Small molecule OGG1 modulators

Abstract

The present application describes small molecule OGG1 modulators, processes for the preparation of these compounds, and the effects of these compounds on the enzymatic and functional activity of OGG1. The method further comprises treating a variety of diseases, including cancer, cardiovascular disease, nervous system disease, inflammatory disease, autoimmune disease, and infectious disease.

Description

[0001] Cross-references related to the application This application claims priority to U.S. Provisional Application Serial No. 63 / 497267, filed April 20, 2023, entitled “Small Molecule OGG1 Modulator”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to a method for preparing small molecule compounds that inhibit the DNA repair enzyme 8-oxoguanine glycosidase 1 (OGG1), and therapeutic drugs that can be prepared from these compounds. Background Technology

[0003] In cells, reactive oxygen species (ROS) damage genomic DNA, particularly by oxidizing individual nucleotide bases. Guanine bases are especially susceptible to oxidation, forming mutagenic shifts such as 8-oxo-guanine (8-oxo-G) or 2,6-diamino-4-hydroxy-5-carboxamide pyrimidine (FapyGua). If not repaired, the 8-oxo-G base is misread by DNA polymerase, and adenine is introduced as a complementary base, replacing cytosine. Therefore, after DNA replication, 8-oxo-G shifts lead to a G:C to T:A base transition. Accumulated translocations cause replication stress, eventually leading to cell cycle arrest and, in extreme cases, cell death. To avoid the mutagenic effects of oxidized bases in DNA, cells utilize the base excision repair (BER) pathway within the DNA damage and response (DDR) pathway, employing specialized enzymes to recognize and remove these harmful bases. 8-O-guanine glycosidase-1 (OGG1) is responsible for recognizing 8-oxo-G lesions in DNA and initiating their removal by cleaving glycosidic bonds. Particularly in cells with high levels of reactive oxygen species (ROS), OGG1 is crucial for removing 8-oxo-G lesions to maintain the integrity of genomic DNA. In addition to its enzymatic role in BER (bioinflammatory morphology), OGG1 also acts as a transcriptional activator of pro-inflammatory genes by binding to oxidative sites in DNA.

[0004] Cancer cells with high levels of reactive oxygen species (ROS) and / or defective mismatch repair machinery (MMR) are particularly dependent on normal functioning OGG1 to avoid accumulation of 8-oxoguanine (8-oxo-G) lesions in cellular and mitochondrial DNA. Inhibition of OGG1 enzymatic activity in these cells leads to replication stress, cell cycle arrest, and apoptosis. Small molecule inhibitors of OGG1 catalytic activity are expected to directly kill cancer cells with high levels of ROS and defective MMR and to sensitize cancer cells to chemotherapeutic drugs that increase ROS or otherwise increase the level of 8-oxo-G lesions in genomic DNA. Thus, OGG1 inhibitor compounds can be used as monotherapy for OGG1-dependent cancers and as combination therapy when the cancer is sensitized to OGG1 inhibition by a second therapeutic agent. Blocking OGG1 enzymatic activity can inhibit the transcriptional activation of proinflammatory genes, and thus OGG1 inhibitor compounds can be useful in the treatment of inflammatory and autoimmune diseases.

[0005] There is still a need for compounds and therapeutic agents that can block OGG1 enzymatic activity to prevent the transcriptional activation of proinflammatory genes, and thus treat inflammatory and autoimmune diseases mediated by OGG1. SUMMARY

[0006] The present application provides a compound as shown in formula (I),

[0007] and stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein the components have been defined in the present application.

[0008] The present application also provides a pharmaceutical composition comprising a compound of the present application, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0009] The present application also provides a compound of the present application, and stereoisomers and pharmaceutically acceptable salts thereof, for use in the treatment of a disease responsive to OGG1 inhibition.

[0010] The present application also provides a compound of the present application, and stereoisomers and pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for the treatment of a disease responsive to OGG1 inhibition.

[0011] The present application also provides a method of treating a disease mediated by OGG1 in a subject, the method comprising administering to the subject a compound of the present application.

[0012] DETAILED DESCRIPTION The following embodiments set forth a variety of exemplary configurations, methods, parameters, and the like. It is to be understood, however, that such descriptions are not intended to limit the scope of the present application, but are described as embodiments.

