (br. d, J = 11.6 Hz, 1H), 2.04 - 1.84 (m, 2H), 1.83 - 1.77 (m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.45 - 1.36 (m, 2H), 1.01 - 0.93 (m, 2H); m/z ES+ [M+H] ⁺ 470.2; and 2-(((R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-((S)-tetrahydro-2H - pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro benzoic acid (27.9 mg, 59.5 μmol, 35%) as an off-white solid, 2 ^nd peak, R.T. 2.03 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (br. s, 1H), 7.71 (ddd, J = 3.2, 8.8, 18.8 Hz, 2H), 7.42 (dd, J = 2.8, 9.2 Hz, 1H), 7.01 - 6.92 (m, 1H), 6.27 (dd, J = 4.4, 9.6 Hz, 1H), 5.49 (q, J = 6.8 Hz, 1H), 4.21 (br. d, J = 10.4 Hz, 1H), 4.14 - 4.02 (m, 1H), 3.89 - 3.78 (m, 1H), 3.77 - 3.69 (m, 1H), 3.55 (dt, J = 2.8, 11.6 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.19 (br. d, J = 13.6 Hz, 1H), 2.07 - 1.97 (m, 1H), 1.94 - 1.84 (m, 1H), 1.82 - 1.77 (m, 1H), 1.66 (d, J = 6.8 Hz, 3H), 1.45 - 1.36 (m, 2H), 1.02 - 0.90 (m, 2H); m/z ES+ [M+H] ⁺ 470.2. Example 268. Preparation of 8-[(1R)-1-(4-fluoro-2-methylsulfonyl-anilino)ethyl]-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one & 8-[(1S)-1-(4-fluoro-2- methylsulfonyl-anilino)ethyl]-3,6-dimethyl-2-tetrahydropyran -4-yl-quinazolin-4-one (Compounds 319 and 320) (single enantiomer with one stereochemistry known and the other arbitrarily assigned) [2486] Step 1. Synthesis of 8-[1-(4-fluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2- tetrahydropyran-4-yl-quinazolin-4-one [2487] To a mixture of 1,4-difluoro-2-methylsulfonyl-benzene (957 mg, 4.98 mmol) and 8- (1-aminoethyl)-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazoli n-4-one (500 mg, 1.66 mmol) in dimethyl acetamide (6 mL) was added cesium carbonate (1.62 g, 4.98 mmol), then the mixture was stirred at 140 °C for 16 hr under nitrogen. The reaction mixture was poured into water (120 mL), extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether / ethyl acetate =10/1 to 1/2) to give 8-[1-(4- fluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl-2-tetrah ydropyran-4-yl-quinazolin-4-one (0.7 g, 1.48 mmol, 89%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 4.0 Hz, 1H), 7.53 - 7.48 (m, 2H), 6.99 - 6.94(m, 1H), 6.54 - 6.48 (m, 2H), 5.60 - 5.57 (m, 1H), 4.20 - 4.15 (m, 2H), 3.72 (s, 3H), 3.62 (t, J = 12.0 Hz, 2H), 3.17 (s, 4H), 2.42 (s, 3H), 2.27 - 2.13 (m, 2H), 1.93 (d, J = 16.0 Hz, 2H), 1.62 (d, J = 8.0 Hz, 3H). [2488] Step 2. Chiral purification [2489] 8-[1-(4-fluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl- 2-tetrahydropyran-4-yl- quinazolin-4-one (0.700 g, 1.48 mmol)was purified by SFC(column: DAICEL CHIRALPAK AD-H(250 mm × 30 mm,5 um);mobile phase: [0.1% ammonium hydroxide isopropanol]; B%: 20%-20%,5.4min) and concentrated under reduced pressure to give 8-[(1R)-1-(4-fluoro-2- methylsulfonyl-anilino)ethyl]-3,6-dimethyl-2-tetrahydropyran -4-yl-quinazolin-4-one (301 mg, 626 μmol, 85%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.44 - 7.38 (m, 2H), 6.93 - 6.80 (m, 1H), 6.48 - 6.39 (m, 2H), 5.51 - 5.50 (m, 1H), 4.09 - 4.06 (m, 2H), 3.63 (s, 3H), 3.53 (t, J = 12.0 Hz, 2H), 3.08 (s, 4H), 2.33 (s, 3H), 2.17 - 2.06 (m, 2H), 1.84 (d, J = 16.0 Hz, 2H), 1.54 (d, J = 8.0 Hz, 3H); m/z ES+ [M+H] ⁺ 474.3; and 8-[(1S)-1-(4-fluoro-2- methylsulfonyl-anilino)ethyl]-3,6-dimethyl-2-tetrahydropyran -4-yl-quinazolin-4-one (228 mg, 459 μmol, 62%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.52 - 7.47 (m, 2H), 6.98 - 6.93 (m, 1H), 6.53 - 6.47 (m, 2H), 5.59 - 5.56 (m, 1H), 4.18 - 4.14 (m, 2H), 3.71 (s, 3H), 3.61 (t, J = 12.0 Hz, 2H), 3.15 (s, 4H), 2.43 (s, 3H), 2.25- 2.13 (m, 2H), 1.92 (d, J = 12.0 Hz, 2H), 1.62 (d, J = 8.0 Hz, 3H); m/z ES+ [M+H] ⁺ 474.3. Example 269. Preparation of (R)-8-(1-((2-(Difluoromethyl)-4-fluorophenyl)amino)ethyl)- 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-on e and (S)-8-(1-((2- (Difluoromethyl)-4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one (Compounds 454 and 455) (stereochemistry arbitrarily assigned) [2490] Step 1. Synthesis of 8-(1-((2-(difluoromethyl)-4-fluorophenyl)amino)ethyl)-3,6- dimethyl-2(tetrah-ydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2491] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazo lin-4- one (200 mg, 663 μmol) and 1-bromo-2-(difluoromethyl)-4-fluoro-benzene (447 mg, 1.99 mmol) in toluene (2 mL) was added dicyclohexyl-[2-[2,6-di(propan-2- yloxy)phenyl]phenyl]phosphane (30.9 mg, 66.3 μmol) and tris(dibenzylideneacetone)dipalladium (60.7 mg, 66.3 μmol) and cesium carbonate (648 mg, 1.99 mmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: UniSil 3-100 C18 UItra (150 x 25mm, 3um);mobile phase: [water(formic acid)-acetonitrile]; B%: 60%- 80%, 7 min) to give 8-[1-[2-(difluoromethyl)-4-fluoro-anilino]ethyl]-3,6-dimethy l-2- tetrahydropyran-4-yl-quinazolin-4-one (200 mg, 448 μmol, 67%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.01 (dd, J = 3.2, 8.4 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.80 - 6.50 (m, 1H), 6.43 (dd, J = 4.4, 9.2 Hz, 1H), 5.45 - 5.35 (m, 1H), 4.83 (s, 1H), 4.16 (d, J = 7.6 Hz, 2H), 3.70 (s, 3H), 3.65 - 3.54 (m, 2H), 3.20 - 3.09 (m, 1H), 2.41 (s, 3H), 2.27 - 2.09 (m, 2H), 1.91 (d, J = 13.6 Hz, 2H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 446.2. [2492] Step 2. Chiral purification [2493] 8-[1-[2-(difluoromethyl)-4-fluoro-anilino]ethyl]-3,6-dimethy l-2-tetrahydropyran-4- yl-quinazolin-4-one (100 mg, 224 μmol) was separated by SFC (column: Daicel ChiralPak IG (250 x 30mm, 10um); mobile phase: [0.1% ammonium hydroxide isopropanol];B%: 40%- 40%,3.7 min) to give 8-[(1R)-1-[2-(difluoromethyl)-4-fluoro-anilino]ethyl]-3,6-di methyl-2- tetrahydropyran-4-yl-quinazolin-4-one (40.4 mg, 90.7 μmol, 40%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 2.8, 8.8 Hz, 1H), 6.89 - 6.82 (m, 1H), 6.81 - 6.52 (m, 1H), 6.44 (dd, J = 4.4, 8.8 Hz, 1H), 5.40 (q, J = 6.8 Hz, 1H), 4.16 (d, J = 8.0 Hz, 2H), 3.70 (s, 3H), 3.64 - 3.54 (m, 2H), 3.18 - 3.09 (m, 1H), 2.41 (s, 3H), 2.27 - 2.09 (m, 2H), 1.91 (d, J = 13.6 Hz, 2H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 446.2. And 8-[(1S)-1-[2-(difluoromethyl)-4-fluoro-anilino]ethyl]-3,6-di methyl-2-tetrahydropyran-4- yl-quinazolin-4-one (46.0 mg, 102 μmol, 45%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 0.8 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 2.8, 8.8 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H), 6.67 (s, 1H), 6.44 (dd, J = 4.4, 8.8 Hz, 1H), 5.42 - 5.35 (m, 1H), 4.22 - 4.13 (m, 2H), 3.70 (s, 3H), 3.65 - 3.55 (m, 2H), 3.17 - 3.07 (m, 1H), 2.41 (s, 3H), 2.28 - 2.10 (m, 2H), 1.91 (d, J = 13.6 Hz, 2H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 446.2. Example 270. Preparation of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethyl]amino]-5-fluoro-N-methoxy-benzamide and 2-[[(1S)-1-(3,6- dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethyl] amino]-5-fluoro-N- methoxybenzamide (Compounds 415 and 416) (stereochemistry arbitrarily assigned) [2494] Step 1. Synthesis of 2-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8 - yl)ethylamino]-5-fluoro-benzoic acid [2495] To a mixture of 8-(1-aminoethyl)-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazo lin-4- one (0.10 g, 332 μmol) and 5-fluoro-2-iodo-benzoic acid (265 mg, 995 μmol) in dimethyl acetamide (1 mL) was added copper power (21.1 mg, 332 μmol) and triethylamine (336 mg, 3.32 mmol), 4A molecular sieve (10 mg), then the mixture was stirred at 110 °C for 2 hr under nitrogen. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid) to give 2-[1-(3,6-dimethyl- 4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethylamino]-5-f luoro-benzoic acid (57 mg, 122 μmol, 37%) as a yellow solid. m/z ES+ [M+H] ⁺ 440.1. [2496] Step 2. Synthesis of 2-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8 - yl)ethylamino]-5-fluoro-N-methoxy-benzamide [2497] To a mixture of 2-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8 - yl)ethylamino]-5-fluoro-benzoic acid (57.0 mg, 130 μmol) in dimethyl acetamide (1 mL) was added O-methylhydroxylamine (108 mg, 1.30 mmol, hydrochloric acid salt) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium hexafluorophosphhate (247 mg, 649 μmol), diisopropylethylamine (83.8 mg, 649 μmol) at 0 °C, then the mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give 2-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethylamino]-5-fluoro-N-methoxy-benzamide (30.0 mg, 62.3 μmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.89 - 8.50 (m, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.77 - 7.67 (m, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.14 – 7.02 (m, 1H), 6.88 - 6.82 (m, 1H), 6.40 - 6.37 (m, 1H), 5.57 - 5. 51 (m, 1H), 4.19 - 4.15 (m, 2H), 3.95 (s, 3H), 3.71 (s, 3H), 3.62 (t, J = 12.0 Hz, 2H), 3.21 - 3.12 (m, 1H), 2.40 (s, 3H), 2.29 - 2.12 (m, 2H), 1.95 - 1. 91 (m, 2H), 1.60 (d, J = 8.0 Hz, 3H); m/z ES+ [M+H] ⁺ 469.2. [2498] Step 3. Chiral purification [2499] 2-[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8 -yl)ethylamino]-5- fluoro-N-methoxy-benzamide (30 mg, 64.0 μmol) was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30mm,10 um); mobile phase: [0.1% ammonium hydroxide Methanl]; B%: 35%-35%, 4.4 min). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 × 25 mm × 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 40%-70%, 8 min) give 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinaz olin-8-yl)ethyl]amino]-5- fluoro-N-methoxy-benzamide (10 mg, 21.1 μmol, 66%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 8.64 - 8.38 (m, 1H), 7.86 (s, 1H), 7.51 - 7.43 (m, 1H), 7.06 - 6.89 (m, 1H), 6.82 - 6.69 (m, 1H), 6.37 - 6.25 (m, 1H), 5.50 - 5.36 (m, 1H), 4.08 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H), 3.62 (s, 3H), 3.53 (t, J = 12.0 Hz, 2H), 3.12 - 2.98 (m, 1H), 2.31 (s, 3H), 2.17 - 2.07 (m, 2H), 1.85 - 1.81 (m, 2H), 1.51 (d, J = 8.0 Hz, 3H); m/z ES+ [M+H] ⁺ 469.2; and the residue was purified by (column: Waters Xbridge 150 × 25 mm × 5 um; mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%:36%-66%, 8 min) to give 2-[[(1S)-1-(3,6-dimethyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]amino]-5-fluoro-N -methoxybenzamide (10 mg, 20.9 μmol, 65%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 - 8.50 (m, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.12 – 7.01 (m, 1H), 6.88 - 6.81 (m, 1H), 6.39 - 6.36 (m, 1H), 5.55 - 5.50 (m, 1H), 4.18 - 4.14 (m, 2H), 3.93 (s, 3H), 3.70 (s, 3H), 3.61 (t, J = 12.0 Hz, 2H), 3.21 - 3.07 (m, 1H), 2.39 (s, 3H), 2.26 - 2.14 (m, 2H), 1.91 (d, J = 12.0 Hz, 2H), 1.59 (d, J = 4.0 Hz, 3H); m/z ES+ [M+H] ⁺ 469.2. Example 271. Preparation of 8-(2-((4-Fluoro-2-(methylsulfonyl)phenyl)amino)propan-2- yl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H )-one (Compound 494) [2500] Step 1. Synthesis of 8-(2-((4-fluoro-2-(methylsulfonyl)phenyl)amino)propan-2-yl)- 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-on e [2501] A mixture of 8-(1-amino-1-methyl-ethyl)-3,6-dimethyl-2-tetrahydropyran-4- yl- quinazolin-4-one (100 mg, 317 μmol), 1,4-difluoro-2-methylsulfonyl-benzene (305 mg, 1.59 mmol), cesium carbonate (310 mg, 951 μmol), molecular sieves (100 mg) in dimethyl acetamide (1 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 140 °C for 5 hr under nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25mm, 10um; mobile phase:[water(ammonium bicarbonate)-acetonitrile];B%: 49%-79%, 8 min) to give 8-(2-((4-fluoro-2-(methylsulfonyl)phenyl)amino)propan-2-yl)- 3,6- dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (35.1 mg, 71.5 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.60 - 7.53 (m, 2H), 6.92 - 6.85 (m, 1H), 6.63 (s, 1H), 6.39 - 6.32 (m, 1H), 4.16 (dd, J = 3.6, 11.2 Hz, 2H), 3.66 (s, 3H), 3.60 - 3.50 (m, 2H), 3.18 (s, 3H), 3.12 - 3.00 (m, 1H), 2.44 (s, 3H), 2.23 - 2.10 (m, 2H), 2.00 (s, 6H), 1.83 (d, J = 13.2 Hz, 2H); m/z ES+ [M+H] ⁺ 488.2. Example 272. Preparation of 2-((2-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydroquinazolin-8-yl)propan-2-yl)amino)-5-fluorobenzoi c acid (Compound 508) [2502] Step 1. Synthesis of methyl 2-((2-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)- 3,4-dihydroquinazolin-8-yl)propan-2-yl)amino)-5-fluorobenzoa te [2503] A mixture of 8-(1-amino-1-methyl-ethyl)-3,6-dimethyl-2-tetrahydropyran-4- yl- quinazolin-4-one (170 mg, 538 μmol), methyl 2-bromo-5-fluoro-benzoate (628 mg, 2.69 mmol), cesium carbonate (527 mg, 1.62 mmol), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5- dichloro-2H-imidazol-1-ium-2-ide;3-chloropyr-idine;dichlorop alladium (52.4 mg, 53.9 μmol) in dioxane (3 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic phase was separated, dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=1/2 to give methyl 2-[[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin- 8- yl)-1-methyl-ethyl]amino]-5-fluoro-benzoate (40 mg, 69.3 μmol, 13%) as a yellow solid. m/z ES+ [M+H] ⁺ 468.2. [2504] Step 2. Synthesis of 2-((2-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4- dihydroquinazolin-8-yl)propan-2-yl)amino)-5-fluorobenzoic acid [2505] To a solution of methyl 2-[[1-(3,6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin- 8-yl)-1-methyl-ethyl]amino]-5-fluoro-benzoate (40 mg, 85.5 μmol) in tetrahydrofuran (0.1 mL), water (0.1 mL) and methanol (0.1 mL) was added lithium hydroxide (6.15 mg, 256 μmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was quenched by addition of 1N hydrochloric acid to pH =6 at 25 °C, and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water(formic acid)-acetonitrile]; B%: 36%-56%, 9 min) to give 2-((2-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-d ihydroquinazolin- 8-yl)propan-2-yl)amino)-5-fluorobenzoic acid (14.4 mg, 31.8 μmol, 37 %) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 - 8.21 (m, 1H), 8.12 (d, J = 1.0 Hz, 1H), 7.94 (dd, J = 3.2, 9.2 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 6.85 - 6.76 (m, 1H), 6.19 (dd, J = 4.8, 8.8 Hz, 1H), 4.15 (dd, J = 3.2, 11.6 Hz, 2H), 3.73 (s, 3H), 3.61 - 3.50 (m, 2H), 3.18 - 3.09 (m, 1H), 2.47 (s, 3H), 2.04 - 1.94 (m, 2H), 1.91 - 1.84 (m, 2H), 1.74 (s, 6H); m/z ES+ [M+H] ⁺ 454.2. Example 273. Preparation of (R)-8-(1-((4-chloro-2-(methylsulfonyl)phenyl)amino)ethyl)- 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-on e (Compound 485) [2506] Step 1. Synthesis of (R)-8-(1-((4-chloro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2507] To a solution of 8-[(1R)-1-aminoethyl]-3, 6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (85 mg, 282 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (229 mg, 705 μmol) and 4-chloro-1-fluoro-2-methylsulfonyl-benzene (88.2 mg, 423 μmol). The mixture was stirred at 140 °C for 6 hr. The reaction mixture diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25mm, 10um;mobile phase: [water(ammonium bicarbonate)-acetonitrile];B%: 42%-72%, 10min) to give (R)-8-(1-((4-chloro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (51 mg, 36%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 2.8, 9.0 Hz, 1H), 6.76 (d, J = 6.8 Hz, 1H), 6.67 (d, J = 8.8Hz, 1H), 5.52 (m, 1H), 4.05 - 3.91 (m, 2H), 3.63 (s, 3H), 3.57 - 3.45 (m, 2H), 3.41 - 3.38 (m, 1H), 3.26 (s, 3H), 2.37 (s, 3H), 1.97 - 1.86 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H), m/z ES+ [M+H] ⁺ 490.1. Example 274. Preparation of (R)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one & (S)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1-yl)phenyl)amino) ethyl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4-yl) quinazolin-4(3H)-one (Compounds 517 and 518) (stereochemistry arbitrarily assigned) [2508] Step 1. Synthesis of 8-(1-((4-fluoro-2-(4-hydroxypiperidin-1-yl)phenyl)amino)ethy l)- 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-on e [2509] To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazo lin-4- one (300 mg, 821 μmol) in dimethyl acetamide (4 mL) was added 1-(2-amino-5-fluoro- phenyl)piperidin-4-ol (518 mg, 2.46 mmol) and diisopropylethylamine (530 mg, 4.11 mmol), the mixture was stirred at 80 °C for 16 hr. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1:0 to 1:3) to give 8-[1-[4- fluoro-2-(4-hydroxy-1-piperidyl)anilino]ethyl]-3,6-dimethyl- 2-tetrahydropyran-4-yl- quinazolin-4-one (270 mg, 529 μmol, 64%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (d, J = 1.2 Hz, 1H), 7.44 (s, 1H), 6.64 (dd, J = 2.8, 10.0 Hz, 1H), 6.46 - 6.37 (m, 1H), 6.25 - 6.12 (m, 1H), 5.17 (d, J = 2.4 Hz, 1H), 4.95 (s, 1H), 4.15 - 4.06 (m, 2H), 3.86 - 3.70 (m, 1H), 3.61 (s, 3H), 3.58 - 3.47 (m, 2H), 3.24 - 3.01 (m, 3H), 2.70 - 2.54 (m, 2H), 2.34 (s, 3H), 2.30 - 2.21 (m, 1H), 2.11 - 2.00 (m, 2H), 1.88 - 1.80 (m, 2H), 1.79 - 1.65 (m, 2H), 1.57 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 495.3. [2510] Step 2. Chiral purification [2511] Compound 8-[1-[4-fluoro-2-(4-hydroxy-1-piperidyl)anilino]ethyl]-3,6-d imethyl-2- tetrahydropyran-4-yl-quinazolin-4-one (260 mg, 525 μmol) was separated by column: DAICEL CHIRALPAK AD (250 mm x 30mm,10um);mobile phase: [0.1% ammonium hydroxide isopropanol];B%: 30%-30%,A2.8;30min] to give 8-[(1R)-1-[4-fluoro-2-(4- hydroxy-1-piperidyl)anilino]ethyl]-3,6-dimethyl-2-tetrahydro pyran-4-yl-quinazolin-4-one (103 mg, 206. μmol, 39%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 2.8, 10.0 Hz, 1H), 6.55 - 6.49 (m, 1H), 6.31 - 6.25 (m, 1H), 5.36 - 5.20 (m, 1H), 5.12 - 4.97 (m, 1H), 4.25 - 4.14 (m, 2H), 3.94 - 3.82 (m, 1H), 3.70 (s, 3H), 3.67 - 3.58 (m, 2H), 3.33 - 3.24 (m, 1H), 3.23 - 3.10 (m, 2H), 2.79 - 2.63 (m, 2H), 2.43 (s, 3H), 2.40 - 2.31 (m, 1H), 2.18 - 2.09 (m, 3H), 2.05 - 1.89 (m, 2H), 1.86 - 1.78 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 495.3; and 8-[(1S)-1-[4-fluoro-2-(4-hydroxy-1- piperidyl)anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl -quinazolin-4-one (97 mg, 196 μmol, 37%) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 6.73 (dd, J = 2.8, 10.0 Hz, 1H), 6.55 - 6.49 (m, 1H), 6.31 - 6.29 (m, 1H), 5.32 - 5.22 (m, 1H), 5.11 - 4.99 (m, 1H), 4.26 - 4.13 (m, 2H), 3.95 - 3.81 (m, 1H), 3.70 (s, 3H), 3.68 - 3.58 (m, 2H), 3.33 - 3.24 (m, 1H), 3.24 - 3.10 (m, 2H), 2.80 - 2.63 (m, 2H), 2.43 (s, 3H), 2.40 - 2.31 (m, 1H), 2.20 - 2.09 (m, 3H), 2.06 - 1.89 (m, 2H), 1.87 - 1.77 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 495.3. Example 275. Preparation of (R)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 517) [2512] Step 1. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyra n-4-yl)quinazolin-4(3H)-one [2513] To a solution of [1-(2-bromo-5-fluoro-phenyl)-4-piperidyl]oxy-tert-butyl-dime thyl- silane (966 mg, 2.49 mmol) and 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (500 mg, 1.66 mmol) in dioxane (10 mL) was added palladium acetate (37.2 mg, 165 μmol), sodium tert-butoxide (478 mg, 4.98 mmol) and (R)-(+)-2,2'- Bis(diphenylphosphino)-1,1'-binaphthyl (103 mg, 165 μmol). The mixture was stirred at 100 °C for 12 hr. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic phase was separated, washed with brine (25 mL x 2), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=40/1 to 1/1) to give 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4- fluoro-anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-qu inazolin-4-one (880 mg, 1.37 mmol, 82%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.38 (s, 1H), 6.61 ( dd, J = 2.4, 10.0 Hz, 1H), 6.35 (dt, J = 2.8, 8.4 Hz, 1H), 6.07 (dd, J = 5.6, 8.8 Hz, 1H), 5.36 - 5.18 (m, 1H), 4.80 (s, 1H), 4.05 - 4.00 (m, 2H), 3.75 ( d, J = 7.2 Hz, 1H), 3.57 (s, 3H), 3.48 ( t, J = 11.2 Hz, 2H), 3.13 - 2.92 (m, 3H), 2.71 - 2.49 (m, 2H), 2.27 (s, 3H), 2.12 - 2.05 (m, 1H), 1.91 - 1.75 (m, 4H), 1.74 - 1.61 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H), 0.82 (s, 9H), 0.00 (s, 6H). [2514] Step 2. Synthesis of (R)-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2515] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4-fluoro- anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazoli n-4-one (880 mg, 1.45 mmol) in dichloromethane (10 mL) was added hydrochloric acid/dioxane (4 M, 5 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x40mmx 15um;mobile phase: [water(formic acid)- acetonitrile];gradient:45%-75% B over 15 min) to give 8-[(1R)-1-[4-fluoro-2-(4-hydroxy-1-piperidyl)anilino]ethyl]- 3,6-dimethyl-2- tetrahydropyran-4-yl-quinazolin-4-one (449 mg, 907 μmol, 62%) as a light yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 2.8, 10.0 Hz, 1H), 6.55 - 6.49 (m, 1H), 6.31 - 6.25 (m, 1H), 5.36 - 5.20 (m, 1H), 5.12 - 4.97 (m, 1H), 4.25 - 4.14 (m, 2H), 3.94 - 3.82 (m, 1H), 3.70 (s, 3H), 3.67 - 3.58 (m, 2H), 3.33 - 3.24 (m, 1H), 3.23 - 3.10 (m, 2H), 2.79 - 2.63 (m, 2H), 2.43 (s, 3H), 2.40 - 2.31 (m, 1H), 2.18 - 2.09 (m, 3H), 2.05 - 1.89 (m, 2H), 1.86 - 1.78 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 495.3.

Example 276. Preparation of (R)-8-(1-((2-(4-hydroxypiperidin-1-yl)phenyl)amino)ethyl)- 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-on e (Compound 543) [2516] Step 1. Synthesis of 1-(2-nitrophenyl)piperidin-4-ol [2517] To a solution of piperidin-4-ol (5 g, 49.4 mmol) in dimethyl acetamide (50 mL) was added 1-fluoro-2-nitro-benzene (5.81 g, 41.1 mmol) and cesium carbonate (40.2 g, 123 mmol), the mixture was stirred at 100 °C for 16 hr. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1-(2-nitrophenyl)piperidin-4- ol (10.5 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 223.1. [2518] Step 2. Synthesis of 1-(2-aminophenyl)piperidin-4-ol [2519] To a solution of 1-(2-nitrophenyl) piperidin-4-ol (10.5 g, 47.2 mmol) in ethanol (100 mL) and water (20 mL) was added iron (13.1 g, 236 mmol) and ammonium chloride (12.6 g, 236 mmol), the mixture was stirred at 80 °C for 2 hr. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1:0 to 1:1) to give 1-(2-aminophenyl)piperidin-4-ol (6.4 g, 33.2 mmol, 70%) as a red solid. ¹ H NMR (400 MHz, DMSO-d6) δ 6.86 (dd, J = 1.2, 7.6 Hz, 1H), 6.80 - 6.74 (m, 1H), 6.64 (dd, J = 1.6, 8.0 Hz, 1H), 6.53 - 6.45 (m, 1H), 4.71 - 4.59 (m, 3H), 3.62 - 3.50 (m, 1H), 3.01 - 2.89 (m, 2H), 2.59 - 2.51 (m, 2H), 1.87 - 1.78 (m, 2H), 1.60 - 1.50 (m, 2H); m/z ES+ [M+H] ⁺ 193.1. [2520] Step 3. Synthesis of 1-(2-bromophenyl)piperidin-4-ol [2521] Concentrated sulfuric acid (3.66 g, 36.6 mmol) was dropped slowly into water (40 mL) stirred and cooled to 0 °C. 1-(2-aminophenyl) piperidin-4-ol (6.4 g, 33.2 mmol) was added slowly into the system and stirred sodium nitrite (2.53 g, 36.6 mmol) was added into water (10 mL), stirred until clarification, and then slowly dropped into the raw material system while controlling the temperature to 0 to 10 °C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 1.5 hr to form a diazonium salt system sodium bromide (13.7 g, 133 mmol) and cuprous bromide (4.78 g, 33.2 mmol) were added into water (10 mL), the mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the mixture was quenched with ammonium hydroxide (40 mL), diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1:0 to 10:1) to give 1-(2- bromophenyl)piperidin-4-ol (5.44 g, 21.1 mmol, 63%) as a yellow oil. m/z ES+ [M+H] ⁺ 256.0. [2522] Step 4. Synthesis of 1-(2-bromophenyl)-4-((tert-butyldimethylsilyl)oxy)piperidine [2523] To a solution of 1-(2-bromophenyl) piperidin-4-ol (5.44 g, 21.2 mmol) in N,N- dimethylformamide (40 mL) was added imidazole (3.61 g, 53.1 mmol) and tert- butylchlorodimethylsilane (4.80 g, 31.8 mmol), the mixture was stirred at 25 °C for 16 hr. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1:0) to give [1-(2-bromophenyl)-4-piperidyl]oxy-tert-butyl- dimethyl-silane (4.3 g, 10.4 mmol, 49%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 1.2, 8.0 Hz, 1H), 7.17 - 7.13 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.84 - 6.75 (m, 1H), 3.79 (d, J = 3.2 Hz, 1H), 3.14 (s, 2H), 2.83 - 2.68 (m, 2H), 1.83 (s, 2H), 1.75 - 1.61 (m, 2H), 0.85 - 0.81 (m, 9H), 0.03 - 0.02 (m, 6H); m/z ES+ [M+H] ⁺ 370.1. [2524] Step 5. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2525] To a solution of [1-(2-bromophenyl)-4-piperidyl]oxy-tert-butyl-dimethyl-silan e (147 mg, 398 μmol) in dioxane (3 mL) was added 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2- tetrahydropyran-4-yl-quinazolin-4-one (60 mg, 199 μmol), sodium tert-butoxide (57.4 mg, 597 μmol), (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (12.4 mg, 19.9 μmol) and palladium(2+);diacetate (4.47 mg, 19.9 μmol), the mixture was stirred at 90 °C for 16 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1:0 to 3:1) and then purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 1:1) to give 8-[(1R)-1-[2-[4-[tert- butyl(dimethyl)silyl]oxy-1-piperidyl]anilino]ethyl]-3,6-dime thyl-2-tetrahydropy-ran-4-yl- quinazolin-4-one (30 mg, 49.2 μmol, 25%) as a yellow solid. m/z ES+ [M+H] ⁺ 591.4. [2526] Step 6. Synthesis of (R)-8-(1-((2-(4-hydroxypiperidin-1-yl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2527] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1- piperidyl]anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl -quinazolin-4-one (30 mg, 50.7 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 63.5 ^L), the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC[column: Phenomenex luna C18150 x 25mm, 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:37%-67% B over 10 min] to give 8-[(1R)-1-[2-(4-hydroxy-1-piperidyl)anilino]ethyl]-3,6-dimet hyl-2- tetrahydropyran-4-yl-quinazolin-4-one (7.6 mg, 15.9 μmol, 31%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.57 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.86 - 6.80 (m, 1H), 6.67 - 6.57 (m, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 - 5.25 (m, 1H), 4.25 - 4.13 (m, 2H), 3.97 - 3.77 (m, 1H), 3.70 (s, 3H), 3.67 - 3.60 (m, 2H), 3.33 - 3.10 (m, 3H), 2.88 - 2.62 (m, 2H), 2.43 (s, 3H), 2.37 (d, J = 2.0 Hz, 1H), 2.21 - 2.09 (m, 3H), 1.93 (d, J = 13.2 Hz, 2H), 1.89 - 1.75 (m, 3H), 1.67 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 477.3. Example 277. Preparation of 8-((R)-1-((4-fluoro-2-((R)-3-hydroxypiperidin-1- yl)phenyl)amino) ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4 (3H)- one (Compound 581) [2528] Step 1. Synthesis of 8-((R)-1-((2-((R)-3-((tert-butyldimethylsilyl)oxy)piperidin- 1-yl)- 4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-py ran-4-yl)quinazolin-4(3H)- one [2529] A mixture of [(3R)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl -dimethyl- silane (193 mg, 497 μmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (100 mg, 331 μmol), cesium carbonate (324 mg, 995 μmol), 1,3-bis[2,6- bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-i de;3- chloropyridine;dichloropalladium (32.2 mg, 33.1 μmol) in dioxane (1 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, Petroleum ether/Ethyl acetate=100/1 to 1/1) to give 8-[(1R)-1-[2-[(3R)-3-[tert- butyl(dimethyl)silyl]oxy-1-piperidyl]-4-fluoro-anilino]ethyl ]-3,6-dimethyl-2- tetrahydropyran-4-yl-quinazolin-4-one (140 mg, 223 μmol, 67%) as a black solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (s, 1H), 7.56 - 7.37 (m, 1H), 6.69 - 6.58 (m, 1H), 6.47 - 6.32 (m, 1H), 6.20 - 5.99 (m, 1H), 5.38 - 5.25 (m, 1H), 4.02 ~ 3.98 (m, 2H), 3.55 (s, 3H), 3.46 (dt, J = 1.6, 11.6 Hz, 2H), 3.13 - 2.94 (m, 2H), 2.52 - 2.43 (m, 1H), 2.25 (s, 3H), 2.10 - 1.98 (m, 2H), 1.81 - 1.73 (m, 3H), 1.47 (br. d, J = 6.8 Hz, 3H), 1.41 (s, 6H), 0.79 (s, 9H), 0.00 (d, J = 3.2 Hz, 6H); m/z ES+ [M+H] ⁺ 609.4. [2530] Step 2. Synthesis of 8-((R)-1-((4-fluoro-2-((R)-3-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2531] To a solution of 8-[(1R)-1-[2-[(3R)-3-[tert-butyl(dimethyl)silyl]oxy-1-piperi dyl]-4- fluoro-anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-qu inazolin-4-one (120 mg, 197 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 1 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(formic acid)- acetonitrile];gradient:45%-75% B over 10 min) to give 8-[(1R)-1-[4-fluoro-2-[(3R)-3- hydroxy-1-piperidyl]anilino]ethyl]-3,6-dimethyl-2-tetrahydro pyran-4-yl-quinazolin-4-one (58.4 mg, 118 μmol, 59%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.57 (s, 1H), 6.74 (dd, J = 2.4, 10.0 Hz, 1H), 6.52 (dt, J = 2.8, 8.4 Hz, 1H), 6.31 - 6.18 (m, 1H), 5.55 - 5.38 (m, 1H), 4.16 (d, J = 10.8 Hz, 2H), 4.07 (s, 1H), 3.71 (s, 3H), 3.65 - 3.58 (m, 2H), 3.15 - 3.10 (m, 1H), 3.08 - 2.96 (m, 2H), 2.94 - 2.78 (m, 1H), 2.42 (s, 3H), 2.27 - 2.05 (m, 3H), 1.98 - 1.88 (m, 3H), 1.85 - 1.71 (m, 2H), 1.60 (br. d, J = 6.8 Hz, 4H); m/z ES+ [M+H] ⁺ 495.3. Example 278. Preparation of 8-((R)-1-((4-fluoro-2-((S)-3-hydroxypiperidin-1- yl)phenyl)amino) ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4 (3H)- one (Compound 582) [2532] Step 1. Synthesis of 8-((R)-1-((2-((S)-3-((tert-butyldimethylsilyl)oxy)piperidin- 1-yl)- 4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-py ran-4-yl)quinazolin-4(3H)- one [2533] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (100 mg, 331 μmol) and [(3S)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy- tert-butyl-dimethyl-silane (128 mg, 331 μmol) in dioxane (2 mL) was added cesium carbonate (324 mg, 995 μmol) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidaz ol-1- ium-2-ide;3-chloropyridine;dichloropalladium (32.2 mg, 33.1 μmol). The mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, Petroleum ether/Ethyl acetate = 100/1 to 1/1) to give 8-[(1R)- 1-[2-[(3S)-3-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-4-f luoro-anilino]ethyl]-3,6-dimethyl- 2-tetrahydropyran-4-yl-quinazolin-4-one (160 mg, 252 μmol, 76%) as a brown solid. m/z ES+ [M+H] ⁺ 609.4. [2534] Step 2. Synthesis of 8-((R)-1-((4-fluoro-2-((S)-3-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2535] To a solution of 8-[(1R)-1-[2-[(3S)-3-[tert-butyl(dimethyl)silyl]oxy-1-piperi dyl]-4- fluoro-anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-qu inazolin-4-one (160 mg, 262 μmol) in dichloromethane (3 mL) was added hydrochloric acid/dioxane (4 M, 3.28 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:58%-82% B over 8 min) to give 8-[(1R)-1-[4-fluoro-2-[(3S)-3-hydroxy- 1-piperidyl]anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4- yl-quinazolin-4-one (85.4 mg, 172 μmol, 65%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.55 (s, 1H), 6.71 (m, 1H), 6.50 (m, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.42 (d, J = 6.0 Hz, 1H), 4.21 - 4.11 (m, 2H), 4.05 (s, 1H), 3.69 (s, 3H), 3.65 - 3.55 (m, 2H), 3.12 (m, 2H), 2.89 (d, J = 4.0 Hz, 2H), 2.41 (s, 3H), 2.30 - 1.99 (m, 4H), 1.90 (d, J = 13.6 Hz, 3H), 1.82 - 1.72 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 495.3. Example 279. Preparation of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-4-fluorobenzoic acid (Compound 613) [2536] Step 1. Synthesis of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)-4-fluorobenzoic acid [2537] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (100 mg, 332 μmol) in dimethyl acetamide (1 mL) was added 4-fluoro-2- iodo-benzoic acid (265 mg, 995 μmol), copper (21.1 mg, 332 μmol) and triethylamine (336 mg, 3.32 mmol) .The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:53%-77% B over 8 min) to give 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]amino]-4-fluoro-b enzoic acid (17.6 mg, 39.8 μmol, 12%) was obtained as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 - 8.32 (m, 1H), 8.01 - 7.92 (m, 2H), 7.53 (d, J = 1.2 Hz, 1H), 6.32 - 6.15 (m, 2H), 5.63 - 5.51 (m, 1H), 4.23 - 4.14 (m, 2H), 3.72 (s, 3H), 3.62 (br. t, J = 11.6 Hz, 2H), 3.21 - 3.11 (m, 1H), 2.42 (s, 3H), 2.36 - 2.27 (m, 1H), 2.21 - 2.12 (m, 1H), 1.97 - 1.89 (m, 2H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 440.2. Example 280. Preparation of (R)-8-(1-((3-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 660)

[2538] Step 1. Synthesis of 1-(2-fluoro-6-nitrophenyl)piperidin-4-ol [2539] To a solution of 1,2-difluoro-3-nitro-benzene (5.00 g, 31.4 mmol) in dimethyl acetamide (50 mL) was added cesium carbonate (30.7 g, 94.3 mmol) and piperidin-4-ol (3.18 g, 31.4 mmol) at 25 °C. The mixture was stirred at 80 °C for 2 hr. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 3/1) to give 1-(2-fluoro-6-nitro-phenyl)piperidin-4-ol (6.67 g, 27.8 mmol, 88%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 - 7.56 (m, 1H), 7.50 (ddd, J = 1.4, 8.4, 12.0 Hz, 1H), 7.27 (dt, J = 5.2, 8.2 Hz, 1H), 4.68 (d, J = 4.4 Hz, 1H), 3.61 (qt, J = 4.0, 8.6 Hz, 1H), 3.14 - 3.06 (m, 2H), 2.94 - 2.85 (m, 2H), 1.82 - 1.71 (m, 2H), 1.50 – 1.40 (m, 2H); m/z ES+[M+H] ⁺ 240.8. [2540] Step 2. Synthesis of 1-(2-amino-6-fluorophenyl)piperidin-4-ol [2541] To a suspension of palladium on activated carbon (532 mg, 500 μmol, 10% loading) in methanol (60 mL) was added 1-(2-fluoro-6-nitro-phenyl)piperidin-4-ol (6.00 g, 25.0 mmol) portionwise under nitrogen atmosphere. The suspension was degassed and purged with hydrogen (3x) and then stirred at 20 °C for 3 h under hydrogen atmosphere (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 3/1) to give 1-(2-amino-6-fluoro-phenyl)piperidin-4-ol (4.55 g, 21.2 mmol, 85%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 6.80 (dt, J = 6.4, 8.0 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 6.24 (ddd, J = 1.2, 8.2, 12.4 Hz, 1H), 5.16 (s, 2H), 4.67 (br. s, 1H), 3.49 (br. s, 1H), 3.08 - 2.68 (m, 4H), 1.85 - 1.75 (m, 2H), 1.54 (br. d, J = 8.8 Hz, 2H); m/z ES ⁺ [M+H] ⁺ 211.0. [2542] Step 3. Synthesis of 1-(2-bromo-6-fluorophenyl)piperidin-4-ol [2543] To a suspension of 1-(2-amino-6-fluoro-phenyl)piperidin-4-ol (4.55 g, 21.6 mmol) in water (33 mL) was added concentrated sulfuric acid (2.38 g, 23.8 mmol), sodium nitrite (1.64 g, 23.8 mmol) and water (8 mL) at 0 °C. The mixture was stirred at 20 °C for 1.5 hr. Then water (8 mL), sodium bromide (8.91 g, 86.6 mmol) and copper(I) bromide (3.10 g, 21.64 mmol) was added sequentially at 20 °C, The mixture was stirred at 80 °C for 1.5 hr. The reaction was neutralized to pH ~ 7 with aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (250 mL ×2). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 3/1) to give 1- (2-bromo-6-fluoro-phenyl)piperidin-4-ol (4.45 g, 15.68 mmol, 73%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.44 (d, J = 8.0 Hz, 1H), 7.19 (ddd, J = 1.4, 8.4, 12.2 Hz, 1H), 7.09 - 7.01 (m, 1H), 4.66 (br. d, J = 3.8 Hz, 1H), 3.62 (br. d, J = 3.8 Hz, 1H), 3.11 (br. s, 2H), 3.02 – 2.92 (m, 2H), 1.87 - 1.76 (m, 2H), 1.61 - 1.46 (m, 2H); m/z ES+ [M+H] ⁺ 275.7. [2544] Step 4. Synthesis of 1-(2-bromo-6-fluorophenyl)-4-((tert- butyldimethylsilyl)oxy)piperidine [2545] To a solution of 1-(2-bromo-6-fluoro-phenyl)piperidin-4-ol (4.83 g, 17.6 mmol) in dimethyl formamide (48 mL) was added imidazole (3.00 g, 44.1 mmol) and tert- butyldimethylsilyl chloride (3.98 g, 26.4 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction was neutralized to pH ~ 7 with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (250 mL × 2). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/0) to give [1-(2-bromo-6-fluoro-phenyl)-4-piperidyl]oxy-tert- butyl-dimethyl-silane (5.54 g, 14.3 mmol, 81%) as a colourless liquid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.41 (m, 1H), 7.19 (ddd, J = 1.4, 8.4, 12.2 Hz, 1H), 7.05 (dt, J = 5.6, 8.0 Hz, 1H), 3.87 (br. d, J = 1.4 Hz, 1H), 3.17 (br. s, 2H), 2.96 (br. s, 2H), 1.82 (ddd, J = 3.2, 5.6, 9.0 Hz, 2H), 1.64 - 1.52 (m, 2H), 0.88 (s, 9H), 0.07 (s, 6H); m/z ES+ [M+H] ⁺ 389.9. [2546] Step 5. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-3- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyra n-4-yl)quinazolin-4(3H)-one [2547] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (200 mg, 664 μmol) in dioxane (10 mL) was added [1-(2-bromo-6-fluoro- phenyl)-4-piperidyl]oxy-tert-butyl-dimethyl-silane (515 mg, 1.33 mmol), 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3 chloropyridine;dichloropalladium (194 mg, 199 μmol) and cesium carbonate (649 mg, 1.99 mmol). The mixture was stirred at 110 °C for 16 hr under nitrogen. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (80 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin- 1-yl)-3-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro -2H-pyran-4-yl)quinazolin- 4(3H)-one (213 mg, 350 μmol, 53%) as a purple solid. m/z ES+ [M+H] ⁺ 609.5. [2548] Step 6. Synthesis of (R)-8-(1-((3-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2549] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 3-fluoro- anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazoli n-4-one (163 mg, 268 μmol) in dichloromethane (1.6 mL) was added hydrochloric acid/dioxane (4 M, 1.67 mL). The mixture was stirred at 20 °C for 1 hr. The mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Welch Ultimate C18 150x25mmx5um;mobile phase: [water(formic acid)-acetonitrile];gradient:37%-67% B over 11 min) followed by lyophilization to give (R)-8-(1-((3-fluoro-2-(4-hydroxypiperidin-1-yl)phenyl)amino) ethyl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (55.1 mg, 111 μmol, 42%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77 (s, 1H), 7.51 (s, 1H), 6.78 - 6.70 (m, 1H), 6.29 - 6.21 (m, 1H), 6.14 (d, J = 7.8 Hz, 1H), 5.81 - 5.72 (m, 1H), 5.47 (br. t, J = 7.0 Hz, 1H), 4.77 (br. d, J = 3.6 Hz, 1H), 4.02 - 3.95 (m, 2H), 3.62 (s, 3H), 3.57 - 3.48 (m, 3H), 3.04 (br. t, J = 12.0 Hz, 2H), 2.92 - 2.76 (m, 2H), 2.39 - 2.30 (m, 4H), 1.95 – 1.85 (m, 7H), 1.60 – 1.50 (m, 4H); m/z ES+ [M+H] ⁺ 495.4. Example 281. Preparation of (R)-8-(1-((5-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 656) [2550] Step 1. Synthesis of 1-(4-fluoro-2-nitrophenyl)piperidin-4-ol [2551] To a solution of 1,4-difluoro-2-nitro-benzene (5.00 g, 31.4 mmol) and piperidin-4-ol (3.18 g, 31.4 mmol) in dimethyl acetamide (50 mL) was added cesium carbonate (30.7 g, 94.2 mmol). The mixture was stirred at 100 °C for 12 hr. On completion, the reaction mixture was diluted with water 150 mL and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=0/1 to 3/1) to give 1- (4-fluoro-2-nitro-phenyl)piperidin-4-ol (5.50 g, 22.6 mmol, 72%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (dd, J = 2.8, 8.4 Hz, 1H), 7.55 - 7.44 (m, 1H), 7.44 - 7.37 (m, 1H), 4.70 (d, J = 4.4 Hz, 1H), 3.62 (dt, J = 4.4, 8.4 Hz, 1H), 3.12 - 3.03 (m, 2H), 2.83 - 2.73 (m, 2H), 1.84 - 1.76 (m, 2H), 1.53 - 1.44 (m, 2H); m/z ES+ [M+H] ⁺ 241.0. [2552] Step 2. Synthesis of 1-(2-amino-4-fluorophenyl)piperidin-4-ol [2553] To a solution of 1-(4-fluoro-2-nitro-phenyl)piperidin-4-ol (0.50 g, 2.08 mmol) in ethanol (1 mL) was added aqueous ammonium chloride (8 M, 20.8 mmol, 2.60 mL) and iron powder (581 mg, 10.4 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was filtered and the filtrate was washed with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(2-amino-4-fluoro-phenyl)piperidin-4-ol (0.4 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 211.1. [2554] Step 3. Synthesis of 1-(2-bromo-4-fluorophenyl)piperidin-4-ol [2555] 1-(2-amino-4-fluoro-phenyl)piperidin-4-ol (0.40 g, 1.90 mmol) was added slowly into a solution of concentrated sulfuric acid (209 mg, 2.09 mmol, 98% purity) in water (2 mL) at 0 °C. Then sodium nitrite (144 mg, 2.09 mmol) was dissolved in water (1 mL) and slowly added into the above mixture, controlling the temperature at 0~10 °C. After that, the mixture was warmed to 25 °C and stirred at 25 °C for 1.5 h to form a diazonium salt. Further, a suspension of sodium bromide (783 mg, 7.61 mmol) and copper(I) bromide (272 mg, 1.90 mmol) in water (1 mL) was added into the above mixture and the mixture was stirred at 80 °C for 1.5 hr under nitrogen. On completion, the reaction mixture was diluted with water 30 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 3/1) to give 1-(2-bromo-4-fluoro- phenyl)piperidin-4-ol (0.30 g, 787 μmol, 41%) as a yellow oil. m/z ES+ [M+H] ⁺ 274.1. [2556] Step 4. Synthesis of 1-(2-bromo-4-fluorophenyl)-4-((tert- butyldimethylsilyl)oxy)piperidine [2557] To a solution of 1-(2-bromo-4-fluoro-phenyl)piperidin-4-ol (0.30 g, 1.09 mmol) in N,N-dimethylformamide (3 mL) was added imidazole (186 mg, 2.74 mmol) and tert-butyl- chloro-dimethyl-silane (247 mg, 1.64 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was quenched by aqueous ammonium chloride (20 mL) at 25 °C, and then diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=15/1 to 5/1) to give [1-(2-bromo-4-fluoro-phenyl)-4-piperidyl]oxy-tert-butyl-dime thyl-silane (0.35 g, 883 μmol, 81%) as a white oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55 - 7.50 (m, 1H), 7.22 - 7.16 (m, 2H), 3.86 (td, J = 4.0, 7.6 Hz, 1H), 3.10 - 3.00 (m, 2H), 2.79 - 2.69 (m, 2H), 1.85 (tdd, J = 3.2, 6.0, 12.0 Hz, 2H), 1.66 - 1.52 (m, 2H), 0.88 (s, 9H), 0.07 (s, 6H); m/z ES+ [M+H] ⁺ 388.0 [2558] Step 5. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-5- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyra n-4-yl)quinazolin-4(3H)-one [2559] To a solution of [1-(2-bromo-4-fluoro-phenyl)-4-piperidyl]oxy-tert-butyl-dime thyl- silane (0.20 g, 514 μmol) and 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (77.6 mg, 257 μmol) in dioxane (2 mL) was added 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (50.0 mg, 51.4 μmol) and cesium carbonate (251 mg, 772 μmol). The mixture was stirred at 110 °C for 3 hr under nitrogen. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 5-fluoro-anilino]ethyl]-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (0.12 g, 197 μmol, 77%) as a purple oil. m/z ES+ [M+H] ⁺ 609.5. [2560] Step 6. Synthesis of (R)-8-(1-((5-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2561] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 5-fluoro- anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazoli n-4-one (80.0 mg, 131 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:41%-71% B over 10 min) to give (R)-8-(1-((5-fluoro-2-(4-hydroxypiperidin-1-yl)phenyl)amino) ethyl)-3,6- dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (42.5 mg, 86.0 μmol, 65%) as a pink solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (s, 1H), 7.62 (s, 1H), 6.98 - 6.85 (m, 1H), 6.22 (br. t, J = 8.8 Hz, 1H), 6.19 - 6.12 (m, 1H), 5.60 (br. d, J = 6.4 Hz, 1H), 5.43 - 5.28 (m, 1H), 4.75 - 4.59 (m, 1H), 3.99 (br. t, J = 9.2 Hz, 2H), 3.62 (s, 3H), 3.56 - 3.50 (m, 2H), 3.01 - 2.81 (m, 2H), 2.65 – 2.55 (m, 2H), 2.38 (s, 3H), 2.00 - 1.86 (m, 7H), 1.70 - 1.53 (m, 6H); m/z ES+ [M+H] ⁺ 495.5. Example 282. Preparation of (R)-8-(1-((4-fluoro-2-((4- hydroxycyclohexyl)(methyl)amino)phenyl)amino)ethyl)-3,6-dime thyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one (Compound 722) [2562] Step 1. Synthesis of 4-((2-bromo-5-fluorophenyl)amino)cyclohexan-1-ol [2563] To a solution of 4-aminocyclohexanol (1.00 g, 8.68 mmol) and 1-bromo-4-fluoro-2- iodo-benzene (2.87 g, 9.55 mmol) in propan-2-ol (10 mL) was added sodium hydroxide (695 mg, 17.4 mmol) and copper iodide (49.6 mg, 260 μmol). The mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 40/60) to give 4-(2-bromo-5-fluoro- anilino)cyclohexanol (600 mg, 1.37 mmol, 3.16%, obtained from 5 batches) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 - 7.33 (m, 1H), 6.80 - 6.27 (m, 2H), 4.55 - 4.21 (m, 1H), 4.03 - 3.65 (m, 1H), 3.53 - 3.06 (m, 1H), 2.26 - 1.48 (m, 8H); m/z ES+ [M+H] ⁺ 288.0. [2564] Step 2. Synthesis of 2-bromo-N-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5- fluoroaniline [2565] To a solution of 4-(2-bromo-5-fluoro-anilino)cyclohexanol (600 mg, 2.08 mmol) in N,N-dimethylformamide (6 mL) was added tert-butylchlorodimethylsilane (471 mg, 3.12 mmol, 384 ^L) and imidazole (354 mg, 5.21 mmol). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 98/2) to give 2-bromo-N-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-5- fluoro-aniline (600 mg, 1.49 mmol, 71%) as a white oil. m/z ES+ [M+H] ⁺ 402.2. [2566] Step 3. Synthesis of 2-bromo-N-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5- fluoro-N-methylaniline [2567] To a solution of 2-bromo-N-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-5-flu oro- aniline (270 mg, 671 μmol) in methanol (2 mL) was added acetic acid (80.6 mg, 1.34 mmol, 76.8 ^L) and formaldehyde (252 mg, 3.35 mmol, 231 ^L, 40% purity). The mixture was stirred at 25 °C for 0.2 h. Then sodium cyanoborohydride (181 mg, 2.89 mmol) was added in portions. The mixture was stirred at 25 °C for 0.8 h. Then the mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1) to give 2-bromo-N-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]- 5-fluoro-N-methyl-aniline (185 mg, 278 μmol, 42%) as a white oil. m/z ES+ [M+H] ⁺ 416.1. [2568] Step 4. Synthesis of (R)-8-(1-((2-((4-((tert- butyldimethylsilyl)oxy)cyclohexyl)(methyl)amino)-4-fluorophe nyl)amino)ethyl)-3,6- dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2569] To a solution of 2-bromo-N-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-5-flu oro-N- methyl-aniline (182 mg, 438 μmol) and 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2- tetrahydropyran-4-yl-quinazolin-4-one (120 mg, 398 μmol) in dioxane (2 mL) was added 1,3- bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1 -ium-2-ide;3- chloropyridine;dichloropalladium (38.7 mg, 39.8 μmol) and cesium carbonate (389 mg, 1.19 mmol). The mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. The reaction mixture was diluted with water 10 mL and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 40/60) and then re-purified by prep-HPLC (column: Welch Ultimate XB-CN 250x50x10um;mobile phase: [Hexane-ethanol];gradient:1%-15% B over 15 min) to give 8- [(1R)-1-[2-[[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-met hyl-amino]-4-fluoro- anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazoli n-4-one (110 mg, 159 μmol, 40%) as a yellow solid. m/z ES+ [M+H] ⁺ 637.3. [2570] Step 5. Synthesis of (R)-8-(1-((4-fluoro-2-((4- hydroxycyclohexyl)(methyl)amino)phenyl)amino)ethyl)-3,6-dime thyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2571] To a solution of 8-[(1R)-1-[2-[[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-m ethyl- amino]-4-fluoro-anilino]ethyl]-3,6-dimethyl-2-tetrahydropyra n-4-yl-quinazolin-4-one (100 mg, 157 μmol) in dioxane (0.5 mL) was added hydrochloric acid/dioxane (0.5 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue.The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water(formic acid)-acetonitrile];gradient:49%-79% B over 10 min) to give (R)-8-(1-((4-fluoro-2-((4- hydroxycyclohexyl)(methyl)amino)phenyl)amino)ethyl)-3,6-dime thyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one (40.7 mg, 77.9 μmol, 50%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.51 (d, J = 12.4 Hz, 1H), 6.83 - 6.75 (m, 1H), 6.57 - 6.41 (m, 1H), 6.29 - 6.15 (m, 1H), 5.45 – 5.35 (m, 1H), 4.18 - 4.12 (m, 2H), 3.99 (s, 1H), 3.69 (s, 3H), 3.64 - 3.58 (m, 2H), 3.16 - 3.06 (m, 1H), 3.01 - 2.83 (m, 1H), 2.65 (d, J = 4.4 Hz, 3H), 2.39 (s, 3H), 2.29 - 2.13 (m, 2H), 2.10 – 2.00 (m, 1H), 1.95 - 1.80 (m, 6H), 1.60 - 1.58 (m, 3H), 1.56 - 1.48 (m, 2H), 1.43 - 1.22 (m, 2H); m/z ES+ [M+H] ⁺ 523.3. Example 283. Preparation of (R)-8-(1-((2-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)oxy)-4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahyd ro-2H-pyran-4- yl)quinazolin-4(3H)-one (Compound 671) [2572] Step 1. Synthesis of 4-(2-bromo-5-fluorophenoxy)tetrahydro-2H-thiopyran [2573] To a solution of 2-bromo-5-fluoro-phenol (800 mg, 4.19 mmol), tetrahydrothiopyran- 4-ol (544 mg, 4.61 mmol) and triphenylphosphane (1.43 g, 5.45 mmol) in anhydrous tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (2.75 g, 5.45 mmol) at 0 °C. The mixture was stirred at 0 °C for 1.5 hr. Then additional tetrahydrothiopyran-4-ol (248 mg, 2.09 mmol), triphenylphosphane (659 mg, 2.51 mmol) and diisopropyl azodicarboxylate (1.27 g, 2.51 mmol) were added, and the mixture was further stirred at 25 °C for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1to 1/1) and then re-purified by prep-TLC (petroleum ether: ethyl acetate = 10:1) to give 4-(2-bromo-5- fluoro-phenoxy)tetrahydrothiopyran (500 mg, 1.72 mmol, 41%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.51 - 7.47 (m, 1H), 6.66 - 6.58 (m, 2H), 4.49 - 4.44 (m, 1H), 3.14 - 3.00 (m, 2H), 2.54 - 2.48 (m, 2H), 2.21 - 2.11 (m, 4H). [2574] Step 2. Synthesis of 4-(2-bromo-5-fluorophenoxy)tetrahydro-2H-thiopyran 1,1- dioxide [2575] To a solution of 4-(2-bromo-5-fluoro-phenoxy)tetrahydrothiopyran (500 mg, 1.72 mmol) in dichloromethane (5 mL) was added 3-chloroperoxybenzoic acid (1.05 g, 5.15 mmol) portionwise at 0 °C. Then the reaction mixture was stirred at 25 °C for 6 hr. The reaction mixture was diluted with water 10 mL and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine 40 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to give 4-(2-bromo-5-fluoro- phenoxy)thiane 1,1-dioxide (350 mg, 1.08 mmol, 63%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ ppm 7.49 (dd, J = 8.8, 6.4 Hz, 1H), 6.67 - 6.55 (m, 2H), 4.55 – 4.40 (m, 1H), 3.15 – 3.00 (m, 2H), 2.60 – 2.48 (m, 2H), 2.20 – 2.10 (m, 4H). [2576] Step 3. Synthesis of (R)-8-(1-((2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)- 4- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyra n-4-yl)quinazolin-4(3H)-one [2577] A mixture of 4-(2-bromo-5-fluoro-phenoxy)thiane 1,1-dioxide (150 mg, 464 μmol), 8- [(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-quin azolin-4-one (210 mg, 696 μmol), cesium carbonate (453 mg, 1.39 mmol), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5- dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine dichloropalladium (45.1 mg, 46.41 μmol) in dioxane (5 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 100 °C for 2 hr under nitrogen atmosphere. The reaction mixture was quenched by water (10 mL), and then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:45%-65% B over 10 min) to give (R)-8-(1-((2-((1,1- dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-4-fluorophenyl)amin o)ethyl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (175 mg, 322 μmol, 69%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.95 (s, 1H), 7.51 (s, 1H), 6.60 - 6.55 (m, 1H), 6.45 - 6.40 (m, 1H), 6.34 - 6.27 (m, 1H), 5.34 (q, J = 6.8 Hz, 1H), 4.63 (s, 1H), 4.15 (d, J = 11.6 Hz, 2H), 3.69 (s, 3H), 3.65 - 3.56 (m, 2H), 3.49- 3.39 (m, 2H), 3.17 - 3.09 (m, 1H), 3.04 (d, J = 14.8 Hz, 2H), 2.62 - 2.51 (m, 2H), 2.50 - 2.40 (m, 5H), 2.26 - 2.06 (m, 2H), 1.95 - 1.86 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+1] ⁺ 544.3. Example 284. Preparation of (R)-8-(1-((3,4-difluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 713) [2578] Step 1. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-3,4- difluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-py ran-4-yl)quinazolin-4(3H)- one [2579] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (70.0 mg, 232 μmol) in dioxane (1 mL) was added [1-(6-bromo-2,3-difluoro- phenyl)-4-piperidyl]oxy-tert-butyl-dimethyl-silane (283 mg, 696 μmol), 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (45.1 mg, 46.4 μmol) and cesium carbonate (227 mg, 696 μmol), the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 1/1) to give 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1- piperidyl]-3,4-difluoro-anilino]ethyl]-3,6-dimethyl-2-tetrah ydropyran-4-yl-quinazolin-4-one (100 mg, 111 μmol, 48%) as a brown solid. m/z ES+ [M+H] ⁺ 627.4. [2580] Step 2. Synthesis of (R)-8-(1-((3,4-difluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2581] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 3,4- difluoro-anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (100 mg, 159 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 0.5 mL), the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC [column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:50%-80% B over 10 min] to give (R)-8-(1-((3,4-difluoro-2-(4-hydroxypiperidin-1-yl)phenyl)am ino)ethyl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (24.5 mg, 46.4 μmol, 29%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.45 (s, 1H), 6.62 (q, J = 9.2 Hz, 1H), 5.97 (d, J = 1.2 Hz, 1H), 5.64 - 5.26 (m, 2H), 4.23 - 4.09 (m, 2H), 3.90 – 3.76 (m, 1H), 3.69 (s, 3H), 3.61 (t, J = 11.6 Hz, 2H), 3.25 - 3.01 (m, 4H), 2.41 (s, 3H), 2.33 - 2.22 (m, 1H), 2.21 - 2.08 (m, 3H), 1.91 (d, J = 13.2 Hz, 3H), 1.79 - 1.68 (m, 2H), 1.59 (d, J = 5.6 Hz, 3H); m/z ES+ [M+H] ⁺ 513.4. Example 285. Preparation of (R)-8-(1-((4,5-difluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 696) [2582] Step 1. Synthesis of 1-(4,5-difluoro-2-nitrophenyl)piperidin-4-ol [2583] To a solution of 1,2,4-trifluoro-5-nitro-benzene (10.0 g, 56.4 mmol), piperidin-4-ol (5.14 g, 50.8 mmol) in acetonitrile (60 mL) was added diisopropylethylamine (21.9 g, 169 mmol). The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by water 100 mL and then extracted with ethyl acetate (100mL x 3). The combined organic layers were washed with brine (90mL), dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 1-(4,5-difluoro-2-nitro- phenyl)piperidin-4-ol (2.00 g, 7.75 mmol, 13.7%) (Note: The structure was confirmed by NOE) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.80 (t, J = 9.3 Hz, 1H), 6.96 (dd, J = 7.2, 12.0 Hz, 1H), 4.00 – 3.90 (m, 1H), 3.30 – 3.20 (m, 2H), 2.90 – 2.80 (m, 2H), 2.10 – 2.00 (m, 2H), 1.80 – 1.70 (m, 2H); m/z ES+ [M+1] ⁺ 259.1. [2584] Step 2. Synthesis of 1-(2-amino-4,5-difluorophenyl)piperidin-4-ol [2585] A mixture of 1-(4,5-difluoro-2-nitro-phenyl)piperidin-4-ol (1.80 g, 6.97 mmol), ammonium chloride (7.46 g, 139 mmol), iron powder (2.34 g, 41.8 mmol) in ethanol (4 mL) and water (0.4 mL) was stirred at 80 °C for 1 hr under nitrogene atmosphere. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 1/1) to give 1-(2-amino-4,5-difluoro-phenyl)piperidin-4-ol (900 mg, 3.88 mmol, 56%) as a white solid. m/z ES+ [M+1] ⁺ 229.1. [2586] Step 3. Synthesis of 1-(2-bromo-4,5-difluorophenyl)piperidin-4-ol [2587] 1-(2-amino-4,5-difluoro-phenyl)piperidin-4-ol (900 mg, 3.94 mmol) was added portionwise into a solution of concentrated sulfuric acid (425 mg, 4.34 mmol) in water (10 mL) at 0 °C. Then sodium nitrite (299 mg, 4.34 mmol) in water (1 mL) was added dropwise into the above solution, controlling the temperature at 0~10 °C. The mixture was then raised to 25 °C, and stirred at 25 °C for 1.5 h. A suspension of sodium bromide (1.62 g, 15.77 mmol) and copper(I) bromide (566 mg, 3.94 mmol) in water (1 mL) was then added and the mixture was stirred at 80 °C for 3 hr. On completion, the mixture was quenched with ammonium hydroxide (40 mL), then diluted with water (100 mL) and extracted with ethyl acetate (100 mL ×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 5/1) to give 1-(2-bromo-4,5-difluoro- phenyl)piperidin-4-ol (900 mg, 3.08 mmol, 78%) as a white solid. m/z ES+ [M+1] ⁺ 292.0. [2588] Step 4. Synthesis of 1-(2-bromo-4,5-difluorophenyl)-4-((tert- butyldimethylsilyl)oxy)piperidine [2589] To a mixture of 1-(2-bromo-4,5-difluoro-phenyl)piperidin-4-ol (900 mg, 3.08 mmol) in N,N-dimethylformamide (10 mL) was added tert-butylchlorodimethylsilane (696 mg, 4.62 mmol) and imidazole (524 mg, 7.70 mmol). The mxiture was stirred at 25 °C for 1 hr. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL ×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 5/1) to give [1-(2-bromo-4,5-difluoro-phenyl)-4- piperidyl]oxy-tert-butyl-dimethyl-silane (900 mg, 2.09 mmol, 68%) as a white solid. m/z ES+ [M+1] ⁺ 408.0 [2590] Step 5. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4,5- difluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-py ran-4-yl)quinazolin-4(3H)- one [2591] A mixture of [1-(2-bromo-4,5-difluoro-phenyl)-4-piperidyl]oxy-tert-butyl- dimethyl- silane (202 mg, 497 μmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (100 mg, 331 μmol), cesium carbonate (324 mg, 995 μmol), 1,3-bis[2,6- bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-i de;3- chloropyridine;dichloropalladium (32.2 mg, 33.1 μmol) in dioxane (1 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched by water (10 mL), and then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-[(1R)-1-[2-[4-[tert- butyl(dimethyl)silyl]oxy-1-piperidyl]-4,5-difluoro-anilino]e thyl]-3,6-dimethyl-2- tetrahydropyran-4-yl-quinazolin-4-one (120 mg, 184 μmol, 55%) as a white solid. m/z ES+ [M+1] ⁺ 627.3. [2592] Step 6. Synthesis of (R)-8-(1-((4,5-difluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2593] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4,5- difluoro-anilino]ethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (120 mg, 191 μmol) in dichloromethane (3 mL) was added hydrochloric acid/dioxane (4 M, 3.16 mL). The mixture was stirred at 25 °C for 0.1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:50%-80% B over 10 min) to give (R)-8-(1-((4,5-difluoro-2-(4-hydroxypiperidin-1-yl)phenyl)am ino)ethyl)- 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-on e (70.39 mg, 137 μmol, 72%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.48 (br. s, 1H), 6.85 - 6.72 (m, 1H), 6.29 - 6.12 (m, 1H), 5.27 - 5.21 (m, 1H), 4.22 - 4.14 (m, 2H), 4.01 - 3.74 (m, 1H), 3.70 (s, 3H), 3.62 (t, J = 12.0 Hz, 2H), 3.18 - 3.08 (m, 2H), 2.90 - 2.50 (m, 2H), 2.43 (s, 3H), 2.40 - 2.30 (m, 1H), 2.14 - 2.09 (m, 2H), 1.96 - 1.91 (m, 2H), 1.85 - 1.75 (m, 2H), 1.64 (d, J = 5.2 Hz, 3H), 1.58 (s, 2H); m/z ES+ [M+1] ⁺ 513.3. Example 286. Preparation of (R)-8-(1-((4-fluoro-2-(3-oxo-1,4-diazepan-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 765) [2594] Step 1. Synthesis of (R)-8-(1-((4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2595] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl-qu inazolin- 4-one (500 mg, 1.66 mmol), 1-bromo-4-fluoro-benzene (1.45 g, 8.30 mmol), cesium carbonate (1.62 g, 4.98 mmol), tris(dibenzylideneacetone)dipalladium (151 mg, 165 μmol) and dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (154 mg, 331 μmol) in toluene (10 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (120 mL ×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give (R)-8-(1-((4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (400 mg, 1.01 mmol, 61%) as a white solid. m/z ES+ [M+1] ⁺ 396.4. [2596] Step 2. Synthesis of (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2597] To a solution of (R)-8-(1-((4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetra hydro- 2H-pyran-4-yl)quinazolin-4(3H)-one (1.55 g, 3.92 mmol) in N,N-dimethylformamide (10 mL) was added 1-bromopyrrolidine-2,5-dione (558 mg, 3.14 mmol) portionwise at 0 °C over 0.2 h. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (120 mL ×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) and then re-purified by reversed- phase HPLC (0.1% formic acid condition) to give (R)-8-(1-((2-bromo-4- fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyra n-4-yl)quinazolin-4(3H)-one (700 mg, 1.29 mmol, 33%) as a white solid. m/z ES+ [M+1] ⁺ 474.1. [2598] Step 3. Synthesis of (R)-8-(1-((4-fluoro-2-(3-oxo-1,4-diazepan-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2599] To a solution of (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (100 mg, 210 μmol), 1,4-diazepan-2- one;hydrochloride (31.7 mg, 210 μmol) in dioxane (4 mL) was added cesium carbonate (206 mg, 632 μmol) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidaz ol-1-ium-2- ide;3-chloropyridine;dichloropalladium (20.5 mg, 21.0 μmol). The mixture was stirred at 100 °C for 12 hr under nitrogen. The reaction mixture was quenched by water (10 mL), and then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:44%-64% B over 9 min) to give (R)-8-(1-((4-fluoro-2-(3-oxo-1,4- diazepan-1-yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro -2H-pyran-4-yl)quinazolin- 4(3H)-one (10.8 mg, 21.24 μmol, 10%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.64 (d, J = 1.4 Hz, 1H), 6.78 - 6.75 (m, 1H), 6.55 - 6.50 (m, 1H), 6.35 - 6.32 (m, 1H), 6.03 - 6.00 (m, 1H), 5.50 – 5.43 (m, 1H), 4.20 - 4.12 (m, 2H), 3.75 (s, 2H), 3.69 (s, 3H), 3.65 - 3.56 (m, 2H), 3.50 - 3.44 (m, 2H), 3.30 - 3.27 (m, 2H), 3.19 - 3.09 (m, 1H), 2.42 (s, 3H), 2.26 - 2.11 (m, 2H), 2.07 - 2.01 (m, 2H), 1.92 - 1.89 (m, 2H), 1.64 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 508.3. Example 287. Preparation of (R)-8-(1-((4-fluoro-2-(5-oxo-1,4-diazepan-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 761) [2600] Step 1. Synthesis of (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2601] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (1.00 g, 3.32 mmol) and (2-bromo-4-fluoro-phenyl)boronic acid (7.26 g, 33.1 mmol) in dichloromethane (20 mL) was added copper acetate (1.21 g, 6.64 mmol), triethylamine (3.36 g, 33.18 mmol) and 4Å molecular sieves (1.00 g, 3.32 mmol). The mixture was stirred at 25 °C for 10 hr under oxygen atmosphere (15 psi). Then (2-bromo-4-fluoro- phenyl)boronic acid (7.26 g, 33.1 mmol) was added and the mixture was stirred at 25 °C for 6 hr under oxygen atmosphere (15 psi). The reaction mixture was diluted with 1 N ammonium chloride (50 mL) and extracted with dichloromethane (30 mL× 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give (R)-8-(1- ((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrah ydro-2H-pyran-4- yl)quinazolin-4(3H)-one (280 mg, 590 μmol, 17.8%) as a white solid. m/z ES+ [M+1] ⁺ 474.1. [2602] Step 2. Synthesis of (R)-8-(1-((4-fluoro-2-(5-oxo-1,4-diazepan-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2603] To a solution of (R)-8-(1-((2-bromo-4-fluorophenyl)amino)ethyl)-3,6-dimethyl- 2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (100 mg, 211 μmol) and 1,4-diazepan-5-one (96.2 mg, 843 μmol) in 2-methylbutan-2-ol (2.0 mL) was added dicyclohexyl-[3,6-dimethoxy- 2-(2,4,6-triisopropylphenyl)phenyl]phosphane;methanesulfonat e;[2-[2- (methylamino)phenyl]phenyl] [2604] palladium(1+) (19.41 mg, 21.0 μmol) and sodium;2-methylpropan-2-olate (2 M in tetrahydrofuran, 316 ^L). The mixture was stirred at 95 °C for 12 hr under nitrogen. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=0/1) and then re-purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:41%-68% B over 9 min) to give (R)-8-(1-((4-fluoro- 2-(5-oxo-1,4-diazepan-1-yl)phenyl)amino)ethyl)-3,6-dimethyl- 2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one (2.5 mg, 4.79 μmol, 2.27%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.48 (s, 1H), 7.42 - 7.29 (m, 1H), 6.75 - 6.67 (m, 1H), 6.55 - 6.50 (m, 1H), 6.26 - 6.22 (m, 1H), 6.05 (s, 1H), 5.44 (q, J = 6.4 Hz, 1H), 4.15 (d, J = 11.2 Hz, 2H), 3.70 (s, 3H), 3.64 - 3.50 (m, 4H), 3.18 - 3.03 (m, 5H), 2.89 - 2.82 (m, 2H), 2.40 (s, 3H), 2.28 - 2.09 (m, 2H), 1.91 (d, J = 12.8 Hz, 2H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+1] ⁺ 508.3. Example 288. Preparation of (R)-8-(1-((4-fluoro-2-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 737) [2605] Step 1. Synthesis of (R)-8-(1-((2-(4-(2-((tert-butyldimethylsilyl)oxy)acetyl)pipe razin- 1-yl)-4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro -2H-pyran-4-yl)quinazolin- 4(3H)-one [2606] A mixture of 1-[4-(2-bromo-5-fluoro-phenyl)piperazin-1-yl]-2-[tert- butyl(dimethyl)silyl]oxy-ethanone (286 mg, 663 μmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl- 2-tetrahydropyran-4-yl-quinazolin-4-one (100 mg, 331 μmol), cesium carbonate (324 mg, 995 μmol), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidaz ol-1-ium-2-ide;3- chloropyridine;dichloropalladium (32.28 mg, 33.1 μmol) in dioxane (2.5 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL× 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 0/1) to give (R)-8-(1-((2-(4-(2-((tert- butyldimethylsilyl)oxy)acetyl)piperazin-1-yl)-4-fluorophenyl )amino)ethyl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (180 mg, 265 μmol, 80%) as a brown oil. ¹ H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 2.8, 10.0 Hz, 1H), 6.37 (dt, J = 2.8, 8.4 Hz, 1H), 6.08 (dd, J = 5.6, 8.8 Hz, 1H), 5.25 (q, J = 6.6 Hz, 1H), 4.22 (s, 2H), 4.03 - 3.93 (m, 4H), 3.74 - 3.60 (m, 2H), 3.55 (s, 3H), 3.49 - 3.41 (m, 2H), 3.03 - 2.95 (m, 1H), 2.85 (br. s, 2H), 2.80 - 2.68 (m, 2H), 2.25 (s, 3H), 2.11 - 1.95 (m, 2H), 1.75 (br. d, J = 14.0 Hz, 2H), 1.44 (d, J = 6.6 Hz, 3H), 0.79 (s, 9H), 0.01 (s, 6H); m/z ES+ [M+H] ⁺ 652.4. [2607] Step 2. Synthesis of (R)-8-(1-((4-fluoro-2-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2608] To a solution of (R)-8-(1-((2-(4-(2-((tert-butyldimethylsilyl)oxy)acetyl)pipe razin-1- yl)-4-fluorophenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2 H-pyran-4-yl)quinazolin- 4(3H)-one (160 mg, 245 μmol) in dichloromethane (1.6 mL) was added hydrochloric acid/dioxane (4 M, 1.60 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:41%-71% B over 10 min) to give (R)-8-(1-((4- fluoro-2-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)amino)eth yl)-3,6-dimethyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (102 mg, 191 μmol, 78%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.46 (br. s, 1H), 6.63 (br. d, J = 8.4 Hz, 1H), 6.55 - 6.44 (m, 1H), 6.42 - 6.23 (m, 1H), 5.34 (br. d, J = 6.4 Hz, 1H), 4.14 (s, 2H), 4.04 (br. d, J = 11.8 Hz, 2H), 3.98 - 3.63 (m, 2H), 3.58 (s, 3H), 3.49 (br. t, J = 11.6 Hz, 2H), 3.43 (br. s, 2H), 3.07 - 2.99 (m, 1H), 2.85 (br. s, 4H), 2.31 (s, 3H), 2.10 - 1.98 (m, 2H), 1.80 (br. s, 1H), 1.77 (br. s, 1H), 1.57 (br. d, J = 6.0 Hz, 3H); m/z ES+ [M+H] ⁺ 538.3. Example 289. Preparation of (R)-8-(1-((4-fluoro-2-(4-propionylpiperazin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one (Compound 738) [2609] Step 1. Synthesis of (R)-8-(1-((4-Fluoro-2-(4-propionylpiperazin-1- yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahydro-2H-pyran-4 -yl)quinazolin-4(3H)-one [2610] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (60.0 mg, 199 μmol), 1-[4-(2-bromo-5-fluoro-phenyl)piperazin-1-yl]propan- 1-one (125 mg, 398 μmol), cesium carbonate (195 mg, 597 μmol) in dioxane (2 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidaz ol-1-ium-2-ide;3- chloropyridine;dichloropalladium (13.6 mg, 13.9 μmol), the mixture was stirred at 100 °C for 12 h under nitrogen protection. On completion, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(formic acid)-acetonitrile];gradient:47%-77% B over 10 min) to give (R)-8-(1-((4-fluoro-2-(4-propionylpiperazin-1-yl)phenyl)amin o)ethyl)-3,6- dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (66.9 mg, 124 μmol, 63%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 6.75 - 6.67 (m, 1H), 6.58 - 6.47 (m, 1H), 6.29 - 6.19 (m, 1H), 5.40 (q, J = 6.8 Hz, 1H), 4.20 - 4.09 (m, 2H), 4.10 – 3.75 (m, 3H), 3.70 (s, 3H), 3.60 (br. t, J = 11.2 Hz, 3H), 3.20 - 3.08 (m, 1H), 3.06 - 2.81 (m, 4H), 2.48 - 2.38 (m, 5H), 2.25 - 2.10 (m, 2H), 1.90 (br. d, J = 13.6 Hz, 2H), 1.60 (d, J = 6.4 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 536.4. Example 290. Preparation of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro-N-(3- hydroxycyclobutyl)benzamide (Compound 723) [2611] Step 1. Synthesis of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid [2612] To a solution of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one (200 mg, 663 μmol) and 5-fluoro-2-iodo-benzoic acid (317 mg, 1.19 mmol) in dioxane (2 mL) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert - butyl-[2-(2,4,6-triisopropylphenyl)phenyl] phosphane (52.7 mg, 66.3 μmol) and cesium carbonate (648 mg, 1.99 mmol). The mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate/methanol = 100/1/0 to 0/10/1) to give (R)-2-((1-(3,6-dimethyl-4- oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl) ethyl)amino)-5-fluorobenzoic acid (290 mg, 646 μmol, 97%) as a brown solid. m/z ES+ [M+H] ⁺ 440.1. [2613] Step 2. Synthesis of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro-N-(3-hydroxycyc lobutyl)benzamide [2614] To a solution of (R)-2-((1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (50.0 mg, 113 μmol) and 3- aminocyclobutanol (11.8 mg, 136 μmol) in N,N-dimethylformamide (0.5 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (103 mg, 273 μmol) and diisopropylethylamine (44.1 mg, 341 μmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:41%-71% B over 10 min) to give (R)-2-((1-(3,6- dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquina zolin-8-yl)ethyl)amino)-5- fluoro-N-(3-hydroxycyclobutyl)benzamide (29.7 mg, 58.4 μmol, 51%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.56 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.90 - 6.74 (m, 1H), 6.40 (dd, J = 4.0, 8.4 Hz, 2H), 5.44 (d, J = 6.8 Hz, 1H), 4.70 - 4.55 (m, 1H), 4.24 - 4.04 (m, 4H), 3.70 (s, 3H), 3.60 (t, J = 12.0 Hz, 2H), 3.21 - 3.09 (m, 1H), 2.98 - 2.88 (m, 2H), 2.58 - 2.42 (m, 1H), 2.39 (s, 3H), 2.26 - 2.10 (m, 2H), 2.06 - 1.96 (m, 2H), 1.95 - 1.84 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 509.3. Example 291. Preparation of (R)-8-(1-((3,4-difluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahyd ro-2H-pyran-4- yl)quinazolin-4(3H)-one & (S)-8-(1-((3,4-difluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahyd ro-2H-pyran-4- yl)quinazolin-4(3H)-one (Compounds 457, 473, and 474) (stereochemistry arbitrarily assigned) [2615] Step 1. Synthesis of 8-(1-((2-bromo-3,4-difluorophenyl)amino)ethyl)-3,6-dimethyl- 2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2616] To a mixture of 8-(1-bromoethyl)-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazo lin-4- one (400 mg, 1.10 mmol) and 2-bromo-3,4-difluoro-aniline (683 mg, 3.29 mmol) in dimethyl acetamide (5 mL) was added diisopropylethylamine (708 mg, 5.48 mmol), then the mixture was stirred at 80 °C for 3 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid, acetonitrile) to give 8-[1-(2-bromo-3,4-difluoro-anilino)ethyl]-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (300 mg, 609 μmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 6.85 - 6.78 (m, 1H), 6.12 - 6.09 (m, 1H), 5.36 (d, J = 6.8 Hz, 1H), 4.96 (d, J = 6.0 Hz, 1H), 4.19 - 4.13 (m, 2H), 3.70 (s, 3H), 3.60 (d, J = 2.0 Hz, 2H), 3.18 - 3.10 (m, 1H), 2.42 (s, 3H), 2.28 - 2.15 (m, 2H), 1.95 - 1.88 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 493.7. [2617] Step 2. Synthesis of 8-(1-((3,4-difluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6- dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2618] To a mixture of 8-[1-(2-bromo-3,4-difluoro-anilino)ethyl]-3,6-dimethyl-2- tetrahydropyran-4-yl-quina-zolin-4-one (200 mg, 406 μmol) and sodium methanesulfinate (207 mg, 2.03 mmol) in dimethylsulfoxide (2 mL) was added (2S)-pyrrolidine-2-carboxylic acid (9.35 mg, 81.2 μmol) and copper iodide (7.74 mg, 40.6 μmol) then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide and acetonitrile condition) to give 8-[1- (3,4-difluoro-2-methylsulfonyl-anilino)ethyl]-3,6-dimethyl-2 -tetrahydropyran-4-yl- quinazolin-4-one (30.0 mg, 61.0 μmol, 15%) as a yellow gum. ¹ H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.57 - 7.47 (m, 2H), 7.01 - 6.95 (m, 1H), 6.18 - 6.15 (m, 1H), 5.57 - 5.45 (m, 1H), 4.20 - 4.10 (m, 2H), 3.70 (s, 3H), 3.64 - 3.58 (m, 2H), 3.33 (s, 3H), 3.20 - 3.10 (m, 1H), 2.42 (s, 3H), 2.25 - 2.12 (m, 2H), 1.92 - 1.90 (m, 2H), 1.59 (s, 3H); m/z ES+ [M+H] ⁺ 492.2. [2619] Step 3. Chiral purification [2620] 8-(1-((3,4-difluoro-2-(methylsulfonyl)phenyl)amino)ethyl)-3, 6-dimethyl-2- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (25 mg, 50.9 μmol) was purification by SFC (column: DAICEL CHIRALCEL OJ(250mm x 30mm,10um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 35%-35%,A3;60min). On completion. Two isomers in solvent were concentrated in vacuo to give (R)-8-(1-((3,4-difluoro-2-(methylsulfonyl)phenyl)amino)ethyl )- 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-on e (9.85 mg, 19.2 μmol, 38%) as a yellow gum. ¹ H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.58 - 7.46 (m, 2H), 7.04 - 6.94 (m, 1H), 6.20 - 6.12 (m, 1H), 5.53 -5.50 (m, 1H), 4.17 - 4.14 (m, 2H), 3.70 (s, 3H), 3.64 -3.58 (m, 2H), 3.33 (s, 3H), 3.19 - 3.11 (m, 1H), 2.42 (s, 3H), 2.27 - 2.12 (m, 2H), 1.92 - 1.90 (m, 2H), 1.59 (s, 3H); m/z ES+ [M+H] ⁺ 492.2; and (S)-8-(1-((3,4-difluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahyd ro-2H-pyran-4-yl)quinazolin- 4(3H)-one (10.7 mg, 21.2 μmol, 42%) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.59 - 7.47 (m, 2H), 7.02 - 6.95 (m, 1H), 6.20 - 6.12 (m, 1H), 5.57 - 5.46 (m, 1H), 4.18 - 4.14 (m, 2H), 3.70 (s, 3H), 3.64 - 3.58 (m, 2H), 3.33 (s, 3H), 3.22 - 3.09 (m, 1H), 2.42 (s, 3H), 2.24 - 2.13 (m, 2H), 1.92 -1.90 (m, 2H), 1.59 (s, 3H); m/z ES+ [M+H] ⁺ 492.2. Example 292. Preparation of (R)-2-((1-(6-bromo-3-methyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 507) [2621] Step 1. Synthesis of (R)-2-((1-(6-bromo-3-methyl-4-oxo-2-(tetrahydro-2H-pyran-4- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2622] To a solution of 8-[(1R)-1-aminoethyl]-6-bromo-3-methyl-2-tetrahydropyran-4-y l- quinazolin-4-one (49 mg, 134 μmol) and 2-iodobenzoic acid (166 mg, 666 μmol) in dimethyl acetamide (1 mL) was added copper (25.5 mg, 401 μmol) and triethylamine (271 mg, 2.68 mmol). The mixture was stirred at 110 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was poured in water (10 mL) then extracted dichloromethane (10 mL x 3). The combined organic layers were washed with brine (30 mL), the organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch ultimate C18150 x 25mm, 7um; mobile phase: [water (formic)-acetontrile]; B%: 40%-70%, 15min) to give 2-[[(1R)-1-(6-bromo-3-methyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]amino]benzoic acid (13.9 mg, 28.6 μmol, 21%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.4 Hz, 1H), 8.26 - 8.14 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.23 - 7.13 (m, 1H), 6.62 - 6.55 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.55 (d, J = 6.0 Hz, 1H), 4.18 (d, J = 11.6 Hz, 2H), 3.71 (s, 3H), 3.65 - 3.55 (m, 2H), 3.20 - 3.08 (m, 1H), 2.30 - 2.15 (m, 2H), 1.95 - 1.88 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H). m/z ES+ [M+H] ⁺ 486.1. Example 293. Preparation of (R)-2-((1-(6-bromo-3-methyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro benzoic acid (Compound 525) [2623] Step 1. Synthesis of (R)-2-((1-(6-bromo-3-methyl-4-oxo-2-(tetrahydro-2H-pyran-4- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid [2624] To a solution of 8-[(1R)-1-aminoethyl]-6-bromo-3-methyl-2-tetrahydropyran-4-y l- quinazolin-4-one (25 mg, 68.3 μmol) and 5-fluoro-2-iodo-benzoic acid (90.8 mg, 341 μmol) in dimethylformamide (0.5 mL) was added copper (4.34 mg, 68.3 μmol) and triethylamine (20.7 mg, 205 μmol). The mixture was stirred at 110 °C for 1 hr. The mixture was poured in water (10 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), the organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];B%: 46%-76%, 10 min) to give (R)-2-((1-(6-bromo-3-methyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl) amino)-5-fluorobenzoic acid (12.5 mg, 24.8 μmol, 36%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.69 - 7.66 (m, 1H), 6.97 - 6.93 (m, 1H), 6.33 - 6.29 (m, 1H), 5.53 - 5.48 (m, 1H), 4.20 - 4.17 (m, 2H), 3.72 (s, 3H), 3.62 (t, J = 12.0 Hz, 2H), 3.20 - 3.12 (m, 1H), 2.27 - 2.17 (m, 2H), 1.93 - 1.90 (m, 2H), 1.65 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 504.2. Example 294. Preparation of (R)-2-((1-(6-bromo-3-cyclopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 560) [2625] Step 1. Synthesis of 2-amino-5-bromo-N-cyclopropyl-3-iodobenzamide [2626] To a solution of 2-amino-5-bromo-3-iodo-benzoic acid (30.0 g, 87.7 mmol) and cyclopropanamine (15.0 g, 263 mmol) in N,N-dimethylformamide (300 mL) was added [dimethylamino(triazolo[4,5-b]pyridine-3-yloxy)methylene]-di methyl- ammonium;hexafluorophosphate (40.0 g, 105 mmol) and diisopropylethylamine (56.7 g, 438 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water (1 L), and then filtered to collect the solid to give 2-amino-5-bromo-N- cyclopropyl-3-iodo-benzamide (34.0 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO- d6) δ 8.50 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 6.50 (s, 2H), 2.85 - 2.79 (m, 1H), 0.72 - 0.65 (m, 2H), 0.59 - 0.54 (m, 2H); m/z ES+ [M+H] ⁺ 380.9. [2627] Step 2. Synthesis of N-(4-bromo-2-(cyclopropylcarbamoyl)-6-iodophenyl)tetrahydro- 2H-pyran-4-carboxamide [2628] To a solution of 2-amino-5-bromo-N-cyclopropyl-3-iodo-benzamide (34.0 g, 89.2 mmol) and tetrahydropyran-4-carboxylic acid (13.9 g, 107 mmol) in pyridine (350 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (170 g, 267 mmol, 50% purity). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction solution was added to water (500 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure. The crude product was triturated with (petroleum ether : ethyl acetate = 10 : 1) at 25 °C for 0.5 hr to give N-[4-bromo-2- (cyclopropylcarbamoyl)-6-iodo-phenyl]tetrahydropyran-4-carbo xamide (33.0 g, 38.8 mmol, 43%) as brown solid. ¹ H NMR (400 MHz, CDCl3) δ 8.11 - 7.49 (m, 2H), 4.14 - 4.05 (m, 1H), 3.59 - 3.40 (m, 1H), 2.91 - 2.76 (m, 4H), 1.99 - 1.84 (m, 2H), 1.79 - 1.61 (m, 2H), 1.10 - 0.99 (m, 2H), 0.92 - 0.85 (m, 1H), 0.69 - 0.57 (m, 1H); m/z ES+ [M+H] ⁺ 493.0. [2629] Step 3. Synthesis of 6-bromo-3-cyclopropyl-8-iodo-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [2630] To a solution of N-[4-bromo-2-(cyclopropylcarbamoyl)-6-iodo- phenyl]tetrahydropyran-4-carboxamide (30.0 g, 60.8 mmol) in acetonitrile (300 mL) was added dichlorozinc (24.8 g, 182 mmol) and [dimethyl-(trimethylsilylamino)silyl]methane (24.5 g, 152 mmol). The mixture was stirred at 80 °C for 4 hr. On completion, the reaction mixture was diluted with water (1 L), filtered out solids and then extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether : ethyl acetate =5:1 (50 mL) at 25 °C for 0.5 hr to give 6-bromo-3-cyclopropyl-8-iodo-2-tetrahydropyran-4-yl-quinazol in-4-one (11.0 g, 19.4 mmol, 31%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 2H), 4.24 - 4.14 (m, 2H), 3.75 - 3.65 (m, 1H), 3.63 - 3.50 (m, 2H), 3.05 - 2.94 (m, 1H), 2.32 - 2.13 (m, 2H), 1.87 (d, J = 13.2 Hz, 2H), 1.44 - 1.35 (m, 2H), 0.92 - 0.88 (m, 2H); m/z ES+ [M+H] ⁺ 474.9. [2631] Step 4. Synthesis of 6-bromo-3-cyclopropyl-8-(1-ethoxyvinyl)-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2632] A mixture of 6-bromo-3-cyclopropyl-8-iodo-2-tetrahydropyran-4-yl-quinazol in-4-one (5.00 g, 10.5 mmol) in toluene (50 mL) was added tributyl(1-ethoxyvinyl)stannane (5.70 g, 15.7 mmol) and dichloropalladium triphenylphosphane (517 mg, 736 μmol) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 80 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition saturated potassium fluoride (100 mL) at 25 °C, the mixture was stirred at 25 °C for 3 hr, then diluted with water (100 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (100 mL× 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was dissolved in dichloromethane (44 mL) was added hydrochloric acid (1 M, 10.4 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was quenched by addition saturated sodium bicarbonate to pH=7 at 0 °C, then the reaction mixture was extracted with dichloromethane (100 mL× 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give 8-acetyl-6-bromo- 3-cyclopropyl-2-tetrahydropyran-4-yl-quinazolin-4-one (1.60 g, 4.07 mmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.00 - 7.89 (m, 1H), 7.65 - 7.53 (m, 1H), 3.77 - 3.53 (m, 2H), 3.33 - 3.16 (m, 1H), 3.13 - 2.97 (m, 2H), 2.55 - 2.40 (m, 1H), 2.34 - 2.34 (m, 1H), 2.43 - 2.26 (m, 2H), 1.66 - 1.48 (m, 2H), 1.31 (d, J = 12.8 Hz, 2H), 1.11 (s, 1H), 0.96 - 0.83 (m, 2H), 0.50 - 0.34 (m, 2H); m/z ES+ [M+H] ⁺ 391.1. [2633] Step 5. Synthesis of (R,E)-N-(1-(6-bromo-3-cyclopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylp ropane-2-sulfinamide [2634] To a solution of 8-acetyl-6-bromo-3-cyclopropyl-2-tetrahydropyran-4-yl-quinaz olin- 4-one (1.20 g, 3.07 mmol) and (R)-2-methylpropane-2-sulfinamide (1.12 g, 9.20 mmol) in anhydrous tetrahydrofuran (12 mL) was added tetraethoxytitanium (3.50 g, 15.3 mmol). The mixture was stirred at 75 °C for 12 hr. On completion, mixture was poured in water (25 mL) and then filter to collected the mixture to give (NE,R)-N-[1-(6-bromo-3-cyclopropyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethyli-dene]-2-methyl-p ropane-2-sulfinamide (1.50 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.46 - 8.31 (m, 1H), 7.92 - 7.57 (m, 1H), 3.78 - 3.65 (m, 2H), 3.60 - 3.50 (m, 2H), 3.01 - 2.94 (m, 1H), 2.92 - 2.87 (m, 2H), 2.56 (s, 1H), 2.06 (s, 3H), 1.81 (d, J = 12.4 Hz, 2H), 1.41 (d, J = 6.8 Hz, 2H), 1.34 (s, 7H), 1.24 - 1.22 (m, 2H), 0.93 (s, 2H); m/z ES+ [M+H] ⁺ 494.1. [2635] Step 6. Synthesis of (R)-N-((R)-1-(6-bromo-3-cyclopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide [2636] To a solution of (NE,R)-N-[1-(6-bromo-3-cyclopropyl-4-oxo-2-tetrahydropyran-4 -yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (1.40 g, 2.83 mmol) in anhydrous tetrahydrofuran (28 mL) was slowly added borane-methyl sulfide complex (10 M, 1.42 mL) under nitrogen atmosphere at -78 °C. The mixture was stirred at -78 °C ~ -30 °C for 2 hr. On completion, the mixture was quenched by methanol (45 mL) at -10 °C. The mixture was stirred at 25 °C for 0.5 hr. Then the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150 x 50mm, 10um;mobile phase: [water(ammonium bicarbonate)-acetonitrile];gradient:39%-69% B over 10 min) to give (R)-N-[(1R)-1-(6-bromo-3-cyclopropyl-4-oxo-2-tetrahydropyran -4-yl- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (900 mg, 1.81 mmol, 64%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 4.95 - 4.77 (m, 2H), 4.20 - 4.10 (m, 2H), 3.80 - 3.70 (m, 1H), 3.64 - 3.50 (m, 2H), 3.02 - 2.90 (m, 1H), 2.19 - 2.04 (m, 2H), 1.91 - 1.82 (m, 2H), 1.64 (s, 3H), 1.42 - 1.36 (m, 2H), 1.25 (s, 9H), 1.00 - 0.90 (m, 2H); m/z ES+ [M+H] ⁺ 496.1. [2637] Step 7. Synthesis of (R)-8-(1-aminoethyl)-6-bromo-3-cyclopropyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2638] To a solution of (R)-N-[(1R)-1-(6-bromo-3-cyclopropyl-4-oxo-2-tetrahydropyran -4- yl-quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (400 mg, 805 μmol) in dichloromethane (4 mL) was added hydrochloric acid/dioxane (4 M, 4 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was filtered, then filter cake was added with water (15 mL), then used ammonium hydroxide adjust pH = 8 and extracted with ethyl acetate (10 mL× 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8- [(1R)-1-aminoethyl]-6-bromo-3-cyclopropyl-2-tetrahydropyran- 4-yl-quinazolin-4-one (180 mg, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 4.81 (q, J = 6.4 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.78 - 3.68 (m, 1H), 3.64 - 3.50 (m, 2H), 3.03 - 2.94 (m, 1H), 2.19 - 2.07 (m, 2H), 1.85 (d, J = 12.8 Hz, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.44 - 1.36 (m, 2H), 0.97 - 0.88 (m, 2H); m/z ES+ [M+H] ⁺ 392.1. [2639] Step 8. Synthesis of (R)-2-((1-(6-bromo-3-cyclopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2640] A mixture of 8-[(1R)-1-aminoethyl]-6-bromo-3-cyclopropyl-2-tetrahydropyra n-4-yl- quinazolin-4-one (90.0g, 229 μmol), 2-iodobenzoic acid (284 mg, 1.15 mmol), copper (33.9 mg, 534 μmol), triethylamine (464 mg, 4.59 mmol) in dimethyl acetamide (1.5 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 110 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water (formic acid)-acetonitirle];gradient: 51%-81% B over 10 min) to give 2-[[(1R)-1-(6-bromo-3-cyclopropyl-4-oxo-2-tetrahydropyran-4- yl- quinazolin-8-yl)ethyl]amino]benzoic acid (52.0 mg, 101 μmol, 44%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 1.6, 8.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.16 - 7.08 (m, 1H), 6.55 - 6.49 (m, 1H), 6.30 (d, J = 8.4 Hz, 1H), 5.52 - 5.40 (m, 1H), 4.09 (d, J = 11.6 Hz, 2H), 3.74 - 3.63 (m, 1H), 3.57 -3.45 (m, 2H), 2.96 - 2.88 (m, 1H), 2.17 - 2.07 (m, 2H), 1.85 - 1.75 (m, 2H), 1.57 (d, J = 6.8 Hz, 3H), 1.40 - 1.25 (m, 2H), 0.92 - 0.85 (m, 2H); m/z ES+ [M+H] ⁺ 512.1. Example 295. Preparation of (R)-2-((1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 487) [2641] Step 1. Synthesis of (R)-2-((1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro-2H-pyran-4- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2642] To a solution of 8-[(1R)-1-aminoethyl]-6-fluoro-3-methyl-2-tetrahydropyran-4- yl- quinazolin-4-one (100 mg, 328 μmol) and 2-iodobenzoic acid (406 mg, 1.64 mmol) in dimethyl acetamide (8 mL) was added copper (62.4 mg, 982 μmol) and triethylamine (663 mg, 6.55 mmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with ammonium chloride 10 mL and extracted with ethyl acetate (8 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 25mm,10um; mobile phase: [water(formic acid)-acetonitrile]; B%: 41%-71%, 10 min) to give 2-[[(1R)-1-(6- fluoro-3-methyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl )ethyl]amino]benzoic acid (85 mg, 200 μmol, 61%) as a off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 - 8.10 (m, 1H), 8.00 - 7.95 (m, 1H), 7.80 - 7.72 (m, 1H), 7.51 - 7.42 (m, 1H), 7.21 - 7.15 (m, 1H), 6.61 - 6.52 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.66 - 5.52 (m, 1H), 4.21 - 4.10 (m, 2H), 3.72 (s, 3H), 3.66 - 3.56 (m, 2H), 3.21 - 3.12 (m, 1H), 2.30 - 2.16 (m, 2H), 1.96 - 1.89 (m, 2H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 426.2. Example 296. Preparation of (R)-6-fluoro-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3-methyl-2-(tetrahydro-2H-pyran-4-yl) quinazolin-4(3H)-one (Compound 561) [2643] Step 1. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1- yl)phenyl)amino)ethyl)-6-fluoro-3-methyl-2-(tetrahydro-2H-py ran-4-yl)quinazolin-4(3H)- one [2644] To a solution of 8-[(1R)-1-aminoethyl]-6-fluoro-3-methyl-2-tetrahydropyran-4- yl- quinazolin-4-one (200 mg, 654 μmol) and [1-(2-bromo-5-fluoro-phenyl)-4-piperidyl]oxy-tert- butyl-dimethyl-silane (381 mg, 982 μmol) in dioxane (2 mL) was added palladium acetate (14.7 mg, 65.5 μmol), sodium tert-butoxide (188 mg, 1.96 mmol) and (R)-(+)-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl (40.7 mg, 65.5 μmol). The mixture was stirred at 100 °C for 12 hr. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was separated, washed with brine (25 mL x 2), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate= 40/1 to 3/1) to give 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4- fluoro-anilino]ethyl]-6-fluoro-3-methyl-2-tetrahydropyran-4- yl-quinazolin-4-one (330 mg, 527 μmol, 80%) as a yellow solid. m/z ES+ [M+H] ⁺ 613.3. [2645] Step 2. Synthesis of (R)-6-Fluoro-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3-methyl-2-(tetrahydro-2H-pyran-4-yl) quinazolin-4(3H)-one [2646] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4-fluoro- anilino]ethyl]-6-fluoro-3-methyl-2-tetrahydropyran-4-yl-quin azolin-4-one (100 mg, 163 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 0.97 mL) at 25 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile;gradient:52%-72% B over 9 min) to give (R)-6-fluoro-8-(1-((4-fluoro-2-(4- hydroxypiperidin-1-yl)phenyl)amino)ethyl)-3-methyl-2-(tetrah ydro-2H-pyran-4- yl)quinazolin-4(3H)-one (47.3 mg, 94.9 μmol, 58%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 3.2, 8.4 Hz, 1H), 7.46 (dd, J = 2.4, 8.8 Hz, 1H), 6.74 (dd, J = 2.0, 10.0 Hz, 1H), 6.50 (dt, J = 2.8, 8.4 Hz, 1H), 6.14 (dd, J = 5.6, 8.4 Hz, 1H), 5.39 - 5.25 (m, 1H), 5.19 - 4.84 (m, 1H), 4.22 - 4.12 (m, 2H), 4.00 - 3.82 (m, 1H), 3.71 (s, 3H), 3.66 - 3.57 (m, 2H), 3.31 - 3.09 (m, 3H), 2.82 - 2.64 (m, 2H), 2.37 - 2.22 (m, 1H), 2.19 - 2.05 (m, 3H), 1.92 ( d, J = 13.2 Hz, 2H), 1.81 ( d, J = 9.2 Hz, 2H), 1.63 (d, J = 6.6 Hz, 3H); m/z ES+ [M+H] ⁺ 499.3. Example 297. Preparation of (R)-4-Fluoro-2-((1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (Compound 611) [2647] Step 1. Synthesis of (R)-4-fluoro-2-((1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro-2H - pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2648] A mixture of 8-[(1R)-1-aminoethyl]-6-fluoro-3-methyl-2-tetrahydropyran-4- yl- quinazolin-4-one (100 mg, 327 μmol), 4-fluoro-2-iodo-benzoic acid (435 mg, 1.64 mmol), copper powder (41.6 mg, 654 μmol) and triethylamine (331 mg, 3.27 mmol) in dimethyl acetamide (1 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 5 hr under nitrogen atmosphere. The reaction mixture was partitioned between saturated ammonium chloride (3 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with brine (5 mL), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:53%-77% B over 8 min) to give (R)-4-fluoro-2-((1-(6-fluoro-3-methyl- 4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoic acid (23.3 mg, 52.6 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, CDC3) δ 8.36 ( d, J = 4.0 Hz, 1H), 8.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.80 (dd, J = 2.8, 8.4 Hz, 1H), 7.46 (dd, J = 2.8, 9.2 Hz, 1H), 6.28 (dt, J = 2.4, 8.4 Hz, 1H), 6.09 (dd, J = 2.4, 12.4 Hz, 1H), 5.65 - 5.48 (m, 1H), 4.19 (dd, J = 2.0, 10.0 Hz, 2H), 3.73 (s, 3H), 3.63 (dt, J = 1.6, 12.0 Hz, 2H), 3.17 (tdd, J = 3.6, 7.6, 11.2 Hz, 1H), 2.33 - 2.14 (m, 2H), 1.94 ( t, J = 14.4 Hz, 2H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 444.2. Example 298. Preparation of (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (Compound 673) [2649] Step 1. Synthesis of (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro-2H - pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2650] To a solution of 8-[(1R)-1-aminoethyl]-6-fluoro-3-methyl-2-tetrahydropyran-4- yl- quinazolin-4-one (100 mg, 328 μmol) and 5-fluoro-2-iodo-benzoic acid (436 mg, 1.64 mmol) in dimethyl acetamide (2 mL) was added triethylamine (331 mg, 3.27 mmol, 456 ^L) and copper powder (41.6 mg, 655 μmol). The mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:45%-75% B over 10 min) to give (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-4-oxo-2-(tetrahydro-2H -pyran-4- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (38.9 mg, 87.7 μmol, 27%) as an off- white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.03 (br. s, 1H), 7.83 - 7.76 (m, 1H), 7.72 - 7.63 (m, 1H), 7.50 - 7.41 (m, 1H), 7.00 - 6.88 (m, 1H), 6.35 - 6.23 (m, 1H), 5.62 - 5.49 (m, 1H), 4.25 - 4.14 (m, 2H), 3.72 (s, 3H), 3.68 - 3.59 (m, 2H), 3.22 - 3.10 (m, 1H), 2.29 - 2.16 (m, 2H), 1.96 - 1.88 (m, 2H), 1.66 (d, J = 6.6 Hz, 3H); m/z ES+ [M+H] ⁺ 444.2. Example 299. Preparation of (R)-2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 554) [2651] Step 1. Synthesis of (R)-2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2652] A mixture of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-tetrahydropyr an-4-yl- quinazolin-4-one (150 mg, 452 μmol), 2-iodobenzoic acid (561 mg, 2.26 mmol), copper (67.0 mg, 1.05 mmol), triethylamine (458 mg, 4.53 mmol) in dimethyl acetamide (2 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 3 hr under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (column: Phenomenex luna C18150 x 25mm, 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:47%-77% B over 10 min) to give (R)-2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-pyr an-4-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (71.2 mg, 157 μmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (d, J = 2.0 Hz, 1H), 8.00 (dd, J = 1.6, 8.0 Hz, 1H), 7.73 (dd, J = 3.2, 8.4 Hz, 1H), 7.45 (dd, J = 2.8, 9.2 Hz, 1H), 7.22 - 7.16 (m, 1H), 6.65 - 6.55 (m, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.53 - 5.53 (m, 1H), 5.62 - 5.52 (m, 1H), 4.18 (d, J = 11.2 Hz, 2H), 3.83 - 3.72 (m, 1H), 3.66 - 3.57 (m, 2H), 3.05 - 2.95 (m, 1H), 2.28 - 2.14 (m, 2H), 1.95 - 1.82 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H), 1.41 (d, J = 7.2 Hz, 2H), 1.01 - 0.95 (m, 2H); m/z ES+ [M+H] ⁺ 452.2. Example 300. Preparation of (R)-2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro benzoic acid (Compound 672)

[2653] Step 1. Synthesis of (R)-2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro benzoic acid [2654] A mixture of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-tetrahydropyr an-4-yl- quinazolin-4-one (100 mg, 301 μmol), 5-fluoro-2-iodo-benzoic acid (240 mg, 905 μmol), copper powder (38.3 mg, 603 μmol) and triethylamine (305 mg, 3.02 mmol) in dimethyl acetamide (1 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 110 °C for 3 hr under nitrogen atmosphere. The reaction mixture was partitioned between saturated ammonium chloride (3 mL) and ethyl acetate (8 mL). The organic phase was separated and washed with brine 5 mL, then dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:47%-77% B over 10 min) to give (R)-2-((1-(3- cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4- dihydroquinazolin-8- yl)ethyl)amino)-5-fluorobenzoic acid (51.8 mg, 110 μmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.05 (br. s, 1H), 7.80 - 7.64 (m, 2H), 7.42 (dd, J = 2.8, 9.2 Hz, 1H), 6.99 - 6.89 (m, 1H), 6.28 (dd, J = 4.4, 9.6 Hz, 1H), 5.53 (q, J = 6.4 Hz, 1H), 4.25 - 4.09 (m, 2H), 3.78 (tt, J = 3.6, 11.2 Hz, 1H), 3.68 - 3.56 (m, 2H), 3.06 - 2.96 (m, 1H), 2.31 - 2.11 (m, 2H), 1.90 (t, J = 13.6 Hz, 2H), 1.65 (d, J = 6.8 Hz, 3H), 1.49 - 1.35 (m, 2H), 1.04 - 0.89 (m, 2H); m/z ES+ [M+H] ⁺ 470.2. Example 301. Preparation of (R)-6-Chloro-3-((1-(3-cyclopropyl-6-fluoro-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl) amino)picolinic acid (Compound 711) [2655] Step 1. Synthesis of tert-butyl (R)-6-chloro-3-((1-(3-cyclopropyl-6-fluoro-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl) amino)picolinate [2656] To a solution of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-tetrahydropyr an-4- yl-quinazolin-4-one (200 mg, 603 μmol) and tert-butyl 3-bromo-6-chloro-pyridine-2- carboxylate (264 mg, 905 μmol) in toluene (4 mL) was added tris(dibenzylideneacetone)dipalladium (55.2 mg, 60.3 μmol), dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl]phosphane (28.1 mg, 60.3 μmol) and cesium carbonate (589 mg, 1.81 mmol). The mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 0/1) to give tert-butyl 6-chloro-3-[[(1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]amino]pyridine-2- carboxylate (150 mg, 240 μmol, 39%) as a brown solid. m/z ES+ [M+H] ⁺ 543.4. [2657] Step 2. Synthesis of (R)-6-chloro-3-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahyd ro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nic acid [2658] A solution of tert-butyl 6-chloro-3-[[(1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]amino]pyridine-2- carboxylate (140 mg, 257 μmol) in trifluoroacetic acid (1.5 mL) was stirred at 60 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:50%-80% B over 10 min) to give (R)-6-chloro-3-((1- (3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3 ,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (75.7 mg, 155 μmol, 60%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 6.4 Hz, 1H), 7.76 (dd, J = 2.8, 8.0 Hz, 1H), 7.38 (dd, J = 3.2, 9.2 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.57 (t, J = 6.4 Hz, 1H), 4.21 - 4.11 (m, 2H), 3.83 - 3.71 (m, 1H), 3.60 (t, J = 11.2 Hz, 2H), 3.05 - 2.94 (m, 1H), 2.23 - 2.01 (m, 2H), 1.94 - 1.83 (m, 2H), 1.67 (d, J = 6.4 Hz, 3H), 1.47 - 1.36 (m, 2H), 1.02 - 0.91 (m, 2H); m/z ES+ [M+H] ⁺ 487.2. Example 302. Preparation of (R)-6-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-2,3-difl uorobenzoic acid (Compound 694) [2659] Step 1. Synthesis of (R)-6-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-2,3-difl uorobenzoic acid [2660] A mixture of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-tetrahydropyr an-4-yl- quinazolin-4-one (100 mg, 301 μmol), 2,3-difluoro-6-iodo-benzoic acid (428 mg, 1.51 mmol), copper powder (38.3 mg, 603 μmol), triethylamine (305 mg, 3.02 mmol) in dimethyl acetamide (1 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with ammonium chloride solution (1 N, 15 mL) and extracted with dichloromethane (15 mL× 3). The combined organic layers were washed with brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:51%-71% B over 10 min) to give (R)-6-((1-(3- cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4- dihydroquinazolin-8- yl)ethyl)amino)-2,3-difluorobenzoic acid (34.4 mg, 69.0 μmol, 22%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.78 - 7.72 (m, 1H), 7.39 (dd, J = 2.8, 9.2 Hz, 1H), 7.06 - 6.96 (m, 1H), 6.11 - 6.02 (m, 1H), 5.50 - 5.40 (m, 1H), 4.25 - 4.15 (m, 2H), 3.87 - 3.74 (m, 1H), 3.63 (br. t, J = 12.0 Hz, 2H), 3.03 - 2.97 (m, 1H), 2.26 - 2.16 (m, 2H), 1.92 - 1.86 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.43 (br. d, J = 6.6 Hz, 2H), 1.01 - 0.95 (m, 2H); m/z ES+ [M+H] ⁺ 488.2. Example 303. Preparation of (R)-2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro -N-methoxybenzamide (Compound 693)