[0013] For the sake of providing a more concise description, certain quantitative expressions given in the present application are not preceded by the term "about." It is to be expressly understood that each quantity given in the present application is preceded by the term "about," whether or not the term "about" actually appears in the description. Every quantity given in the present application is intended to mean both the actual given value as well as an approximate value close to the actual given value, including values equivalent to the actual given value and values approximately the same as the actual given value, due to experimental and / or measurement conditions. When a yield is given as a percentage, the yield refers to the ratio of the mass of the given entity to the maximum mass of the entity obtainable under the given stoichiometric conditions. Concentrations given as percentages refer to mass ratios, unless otherwise specified.

[0014] "Alkyl" in the present application refers to a straight chain or branched chain saturated hydrocarbon group. Alkyl groups can be used alone or as part of another group, for example, -O-alkyl. In certain embodiments, alkyl groups in the present application have 1 to 20 carbon atoms ((C 1-20 )alkyl), 1 to 12 carbon atoms ((C 1-12 )alkyl), 1 to 10 carbon atoms ((C 1-10 )alkyl), 1 to 8 carbon atoms (C 1-8 alkyl), 1 to 6 carbon atoms (C 1-6 alkyl), 1 to 4 carbon atoms (C 1-4 alkyl), or 1 to 3 carbon atoms (C 1-3 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named, all geometric isomers having that number of carbon atoms are intended to be included. For example, "butyl" can include n-butyl, sec-butyl, isobutyl, and t-butyl, while "propyl" can include n-propyl and isopropyl.

[0015] "Alkenyl" in the present application refers to a straight chain or branched chain hydrocarbon group. Alkenyl groups contain at least one double bond. The double bond of an alkenyl group can be conjugated or unconjugated to another group. Alkenyl groups can be branched or straight chained. In certain embodiments, alkenyl groups in the present application have 2 to 20 carbon atoms ((C 2-20 )alkenyl), 2 to 12 carbon atoms ((C 2-12 )alkenyl), 2 to 10 carbon atoms ((C 2-10 )alkenyl), 2 to 8 carbon atoms ((C 2-8 )alkenyl), 2 to 6 carbon atoms ((C 2-6 )alkenyl), 2 to 4 carbon atoms ((C 2-4 )alkenyl), or 2 to 3 carbon atoms ((C 2-3 )alkenyl).)alkenyl). Examples of alkenyl groups include, but are not limited to, ethenyl, ethynyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butenyl)-pentenyl, and the like. When naming an alkenyl residue having a particular number of carbon atoms, all geometric isomers and E-Z isomers having that number of carbon atoms can be included.

[0016] "Alkynyl" in the present application refers to a straight-chain or branched-chain unsaturated hydrocarbon chain. Alkynyl groups contain at least one triple bond. Alkynyl groups can be branched or straight. The triple bond in an alkynyl group can be conjugated or unconjugated to another group. In certain embodiments, alkynyl groups referred to in the present application have 2 to 50 carbon atoms ((C 2-50 )alkynyl), 2 to 20 carbon atoms ((C 2-20 )alkynyl), 2 to 12 carbon atoms ((C 2-12 )alkynyl), 2 to 10 carbon atoms ((C 2-10 )alkynyl), 2 to 8 carbon atoms ((C 2-8 )alkynyl), 2 to 6 carbon atoms ((C 2-6 )alkynyl), 2 to 4 carbon atoms ((C 2-4 )alkynyl), or 2 to 3 carbon atoms ((C 2-3 )alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2-pentynyl, 4-butyl-2-hexynyl, and the like. When naming an alkynyl residue having a particular number of carbon atoms, all geometric isomers having that number of carbon atoms can be included.

[0017] "Cycloalkyl" in the present application refers to saturated or partially saturated, monocyclic, condensed or spirocyclic carbocyclic rings containing 3 to 18 carbon atoms. The cycloalkyl ring or carbocyclic ring can be unsubstituted or substituted by one or more substituents, for example 1 to 5 substituents at any point of attachment. The substituents themselves can also be unsubstituted or substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentadienyl, cyclopentadienyl, bicyclo[2.2.2]octyl, bicyclo[2.2.2]octenyl, decahydronaphthyl, octahydro-lH-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-l,4-dienyl, cyclohexa-l,3-dienyl, 1,2,3,4-tetrahydronaphthyl, octahydro-pentenyl, 3a,4,5,6,7,7a-hexahydro-lH-indenyl, 1,2,3,3a-tetrahydro-pentenyl, bicyclo[3.1.0]hexenyl, bicyclo[2.1.0]pentenyl, spiro[3.3]heptenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octyl, 6-methylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, and derivatives thereof.

[0018] "Heterocycle," "heterocyclic," "heterocyclyl," or "heterocyclyl diradical" in the present invention means a saturated or partially unsaturated and non-aromatic monocyclic, fused polycyclic, or spiro polycyclic ring structure containing from 4 to 18 carbon atoms and heteroatoms from oxygen, nitrogen, or sulfur, wherein there are no shared pi electrons (aromaticity) between all ring carbon atoms or heteroatoms. The heterocyclyl ring structure is attached to a single point of a group recited in the present invention, while the heterocyclyl diradical ring structure is attached to two points of a group or groups recited in the present invention. The heterocycle, heterocyclyl, or heterocyclyl diradical ring structure can be unsubstituted or substituted with one or more substituents. The substituents themselves can be unsubstituted or substituted.Heterocycle, heterocyclyl, or heterocyclyl diradical rings include, for example, but are not limited to, oxetanyl, pyrazolidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, oxazolidinyl, thiazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, pyrazinyl, oxypyrazinyl, dipyrazinyl, tolanyl, homotolanyl, dihydrothiophene-2(3H)- ketone, tetrahydrothiophene 1,1-dioxide, 2,5-dihydro-1H-pyrrolyl, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolane-2-one, isothiazolidine-1,1-dioxide, 4,5-dihydro-1H-imidazolyl, 4,5-dihydrooxazolyl, epoxy, pyrazolidinyl, 4H-1,4-thiazolyl, thiazolinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrazinyl, 1,3-oxazolidin-2-one, tetrahydro-2H-thiopyranyl-1,1-dioxide, 7-oxabicyclo[2.2.1]heptanyl, 1,2-thiazolidine-1,1-dioxide, octahydro-2H-quinolizinyl, 1,3-diazabicyclo[2.2.2]octanyl, 2,3-dihydrobenzo[b][1,4]dioxin, 3-azabicyclo[3.2.1]octane, 8-azaspiro[4.5]decane, 8-oxa-3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.1]heptane, 2,8-diazaspiro[5.5]undecanyl, 2-azaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl, decahydroisoquinolinyl, 1-oxa-8-azaspiro[4.5]decanyl, 8-azabicyclo[3.2.1]octanyl, 1,4’-bipiperidinyl, pyrazolyl, 8-oxa-3-pyrazolylcyclooctanyl, 3,4-dihydro-2H-benzo[b][1,4]oxazolyl, 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridinyl, 1,4-dipyrazolyl, phenoxathiinyl, benzo[d][1,3]dioxolanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxanyl, 4-(piperidin-4-yl)morpholinyl, 3-azaspiro[5.5]undecanyl, decahydroquinolinyl, piperazin-2-one, 1-(pyrrolidin-2-ylmethyl)pyrrolidinyl, 1,3’-bipyrrolidinyl, and 6,7,8,9-tetrahydro-1H,5H-pyrazolo[1,2-a][1,2]diazepinyl.