[2661] Step 1. Synthesis of (R)-2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro benzoic acid [2662] A mixture of 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-tetrahydropyr an-4-yl- quinazolin-4-one (300 mg, 905 μmol), 5-fluoro-2-iodo-benzoic acid (1.20 g, 4.53 mmol), copper powder (115 mg, 1.81 μmol), triethylamine (916 mg, 9.05 mmol) in dimethyl acetamide (3 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 110 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with ammonium chloride solution (1 N, 10 mL) and extracted with dichloromethane (10 mL× 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give 2-[[(1R)- 1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyran-4-yl-quina zolin-8-yl)ethyl]amino]-5- fluoro-benzoic acid (180 mg, 360 μmol, 40%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 8.00 (br. s, 1H), 7.75 (dd, J = 2.8, 8.4 Hz, 1H), 7.68 (dd, J = 3.2, 9.6 Hz, 1H), 7.43 (dd, J = 3.0, 9.2 Hz, 1H), 6.99 - 6.90 (m, 1H), 6.31 (dd, J = 4.4, 9.2 Hz, 1H), 5.58 - 5.48 (m, 1H), 4.26 - 4.10 (m, 2H), 3.79 (tt, J = 3.6, 11.2 Hz, 1H), 3.68 - 3.55 (m, 2H), 3.05 - 2.97 (m, 1H), 2.27 - 2.14 (m, 2H), 1.95 - 1.86 (m, 2H), 1.66 (d, J = 6.4 Hz, 3H), 1.46 - 1.39 (m, 2H), 1.03 - 0.92 (m, 2H); m/z ES+ [M+H] ⁺ 470.2. [2663] Step 2. Synthesis of (R)-2-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro -N-methoxybenzamide [2664] To a solution of 2-[[(1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyran-4 -yl- quinazolin-8-yl)ethyl]amino]-5-fluoro-benzoic acid (160 mg, 340 μmol) and O- methylhydroxylamine (85.3 mg, 1.02 mmol, HCl) in dichloromethane (2 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (259 mg, 681 μmol) and diisopropylethylamine (220 mg, 1.70 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water 10 mL and extracted with dichloromethane (10 mL× 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:42%-72% B over 25 min) to give (R)-2-((1-(3-cyclopropyl-6- fluoro-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazo lin-8-yl)ethyl)amino)-5- fluoro-N-methoxybenzamide (105 mg, 211 μmol, 62%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (br. s, 1H), 7.64 (dd, J = 2.8, 8.4 Hz, 1H), 7.39 (dd, J = 2.8, 9.2 Hz, 1H), 7.07 - 6.90 (m, 1H), 6.82 - 6.69 (m, 1H), 6.29 - 6.16 (m, 1H), 5.41 (q, J = 6.8 Hz, 1H), 4.07 (br. d, J = 11.8 Hz, 2H), 3.86 (s, 3H), 3.67 (tt, J = 3.6, 11.2 Hz, 1H), 3.52 (br. t, J = 11.2 Hz, 2H), 2.95 - 2.87 (m, 1H), 2.16 - 1.97 (m, 2H), 1.80 (br. t, J = 12.4 Hz, 2H), 1.52 (d, J = 6.6 Hz, 3H), 1.36 - 1.29 (m, 2H), 0.93 - 0.85 (m, 2H); m/z ES+ [M+H] ⁺ 499.3. Example 304. Preparation of (R)-3-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-(trifl uoromethyl)picolinic acid (Compound 708) [2665] Step 1. Synthesis of methyl (R)-3-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-(tr ifluoromethyl)picolinate [2666] To a solution of methyl 3-bromo-6-(trifluoromethyl)pyridine-2-carboxylate (300 mg, 1.06 mmol) and 8-[(1R)-1-aminoethyl]-3-cyclopropyl-6-fluoro-2-tetrahydropyr an-4-yl- quinazolin-4-one (233 mg, 704 μmol) in toluene (5 mL) was added cesium carbonate (688 mg, 2.11 mmol), dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phospha ne (32.8 mg, 70.4 μmol) and tris(dibenzylideneacetone)dipalladium (64.4 mg, 70.4 μmol). The mixture was stirred at 110 °C for 12 hr under nitrogen. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was separated, washed with brine (25 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 1/1) to give methyl 3-[[(1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]amino]-6-(trifluo romethyl)pyridine-2-carboxylate (180 mg, 296 μmol, 42%) as a yellow solid. m/z ES+ [M+H] ⁺ 535.2. [2667] Step 2. Synthesis of (R)-3-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-(trifl uoromethyl)picolinic acid [2668] To a solution of methyl 3-[[(1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyran- 4-yl-quinazolin-8-yl)ethyl]amino]-6-(trifluoromethyl)pyridin e-2-carboxylate (160 mg, 299 μmol) in water (0.8 mL), tetrahydrofuran (0.8 mL) and methanol (0.8 mL) was added lithium hydroxide monohydrate (80.0 mg, 1.91 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction was diluted water 5 mL and then acidified with 1N hydrochloric acid to pH ~ 5, which was further extracted with ethyl acetate (10 mL× 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:56%-76% B over 9 min) to give (R)-3-((1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-pyr an-4-yl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-(trifluoromethyl)p icolinic acid (62.8 mg, 119 μmol, 40%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 10.94 (br. s, 1H), 8.59 (d, J = 6.4 Hz, 1H), 7.77 (dd, J = 2.8, 8.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 2.8, 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.62 (q, J = 6.4 Hz, 1H), 4.22 - 4.12 (m, 2H), 3.78 (tt, J = 3.6, 11.2 Hz, 1H), 3.60 (t, J = 11.6 Hz, 2H), 3.05 - 2.95 (m, 1H), 2.27 - 2.02 (m, 2H), 1.92 - 1.85 (m, 2H), 1.70 (d, J = 6.8 Hz, 3H), 1.46 - 1.39 (m, 2H), 1.00 - 0.92 (m, 2H); m/z ES+ [M+H] ⁺ 521.2. Example 305. Preparation of (S)-8-(2,2-difluoro-1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahyd ro-2H-pyran-4- yl)quinazolin-4(3H)-one (Compound 502) [2669] Step 1. Synthesis of 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-8-vinylquinazolin- 4(3H)-one [2670] To a solution of 8-bromo-3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin- 4(3H)-one (7 g, 20.7 mmol), potassium;trifluoro(vinyl)boranuide (11.1 g, 83.0 mmol) in dioxane (125 mL) and water (15 mL) was added potassium phosphate (13.2 g, 62.3 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-bi phenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (1.63 g, 2.08 mmol) and stirred at 95 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 100 mL/min) to give 3,6-dimethyl-2-(tetrahydro-2H-pyran- 4-yl)-8-vinylquinazolin-4(3H)-one (4.1 g, 70%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 - 7.96 (m, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.75 - 7.66 (m, 1H), 5.96 - 5.88 (m, 1H), 5.45 - 5.38 (m, 1H), 4.18 - 4.11 (m, 2H), 3.67 (s, 3H), 3.63 - 3.54 (m, 2H), 3.18 - 3.01 (m, 1H), 2.48 (s, 3H), 2.28 - 2.12 (m, 2H), 1.91 - 1.82 (m, 2H); m/z ES+ [M+H] ⁺ 285.2. [2671] Step 2. Synthesis of 3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4- dihydroquinazoline-8-carbaldehyde [2672] To a solution of 3,6-dimethyl-2-tetrahydropyran-4-yl-8-vinyl-quinazolin-4-one (4.1 g, 14.4 mmol) in tetrahydrofuran (100 mL) and water (25 mL) was added sodium periodate (12.3 g, 57.7 mmol) and dipotassium dioxido(dioxo)osmium dihydrate (106 mg, 288 μmol), the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was quenched with water (300 mL) and extracted with ethyl acetate (200 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ethergradient @ 100 mL/min) to give 3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4- dihydroquinazoline-8-carbaldehyde (3.35 g, 81%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.1 (s, 1H), 8.33 - 8.30 (m, 1H), 8.11 (d, J = 2.0 Hz, 1H), 4.19 - 4.17 (m, 2H), 3.71 (s, 3H), 3.62 (d, J = 1.6 Hz, 2H), 3.14 - 3.10 (m, 1H), 2.53 (s, 3H), 2.26 - 2.18 (m, 4H); m/z ES+ [M+H] ⁺ 287.1. [2673] Step 3. Synthesis of (R)-N-((3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4- dihydroquinazolin-8-yl)methylene)-2-methylpropane-2-sulfinam ide [2674] To a solution of 3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4- dihydroquinazoline-8-carbaldehyde(3.35 g, 11.7 mmol), (R)-2-methylpropane-2-sulfinamide (4.25 g, 35.1 mmol) in tetrahydrofuran (60 mL) was added propan-2-olate titanium(4+) (10.7 g, 46.8 mmol) and stirred at 75 °C for 16 hr. On completion, the reaction mixture was poured into water (20 mL) at 25 °C, and then filtered with cilte and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase HPLC (ammonium hydroxide condition) and flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 100 mL/min) to give (R)-N-((3,6-dimethyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)methyl ene)-2-methylpropane-2- sulfinamide (1 g, 22%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.70 (s, 1H), 8.28 - 8.19 (m, 2H), 4.23 - 4.06 (m, 2H), 3.70 (s, 3H), 3.61 - 3.51 (m, 2H), 3.16 - 3.04 (m, 1H), 2.54 (s, 3H), 2.30 - 2.11 (m, 2H), 1.92 - 1.79 (m, 2H), 1.32 (s, 9H); m/z ES+ [M+H] ⁺ 390.2. [2675] Step 4. Synthesis of (R)-N-(1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3, 4- dihydroquinazolin-8-yl)-2,2-difluoro-2-(phenylsulfonyl)ethyl )-2-methylpropane-2- sulfinamide [2676] To a solution of (R)-N-((3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4- dihydroquinazolin-8-yl)methylene)-2-methylpropane-2-sulfinam ide (2.4 g, 6.16 mmol) and difluoromethylsulfonylbenzene (2.37 g, 12.3 mmol) in anhydrous tetrahydrofuran (30 mL) was added [bis(trimethylsilyl)amino]lithium (1 M, 18.5 mL) at -78 °C under nitrogen atmosphere and stirred at -78 °C to 25 °C for 16 hr. On completion, the reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase HPLC (ammonium hydroxide condition) to give (R)-N-(1-(3,6-dimethyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)-2,2-d ifluoro-2 (phenylsulfonyl)ethyl)-2-methylpropane-2-sulfinamide (1.9 g, 49%) as a yellow solid. m/z ES+ [M+H] ⁺ 582.2. [2677] Step 5. Synthesis of (R)-N-((S)-1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl )- 3,4-dihydroquinazolin-8-yl)-2,2-difluoroethyl)-2-methylpropa ne-2-sulfinamide [2678] To a solution of (R)-N-(1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3, 4- dihydroquinazolin-8-yl)-2,2-difluoro-2-(phenylsulfonyl)ethyl )-2-methylpropane-2- sulfinamide (1.8 g, 3.09 mmol) in N,N-dimethylformamide (72 mL) was added a solution of sodium acetate (2.54 g, 30.9 mmol) and acetic acid (8.54 g, 30.9 mmol) in water (18 mL) and stirred at 25 °C for 15 min, then magnesium (1.13 g, 46.4 mmol) was added in portions below at 45 °C under nitrogen atmosphere. Then the mixture was stirred at 60 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition water (300 mL) at 0°C, and then extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase HPLC (0.1% FA condition) to give (R)-N-((S)-1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)-2,2-difluoroethyl)-2 -methylpropane-2-sulfinamide (900 mg, 59%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.54 (d, J = 1.6 Hz, 1H), 6.43 - 6.05 (m, 1H), 5.31 (d, J = 9.2 Hz, 1H), 4.88 - 4.61 (m, 1H), 4.21 - 4.09 (m, 2H), 3.75 - 3.66 (m, 3H), 3.64 - 3.53 (m, 2H), 3.19 - 3.06 (m, 1H), 2.48 (s, 3H), 2.12 - 1.99 (m, 2H), 1.94 - 1.84 (m, 2H), 1.27 (s, 9H); m/z ES+ [M+H] ⁺ 442.2. [2679] Step 6. Synthesis of (S)-8-(1-amino-2,2-difluoroethyl)-3,6-dimethyl-2-(tetrahydro - 2H-pyran-4-yl)quinazolin-4(3H)-one [2680] The mixture of (R)-N-((S)-1-(3,6-dimethyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl )-3,4- dihydroquinazolin-8-yl)-2,2-difluoroethyl)-2-methylpropane-2 -sulfinamide (400 mg, 906 μmol) in dichloromethane (3 mL) and hydrochloric acid/dioxane (1 mL) was stirred at 25 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed phase HPLC (0.1% ammonium hydroxide condition) to give (S)-8-(1-amino-2,2-difluoroethyl)-3,6-dimethyl-2-(tetrahydro -2H-pyran-4-yl)quinazolin- 4(3H)-one (300 mg, 98% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.59 (d, J = 1.6 Hz, 1H), 6.48 - 6.02 (m, 1H), 4.89 - 4.67 (m, 1H), 4.19 - 4.11 (m, 2H), 3.68 (s, 3H), 3.62 - 3.54 (m, 2H), 3.16 - 3.06 (m, 1H), 2.49 (s, 3H), 2.16 - 2.00 (m, 2H), 1.90 - 1.85 (m, 2H); m/z ES+ [M+H] ⁺ 338.2. [2681] Step 7. Synthesis of (S)-8-(2,2-difluoro-1-((4-fluoro-2- (methylsulfonyl)phenyl)amino)ethyl)-3,6-dimethyl-2-(tetrahyd ro-2H-pyran-4-yl)quinazolin- 4(3H)-one [2682] To a solution of (S)-8-(1-amino-2,2-difluoroethyl)-3,6-dimethyl-2-(tetrahydro -2H- pyran-4-yl)quinazolin-4(3H)-one (260 mg, 771 μmol), 1-bromo-4-fluoro-2-methylsulfonyl- benzene (585 mg, 2.31 mmol), cesium carbonate (753 mg, 2.31 mmol) in dioxane (5 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidaz ol-1-ium-2-ide;3- chloropyridine;dichloropalladium (112 mg, 116 μmol) and stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 250×50mm×10um;mobile phase: [water (ammonium bicarbonate)-acetonitrile];B%: 40%- 70%, 10 min) to give (S)-8-(2,2-difluoro-1-((4-fluoro-2-(methylsulfonyl)phenyl)am ino)ethyl)- 3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-on e (120 mg, 46%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.59 - 7.50 (m, 2H), 7.13 - 7.02 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.66 - 6.58 (m, 1H), 6.50 - 6.15 (m, 1H), 5.80 - 5.68 (m, 1H), 4.22 - 4.09 (m, 2H), 3.71 (s, 3H), 3.65 - 3.56 (m, 2H), 3.20 - 3.11 (m, 4H), 2.45 (s, 3H), 2.25 - 2.08 (m, 2H), 1.96 - 1.87 (m, 2H); m/z ES+ [M+H] ⁺ 510.2. Example 306. Preparation of (R)-2-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethoxy)benzoic acid & (S)-2-(1-(3-cyclopropyl-6- fluoro-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazo lin-8-yl)ethoxy)benzoic acid (Compounds 680 and 681) (stereochemistry arbitrarily assigned) [2683] Step 1. Synthesis of methyl 2-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethoxy)benzoate [2684] A mixture of 3-cyclopropyl-6-fluoro-8-(1-hydroxyethyl)-2-tetrahydropyran- 4-yl- quinazolin-4-one (500 mg, 1.50 mmol), methyl 2-hydroxybenzoate (572 mg, 3.76 mmol) and triphenylphosphine (591 mg, 2.26 mmol) in tetrahydrofuran (10 mL) was stirred at 20 °C for 30 min. Then diisopropyl azodicarboxylate (456 mg, 2.26 mmol) was added at 0 °C under nitrogen. The reaction mixture was stirred at 20 °C for 12 hr. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give methyl 2-[1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyran-4-yl-qu inazolin-8- yl)ethoxy]benzoate (450 mg, 965 μmol, 64%) as a colorless oil. m/z ES+ [M+H] ⁺ 467.3. [2685] Step 2. Synthesis of 2-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-pyran-4- yl)-3,4-dihydroquinazolin-8-yl)ethoxy)benzoic acid [2686] To a mixture of methyl 2-[1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethoxy]benzoate (200 mg, 428 μmol) in methanol (1 mL), tetrahydrofuran (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (89.9 mg, 2.14 mmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was pured into water (30 mL) and then adjusted to pH ~ 5 with formic acid. The mixture was then filtered and the filtered cake was concentrated in vacuo to give 2-[1-(3-cyclopropyl-6-fluoro-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethoxy]benzoic acid (120 mg, 265 μmol, 62%) as a white solid. m/z ES+ [M+H] ⁺ 453.2. [2687] Step 3. Chiral purification [2688] 2-[1-(3-cyclopropyl-6-fluoro-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8- yl)ethoxy]benzoic acid (90 mg, 199 μmol) was separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [carbon dioxide-methanol];B%:40%, isocratic elution mode) to give (R)-2-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethoxy)benzoic acid (36.2 mg, 80.0 μmol, 40%) as an off-white solid,1 ^st peak, R.T. 1.72 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.00 (br. s, 1H), 8.20 (dd, J = 1.6, 8.0 Hz, 1H), 7.82 (dd, J = 2.8, 8.0 Hz, 1H), 7.48 (dd, J = 2.8, 8.8 Hz, 1H), 7.36 (dt, J = 2.0, 8.0 Hz, 1H), 7.13 - 7.04 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.57 (q, J = 6.8 Hz, 1H), 4.20 - 4.07 (m, 2H), 3.77 (tt, J = 3.6, 11.4 Hz, 1H), 3.65 - 3.53 (m, 2H), 3.06 - 2.95 (m, 1H), 2.19 - 2.01 (m, 2H), 1.87 (s, 2H), 1.85 (s, 3H), 1.46 - 1.39 (m, 2H), 1.03 - 0.93 (m, 2H); m/z ES+ [M+H] ⁺ 453.2; and (S)-2-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-pyra n-4- yl)-3,4-dihydroquinazolin-8-yl)ethoxy)benzoic acid (45.6 mg, 101 μmol, 51%) as a white solid, 2 ^nd peak, R.T. 1.93 min. ¹ H NMR (400 MHz, CDCl3) δ 11.00 (br. s, 1H), 8.20 (dd, J = 1.6, 7.6 Hz, 1H), 7.82 (dd, J = 2.8, 8.0 Hz, 1H), 7.48 (dd, J = 2.8, 8.8 Hz, 1H), 7.41 - 7.32 (m, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.57 (q, J = 6.4 Hz, 1H), 4.20 - 4.10 (m, 2H), 3.77 (tt, J = 3.6, 11.2 Hz, 1H), 3.64 - 3.54 (m, 2H), 3.06 - 2.94 (m, 1H), 2.18 - 2.02 (m, 2H), 1.87 (s, 2H), 1.85 (s, 3H), 1.46 - 1.39 (m, 2H), 1.01 - 0.94 (m, 2H); m/z ES+ [M+H] ⁺ 453.3. Example 307. Preparation of (R)-6-Chloro-3-(1-(3-cyclopropyl-6-fluoro-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethoxy )picolinic acid & (S)-6- Chloro-3-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H-p yran-4-yl)-3,4- dihydroquinazolin-8-yl)ethoxy) picolinic acid (Compounds 720 and 721) (stereochemistry arbitrarily assigned)

[2689] Step 1. Synthesis of 8-(1-((2-bromo-6-chloropyridin-3-yl)oxy)ethyl)-3-cyclopropyl - 6-fluoro-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2690] A solution of 3-cyclopropyl-6-fluoro-8-(1-hydroxyethyl)-2-tetrahydropyran- 4-yl- quinazolin-4-one (400 mg, 1.20 mmol), 2-bromo-6-chloro-pyridin-3-ol (501 mg, 2.41 mmol) and triphenylphosphane (473 mg, 1.81 mmol) in anhydrous tetrahydrofuran (8 mL) was stirred at 25 °C for 0.5 hr. Then diisopropyl azodicarboxylate (365 mg, 1.81 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 12 hr under nitrogen. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 1/1) to give 8-[1-[(2- bromo-6-chloro-3-pyridyl)oxy]ethyl]-3-cyclopropyl-6-fluoro-2 -tetrahydropyran-4-yl- quinazolin-4-one (230 mg, 385 μmol, 32%) as a white solid. m/z ES+ [M+H] ⁺ 522.1. [2691] Step 2. Synthesis of methyl 6-chloro-3-(1-(3-cyclopropyl-6-fluoro-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethoxy )picolinate [2692] To a solution of 8-[1-[(2-bromo-6-chloro-3-pyridyl)oxy]ethyl]-3-cyclopropyl-6 - fluoro-2-tetrahydropyran-4-yl-quinazolin-4-one (120 mg, 229 μmol) and triethylamine (69.7 mg, 689 μmol) in dimethylsulfoxide (8 mL) and methanol (8 mL) was added dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (18.7 mg, 22.9 μmol). The suspension was degassed and purged with carbon monoxide (3x) and then stirred at 60 °C for 12 hr under carbon monoxide (50 psi) atmosphere. On completion, the mixture was filtered and concentrated under reduced pressure to give methyl 6-chloro-3-[1-(3-cyclopropyl-6- fluoro-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethoxy]p yridine-2-carboxylate (80.0 mg, crude, really poor solubility, challenging purification) as a yellow oil. m/z ES+ [M+H] ⁺ 502.2 [2693] Step 3. Synthesis of 6-chloro-3-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H - pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethoxy)picolinic acid [2694] To a solution of methyl 6-chloro-3-[1-(3-cyclopropyl-6-fluoro-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethoxy]pyridine-2-carbo xylate (80.0 mg, 159 μmol) in anhydrous tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (19.1 mg, 797 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the mixture was adjusted to pH ~ 6 with saturated ammonium chloride solution, then washed with ethyl acetate (20 mL x 3). The aqueous layer was further extracted with dichloromethane (20 mL x 8). The combined organic layers were concentrated under reduced pressure to give 6-chloro-3-[1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyra n-4-yl- quinazolin-8-yl)ethoxy]pyridine-2-carboxylic acid (50.0 mg, 97.6 μmol, 61%) as a white solid. m/z ES+ [M+H] ⁺ 488.2. [2695] Step 4. Chiral purification [2696] 6-Chloro-3-[1-(3-cyclopropyl-6-fluoro-4-oxo-2-tetrahydropyra n-4-yl-quinazolin-8- yl)ethoxy] pyridine-2-carboxylic acid (50.0 mg, 97.6 μmol) was separated by SFC (column: Daicel ChiralPak IG (250*30mm, 10um);mobile phase: [carbon dioxide-ethanol];B%:40%, isocratic elution mode) to give (R)-6-chloro-3-(1-(3-cyclopropyl-6-fluoro-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethoxy ) picolinic acid (19.86 mg, 39.7 μmol, 39%) as an off-white solid, 1 ^st peak, R.T. 2.00 min. ¹ H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 2.8, 9.6 Hz, 1H), 7.60 (dd, J = 3.2, 8.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.26 (q, J = 6.0 Hz, 1H), 4.00 (br. d, J = 11.2 Hz, 2H), 3.75 (br dd, J = 3.2, 4.4 Hz, 1H), 3.56 - 3.46 (m, 2H), 3.10 (dt, J = 4.0, 7.2 Hz, 1H), 1.99 - 1.89 (m, 4H), 1.58 (d, J = 6.4 Hz, 3H), 1.27 - 1.23 (m, 2H), 0.91 (br. d, J = 2.4 Hz, 2H); m/z ES+ [M+H] ⁺ 488.2; and (S)- 6-chloro-3-(1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H -pyran-4-yl)-3,4- dihydroquinazolin-8-yl)ethoxy)picolinic acid (29.69 mg, 60.0 μmol, 59%) as an off-white solid, 2 ^nd peak, R.T. 2.22 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.95 (dd, J = 2.8, 9.6 Hz, 1H), 7.60 (dd, J = 3.2, 8.4 Hz, 1H), 7.09 (dd, J = 3.2, 8.8 Hz, 1H), 6.98 (dd, J = 4.8, 8.8 Hz, 1H), 6.27 (q, J = 5.6 Hz, 1H), 4.00 (br. d, J = 11.2 Hz, 2H), 3.81 - 3.69 (m, 1H), 3.56 - 3.46 (m, 2H), 3.14 - 3.06 (m, 1H), 2.00 - 1.89 (m, 4H), 1.58 (d, J = 6.4 Hz, 3H), 1.35 - 1.25 (m, 2H), 0.90 (br. d, J = 1.6 Hz, 2H); m/z ES+ [M+H] ⁺ 488.2. Example 308. Preparation of (R)-6-Fluoro-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3-methyl-2-(4-methyltetrahydro-2H-pyr an-4-yl)quinazolin- 4(3H)-one (Compound 651) [2697] Step 1. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- fluorophenyl)amino)ethyl)-6-fluoro-3-methyl-2-(4-methyltetra hydro-2H-pyran-4- yl)quinazolin-4(3H)-one [2698] A mixture of (R)-8-(1-aminoethyl)-6-fluoro-3-methyl-2-(4-methyltetrahydro -2H- pyran-4-yl)quinazolin-4(3H)-one (100 mg, 313 μmol), [1-(2-bromo-5-fluoro-phenyl)-4- piperidyl]oxy-tert-butyl-dimethyl-silane (146 mg, 376 μmol), 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (30.5 mg, 31.3 μmol), cesium carbonate (306 mg, 939 μmol) in dioxane (1.00 mL) was degassed and purged with nitrogen (3x), and then the mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=1/1) to give (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- fluorophenyl)amino)ethyl)-6-fluoro-3-methyl-2-(4-methyltetra hydro-2H-pyran-4- yl)quinazolin-4(3H)-one (90.0 mg, 94.6 μmol, 30%) as a yellow oil. m/z ES+ [M+H] ⁺ 627.3. [2699] Step 2. Synthesis of (R)-6-Fluoro-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3-methyl-2-(4-methyltetrahydro-2H-pyr an-4-yl)quinazolin-4(3H)- one [2700] To a solution of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- fluorophenyl)amino)ethyl)-6-fluoro-3-methyl-2-(4-methyltetra hydro-2H-pyran-4- yl)quinazolin-4(3H)-one (90.0 mg, 143 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 1 mL), the mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(formic acid)- acetonitrile];gradient:46%-76% B over 10 min) to give (R)-6-fluoro-8-(1-((4-fluoro-2-(4- hydroxypiperidin-1-yl)phenyl)amino)ethyl)-3-methyl-2-(4-meth yltetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one (44.4 mg, 86.1 μmol, 60%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 2.4, 8.0 Hz, 1H), 7.48 (br dd, J = 2.4, 7.6 Hz, 1H), 6.84 - 6.69 (m, 1H), 6.58 - 6.43 (m, 1H), 6.15 - 6.01 (m, 1H), 5.36 - 5.21 (m, 1H), 5.11 - 4.71 (m, 1H), 3.97 - 3.86 (m, 1H), 3.83 (br. t, J = 5.2 Hz, 4H), 3.76 (s, 3H), 3.34 - 3.08 (m, 2H), 2.90 - 2.63 (m, 2H), 2.60 - 2.48 (m, 2H), 2.18 - 2.05 (m, 2H), 1.94 (br dd, J = 6.8, 12.4 Hz, 2H), 1.87 - 1.73 (m, 2H), 1.61 (s, 3H), 1.59 (br. s, 3H); m/z ES+ [M+H] ⁺ 513.3. Example 309. Preparation of (R)-6-Fluoro-8-(1-((4-fluoro-2-(3-hydroxyazetidine-1- carbonyl)phenyl)amino)ethyl)-3-methyl-2-(4-methyltetrahydro- 2H-pyran-4- yl)quinazolin-4(3H)-one (Compound 751) [2701] Step 1. Synthesis of (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-2-(4-methyltetrahydro- 2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoic acid [2702] To a solution of 8-[(1R)-1-aminoethyl]-6-fluoro-3-methyl-2-(4- methyltetrahydropyran-4-yl)quinazolin-4-one (200 mg, 626 μmol) in dioxane (2 mL) was added 5-fluoro-2-iodo-benzoic acid (333 mg, 1.25 mmol), cesium carbonate (612 mg, 1.88 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert -butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (49.7 mg, 62.6 μmol), then degassed and purged with nitrogen (3x), the mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. The reaction mixture was partitioned between saturated ammonium chloride (20 mL) and ethyl acetate (30 mL). The organic phase was separated, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-2-(4- methyltetrahydro-2H-pyran-4-yl)-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid (130 mg, 241 μmol, 39%) as a yellow oil. m/z ES+ [M+H] ⁺ 458.2. [2703] Step 2. Synthesis of (R)-6-fluoro-8-(1-((4-fluoro-2-(3-hydroxyazetidine-1- carbonyl)phenyl)amino)ethyl)-3-methyl-2-(4-methyltetrahydro- 2H-pyran-4-yl)quinazolin- 4(3H)-one [2704] To a solution of (R)-5-fluoro-2-((1-(6-fluoro-3-methyl-2-(4-methyltetrahydro- 2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoic acid (130 mg, 284 μmol), azetidin-3-ol;hydrochloride (37.3 mg, 341 μmol) in dimethyl formamide (1.5 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethy luronium hexafluorophosphate(V) (129 mg, 341 μmol) and diisopropylethylamine (110 mg, 852 μmol). The mixture was stirred at 25 °C for 12 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150x25mmx10um;mobile phase: [water(formic acid)-acetonitrile];gradient:36%-66% B over 10 min) to give (R)-6-fluoro-8-(1-((4-fluoro-2-(3-hydroxyazetidine-1- carbonyl)phenyl)amino)ethyl)-3-methyl-2-(4-methyltetrahydro- 2H-pyran-4-yl)quinazolin- 4(3H)-one (73.0 mg, 138 μmol, 49%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 2.8, 8.0 Hz, 1H), 7.52 (dd, J = 2.8, 9.2 Hz, 1H), 6.96 (dd, J = 2.8, 9.2 Hz, 1H), 6.86 - 6.77 (m, 1H), 6.25 (br dd, J = 4.4, 9.2 Hz, 1H), 5.39 (q, J = 6.4 Hz, 1H), 4.82 - 4.70 (m, 1H), 4.60 - 4.43 (m, 2H), 4.17 (br. s, 2H), 3.83 (br. t, J = 5.2 Hz, 4H), 3.75 (s, 3H), 2.79 - 2.58 (m, 1H), 2.56 - 2.44 (m, 2H), 2.00 - 1.88 (m, 2H), 1.64 - 1.55 (m, 6H); m/z ES+ [M+H] ⁺ 513.3. Example 310. Preparation of (R)-2-((1-(3-(Difluoromethyl)-6-methyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl) amino)-5-fluorobenzoic acid (Compound 514) [2705] Step 1. Synthesis of (R)-2-((1-(3-(difluoromethyl)-6-methyl-4-oxo-2-(tetrahydro-2 H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro benzoic acid [2706] To a mixture of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-methyl-2- tetrahydropyran-4-yl-quinazolin-4-one (30 mg, 88.9 μmol), copper powder (16.9 mg, 266 μmol) and 5-fluoro-2-iodo-benzoic acid (118 mg, 444 μmol) in dimethyl acetamide (0.6 mL) was added triethylamine (179 mg, 1.78 mmol) and the mixture was stirred at 110 °C for 1 hr. On completion, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water(ammonium bicarbonate)-acetonitrile];B%: 24%-54%, 10 min) to give (R)-2-((1-(3- (difluoromethyl)-6-methyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl) -3,4-dihydroquinazolin-8- yl)ethyl)amino)-5-fluorobenzoic acid (11 mg, 25%) as brown gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 - 7.92 (m, 3H), 7.65 (dd, J = 3.2, 9.6 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 6.94 (ddd, J = 3.2, 7.6, 9.2 Hz, 1H), 6.34 (dd, J = 4.4, 9.2 Hz, 1H), 5.52 (br. d, J = 6.8 Hz, 1H), 4.15 (br dd, J = 3.6, 11.6 Hz, 2H), 3.60 (br. t, J = 12.0 Hz, 2H), 3.46 - 3.36 (m, 1H), 2.41 (s, 3H), 2.29 - 2.21 (m, 2H), 1.93 (br. s, 2H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 476.2. Example 311. Preparation of (R)-2-((1-(3-(Difluoromethyl)-6-methyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid (Compound 516) [2707] Step 1. Synthesis of (R)-2-((1-(3-(Difluoromethyl)-6-methyl-4-oxo-2-(tetrahydro-2 H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2708] To a mixture of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-methyl-2- tetrahydropyran-4-yl-quinazolin-4-one (50 mg, 148 μmol) and 2-iodobenzoic acid (183 mg, 741 μmol) in dimethyl acetamide (0.1 mL) was added Cu (28.2 mg, 444 μmol) and triethylamine (300 mg, 2.96 mmol) under nitrogen atmosphere and stirred at 110 °C for 1 hr. On completion, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25mm 10um; mobile phase: [water(ammonium bicarbonate)-acetonitrile];B%: 25%-55%, 10 min) to give (R)-2-((1- (3-(difluoromethyl)-6-methyl-4-oxo-2-(tetrahydro-2H-pyran-4- yl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (9.5 mg, 14%) was obtained as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 - 7.89 (m, 4H), 7.63 (s, 1H), 7.22 - 7.15 (m, 1H), 6.60 - 6.52 (m, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.58 (d, J = 6.4 Hz, 1H), 4.15 (d, J = 8.8 Hz, 2H), 3.65 - 3.50 (m, 2H), 3.47 - 3.31 (m, 1H), 2.40 (s, 3H), 2.25 (d, J = 0.8 Hz, 2H), 1.99-1.85 (m, 2H), 1.65 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 458.1. Example 312. Preparation of (R)-2-((1-(3-(Difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-flu orobenzoic acid (Compound 515) [2709] Step 1. Synthesis of (R)-2-((1-(3-(difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydro-2 H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluoro benzoic acid [2710] To a mixture of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-fluoro-2- tetrahydropyran-4-yl-quinazolin-4-one (8.00 g, 23.4 mmol) and 5-fluoro-2-iodo-benzoic acid (31.2 g, 117 mmol) in dimethyl acetamide (80 mL) was added triethylamine (47.4 mg, 469 mmol), then copper (1.49 g, 23.4 mmol,) was added under nitrogen, the reaction mixture was stirred at 110 °C for 1 hr. On completion, the reaction mixture was added ammonium hydroxide (5 mL) and then filtered, the filtered liquor was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 (250*70mm,10 um);mobile phase: [water(FA)-acetonitrile];gradient:50%-80% B over 20 min) to give 2- [[(1R)-1-[3-(difluoromethyl)-6-fluoro-4-oxo-2-tetrahydropyra n-4-yl-quinazolin-8- yl]ethyl]amino]-5-fluoro-benzoic acid (150 mg, 71%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 - 7.89 (m, 2H), 7.78 (dd, J = 2.8, 7.6 Hz, 1H), 7.69 (dd, J = 3.2, 9.6 Hz, 1H), 7.52 (dd, J = 2.8, 9.2 Hz, 1H), 6.94 (ddd, J = 3.2, 7.6, 9.2 Hz, 1H), 6.23 (dd, J = 4.4, 9.2 Hz, 1H), 5.53 (br. d, J = 5.6 Hz, 1H), 4.24 - 4.11 (m, 2H), 3.62 (dt, J = 1.6, 12.0 Hz, 2H), 3.43 (br. t, J = 10.4 Hz, 1H), 2.34 - 2.17 (m, 2H), 2.02 - 1.91 (m, 2H), 1.66 (d, J = 6.4 Hz, 3H). m/z ES+ [M+H] ⁺ 480.2. Example 313. Preparation of (R)-2-((1-(3-(Difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (Compound 528) [2711] Step 1. Synthesis of (R)-2-((1-(3-(difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydro-2 H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2712] To a mixture of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-fluoro-2- tetrahydropyran-4-yl-quinazolin-4-one(720 mg, 2.11 mmol), 2-iodobenzoic acid (2.09 g, 8.44 mmol) and triethylamine (4.27 g, 42.1 mmol) in dimethyl acetamide (7 mL) was added copper (134 mg, 2.11 mmol) and the reaction mixture was stirred at 110 °C for 2 hr. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-acetonitrile];B%: 52%-82%, 10 min) to give (R)-2-((1-(3- (difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydro-2H-pyran-4-yl) -3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (143 mg, 309 μmol, 20%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 - 7.96 (m, 3H), 7.74 (dd, J = 2.8, 8.0 Hz, 1H), 7.55 (dd, J = 3.2, 9.2 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1H), 6.62 (t, J = 7.2 Hz, 1H), 5.60 - 5.56 (m, 1H), 4.17 - 4.14 (m, 2H), 3.60 (t, J = 12.0 Hz, 2H), 3.42 (t, J = 12.0 Hz, 1H), 2.92 - 2.19 (m, 2H), 1.99 - 1.92 (m, 2H), 1.67 (d, J = 6.4 Hz, 3H). m/z ES+ [M+H] ⁺ 462.1. Example 314. Preparation of (R)-2-((1-(3-(Difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-4-flu orobenzoic acid (Compound 667) [2713] Step 1. Synthesis of (R)-2-((1-(3-(difluoromethyl)-6-fluoro-4-oxo-2-(tetrahydro-2 H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-4-fluoro benzoic acid [2714] To a mixture of 8-[(1R)-1-aminoethyl]-3-(difluoromethyl)-6-fluoro-2- tetrahydropyran-4-yl-quinazolin-4-one (200 mg, 585 μmol) and 4-fluoro-2-iodo-benzoic acid (779 mg, 2.93 mmol) in dimethyl acetamide (2 mL) was added triethylamine (1.19 g, 11.7 mmol) and copper powder (37.2 mg, 585 μmol), the reaction mixture was stirred at 110 °C for 1 hr under nitrogen. On completion, the reaction mixture was quenched with ammonium hydroxide (1 mL) and diluted with water (30 mL). The mixture was then filtered and the filtrate was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- acetonitrile];gradient:55%-85% B over 10 min) to give (R)-2-((1-(3-(difluoromethyl)-6-fluoro- 4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-y l)ethyl)amino)-4- fluorobenzoic acid (89.7 mg, 183 μmol, 31%) as a light yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.36 (br. d, J = 5.2 Hz, 1H), 8.11 (t, J = 59.2 Hz, 1H), 8.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.79 (dd, J = 2.8, 7.6 Hz, 1H), 7.52 (dd, J = 2.8, 8.8 Hz, 1H), 6.33 - 6.25 (m, 1H), 6.01 (dd, J = 2.4, 12.0 Hz, 1H), 5.53 (q, J = 6.4 Hz, 1H), 4.25 - 4.11 (m, 2H), 3.62 (br. t, J = 11.6 Hz, 2H), 3.44 (br. t, J = 11.2 Hz, 1H), 2.28 (dq, J = 4.4, 12.0 Hz, 2H), 2.04 - 1.91 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 480.2. Example 315. Preparation of (R)-8-(1-((4-Chloro-2- (methylsulfonyl)phenyl)amino)ethyl)-5-fluoro-3,6-dimethyl-2- (tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one (Compound 542)

[2715] Step 1. Synthesis of 8-bromo-5-fluoro-3, 6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one [2716] To a solution of 2-amino-3-bromo-6-fluoro-N,5-dimethyl-benzamide (6 g, 22.9 mmol) in ethanol (60 mL) was added iodine (10.3 g, 40.5 mmol) and tetrahydropyran-4-carbaldehyde (3.15 g, 27.6 mmol). The mixture was stirred at 80 °C for 16 hr. The mixture was quenched with saturated sodium sulfite aqueous solution (100 mL), remove ethanol concentrated to give a residue. The crude product was triturated with water at 25 °C for 30 min. The crude product was triturated with ethyl acetate (50 mL) at 25 °C for 10 min to give 8-bromo-5-fluoro-3, 6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (5.5 g, 15.48 mmol, 67.4%) was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.2 Hz, 1H), 4.20 - 4.13 (m, 2H), 3.64 (s, 3H), 3.59 (dt, J = 2.0, 12.0 Hz, 2H), 3.09 (tt, J = 3.6, 10.8 Hz, 1H), 2.36 (d, J = 2.4 Hz, 3H), 2.28 - 2.16 (m, 2H), 1.87 (br. d, J = 13.6 Hz, 2H); m/z ES+ [M+H] ⁺ 355.1. [2717] Step 2. Synthesis of 8-acetyl-5-fluoro-3, 6-dimethyl-2-tetrahydropyran-4-yl- quinazolin-4-one [2718] To a solution of 8-bromo-5-fluoro-3, 6-dimethyl-2-tetrahydropyran-4-yl-quinazolin- 4-one (5.5 g, 15.5 mmol) and tributyl (1-ethoxyvinyl) stannane (16.8 g, 46.5 mmol) in toluene (55 mL) was added dichloropalladium; triphenylphosphane (1.09 g, 1.55 mmol). The mixture was stirred at 130 °C for 16 hr under nitrogen atmosphere. Then the reaction mixture added saturated potassium fluoride solution 100 mL at 25 °C and stirred at 25 °C for 1 h. The reaction was extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (200 mL ×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in water (50 mL) and hydrochloric acid (1 M, 125 mL). The mixture was stirred at 25 °C for 1 hr. The reaction was was neutralized to pH = 9 with aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL ×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ethergradient @ 60 mL/min) to give 8- acetyl-5-fluoro-3, 6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one (3.2 g, 10.05 mmol, 69.6%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.93 (br. d, J = 7.6 Hz, 1H), 4.18 - 4.11 (m, 2H), 3.66 (d, J = 1.2 Hz, 3H), 3.57 (br. t, J = 12.0 Hz, 2H), 3.12 (br. t, J = 11.6 Hz, 1H), 2.87 (d, J = 1.2 Hz, 3H), 2.38 (s, 3H), 2.16 - 2.04 (m, 2H), 1.87 (br. d, J = 13.2 Hz, 2H) ; m/z ES+ [M+H] ⁺ 319.2. [2719] Step 3. Synthesis of (NE,R)-N-[1-(5-fluoro-3, 6-dimethyl-4-oxo-2-tetrahydropyran-4- yl-quinazolin-8-yl) ethylidene]-2-methyl-propane-2-sulfinamide [2720] To a solution of 8-acetyl-5-fluoro-3, 6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4- one (3.2 g, 10.1 mmol) in 2-methyltetrahydrofuran (32 mL) was added tetraethyl titanate (11.5 g, 50.3 mmol) and (R) -2-methylpropane-2-sulfinamide (3.65 g, 30.2 mmol). The mixture was stirred at 75 °C for 16 hr. The reaction mixture was diluted with anhydrous tetrahydrofuran (30 mL) and poured to water (50 mL), filtered and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~60% ethyl acetate/petroleum ethergradient @ 60 mL/min) to give a yellow oil. Then further purified by reversed-phase (0.1% basic condition) to give (NE, R)-N-[1-(5-fluoro- 3, 6-dimethyl-4-oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethy lidene]-2-methyl-propane-2- sulfinamide (3 g, 7.12 mmol, 70.8%) was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.68 (q, J = 6.0 Hz, 1H), 4.12 - 4.07 (m, 2H), 3.66 - 3.61 (m, 3H), 3.55 (br. t, J = 12.0 Hz, 2H), 3.13 - 3.01 (m, 1H), 2.38 (d, J = 2.0 Hz, 4H), 2.01 (br. s, 2H), 1.83 (br. d, J = 13.6 Hz, 2H), 1.33 (s, 6H), 1.20 (s, 3H) ; m/z ES+ [M+H] ⁺ 319.2. [2721] Step 4. Synthesis of (R)-N-[(1R)-1-(5-fluoro-3,6-dimethyl-4-oxo-2-tetrahydropyran - 4-yl-quinazolin-8-yl) ethyl]-2-methyl-propane-2-sulfinamide [2722] To a solution of sodium borohydride (179 mg, 4.74 mmol) in anhydrous tetrahydrofuran (10 mL) was added (NE,R)-N-[1-(5-fluoro-3,6-dimethyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl) ethylidene]-2-methyl-propane-2-sulfinamide (1 g, 2.37 mmol) at -60 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 1 hr. The mixture was quenched by water (50 mL) and saturated ammonium chloride solution (25 mL) at 0 °C. Then the mixture was extracted with ethyl acetate (50 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 250x50 mmx10um; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 28%-58%, 8 min) followed by lyophilisation to give (R) -N-[ (1R) -1-(5-fluoro-3, 6-dimethyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl) ethyl]-2-methyl-propane-2-sulfinamide (400 mg, 944.41 μmol, 39.8%) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.2 Hz, 1H), 4.79 (br. s, 1H), 4.16 - 4.10 (m, 2H), 3.63 (s, 3H), 3.58 (br. t, J = 12.0 Hz, 2H), 3.09 (tt, J = 3.6, 11.6 Hz, 1H), 2.35 (d, J = 2.4 Hz, 3H), 2.20 - 2.06 (m, 2H), 1.93 - 1.82 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.22 (s, 9H) ; m/z ES+ [M+H] ⁺ 424.3. [2723] Step 5. Synthesis of (R)-8-(1-aminoethyl)-5-fluoro-3,6-dimethyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2724] To a solution of (R)-N-[(1R)-1-(5-fluoro-3,6-dimethyl-4-oxo-2-tetrahydropyran -4-yl- quinazolin-8-yl)ethyl]-2-methylpropane-2-sulfinamide (200 mg, 472 μmol) in dichloromethane (2 mL) was added hydrochloric acid/dioxane (4 M, 2 mL). The mixture was stirred at 25 °C for 10 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (0.1% formic acid condition) followed by lyophilization to give 8-[(1R)-1-aminoethyl]-5-fluoro-3,6- dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one(110 mg, 344 μmol, 73%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.2 Hz, 1H), 4.92 - 4.82 (m, 1H), 4.13 (d, J = 11.6Hz, 2H), 3.64 (s, 3H), 3.60 - 3.50 (m, 2H), 3.15-3.05 (m, 1H), 2.35 (d, J = 2.0 Hz, 3H), 2.11 - 2.00 (m, 2H), 1.88 (d, J = 11.6 Hz, 2H), 1.74 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 320.2. [2725] Step 6. Synthesis of (R)-8-(1-((4-chloro-2-(methylsulfonyl)phenyl)amino)ethyl)-5- fluoro-3,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4 (3H)-one [2726] To a solution of 8-[(1R)-1-aminoethyl]-5-fluoro-3,6-dimethyl-2-tetrahydropyra n-4-yl- quinazolin-4-one (60 mg, 188 μmol) in dimethyl acetamide (1 mL) was added cesium carbonate (306 mg, 939 μmol) and 4-chloro-1-fluoro-2-methylsulfonyl-benzene (196 mg, 939 μmol). The mixture was stirred at 140 °C for 5 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (fromic acid)- acetonitrile]; gradient: 53%-83% B over 10 min) followed by lyophilization to give 8-[(1R)-1- (4-chloro-2-methylsulfonyl-anilino)ethyl]-5-fluoro-3,6-dimet hyl-2-tetrahydropyran-4- ylquinazolin-4-one (46.5 mg, 89.7 μmol, 48%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.15 (dd, J = 2.4, 8.8Hz, 1H), 6.69 (s, 1H), 6.44 (d, J = 9.2 Hz, 1H), 5.57 - 5.45 (m, 1H), 4.18 - 4.13 (m, 2H), 3.67 (s, 3H), 3.65 - 3.50 (m, 2H), 3.14 (s, 3H), 3.11 (d, J = 3.6 Hz, 1H), 2.30 (d, J = 2.4 Hz, 3H), 2.20 - 2.11 (m, 2H), 1.91 (d, J = 13.2 Hz, 2H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 508.1. Example 316. Preparation of (R)-2-((1-(6-chloro-3-isopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 675) [2727] Step 1. Synthesis of 2-amino-3-bromo-5-chlorobenzoic acid [2728] To a mixture of 2-amino-5-chloro-benzoic acid (10.0 g, 58.3 mmol) in acetic acid (170 mL) was added bromine (10.3 g, 64.1 mmol) dropwise at 0 °C. Then the mixture was stirred at 15 °C for 2 hr. On completion, the reaction mixture was carefully quenched with water (400 mL) and extracted with petroleum ether (100 mL × 2). The combined organic layers were washed with water (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with water (100 mL) at 20 °C for 30 min, filtered and solid was dried under reduce pressure to give 2-amino-3-bromo-5-chloro-benzoic acid (14.0 g, 55.9 mmol, 96%) as a white solid. m/z ES+ [M+H] ⁺ 251.6. [2729] Step 2. Synthesis of 2-amino-3-bromo-5-chloro-N-isopropylbenzamide [2730] To a mixture of 2-amino-3-bromo-5-chloro-benzoic acid (14.0 g, 55.9 mmol) and propan-2-amine (3.30 g, 55.9 mmol) in N,N-dimethylformamide (140 mL) was added diisopropylethylamine (36.1 g, 279 mmol) and [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (34.0 g, 89.4 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 hr. On completion, the reaction mixture was slowly quenched with water (300 mL) and then filtered. The filtered cake was washed with petroleum ether (100 mL × 2) and then concentrated under reduced pressure to give 2-amino-3-bromo-5- chloro-N-isopropyl-benzamide (14.0 g, 48.0 mmol, 86%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 6.52 (s, 2H), 4.10 – 4.00 (m, 1H), 1.15 (d, J = 6.4 Hz, 6H); m/z ES+ [M+H] ⁺ 290.9/292.9. [2731] Step 3. Synthesis of N-(2-bromo-4-chloro-6-(isopropylcarbamoyl)phenyl)tetrahydro- 2H-pyran-4-carboxamide [2732] To a mixture of 2-amino-3-bromo-5-chloro-N-isopropyl-benzamide (7.30 g, 25.0 mmol) and tetrahydropyran-4-carboxylic acid (3.91 g, 30.0 mmol) in pyridine (75 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (47.8 g, 75.1 mmol, 50% purity) dropwise at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (500 mL) and then filtered. The filtered cake was washed with water (100 mL x 3), dried under reudced pressure to give N-[2-bromo-4-chloro-6- (isopropylcarbamoyl)phenyl]tetrahydropyran-4-carboxamide (8.70 g, 21.3 mmol, 99%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 8.12 (br. d, J = 7.4 Hz, 1H), 7.90 (s, 1H), 7.43 (br. s, 1H), 3.97 - 3.90 (m, 1H), 3.88 (br. d, J = 9.6 Hz, 2H), 3.36 (t, J = 11.2 Hz, 2H), 2.65 - 2.57 (m, 1H), 1.74 - 1.61 (m, 4H), 1.09 (br. d, J = 6.4 Hz, 6H); m/z ES+ [M+H] ⁺ 404.7. [2733] Step 4. Synthesis of 8-bromo-6-chloro-3-isopropyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [2734] To a mixture of N-[2-bromo-4-chloro-6- (isopropylcarbamoyl)phenyl]tetrahydropyran-4-carboxamide (8.70 g, 21.6 mmol) in dimethyl acetamide (90 mL) was added [dimethyl-(trimethylsilylamino)silyl]methane (8.70 g, 53.9 mmol) and dichlorozinc (8.81 g, 64.65 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (300 mL) and lots of solid formed. The resulting mixture was filtered and the filtered cake was collected. The filtered cake was triturated with dichloromethane (300 mL) at 25 °C for 15 min and then filtered. The filtrate was concentrated under reduced pressure to give 8-bromo-6-chloro-3-isopropyl-2-tetrahydropyran-4-yl- quinazolin-4-one (5.70 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 4.87 - 4.51 (m, 1H), 4.22 - 4.09 (m, 2H), 3.59 (dt, J = 2.0, 11.8 Hz, 2H), 3.09 (tt, J = 3.2, 10.6 Hz, 1H), 2.35 - 2.17 (m, 2H), 1.89 - 1.80 (m, 2H), 1.67 (d, J = 6.8 Hz, 6H); m/z ES+ [M+H] ⁺ 385.0. [2735] Step 5. Synthesis of 8-acetyl-6-chloro-3-isopropyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [2736] To a mixture of 8-bromo-6-chloro-3-isopropyl-2-tetrahydropyran-4-yl-quinazol in-4- one (4.70 g, 12.2 mmol) in toluene (50 mL) was added dichloropalladium triphenylphosphane (1.71 g, 2.44 mmol) and tributyl (1-ethoxyvinyl) stannane (6.60 g, 18.28 mmol, 6.18 mL) under nitrogen. The mixture was stirred at 100 °C for 16 hr under nitrogen. The reaction mixture was quenched by saturated potassium fluoride solution (20 mL) at 25 °C and stirred at 25 °C for 1 hr, which was then extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in dichloromethane (42 mL) and then formic acid (6 mL) was added. The mixture was stirred at 25 °C for 1 h. The mixture was adjusted to pH ~ 7 with saturated sodium bicarbonate solution, which was further extracted with dichloromethane (300 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 0/1 to 3/1) to give 8-acetyl-6-chloro-3-isopropyl-2-tetrahydropyran-4-yl-quinazo lin- 4-one (1.50 g, 4.30 mmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 4.93 - 4.57 (m, 1H), 4.14 (dd, J = 3.6, 11.2 Hz, 2H), 3.65 - 3.52 (m, 2H), 3.12 (br. t, J = 11.2 Hz, 1H), 2.89 (s, 3H), 2.23 - 2.08 (m, 2H), 1.85 (br. d, J = 14.0 Hz, 2H), 1.70 (d, J = 6.8 Hz, 6H); m/z ES+ [M+H] ⁺ 349.1. [2737] Step 6. Synthesis of (R)-N-(1-(6-Chloro-3-isopropyl-4-oxo-2-(tetrahydro-2H-pyran- 4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane -2-sulfinamide [2738] To a mixture of 8-acetyl-6-chloro-3-isopropyl-2-tetrahydropyran-4-yl-quinazo lin-4- one (1.45 g, 4.16 mmol) and (R)-2-methylpropane-2-sulfinamide (1.51 g, 12.5 mmol) in 2- methyltetrahydrofuran (30 mL) was added tetraethoxytitanium (4.74 g, 20.78 mmol). The mixture was stirred at 75 °C for 4 hr. The reaction mixture was poured into water (200 mL) and then filtered. The filtrate and aqueous layer was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 2/3) to give (R)-N-(1-(6-chloro-3-isopropyl-4-oxo-2-(tetrahydro-2H-pyran- 4-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.38 g, 3.05 mmol, 73%) as a yellow solid. m/z ES+ [M+H] ⁺ 452.1 [2739] Step 7. Synthesis of (R)-N-((R)-1-(6-Chloro-3-isopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide [2740] To a solution of (R)-N-(1-(6-chloro-3-isopropyl-4-oxo-2-(tetrahydro-2H-pyran- 4-yl)- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide (1.58 g, 3.50 mmol) in anhydrous tetrahydrofuran (20 mL) was added borane-dimethyl sulfide complex (10 M in tetrahydrofuran, 1.75 mL) dropwise at -75 °C for 30 min under nitrogen. The mixture was then stirred at 0 °C for 1 hr under nitrogen. The mixture was quenched by methanol 30 mL dropwise at 0 °C under nitrogen and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 150x25 mmx5um; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; gradient: 45%-65% B over 10 min) followed by lyophilization to give (R)-N-((R)-1-(6-chloro-3-isopropyl-4-oxo-2- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl) -2-methylpropane-2- sulfinamide (520 mg, 1.10 mmol, 31%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 4.93 - 4.80 (m, 2H), 4.74 - 4.49 (m, 1H), 4.19 - 4.13 (m, 2H), 3.58 (t, J = 12.0 Hz, 2H), 3.08 (br. t, J = 11.2 Hz, 1H), 2.23 - 2.08 (m, 2H), 1.86 (br dd, J = 1.6, 13.6 Hz, 2H), 1.68 (d, J = 6.8 Hz, 6H), 1.65 - 1.62 (m, 3H), 1.24 (s, 9H); m/z ES+ [M+H] ⁺ 454.2. [2741] Step 8. Synthesis of (R)-8-(1-aminoethyl)-6-chloro-3-isopropyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2742] To a mixture of (R)-N-((R)-1-(6-chloro-3-isopropyl-4-oxo-2-(tetrahydro-2H-py ran-4- yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide (520 mg, 1.15 mmol) in dichloromethane (6 mL) was added hydrochloric acid/dioxane (4 M, 6 mL). The mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) and followed by lyophlization to give (R)-8-(1-aminoethyl)-6-chloro-3-isopropyl-2-(tetrahydro- 2H-pyran-4-yl)quinazolin-4(3H)-one (370 mg, 1.05 mmol, 91%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 5.02 - 4.91 (m, 1H), 4.81 - 4.55 (m, 1H), 4.20 - 4.12 (m, 2H), 3.58 (br. t, J = 12.0 Hz, 2H), 3.16 - 3.06 (m, 1H), 2.24 - 1.99 (m, 4H), 1.85 (br. d, J = 6.8 Hz, 3H), 1.71 - 1.66 (m, 6H); m/z ES+ [M+H] ⁺ 350.2. [2743] Step 9. Synthesis of (R)-2-((1-(6-chloro-3-isopropyl-4-oxo-2-(tetrahydro-2H-pyran -4- yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2744] To a mixture of (R)-8-(1-aminoethyl)-6-chloro-3-isopropyl-2-(tetrahydro-2H-p yran-4- yl)quinazolin-4(3H)-one (70 mg, 200 μmol) and 2-iodobenzoic acid (89.3 mg, 360 μmol) in dioxane (2 mL) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert - butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (15.89 mg, 20.0 μmol) and cesium carbonate (196 mg, 600 μmol) under nitrogen. The mixture was stirred at 90 °C for 2 h under nitrogen. The reaction mixture was