[0019] "Aryl" in the present application refers to a monocyclic or polycyclic radical containing at least one hydrocarbon aromatic ring, wherein all ring atoms of the at least one aromatic hydrocarbon ring are carbon atoms. Aryl groups can include groups containing only one aromatic ring (e.g., phenyl) as well as groups containing multiple covalent aromatic rings (e.g., naphthyl, anthracenyl). Aryl groups can also include groups having one or more aromatic hydrocarbon rings "fused" to one or more non-aromatic hydrocarbon rings (e.g., fluorenyl; 2,3-dihydro-lH-inden; 1,2,3,4-tetrahydronaphthyl). In certain embodiments, aryl groups include groups having an aromatic hydrocarbon ring "fused" to a non-aromatic ring, wherein the non-aromatic ring contains at least one ring heteroatom independently selected from N, O, and S. For example, in certain embodiments, aryl groups include groups having a benzene ring "fused" to a non-aromatic ring, wherein the non-aromatic ring contains at least one ring heteroatom independently selected from N, O, and S (e.g., chromanyl; thiochromanyl; 2,3-dihydrobenzofuranyl; indolinyl). In certain embodiments, aryl groups used in the present application have 6 to 14 carbon atoms (C6-C 14 ) aryl groups), or 6 to 10 carbon atoms (C6-C 10 ) aryl groups). When the aryl group contains a fused ring, the aryl group can be attached to one or more substituents or groups depicted in the present application through any atom of the fused ring that allows for the indicated valence.

[0020] "Heteroaryl" in the present application refers to a monocyclic or polycyclic group containing at least one aromatic ring, wherein the aromatic ring contains at least one ring heteroatom selected from N, O, and S. The heteroaryl group can contain 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon atoms and heteroatoms in one or more rings (e.g., 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, or 12-membered heteroaryl). In certain embodiments, heteroaryl includes groups having an aromatic ring containing at least one ring heteroatom selected from N, O, and S (e.g., pyridyl, pyrazinyl, furanyl, thienyl). In certain embodiments, heteroaryl includes polycyclic groups having an aromatic ring containing at least one ring heteroatom "fused" to a non-aromatic hydrocarbon ring (e.g., 5,6,7,8-tetrahydroquinolinyl; 4,5,6,7-tetrahydroiso- benzofuranyl). In certain embodiments, heteroaryl includes polycyclic groups having an aromatic ring containing at least one ring heteroatom "fused" to an aromatic hydrocarbon ring (e.g., quinolinyl, quinolinthiazolyl, benzothiazolyl). In yet other embodiments, heteroaryl includes polycyclic groups having a biaromatic ring containing at least one ring heteroatom in each ring (e.g., naphthyridinyl). Heteroaryl can include groups containing 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each ring heteroatom is independently selected from N, O, and S. For example, heteroaryl has 3 to 8 ring carbon atoms, wherein 1 to 3 ring heteroatoms are independently selected from N, O, and S. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl.

[0021] In the present application, the term "substituted" means that the designated group or fragment bears one or more suitable substituents, wherein the substituents can be attached to the designated group or fragment at one or more positions. For example, aryl substituted by cycloalkyl can mean that the cycloalkyl is attached to an atom of the aryl group by a bond, or "fused" to the aryl group (sharing two or more common atoms).

[0022] In the present application, the term "unsubstituted" means that the designated group does not contain any substituents.

[0023] In the present application, the term "amino" refers to a substituent containing at least one nitrogen atom. For example, primary amines, secondary amines, or alkylamines, tertiary amines or dialkylamines, amides, carboxamides, ureas, and sulfonamides are all within the scope of "amino".

[0024] In the present application, the term "cyano" refers to a substituent in which a carbon atom is attached to a nitrogen atom by a triple bond, i.e. .

[0025] In the present application, "hydroxy" or "hydroxy group" means an OH group.

[0026] In the present application, "halogen" or "halo" means a fluoro, chloro, bromo, or iodo group.

[0027] In the present application, the term "haloalkyl" means an alkyl group substituted with one or more halogen.

[0028] In the present application, "halocycloalkyl" means a cycloalkyl group substituted with one or more halogen.

[0029] In the present application, "haloaryl" means an aryl group substituted with one or more halogen.

[0030] In the present application, the term "oxo" means a "=0" group in the present specification.

[0031] It is to be understood that when a range is listed, it is intended to encompass each value within the range and subranges thereof. For example, "C 1-6 "alkyl" (which can also be referred to as Ci-C6alkyl, Ci-C6alkyl, or Ci-6alkyl) is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl groups.

[0032] It is also to be understood that any carbon and heteroatom occurring in the text, figures, examples, and tables of the present application, which has an unsatisfied valence, is assumed to have sufficient number of hydrogen atoms to satisfy its valence.

[0033] In the present application, hydrogen can also mean deuterium, if desired. The term "deuterium" as used in the present application means a stable hydrogen isotope having an odd number of both protons and neutrons.

[0034] Each compound can exist in its tautomeric form, if desired (e.g., in amide or imino ether form). All such tautomeric forms are considered to be part of the present application.

[0035] It is understood that the application encompasses all isomeric forms, including mixtures thereof. If a compound contains a double bond, the substituents can be in either the E or Z configuration. If a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can have either the cis- or trans-configuration.

[0036] Various compounds can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. The present application encompasses all stereoisomeric forms of the compounds depicted in the various formulae, as well as mixtures thereof, including racemic mixtures. In certain embodiments, the isomers of the compounds of the application are stereoisomers. Also included are all geometric isomers and positional isomers. For example, if a compound contains a double bond, the cis and trans forms, as well as mixtures thereof, are within the scope of the application. Each compound disclosed in the present application contains all of the enantiomers that correspond to the general structure of that compound. The compounds can be in racemic form, enantiomerically pure form, or any other stereoisomeric form. Test results can reflect data for racemic form, enantiomerically pure form, or any other stereoisomeric form.

[0037] Mixtures of chiral isomers can be separated by methods known to those skilled in the art, based on the physical chemical differences between the isomers, for example by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the mixture of enantiomers into a mixture of isomers, separating the isomers, and converting each isomer to the corresponding pure enantiomer, for example by hydrolysis. Also certain compounds can be atropisomers (e.g., substituted biaryl compounds), and are considered part of the present application. Enantiomers can also be separated by using chiral HPLC columns.

[0038] In certain embodiments, the compounds as shown in formulae I, II, Ilia, Illb, IVa, IVb, and pharmaceutically acceptable salts thereof, are enantiomers. In certain embodiments, the compounds and pharmaceutically acceptable salts thereof are (S)-enantiomers. In certain embodiments, the compounds and pharmaceutically acceptable salts thereof are (R)-enantiomers. In certain embodiments, the compounds and pharmaceutically acceptable salts thereof are (+) enantiomers or (-) enantiomers.

[0039] Certain embodiments relate to isotopically-labeled compounds described herein, which are identical to those recited in the application but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The isotopically-labeled compounds of this application can be prepared by carrying out the procedures disclosed in the application, or known in the art, using appropriate isotopically-labeled reagents in place of the non-labeled reagents previously employed. 2 H (or D), and 3H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl.

[0040] Some compounds are labeled with isotopes (e.g., those labeled with...). 3 H and 14 Compounds of C have practical value in compound and / or substrate tissue distribution assays. Tritium (i.e., ³H) and carbon-14 (i.e., ¹H) are also valuable. 4 C) Isotopes are particularly favored due to their ease of preparation and detection. Furthermore, heavier isotopes (such as deuterium, i.e., 2 Substituting H) may offer certain therapeutic advantages, such as greater metabolic stability (e.g., prolonged in vivo half-life or reduced dose requirements), and may therefore be preferred in some cases. Isotope-labeled compounds of various formulations can generally be prepared by replacing non-isotope-labeled reagents with appropriate isotope-labeled reagents, following similar experimental procedures provided in the experimental roadmap and / or embodiments of this invention.

[0041] In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compound of the present invention may be replaced or substituted by a deuterium atom. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms.

[0042] Compounds such as those represented by formulas I, II, IIIa, IIIb, IVa, and IVb can form salts, which are also within the scope of this invention. Unless otherwise stated, this should be understood to include their salts.

[0043] This invention relates to the compounds described herein, their stereoisomers, and pharmaceutically acceptable salts, and also to pharmaceutical compositions comprising one or more compounds as described herein, their stereoisomers, and pharmaceutically acceptable salts.

[0044] As used in this invention, "pharmaceutically acceptable" refers to a substance useful in the preparation of a generally safe, non-toxic, and biologically or otherwise harmless pharmaceutical formulation, including substances suitable for veterinary and human pharmaceutical use. For example, this invention provides a pharmaceutical composition comprising a compound as shown in formula I, II, IIIa, IIIb, IVa, or IVb, its stereoisomers, a pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.