filtered and poured into ethyl acetate (50 mL) and water (50 mL). the organic layer was washed with water (50 mL x 2), which was further dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25 mmx 10um; mobile phase: [water (formic acid) -acetonitrile]; gradient: 55%-85% B over 10 min) followed by lyophlization to give (R)-2-((1-(6-chloro-3-isopropyl-4-oxo-2-(tetrahydro-2H-pyran -4-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (23.96 mg, 50.98 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (br. s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 1.6, 8.0 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.23 - 7.16 (m, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.61 - 5.45 (m, 1H), 4.89 - 4.54 (m, 1H), 4.17 (br dd, J = 2.0, 11.6 Hz, 2H), 3.69 - 3.56 (m, 2H), 3.14 (br. t, J = 10.8 Hz, 1H), 2.35 - 2.15 (m, 2H), 1.89 (br. d, J = 13.2 Hz, 2H), 1.72 (t, J = 6.4 Hz, 6H), 1.66 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 470.3. Example 317. Preparation of (R)-2-((1-(6-Chloro-3-cyclopropyl-2-(4-methyltetrahydro- 2H-pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzoic acid (Compound 678) [2745] Step 1. Synthesis of 2-amino-3-bromo-5-chloro-N-cyclopropylbenzamide [2746] To a solution of 2-amino-3-bromo-5-chloro-benzoic acid (9.00 g, 35.93 mmol), cyclopropane amine (6.15 g, 107 mmol) in N,N-dimethylformamide (40 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (20.49 g, 53.9 mmol) and diisopropylethylamine (23.2 g, 179 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction solution was poured into water (100 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure, which was further triturated with petroleum ether/ethyl acetate (50/10 mL) at 25 ^o C for 30 min, filtered and solid was concentrated under reduce pressure to give 2-amino-3-bromo-5-chloro-N-cyclopropyl-benzamide (6.00 g, 20.49 mmol, 57%) as a white solid. m/z ES+ [M+H] ⁺ 289.0. [2747] Step 2. Synthesis of N-(2-bromo-4-chloro-6-(cyclopropylcarbamoyl)phenyl)-4- methyltetrahydro-2H-pyran-4-carboxamide [2748] To a solution of 4-methyl tetrahydropyran-4-carboxylic acid (2.99 g, 20.7 mmol) in acetonitrile (100 mL) was added N-(chloro(dimethylamino)methylene)-N- methylmethanaminium hexafluorophosphate(V) (7.27 g, 25.9 mmol), 1-methyl-1H-imidazole (4.25 g, 51.8 mmol) and 2-amino-3-bromo-5-chloro-N-cyclopropyl-benzamide (5.00 g, 17.2 mmol) at 25 °C. The mixture was stirred at 60 °C for 36 hr. On completion, the reaction mixture was poured into water (200 mL) and much solid was precipitated. The solid was collected via filtration, which was further triturated with acetonitrile (20 mL) at 25 ^o C for 30 minutes and then filtered to give N-[2-bromo-4-chloro-6-(cyclopropylcarbamoyl)phenyl]-4-methyl - tetrahydropyran-4-carboxamide (4.50 g, 10.6 mmol, 61%) as a white solid. m/z ES+ [M+H] ⁺ 417.0. [2749] Step 3. Synthesis of 8-bromo-6-chloro-3-cyclopropyl-2-(4-methyltetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2750] To a solution of N-[2-bromo-4-chloro-6-(cyclopropylcarbamoyl)phenyl]-4-methyl - tetrahydropyran-4-carboxamide (4.00 g, 9.62 mmol) in dimethyl acetamide (40 mL) was added zinc(II) chloride (3.93 g, 28.8 mmol) and hexamethyldisilazane (3.88 g, 24.0 mmol). The mixture was stirred at 120 °C for 36 hr in a sealed tube. On completion, the reaction mixture was poured into water (400 mL) and much solid was precipitated. The solid was collected via filtration and then dried in vacuo to give 8-bromo-6-chloro-3-cyclopropyl-2-(4- methyltetrahydropyran-4-yl)quinazolin-4-one (4.20 g, 9.61 mmol, 99%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 3.74 - 3.63 (m, 2H), 3.59 - 3.50 (m, 2H), 3.25 – 3.18 (m, 1H), 2.59 - 2.52 (m, 2H), 1.99 - 1.88 (m, 2H), 1.56 (s, 3H), 1.18 (d, J = 6.0 Hz, 2H), 0.89 - 0.80 (m, 2H); m/z ES+ [M+H] ⁺ 399.0. [2751] Step 4. Synthesis of 8-acetyl-6-chloro-3-cyclopropyl-2-(4-methyltetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2752] To a solution of 8-bromo-6-chloro-3-cyclopropyl-2-(4-methyltetrahydropyran-4- yl)quinazolin-4-one (2.00 g, 5.03 mmol) in toluene (40 mL) was added dichloropalladium triphenylphosphane (176 mg, 251 μmol) and tributyl(1-ethoxyvinyl)stannane (3.63 g, 10.0 mmol). The mixture was stirred at 80 °C for 4 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by saturated potassium fluoride solution (500 mL), and then diluted with water (500 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with brine (500 mL) and then concentrated under reduced pressure to give a residue. The residue was dissolved in dichloromethane (5 mL) and then formic acid (5 mL) was added. The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was quenched by saturated sodium bicarbonate solution 50 mL at 0 °C, and then diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 0/1) to give 8-acetyl- 6-chloro-3-cyclopropyl-2-(4-methyltetrahydropyran-4-yl)quina zolin-4-one (1.30 g, 2.92 mmol, 57%) as a brown solid. m/z ES+ [M+H] ⁺ 361.1. [2753] Step 5. Synthesis of (R)-N-(1-(6-chloro-3-cyclopropyl-2-(4-methyltetrahydro-2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-m ethylpropane-2-sulfinamide [2754] To a solution of 8-acetyl-6-chloro-3-cyclopropyl-2-(4-methyltetrahydropyran-4 - yl)quinazolin-4-one (1.30 g, 3.60 mmol) in anhydrous tetrahydrofuran (20 mL) was added tetraethoxytitanium (4.11 g, 18.0 mmol) and (R)-2-methylpropane-2-sulfinamide (654 mg, 5.40 mmol). The mixture was stirred at 75 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was poured into water (50 mL) and diluted with ethyl acetate (50 mL). The resulting mixture was filtered and the filtrate was separated. The filtered cake was diluted with ethyl acetate (50 mL) and stirred at 25 °C for 0.5 hr and then filtered. Repeating the above operation (3x), then combining the organic layers and washing them with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give (R)-N-(1-(6-chloro-3- cyclopropyl-2-(4-methyltetrahydro-2H-pyran-4-yl)-4-oxo-3,4-d ihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 2.68 mmol, 74%) as a brown solid. m/z ES+ [M+H] ⁺ 464.3. [2755] Step 6. Synthesis of (R)-N-((R)-1-(6-chloro-3-cyclopropyl-2-(4-methyltetrahydro-2 H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methyl propane-2-sulfinamide [2756] To a solution of (R)-N-(1-(6-chloro-3-cyclopropyl-2-(4-methyltetrahydro-2H-py ran- 4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylp ropane-2-sulfinamide (1.50 g, 3.23 mmol) in anhydrous tetrahydrofuran (15 mL) was added borane-tetrahydrofuran complex (1 M, 6.47 mL) dropwise at -30 °C. The mixture was then stirred at -30 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition methanol (1 mL) at -10 °C, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Kromasil Eternity XT 250*80mmx10um;mobile phase: [water (ammonia hydroxide v/v)-acetonitrile];gradient:36%-66% B over 20 min) to give (R)- N-((R)-1-(6-chloro-3-cyclopropyl-2-(4-methyltetrahydro-2H-py ran-4-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (800 mg, 1.72 mmol, 53%) as a white solid. m/z ES+ [M+H] ⁺ 466.3. [2757] Step 7. Synthesis of (R)-8-(1-aminoethyl)-6-chloro-3-cyclopropyl-2-(4- methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [2758] To a solution of (R)-N-((R)-1-(6-chloro-3-cyclopropyl-2-(4-methyltetrahydro-2 H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methyl propane-2-sulfinamide (400 mg, 858 μmol) in dichloromethane (4 mL) was added hydrochloric acid/dioxane (4 M, 4.29 mL) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC (0.1% ammonium hydroxide) to give (R)-8-(1-aminoethyl)-6-chloro-3-cyclopropyl-2- (4-methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (280 mg, 649 μmol, 75%) as a white solid. m/z ES+ [M+H] ⁺ 362.3. [2759] Step 8. Synthesis of (R)-2-((1-(6-chloro-3-cyclopropyl-2-(4-methyltetrahydro-2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoic acid [2760] To a solution of (R)-8-(1-aminoethyl)-6-chloro-3-cyclopropyl-2-(4-methyltetra hydro- 2H-pyran-4-yl)quinazolin-4(3H)-one (50.0 mg, 138 μmol) and 2-iodobenzoic acid (34.2 mg, 138 μmol) in dioxane (1 mL) was added 2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]p hosphane (10.9 mg, 13.8 μmol) and cesium carbonate (135 mg, 414 μmol). The mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 0/1) and then re-purified by prep- HPLC (column: Phenomenex luna C18150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:57%-87% B over 10 min) to give (R)-2-((1-(6-chloro-3-cyclopropyl-2- (4-methyltetrahydro-2H-pyran-4-yl)-4-oxo-3,4-dihydroquinazol in-8-yl)ethyl)amino)benzoic acid (22.8 mg, 47.4 μmol, 34%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.15 (br. s, 1H), 8.06 - 7.96 (m, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.61 (t, J = 7.6 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.50 - 5.40 (m, 1H), 3.90 - 3.78 (m, 2H), 3.74 - 3.63 (m, 2H), 3.23 - 3.12 (m, 1H), 2.75 - 2.62 (m, 2H), 2.13 - 2.02 (m, 2H), 1.67 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.41 - 1.26 (m, 2H), 1.05 - 0.91 (m, 2H); m/z ES+ [M+H] ⁺ 482.3. Example 318. Preparation of (R)-2-((1-(6-Chloro-3-cyclopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 556) [2761] Step 1. Synthesis of 2-amino-3-bromo-5-chloro-N-cyclopropylbenzamide [2762] To a solution of 2-amino-3-bromo-5-chloro-benzoic acid (9 g, 35.93 mmol), cyclopropane amine (6.15 g, 107 mmol) in N,N-dimethylformamide (40 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (20.5 g, 53.9 mmol) and diisopropyleth-ylamine (23.2 g, 179 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction solution was added to water (100 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure. The crude product was triturated with petroleum ether : ethyl acetate =5:1 (60 mL) at 25 ^o C for 30 min to give 2-amino-3-bromo-5-chloro-N- cyclopropyl-benzamide (6 g, 20.35 mmol, 57%) as a white solid. m/z ES+ [M+H] ⁺ 289.0. [2763] Step 2. Synthesis of N-(2-bromo-4-chloro-6- (cyclopropylcarbamoyl)phenyl)tetrahydro-2H-pyran-4-carboxami de [2764] To a solution of 2-amino-3-bromo-5-chloro-N-cyclopropyl-benzamide (6.1 g, 21.0 mmol) and tetrahydropyran-4-carboxylic acid (3.29 g, 25.2 mmol) in pyridine (60 mL) was added propylphosphonicanhydride (40.2 g, 63.2 mmol) dropwise. The mixture was stirred at 25 °C for 12 hr. The reaction solution was added to water (100 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure. The crude product was triturated with petroleum ether (50 mL) and ethyl acetate (10 mL) at 25 ^o C for 30 min to give N-[2-bromo-4-chloro-6-(cyclopropylcarbam- oyl)phenyl]tetrahydropyran-4-carboxamide (5.6 g, 11.1 mmol, 53%) as a white solid. m/z ES+ [M+H] ⁺ 401.0. [2765] Step 3. Synthesis of 8-bromo-6-chloro-3-cyclopropyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [2766] To a solution of N-[2-bromo-4-chloro-6- (cyclopropylcarbamoyl)phenyl]tetrahydropyran-4-carboxamide(5 g, 12.4 mmol) in acetonitrile (100 mL) was added dichlorozinc (5.09 g, 37.3 mmol), [dimethyl- (trimethylsilylamino)silyl]methane (5.02 g, 31.1 mmol). The mixture was stirred at 80 °C for 3 hr. The reaction solution was added to water (100 mL) slowly and solid was precipitated. The mixture was filtered and the solid was concentrated under reduced pressure to give 8-bromo- 6-chloro-3-cyclopropyl-2-tetrahydropyran-4-yl-quinazolin-4-o ne (4 g, 9.75 mmol, 78%) as a white solid. m/z ES+ [M+1] ⁺ 383.0. [2767] Step 4. Synthesis of 8-(1-Butoxyvinyl)-6-chloro-3-cyclopropyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2768] A mixture of 8-bromo-6-chloro-3-cyclopropyl-2-tetrahydropyran-4-yl-quinaz olin-4- one (4 g, 10.4 mmol), 1-vinyloxybutane (3.13 g, 31.2 mmol) in butan-1-ol (40 mL) was added [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (561 mg, 1.04 mmol), diacetoxypalladium (280 mg, 1.25 mmol) and N-ethyl-N-isopropyl-propan-2-amine (4.04 g, 31.2 mmol). Then the mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was dissolved in butan-1-ol (40 mL) was added hydrogen chloride (1 M, 9.93 mL). The mixture was stirred at 25 °C for 0.1 hr. The reaction mixture was quenched by addition of water (10 mL), and sodium bicarbonate aq. solution (20 mL) was added to adjust pH=8. The residue was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to1/1) to give 8-acetyl-6-chloro-3-cyclopropyl-2- tetrahydropyran-4-yl-quinazolin-4-one (2.5 g, 7.21 mmol, 73%) as a yellow solid. m/z ES+ [M+1] ⁺ 347.1. [2769] Step 5. Synthesis of (R,E)-N-(1-(6-chloro-3-cyclopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylp ropane-2-sulfinamide [2770] To a solution of 8-acetyl-6-chloro-3-cyclopropyl-2-tetrahydropyran-4-yl-quina zolin- 4-one (2.5 g, 7.21 mmol), (R)-2-methylpropane-2-sulfinamide (1.31 g, 10.8 mmol) in anhydrous tetrahydrofuran (70 mL) was added titanium tetraethoxy (8.22 g, 36.0 mmol). The mixture was stirred at 75 °C for 12 hr. The reaction solution was added to water (100 mL) slowly and solid was precipitated. then filtered and filtrate was concentrated under reduced pressure to give (NE,R)-N-[1-(6-chloro-3-cyclopropyl-4-oxo-2-tetrahydropyran- 4-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (1.7 g, crude) as a yellow solid. m/z ES+ [M+1] ⁺ 450.2. [2771] Step 6. Synthesis of (R)-N-((R)-1-(6-chloro-3-cyclopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide [2772] To a solution of (NE,R)-N-[1-(6-chloro-3-cyclopropyl-4-oxo-2-tetrahydropyran- 4-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (1.5 g, 3.33 mmol) in anhydrous tetrahydrofuran (15 mL) was added borane-methyl sulfide complex (10 M, 1.67 mL) at -78 °C. The mixture was stirred at -78 °C for 0.5 hr and at 0 °C for 0.5 hr under nitrogen atmosphere. The reaction mixture was quenched by addition methanol (20 mL) at 0 °C and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.1% ammonium hydroxide) to give (R)-N-[(1R)-1-(6-chloro-3-cyclopropyl-4-oxo-2- tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]-2-methyl-propane -2-sulfinamide (400 mg, 0.89 mmol, 27%) as a white solid. m/z ES+ [M+H] ⁺ 452.2. [2773] Step 7. Synthesis of (R)-8-(1-aminoethyl)-6-chloro-3-cyclopropyl-2-(tetrahydro-2H - pyran-4-yl)quinazolin-4(3H)-one [2774] To a solution of (R)-N-[(1R)-1-(6-chloro-3-cyclopropyl-4-oxo-2-tetrahydropyra n-4- yl-quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (200 mg, 442 μmol) in dichloromethane (4 mL) was added hydrochloric acid/dioxane (2 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 8- [(1R)-1-aminoethyl]-6-chloro-3-cyclopropyl-2-tetrahydropyran -4-yl-quinazolin-4-one (150 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 348.1. [2775] Step 8. Synthesis of (R)-2-((1-(6-chloro-3-cyclopropyl-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2776] A mixture of 8-[(1R)-1-aminoethyl]-6-chloro-3-cyclopropyl-2-tetrahydropyr an-4-yl- quinazolin-4-one (130 mg, 373 μmol), 2-iodobenzoic acid (463 mg, 1.87 mmol), trimethylamine (378 mg, 3.74 mmol), copper (71.3 mg, 1.12 mmol) in dimethyl acetamide (2 mL) was degassed and purged with nitrogen atmosphere (3x), and then the mixture was stirred at 110 °C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water(formic acid)- acetonitrile];gradient:50%-80% B over 10 min) to give 2-[[(1R)-1-(6-chloro-3-cyclopropyl-4- oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]amino]benzo ic acid (84.9 mg, 0.16 mmol, 43%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.9 - 12.6 (m, 1H), 8.52 - 8.38 (m, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.63 (s, 1H), 7.21 - 7.13 (m, 1H), 6.58 - 6.49 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.55 - 5.42 (m, 1H), 4.00 (d, J = 11.2 Hz, 2H), 3.84 - 3.72 (m, 1H), 3.54 - 3.46 (m, 2H), 3.17 - 3.06 (m, 1H), 2.01 - 1.91 (m, 4H), 1.59 (d, J = 6.8 Hz, 3H), 1.28 - 1.22 (m, 4H); m/z ES+ [M+H] ⁺ 468.2. Example 319. Preparation of (R)-6-chloro-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3-methyl-2-(tetrahydro-2H-pyran-4-yl) quinazolin-4(3H)-one (Compound 577) [2777] Step 1. Synthesis of 2-amino-3-bromo-5-chloro-N-methylbenzamide [2778] To a solution of 2-amino-3-bromo-5-chloro-benzoic acid (10.0 g, 40.0 mmol) in N,N- dimethylformamide (100 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (22.8 g, 59.9 mmol), diisopropylethylamine (20.6 g, 160 mmol, 27.8 mL) and methanamine hydrochloride (5.39 g, 79.9 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was poured into water (500 mL) and filtered to give 2-amino-3-bromo-5-chloro-N-methyl-benzamide (9.50 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51 (d, J =2.0 Hz, 1 H) 7.28 (s, 1 H) 6.04 (s, 2 H) 2.99 (d, J =4.8 Hz, 3 H). m/z ES+ [M+H] ⁺ 264.9. [2779] Step 2. Synthesis of N-(2-bromo-4-chloro-6-(methylcarbamoyl)phenyl)tetrahydro- 2H-pyran-4-carboxamide [2780] To a solution of 2-amino-3-bromo-5-chloro-N-methyl-benzamide (9.50 g, 36.1 mmol) and tetrahydropyran-4-carboxylic acid (5.63 g, 43.7 mmol) in pyridine (950 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (68.8 g, 108 mmol, 64.4 mL, 50% purity) dropwise. The mixture was stirred at 25 °C for 12 hr . The reaction solution was added to water (150 mL) slowly, then extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to give N-[2-bromo-4-chloro-6- (methylcarbamoyl)phenyl]tetrahydropyran-4-carboxamide (7.00 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.52 - 7.41 (m, 1H), 3.88 (d, J=8.8 Hz, 2H), 3.35 (t, J =10.0 Hz, 2H), 2.67 (s, 3 H), 2.61 (s, 1 H) 1.72 - 1.55 (m, 4 H). [2781] Step 3. Synthesis of 8-bromo-6-chloro-3-methyl-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [2782] To a solution of N-[2-bromo-4-chloro-6-(methylcarbamoyl)phenyl]tetrahydropyra n- 4-carboxamide (6.50 g, 17.3 mmol) in acetonitrile (65 mL) was added dichlorozinc (7.08 g, 51.9 mmol) and [dimethyl-(trimethylsilylamino)silyl]methane (6.98 g, 43.3 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was poured into water (500 mL) and filtered to give residue. The crude product was purified by re-crystallization from petroleum ether (100 mL) at 25 ^o C to give 8-bromo-6-chloro-3-methyl-2-tetrahydropyran-4- yl-quinazolin-4-one (6.00 g, 15.9 mmol, 92%) as a white solid. ¹ H NMR (400 MHz, DMSO- d6) δ 8.23 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 4.02 - 3.91 (m, 2H), 3.61 (s, 3H), 3.56 - 3.44 (m, 2H), 3.31 - 3.26 (m, 1H), 1.97 - 1.80 (m, 4H). m/z ES+ [M+H] ⁺ 359.0. [2783] Step 4. Synthesis of 8-(1-butoxyvinyl)-6-chloro-3-methyl-2-(tetrahydro-2H-pyran-4 - yl)quinazolin-4(3H)-one [2784] To a solution of 8-bromo-6-chloro-3-methyl-2-tetrahydropyran-4-yl-quinazolin- 4-one (4.00 g, 11.2 mmol) and 1-vinyloxybutane (3.36 g, 33.6 mmol) in n-butyl alcohol (40 mL) was added [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (602 mg, 1.12 mmol), diacetoxypalladium (151 mg, 671 μmol) and diisopropylethylamine (4.34 g, 33.6 mmol, 5.84 mL). The mixture was stirred at 95 °C for 12 hr. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate 90 mL (30 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was dissolved in n-butyl alcohol (30 mL) was added hydrochloric acid (1 M, 10.6 mL) and stirred at 25 °C for 15 min .The reaction mixture was diluted with sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give 8-acetyl-6-chloro-3-methyl-2-tetrahydropyran-4-yl-quinazolin -4- one (1.00 g, 2.46 mmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 4.18 - 4.11 (m, 2H), 3.70 (s, 3H), 3.62 - 3.53 (m, 2H), 3.18 - 3.09 (m, 1H), 2.88 (s, 3H), 2.18 - 2.07 (m, 2H), 1.87 (d, J = 13.2 Hz, 2H); m/z ES+ [M+H] ⁺ 321.2. [2785] Step 5. Synthesis of (R,E)-N-(1-(6-chloro-3-methyl-4-oxo-2-(tetrahydro-2H-pyran-4 - yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2 -sulfinamide [2786] To a solution of 8-acetyl-6-chloro-3-methyl-2-tetrahydropyran-4-yl-quinazolin -4-one (900 mg, 2.81 mmol) in anhydrous tetrahydrofuran (9 mL) was added tetraethoxytitanium (3.20 g, 14.0 mmol) and (R)-2-methylpropane-2-sulfinamide (1.02 g, 8.42 mmol). The mixture was stirred at 75 °C for 12 hr. The reaction solution was added to water (100 mL) slowly and solid was precipitated. The mixture was filtered. The filtrate was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give (NE,R)-N-[1-(6-chloro-3-methyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (900 mg, 2.01 mmol, 72%) as a yellow oil. m/z ES+ [M+H] ⁺ 424.2. [2787] Step 6. Synthesis of (R)-N-((R)-1-(6-chloro-3-methyl-4-oxo-2-(tetrahydro-2H-pyran - 4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-su lfinamide [2788] To a solution of (NE,R)-N-[1-(6-chloro-3-methyl-4-oxo-2-tetrahydropyran-4-yl- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide (800 mg, 1.89 mmol) in anhydrous tetrahydrofuran (0.8 mL) was added borane methylsulfanylmethane (10 M, 944 ^L). The mixture was stirred at -50 °C for 1 hr. The mixture was quenched by methanol (10 mL) at -10 °C slowly, the mixture was stirred at 25 °C for 0.5 hr. Then the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (8 mL× 3). The combined organic layers were washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um;mobile phase: [water (ammonia hydroxide v/v)- acetonitrile];gradient:38%-68% B over 9 min) to give (R)-N-[(1R)-1-(6-chloro-3-methyl-4- oxo-2-tetrahydropyran-4-yl-quinazolin-8-yl)ethyl]-2-methyl-p ropane-2-sulfinamide (240 mg, 473 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 4.96 - 4.81 (m, 2H), 4.21 - 4.09 (m, 2H), 3.67 (s, 3H), 3.58 (t, J = 12.0 Hz, 2H), 3.16 - 3.06 (m, 1H), 2.19 - 2.08 (m, 2H), 1.89 (d, J = 12.0 Hz, 2H), 1.59 (s, 3H), 1.23 (s, 9H). [2789] Step 7. Synthesis of (R)-8-(1-aminoethyl)-6-chloro-3-methyl-2-(tetrahydro-2H- pyran-4-yl)quinazolin-4(3H)-one [2790] To a solution of (R)-N-[(1R)-1-(6-chloro-3-methyl-4-oxo-2-tetrahydropyran-4-y l- quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (300 mg, 704 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (0.5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Then the residue was added ammonium hydroxide to adjust PH=7, then extracted with ethyl acetate (3 mL x 2). The combined organic layers were washed with brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-[(1R)-1-aminoethyl]-6-chloro-3-methyl-2-tetrahydropyran-4- yl-quinazolin- 4-one (150 mg, 466 μmol, 66%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 4.87 - 4.78 (m, 1H), 4.19 - 4.11 (m, 2H), 3.68 (s, 3H), 3.63 - 3.53 (m, 2H), 3.17 - 3.06 (m, 1H), 2.20 - 2.11 (m, 2H), 1.87 (d, J = 13.2 Hz, 2H), 1.53 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+322.1. [2791] Step 8. Synthesis of (R)-8-(1-((2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl )-4- fluorophenyl)amino)ethyl)-6-chloro-3-methyl-2-(tetrahydro-2H -pyran-4-yl)quinazolin- 4(3H)-one [2792] To a solution of 8-[(1R)-1-aminoethyl]-6-chloro-3-methyl-2-tetrahydropyran-4- yl- quinazolin-4-one (200 mg, 622 μmol) and [1-(2-bromo-5-fluoro-phenyl)-4-piperidyl]oxy-tert- butyl-dimethyl-silane (362 mg, 932 μmol) in dioxane (0.5 mL) was added cesium carbonate (608 mg, 1.86 mmol) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidaz ol-1- ium-2-ide;3-chloropyridine;dichloropalladium (60.5 mg, 62.2 μmol). The mixture was stirred at 100 °C for 3 hr under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 2/1) to give 8-[(1R)-1-[2-[4-[tert- butyl(dimethyl)silyl]oxy-1-piperidyl]-4-fluoro-anilino]ethyl ]-6-chloro-3-methyl-2- tetrahydropyran-4-yl-quinazolin-4-one (90.0 mg, 128 μmol, 21%) as a green oil. ¹ H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.64 (s, 1H), 6.80 - 6.71 (m, 1H), 6.55 - 6.42 (m, 1H), 6.15 - 6.07 (m, 1H), 5.36 (d, J = 6.0 Hz, 1H), 5.01 - 4.81 (m, 1H), 4.17 - 4.13 (m, 2H), 3.70 (s, 3H), 3.60 (t, J = 11.6 Hz, 2H), 3.29 - 3.20 (m, 1H), 3.16 - 3.05 (m, 2H), 2.88 - 2.62 (m, 2H), 2.22 - 2.11 (m, 2H), 2.02 - 1.96 (m, 2H), 1.91 (d, J = 13.2 Hz, 2H), 1.83 - 1.75 (m, 2H), 1.56 (s, 3H), 0.95 (s, 9H), 0.13 (s, 6H); m/z ES+ [M+H] ⁺ 629.4. [2793] Step 9. Synthesis of (R)-6-chloro-8-(1-((4-fluoro-2-(4-hydroxypiperidin-1- yl)phenyl)amino)ethyl)-3-methyl-2-(tetrahydro-2H-pyran-4-yl) quinazolin-4(3H)-one [2794] To a solution of 8-[(1R)-1-[2-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]- 4-fluoro- anilino]ethyl]-6-chloro-3-methyl-2-tetrahydropyran-4-yl-quin azolin-4-one (90.0 mg, 143 μmol) in dichloromethane (0.5 mL) was added hydrochloric acid/dioxane (0.5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:51%-81% B over 10 min) to give 6-chloro-8-[(1R)-1-[4-fluoro-2-(4- hydroxy-1-piperidyl)anilino]ethyl]-3-methyl-2-tetrahydropyra n-4-yl-quinazolin-4-one (32.1 mg, 62.3 μmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 2.4 Hz, 1H), 7.66 (s, 1H), 6.86 - 6.69 (m, 1H), 6.63 - 6.45 (m, 1H), 6.32 - 6.12 (m, 1H), 5.27 (d, J = 4.0 Hz, 1H), 4.23 - 4.11 (m, 2H), 4.01 - 3.79 (m, 1H), 3.70 (s, 3H), 3.65 - 3.56 (m, 2H), 3.28 - 3.03 (m, 3H), 2.90 - 2.60 (m, 2H), 2.39 - 2.05 (m, 4H), 1.94 - 1.88 (m, 2H), 1.86 - 1.77 (m, 2H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H] ⁺ 515.3.

Example 320. Preparation of (R)-2-((1-(3-cyclopropyl-6,7-difluoro-4-oxo-2-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (Compound 787) [2795] Step 1. Synthesis of 2-amino-3-bromo-4,5-difluorobenzoic acid [2796] To a solution of 2-amino-4,5-difluoro-benzoic acid (23.0 g, 132 mmol) in dichloromethane (600 mL) was added bromine (21.2 g, 132 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 10 hr. On completion, the mixture was concentrated in vacuo to give 2-amino-3-bromo-4,5-difluoro-benzoic acid (34.0 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 9.2, 11.2 Hz, 1H); m/z ES+ [M+H] ⁺ 251.7. [2797] Step 2. Synthesis of 2-amino-3-bromo-N-cyclopropyl-4,5-difluorobenzamide [2798] To a solution of 2-amino-3-bromo-4,5-difluoro-benzoic acid (15.0 g, 59.5 mmol) in N,N-dimethylformamide (150 mL) was added diisopropylethylamine (23.1 g, 178 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethylammonium;hexafluorophosphate (27.1 g, 71.4 mmol) and cyclopropanamine (3.74 g, 65.4 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the mixture was diluted with water (400 mL) and filtered. The filtered cake was concentrated in vacuo to give 2-amino- 3-bromo-N-cyclopropyl-4,5-difluoro-benzamide (14.3 g, 46.6 mmol, 78%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J = 2.8 Hz, 1H), 7.67 (dd, J = 8.8, 11.6 Hz, 1H), 6.73 (s, 2H), 2.85 – 2.75 (m, 1H), 0.73 - 0.65 (m, 2H), 0.60 - 0.51 (m, 2H); m/z ES+ [M+H] ⁺ 290.8. [2799] Step 3. Synthesis of N-(2-bromo-6-(cyclopropylcarbamoyl)-3,4- difluorophenyl)tetrahydro-2H-pyran-4-carboxamide [2800] To a solution of 2-amino-3-bromo-N-cyclopropyl-4,5-difluoro-benzamide (1.00 g, 3.44 mmol) and tetrahydropyran-4-carboxylic acid (491 mg, 3.78 mmol) in pyridine (10 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (6.56 g, 10.3 mmol), the mixture was stirred at 25 °C for 12 hr. On completion, the mixture was diluted with water (50 mL) and then filtered. The filtered cake was concentrated to give N-[2-bromo-6- (cyclopropylcarbamoyl)-3,4-difluoro-phenyl]tetrahydropyran-4 -carboxamide (1.10 g, 2.43 mmol, 71%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.28 (d, J = 3.6 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H), 3.89 (d, J = 11.2 Hz, 2H), 3.45 - 3.33 (m, 2H), 2.74 - 2.58 (m, 2H), 1.80 - 1.55 (m, 4H), 0.73 - 0.57 (m, 2H), 0.55 - 0.42 (m, 2H); m/z ES+ [M+H] ⁺ 402.9. [2801] Step 4. Synthesis of 8-bromo-3-cyclopropyl-6,7-difluoro-2-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one [2802] To a solution of N-[2-bromo-6-(cyclopropylcarbamoyl)-3,4-difluoro- phenyl]tetrahydropyran-4-carboxamide (6.00 g, 14.8 mmol) in dimethyl acetamide (60 mL) was added zinc chloride (6.08 g, 44.6 mmol) and hexamethyldisilazane (6.00 g, 37.2 mmol), the mixture was stirred at 90 °C for 2 hr. On completion, the mixture was diluted with water (200 mL) and filtered. The filtered cake was concentrated to give 8-bromo-3-cyclopropyl-6,7- difluoro-2-tetrahydropyran-4-yl-quinazolin-4-one (5.70 g, 14.1 mmol, 94%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.97 (t, J = 9.2 Hz, 1H), 3.99 (d, J = 11.2 Hz, 2H), 3.80 - 3.69 (m, 1H), 3.55 - 3.41 (m, 2H), 3.16 - 3.04 (m, 1H), 1.98 - 1.86 (m, 4H), 1.32 - 1.18 (m, 2H), 0.96 - 0.83 (m, 2H); m/z ES+ [M+H] ⁺ 384.7/386.7. [2803] Step 5. Synthesis of 8-acetyl-3-cyclopropyl-6,7-difluoro-2-(tetrahydro-2H-pyran-4 - yl)quinazolin-4(3H)-one [2804] To a solution of 8-bromo-3-cyclopropyl-6,7-difluoro-2-tetrahydropyran-4-yl- quinazolin-4-one (3.00 g, 7.79 mmol) in toluene (30 mL) was added dichloropalladium triphenylphosphane (546 mg, 778 μmol) and tributyl(1-ethoxyvinyl)stannane (4.22 g, 11.6 mmol) at 25 °C, the mixture was stirred at 100 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by saturated potassium fluoride solution (100 mL) at 25 °C and then stirred at 25 °C for 3 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid. The solid was dissolved in dichloromethane (30 mL) and then formic acid (3 mL) was added. The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was quenched with sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give 8-acetyl-3-cyclopropyl-6,7- difluoro-2-tetrahydropyran-4-yl-quinazolin-4-one (2.40 g, 6.48 mmol, 81%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 8.8, 9.6 Hz, 1H), 4.11 (dd, J = 3.6, 11.2 Hz, 2H), 3.70 (tt, J = 3.6, 11.2 Hz, 1H), 3.60 - 3.49 (m, 2H), 3.01 - 2.92 (m, 1H), 2.72 (s, 3H), 2.11 - 1.96 (m, 2H), 1.80 (d, J = 12.0 Hz, 2H), 1.44 - 1.34 (m, 2H), 0.96 - 0.87 (m, 2H); m/z ES+ [M+H] ⁺ 349.1. [2805] Step 6. Synthesis of (R)-N-(1-(3-cyclopropyl-6,7-difluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylp ropane-2-sulfinamide [2806] To a solution of 8-acetyl-3-cyclopropyl-6,7-difluoro-2-tetrahydropyran-4-yl- quinazolin-4-one (2.40 g, 6.89 mmol) in anhydrous tetrahydrofuran (40 mL) was added (R)-2- methylpropane-2-sulfinamide (4.18 g, 34.4 mmol) and tetraethoxytitanium (7.86 g, 34.4 mmol), the mixture was stirred at 80 °C for 24 hr. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give (R)-N-(1-(3-cyclopropyl-6,7-difluoro-4-oxo-2-(tetrahydro-2H- pyran-4-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.10 g, 2.17 mmol, 31%) as a yellow solid. m/z ES+ [M+H] ⁺ 451.9. [2807] Step 7. Synthesis of (R)-N-((R)-1-(3-cyclopropyl-6,7-difluoro-4-oxo-2-(tetrahydro - 2H-pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide [2808] To a solution of (R)-N-(1-(3-cyclopropyl-6,7-difluoro-4-oxo-2-(tetrahydro-2H- pyran- 4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane -2-sulfinamide (600 mg, 1.33 mmol) in anhydrous tetrahydrofuran (6 mL) was added borane-dimethyl sulfide complex (10 M in tetrahydrofuran, 664 ^L) dropwise at -78 °C. The mixture was stirred at -10 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was carefully quenched with methanol (50 mL) and then concentrated in vacuo to give a residue. The residue was purified by prep- HPLC [column: Waters Xbridge BEH C18 250*50mm*10um;mobile phase: [water (ammonium hydroxide)-acetonitrile];gradient:39%-69% B over 10 min] to give (R)-N-((R)-1- (3-cyclopropyl-6,7-difluoro-4-oxo-2-(tetrahydro-2H-pyran-4-y l)-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 436 μmol, 33%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (t, J = 9.2 Hz, 1H), 5.46 - 5.29 (m, 1H), 5.02 - 4.74 (m, 1H), 4.21 - 4.12 (m, 2H), 3.74 (tt, J = 3.2, 11.6 Hz, 1H), 3.56 (t, J = 12.0 Hz, 2H), 3.02 - 2.92 (m, 1H), 2.20 - 2.06 (m, 1H), 2.04 - 1.94 (m, 1H), 1.85 (d, J = 12.4 Hz, 2H), 1.77 (d, J = 6.8 Hz, 3H), 1.45 - 1.36 (m, 2H), 1.16 (s, 9H), 0.97 - 0.91 (m, 2H); m/z ES+ [M+H] ⁺ 454.1. [2809] Step 8. Synthesis of (R)-8-(1-aminoethyl)-3-cyclopropyl-6,7-difluoro-2-(tetrahydr o- 2H-pyran-4-yl)quinazolin-4(3H)-one [2810] To a solution of (R)-N-[(1R)-1-(3-cyclopropyl-6,7-difluoro-4-oxo-2-tetrahydro pyran- 4-yl-quinazolin-8-yl)ethyl]-2-methyl-propane-2-sulfinamide (200 mg, 440 μmol) in dichloromethane (2 mL) was added hydrochloric acid/dioxane (4 M, 0.5 mL), the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by reversed-phase HPLC ([water(0.1% formic acid)-acetonitrile];30min) to give (R)-8-(1-aminoethyl)-3-cyclopropyl-6,7-difluoro-2-(tetrahydr o-2H-pyran-4- yl)quinazolin-4(3H)-one (120 mg, 336 μmol, 76%) as a white solid. m/z ES+ [M+H] ⁺ 350.2. [2811] Step 9. Synthesis of (R)-2-((1-(3-cyclopropyl-6,7-difluoro-4-oxo-2-(tetrahydro-2H - pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [2812] To a solution of (R)-8-(1-aminoethyl)-3-cyclopropyl-6,7-difluoro-2-(tetrahydr o-2H- pyran-4-yl)quinazolin-4(3H)-one (100 mg, 286 μmol) in dimethyl acetamide (4 mL) was added 2-iodobenzoic acid (354 mg, 1.43 mmol), copper powder (181 mg, 2.86 mmol) and triethylamine (289 mg, 2.86 mmol), the mixture was stirred at 110 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC ([column: Phenomenex luna C18 150x25mmx 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:43-%-73% B over 10 min] to give (R)-2-((1-(3-cyclopropyl-6,7-difluoro- 4-oxo-2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoic acid (3.33 mg, 7.09 μmol, 2.5%) as a yellow gum. ¹ H NMR (400 MHz, CDCl3) δ 8.45 (br. s, 1H), 7.92 (dd, J = 1.6, 8.0 Hz, 1H), 7.90 - 7.81 (m, 1H), 7.24 (s, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 5.75 - 5.59 (m, 1H), 4.21 (dt, J = 3.6, 12.0 Hz, 2H), 3.84 - 3.70 (m, 1H), 3.61 (q, J = 11.2 Hz, 2H), 3.00 – 2.90 (m, 1H), 2.45 – 2.35 (m, 1H), 2.20 - 2.15 (m, 1H), 1.87 (d, J = 12.4 Hz, 2H), 1.80 (d, J = 6.8 Hz, 3H), 1.43 - 1.35 (m, 2H), 1.02 - 0.87 (m, 2H); m/z ES+ [M+H] ⁺ 470.0. Example 321. Synthesis and Characterization of Additional Exemplary Compounds [2813] Other exemplary compounds were further synthesized following the procedures described herein, and characterizations of these further synthesized exemplary compounds are shown in Table A below. Table A

Example 322. Biological Activity of Exemplary Compounds of the Present Disclosure [2814] The biological activity of exemplary compounds of the present disclosure was determined utilizing a p-AKT S473 assay described herein. [2815] Briefly, MCF10A-PI3KĮ-WT, MCF10A- PI3KĮ-H1047R and MCF10A- PI3KĮ- E545K cells were grown in DMEM/F12 supplemented with Horse Serum, EGF, Hydrocortisone, Cholera toxin and Insulin. The cells were dissociated with TryPLE, washed with media and plated in 384 wells plate. The next day, serial dilution of compounds were applied to the cell for 2 hours and p-AKT S473 was measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol. To measure p-AKT S473 levels using the kit, the cells were lysed, antibodies mixed with detection buffer were then added to the lysate and incubated overnight in the dark. The next day luminescence was read on a Ensight plate reader at 665 nm and 620 nm wavelengths. Without wishing to be bound by theory, a decrease in p-AKT S473 levels indicate a downregulation of the PI3KĮ pathway and cell proliferation, thereby indicating inhibition of the PI3KĮ protein by the compounds of the present disclosure. [2816] Table B and Table C assign each compound a code for potency in the assay described above: A, B, C, D, or E. According to the code, A represents an IC50 value <100 nM; B represents an IC ₅₀ value ^100 nM and <500 nM; C represents an IC ₅₀ value ^500 nM and <1000 nM; D represents an IC ₅₀ value ^1000 nM and <10,000 nM; and E represents an IC ₅₀ value ^10,000 nM. Table B

Table C Example 323. Biological Activity of Exemplary Compounds of the Present Disclosure [2817] The biological activity of exemplary compounds of the present disclosure was determined utilizing a HCT-116 assay described herein. [2818] HCT-116-PIK3Ca-WT and HCT-116-PIK3Ca-H1047R are grown in RPMI supplemented with 10% fetal bovine serum. [2819] HCT-116-PIK3Ca-WT and HCT-116-PIK3Ca-H1047R cells are dissociated with TryPLE, wash with media and plated in 384 wells plate (density: WT & H1047R: 15K/well). [2820] The next day, serial dilution of compounds is applied to the cell for 2 hours and p-AKT S473 is measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol. Briefly, cells are lysed, antibodies mix with detection buffer is then added to the lysate and incubate overnight in the dark. The next day luminescence is read on a Ensight plate reader at 665 nm and 620 nm wavelengths. [2821] Table D assigns each compound a code for potency in the assay described above: A, B, C, D, E, or F. According to the code, A represents an IC50 value <100 nM; B represents an IC50 value ^100 nM and <500 nM; C represents an IC50 value ^500 nM and <1000 nM; D represents an IC50 value ^1000 nM and <10,000 nM; E represents an IC50 value ^10,000 nM and <30,000; F represents an IC50 value ^30,000 nM. Table D EXEMPLARY EMBODIMENTS [2822] Embodiment 1: A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R ² is H, halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl; R ³ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3- C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is halogen, -OH, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl; or two R ^3a , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl; R ⁴ is –(C ₁ -C ₆ alkyl)-(3- to 12-membered heterocycloalkyl), C ₃ -C ₁₂ cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, -C(=O)-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C6-C10 aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen or cyano; R ⁵ is H, halogen, cyano, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxyl; T is -O-*, -NR ^T -*, -C(=O)NR ^T -*, -NR ^T C(=O)-*, -(C1-C6 alkyl)-*, -(C3-C12 cycloalkyl)- *, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NR ^T -*, -NR ^T -(C1-C6 alkyl)-*, -(C1- C ₆ alkyl)-NR ^T -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ haloalkyl)-*, -(C ₁ -C ₆ haloalkyl)-O-*, -O-(C ₁ -C ₆ haloalkyl)-*, -(C ₁ -C ₆ haloalkyl)-NR ^T -*, -S(=O) ₂ NR ^T -*, or -NR ^T -(C ₁ -C ₆ haloalkyl)- *, wherein * denotes attachment to A; each R ^T is H or C ₁ -C ₆ alkyl; A is C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is oxo, halogen, -OH, -O(C ₃ -C ₁₂ heterocycloalkyl), cyano, -NH ₂ , -N(R ^A1 )2, -B(OH)2, -NO2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)O(C3-C12 heterocycloalkyl), -C(=O)N(R ^A1 )2, -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl) ₂ , -S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ N(R ^A1 ) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), -S(=O) ₂ (C ₃ -C ₁₂ cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)O(C ₃ -C ₁₂ heterocycloalkyl), -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 ; each R ^A1 independently is H, oxo, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C ₆ alkoxyl, C ₃ -C ₁₂ heterocycloalkyl, or C ₃ -C ₁₂ cycloalkyl, wherein the -C(=O)(C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₃ -C ₁₂ heterocycloalkyl, or C ₃ -C ₁₂ cycloalkyl is optionally substituted with one or more R ^A2 ; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C ₃ -C ₁₂ cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2; or each R ^A2 independently is -OH, cyano, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ cycloalkyl, or C ₃ -C ₁₂ heterocycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₁₂ heterocycloalkyl is optionally substituted with one or more halogen or C1-C6 alkyl. [2823] Embodiment 2: A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxyl; R ² is H, halogen; R ³ is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C12 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is -OH, cyano, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12- membered heterocycloalkyl; R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ alkoxyl; R ⁵ is H, or C ₁ -C ₆ alkoxyl; T is -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, -(C1-C6 alkyl)-NR ^T -*, wherein * denotes attachment to A; each R ^T is H; A is 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is halogen, cyano, -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)N(R ^A1 )2, -C(=O)(C1-C6 alkyl), -S(=O)(=NR ^A1 )R ^A1 , -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C ₁ -C ₆ alkoxyl, or 3- to 12-membered heterocycloalkyl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), - C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, or C1-C6 alkoxyl is optionally substituted with one or more R ^A1 ; and each R ^A1 independently is H, halogen, -OH, -NH _2, -C(=O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl is optionally substituted with - OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more oxo. [2824] Embodiment 3: The compound of any one of the preceding embodiments, wherein R ¹ is H, or halogen. [2825] Embodiment 4: The compound of any one of the preceding embodiments, wherein R ¹ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. [2826] Embodiment 5: The compound of any one of the preceding embodiments, wherein R ² is H, halogen, or cyano. [2827] Embodiment 6: The compound of any one of the preceding embodiments, wherein R ² is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. [2828] Embodiment 7: The compound of any one of the preceding embodiments, wherein R ³ is H. [2829] Embodiment 8: The compound of any one of the preceding embodiments, wherein R ³ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a . [2830] Embodiment 9: The compound of any one of the preceding embodiments, wherein each R ^3a independently is -OH, or cyano. [2831] Embodiment 10: The compound of any one of the preceding embodiments, wherein each R ^3a independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl. [2832] Embodiment 11: The compound of any one of the preceding embodiments, wherein R ⁴ is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a . [2833] Embodiment 12: The compound of any one of the preceding embodiments, wherein R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a . [2834] Embodiment 13: The compound of any one of the preceding embodiments, wherein R ⁴ is 3- to 12-membered heterocycloalkyl. [2835] Embodiment 14: The compound of any one of the preceding embodiments, wherein each R ^4a independently is halogen. [2836] Embodiment 15: The compound of any one of the preceding embodiments, wherein each R ^4a independently is C1-C6 alkyl, or C1-C6 alkoxyl. [2837] Embodiment 16: The compound of any one of the preceding embodiments, wherein R ⁵ is H, halogen, or cyano. [2838] Embodiment 17: The compound of any one of the preceding embodiments, wherein R ⁵ is C1-C6 alkoxyl. [2839] Embodiment 18: The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [2840] Embodiment 19: The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-O-*, wherein * denotes attachment to A. [2841] Embodiment 20: The compound of any one of the preceding embodiments, wherein T is -(C ₁ -C ₆ haloalkyl)-NR ^T -*, wherein * denotes attachment to A. [2842] Embodiment 21: The compound of any one of the preceding embodiments, wherein each R ^T is H. [2843] Embodiment 22: The compound of any one of the preceding embodiments, wherein each R ^T is or C ₁ -C ₆ alkyl. [2844] Embodiment 23: The compound of any one of the preceding embodiments, wherein A is C ₃ -C ₁₂ cycloalkyl optionally substituted with one or more R ^A . [2845] Embodiment 24: The compound of any one of the preceding embodiments, wherein A is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R ^A . [2846] Embodiment 25: The compound of any one of the preceding embodiments, wherein A is C ₆ -C ₁₀ aryl optionally substituted with one or more R ^A . [2847] Embodiment 26: The compound of any one of the preceding embodiments, wherein A is phenyl substituted with one or more R ^A . [2848] Embodiment 27: The compound of any one of the preceding embodiments, wherein A is 5- to 10-membered heteroaryl optionally substituted with one or more R ^A . [2849] Embodiment 28: The compound of any one of the preceding embodiments, wherein each R ^A independently is oxo, halogen, -OH, cyano, or -NH ₂ . [2850] Embodiment 29: The compound of any one of the preceding embodiments, wherein each R ^A independently is 3- to 12-membered heterocycloalkyl. [2851] Embodiment 30: The compound of any one of the preceding embodiments, wherein each R ^A independently is -C(=O)OH. [2852] Embodiment 31: The compound of any one of the preceding embodiments, wherein each R ^A independently is -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)N(R ^A1 ) ₂ , -C(=O)N(OR ^A1 )R ^A1 , - C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ N(R ^A1 ) ₂ , -S(=O) ₂ (C ₁ - C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 . [2853] Embodiment 32: The compound of any one of the preceding embodiments, wherein each R ^A1 independently is H, halogen, -OH, or -NH2. [2854] Embodiment 33: The compound of any one of the preceding embodiments, wherein each R ^A1 independently is -C(=O)OH. [2855] Embodiment 34: The compound of any one of the preceding embodiments, wherein each R ^A1 independently is -C(=O)(C ₁ -C ₆ alkyl), -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl is optionally substituted with -OH. [2856] Embodiment 35: The compound of any one of the preceding embodiments, wherein two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH ₂ . [2857] Embodiment 36: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), or (I-i), or a pharmaceutically acceptable salt or stereoisomer thereof. [2858] Embodiment 37: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-j), or a pharmaceutically acceptable salt or stereoisomer thereof. [2859] Embodiment 38: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-k), or a pharmaceutically acceptable salt or stereoisomer thereof. [2860] Embodiment 39: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-l), or Formula (I-m), or a pharmaceutically acceptable salt or stereoisomer thereof. [2861] Embodiment 40: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-n), or a pharmaceutically acceptable salt or stereoisomer thereof. [2862] Embodiment 41: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-o), or a pharmaceutically acceptable salt or stereoisomer thereof. [2863] Embodiment 42: The compound of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof. [2864] Embodiment 43: A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in Schemes 1-4. [2865] Embodiment 44: A pharmaceutical composition comprising the compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. [2866] Embodiment 45: The pharmaceutical composition of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1 or Table 2. [2867] Embodiment 46: A method of modulating PI3KĮ activity, comprising contacting a cell with an effective amount of the compound of any one of the preceding embodiments; optionally the activity is in vitro or in vivo. [2868] Embodiment 47: A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding embodiments. [2869] Embodiment 48: The compound or pharmaceutical composition of any one of the preceding embodiments for use in modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. [2870] Embodiment 49: The compound or pharmaceutical composition of any one of the preceding embodiments for use in treating or preventing a disease or disorder. [2871] Embodiment 50: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. [2872] Embodiment 51: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing a disease or disorder. [2873] Embodiment 52: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. [2874] Embodiment 53: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome. [2875] Embodiment 54: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is PIK3CA-related overgrowth syndrome. [2876] Embodiment 55: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is cancer. [2877] Embodiment 56: A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of any one of the preceding embodiments. [2878] Embodiment 57: A compound of any one of the preceding embodiments for treating or preventing cancer in a subject. [2879] Embodiment 58: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject. [2880] Embodiment 59: Use of the compound of any one of the preceding embodiments for treating or preventing cancer in a subject. [2881] Embodiment 60: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene. [2882] Embodiment 61: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic variant of the PI3KĮ protein. [2883] Embodiment 62: The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one oncogenic mutation in the PIK3CA gene. [2884] Embodiment 63: The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of PI3KĮ protein. [2885] Embodiment 64: The method, compound, or use of any one of the preceding embodiments, wherein the oncogenic mutation of the PI3KĮ protein is any one of E542K, E545K and H1047R. [2886] Embodiment 65: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer. [2887] Embodiment 1A: A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R ² is H, halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl; R ³ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3- C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is -OH, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C ₆ alkoxyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl; R ⁴ is C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C1-C6 alkoxyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; R ⁵ is H, halogen, cyano, or C1-C6 alkoxyl; T is -O-*, -NR ^T -*, -C(=O)NR ^T -*, -NR ^T C(=O)-*, -(C ₁ -C ₆ alkyl)-*, -(C ₁ -C ₆ alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NR ^T -*, -NR ^T -(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NR ^T -*, or -NR ^T -(C1-C6 haloalkyl)- *, wherein * denotes attachment to A; each R ^T is H or C1-C6 alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C ₃ -C ₁₂ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ₆ - C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is oxo, halogen, -OH, cyano, -NH2, -C(=O)OH, -C(=O)O(C1- C ₆ alkyl), -C(=O)N(R ^A1 ) ₂ , -C(=O)N(OR ^A1 )R ^A1 , -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , - S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ N(R ^A1 ) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ - C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 ; and each R ^A1 independently is H, halogen, -OH, -NH _2, -C(=O)OH, -C(=O)(C ₁ -C ₆ alkyl), - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C ₁₂ cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH ₂ . [2888] Embodiment 2A: A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxyl; R ² is H, halogen; R ³ is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C12 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one or more R ^3a ; each R ^3a independently is -OH, cyano, C ₁ -C ₆ alkoxyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12- membered heterocycloalkyl; R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a ; each R ^4a independently is halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; R ⁵ is H, or C ₁ -C ₆ alkoxyl; T is -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, -(C1-C6 alkyl)-NR ^T -*, wherein * denotes attachment to A; each R ^T is H; A is 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A ; each R ^A independently is halogen, cyano, -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)N(R ^A1 )2, -C(=O)(C1-C6 alkyl), -S(=O)(=NR ^A1 )R ^A1 , -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, or C ₁ -C ₆ alkoxyl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)(C ₁ -C ₆ alkyl), -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxyl is optionally substituted with one or more R ^A1 ; and each R ^A1 independently is H, halogen, -OH, -NH2, -C(=O)OH, C1-C6 alkyl, C1-C6 alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl is optionally substituted with - OH; or two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more oxo. [2889] Embodiment 3A: The compound of any one of the preceding embodiments, wherein R ¹ is H, or halogen. [2890] Embodiment 4A: The compound of any one of the preceding embodiments, wherein R ¹ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. [2891] Embodiment 5A: The compound of any one of the preceding embodiments, wherein R ² is H, halogen, or cyano. [2892] Embodiment 6A: The compound of any one of the preceding embodiments, wherein R ² is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl. [2893] Embodiment 7A: The compound of any one of the preceding embodiments, wherein R ³ is H. [2894] Embodiment 8A: The compound of any one of the preceding embodiments, wherein R ³ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₂ cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R ^3a . [2895] Embodiment 9A: The compound of any one of the preceding embodiments, wherein each R ^3a independently is -OH, or cyano. [2896] Embodiment 10A: The compound of any one of the preceding embodiments, wherein each R ^3a independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl. [2897] Embodiment 11A: The compound of any one of the preceding embodiments, wherein R ⁴ is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C ₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a . [2898] Embodiment 12A: The compound of any one of the preceding embodiments, wherein R ⁴ is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^4a . [2899] Embodiment 13A: The compound of any one of the preceding embodiments, wherein R ⁴ is 3- to 12-membered heterocycloalkyl. [2900] Embodiment 14A: The compound of any one of the preceding embodiments, wherein each R ^4a independently is halogen. [2901] Embodiment 15A: The compound of any one of the preceding embodiments, wherein each R ^4a independently is C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxyl. [2902] Embodiment 16A: The compound of any one of the preceding embodiments, wherein R ⁵ is H, halogen, or cyano. [2903] Embodiment 17A: The compound of any one of the preceding embodiments, wherein R ⁵ is C1-C6 alkoxyl. [2904] Embodiment 18A: The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [2905] Embodiment 19A: The compound of any one of the preceding embodiments, wherein T is -(C ₁ -C ₆ alkyl)-O-*, wherein * denotes attachment to A. [2906] Embodiment 20A: The compound of any one of the preceding embodiments, wherein T is -(C1-C6 haloalkyl)-NR ^T -*, wherein * denotes attachment to A. [2907] Embodiment 21A: The compound of any one of the preceding embodiments, wherein each R ^T is H. [2908] Embodiment 22A: The compound of any one of the preceding embodiments, wherein each R ^T is or C ₁ -C ₆ alkyl. [2909] Embodiment 23A: The compound of any one of the preceding embodiments, wherein A is C3-C12 cycloalkyl optionally substituted with one or more R ^A . [2910] Embodiment 24A: The compound of any one of the preceding embodiments, wherein A is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R ^A . [2911] Embodiment 25A: The compound of any one of the preceding embodiments, wherein A is C6-C10 aryl optionally substituted with one or more R ^A . [2912] Embodiment 26A: The compound of any one of the preceding embodiments, wherein A is phenyl substituted with one or more R ^A . [2913] Embodiment 27A: The compound of any one of the preceding embodiments, wherein A is 5- to 10-membered heteroaryl optionally substituted with one or more R ^A . [2914] Embodiment 28A: The compound of any one of the preceding embodiments, wherein each R ^A independently is oxo, halogen, -OH, cyano, or -NH2. [2915] Embodiment 29A: The compound of any one of the preceding embodiments, wherein each R ^A independently is -C(=O)OH. [2916] Embodiment 30A: The compound of any one of the preceding embodiments, wherein each R ^A independently is -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)N(R ^A1 ) ₂ , -C(=O)N(OR ^A1 )R ^A1 , - C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O)(=NR ^A1 )R ^A1 , -S(=O) ₂ N(R ^A1 ) ₂ , -S(=O) ₂ (C ₁ - C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C ₁ -C ₆ alkyl), -C(=O)(C ₁ -C ₆ alkyl), -P(=O)(C ₁ -C ₆ alkyl) ₂ , -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^A1 . [2917] Embodiment 31A: The compound of any one of the preceding embodiments, wherein each R ^A1 independently is H, halogen, -OH, or -NH2. [2918] Embodiment 32A: The compound of any one of the preceding embodiments, wherein each R ^A1 independently is -C(=O)OH. [2919] Embodiment 33A: The compound of any one of the preceding embodiments, wherein each R ^A1 independently is -C(=O)(C ₁ -C ₆ alkyl), -S(=O) ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, or C ₃ -C ₁₂ cycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl is optionally substituted with -OH. [2920] Embodiment 34A: The compound of any one of the preceding embodiments, wherein two R ^A1 , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH ₂ . [2921] Embodiment 35A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), or (I-i), or a pharmaceutically acceptable salt or stereoisomer thereof. [2922] Embodiment 36A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-j), or a pharmaceutically acceptable salt or stereoisomer thereof. [2923] Embodiment 37A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-k), or a pharmaceutically acceptable salt or stereoisomer thereof. [2924] Embodiment 38A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-l), or Formula (I-m), or a pharmaceutically acceptable salt or stereoisomer thereof. [2925] Embodiment 39A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-n), or a pharmaceutically acceptable salt or stereoisomer thereof. [2926] Embodiment 40A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-o), or a pharmaceutically acceptable salt or stereoisomer thereof. [2927] Embodiment 41A: The compound of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof. [2928] Embodiment 42A: A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in Schemes 1-4. [2929] Embodiment 43A: A pharmaceutical composition comprising the compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. [2930] Embodiment 44A: The pharmaceutical composition of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1. [2931] Embodiment 45A: A method of modulating PI3KĮ activity, comprising contacting a cell with an effective amount of the compound of any one of the preceding embodiments; optionally the activity is in vitro or in vivo. [2932] Embodiment 46A: A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding embodiments. [2933] Embodiment 47A: The compound or pharmaceutical composition of any one of the preceding embodiments for use in modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. [2934] Embodiment 48A: The compound or pharmaceutical composition of any one of the preceding embodiments for use in treating or preventing a disease or disorder. [2935] Embodiment 49A: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. [2936] Embodiment 50A: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing a disease or disorder. [2937] Embodiment 51A: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. [2938] Embodiment 52A: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome. [2939] Embodiment 53A: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is PIK3CA-related overgrowth syndrome. [2940] Embodiment 54A: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is cancer. [2941] Embodiment 55A: A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of any one of the preceding embodiments. [2942] Embodiment 56A: A compound of any one of the preceding embodiments for treating or preventing cancer in a subject. [2943] Embodiment 57A: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject. [2944] Embodiment 58A: Use of the compound of any one of the preceding embodiments for treating or preventing cancer in a subject. [2945] Embodiment 59A: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene. [2946] Embodiment 60A: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic variant of the PI3KĮ protein. [2947] Embodiment 61A: The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one oncogenic mutation in the PIK3CA gene. [2948] Embodiment 62A: The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of PI3KĮ protein. [2949] Embodiment 63A: The method, compound, or use of any one of the preceding embodiments, wherein the oncogenic mutation of the PI3KĮ protein is any one of E542K, E545K and H1047R. [2950] Embodiment 64A: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer. EQUIVALENTS [2951] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. [2952] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.