[0045] "Pharmaceutically acceptable salt" as used herein refers to salts that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include salts that are useful in veterinary use as well as in human pharmaceutical use. Such salts can include acid and base salts. Acid addition salts can be formed with inorganic acids such as hydrochloric acid, hydrogen bromide acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanepropionic acid, dodecylsulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galacturonic acid, glyconic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malonic acid, malic acid, malic acid, malic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, uric acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyrrolidinecarboxylic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, or undecylenic acid. Salts from inorganic bases can include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts from organic bases can include, but are not limited to, salts of primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrocortisone, choline, betaine, phenethylamine, phenylmethylamine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, trimethylamine, purines, piperazine, piperidine, or N-ethylpiperidine.

[0046] The term "carrier" as used in the present application encompasses carriers, adjuvants and diluents, and refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, adjuvant, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical from one organ, or portion of the body, to another organ, or portion of the body. The selection of a carrier will be based on compatibility with the target dosage form and release characteristics. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like.

[0047] "Pharmaceutically compatible carrier materials" may include, for example, gum arabic, gelatin, colloidal silica, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soybean lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, etc. See, for example: Howard, John E., *Remington Pharmaceutical Sciences*, Mack Publishing, Eastton, PA, 1975.

[0048] As used in this invention, "solvent" refers to a variable molar ratio complex formed by a solute and a solvent. Such solvents must not interfere with the biological activity of the solute. Suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Solvents using water as the solvent molecule are generally called hydrates. Hydrates include systems containing a fixed amount of water molecules, as well as systems containing a variable amount of water molecules.

[0049] compound This invention provides a compound as shown in formula (I),

[0050] Or its stereoisomer, or its pharmaceutically acceptable salt, wherein: X1, X2, and X3 are each independently CH, C, or N; R1 can be R, halogen, tert-butyl, cyclopropyl, cyclobutyl, CF3, CHF2, CH2F, OH, CN, CHO, C(O)Me, C(O)OMe, C(O)NH2, CHCH2, NR'R”, R'NR”R”'; R2 is unsubstituted, C1-C3 alkyl, C1-C3 alkenyl, NR'R", NHR'NR"R"', R'NR"R'"; NHC(O)R'NR"R"', OR, CN, NO2, C(O)R, R'OR", R'NR"C(O)R"', C(O)OR, C(O)NR'R", C(O)NHR'NR"R"', P(O)R'R", R'NR"S(O)2R"', -O-R'NR"R"', halogen, CF3, A 1 B 1 -ORA 1 -ORB 1 -OA 1 -OB 1 ROA 1 ROB 1 ,NR'R”A 1 ,NR'R”B 1 N(R)B 1 N(R)A 1 ,NR'C(O)R”A 1, NR'C(O)R”B 1 N(R)C(O)A 1 N(R)C(O)B 1 RA 1 RB 1 ; Y is CR'R", C(O), O, S or NR; W can be CH2, O, S, NR, or a single bond; Q is A 2 Optionally, it may include one or more O, N, or NR; Z can be CH2, S, O, NR, or a single bond; R3 is A3, B2, or a fused biaromatic ring system, wherein the fused biaromatic ring system optionally comprises one or more N, NR, O, or S; A 1 A 2 and A 3 Each is an independent carbon ring or heterocycle ranging from 3 to 7 members; B 1 and B 2 Each is an independent aromatic ring or heteroaromatic ring consisting of 5 or 6 elements; R, R', R” and R”' are each independently H, C1-6 alkyl or C1-6 alkenyl; Among them, R, R', R”, R”', A 1 A 2 A 3 B 1 B 2 The fused bicyclic aromatic ring system is either unsubstituted or substituted by one or more substituents selected from the following groups: CN, CF3, OR, =O, ROH, NR'R", C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Alkenes, halogens, and 3- to 7-membered carbon rings or heterocycles.

[0051] In some embodiments, the compound or its stereoisomer, or a pharmaceutically acceptable salt thereof, is shown as in formula (II): , in: X1, X2, and X3 are each independently CH, C, or N; R1 can be R, halogen, tert-butyl, cyclopropyl, cyclobutyl, CF3, CHF2, CH2F, OH, CN, CHO, C(O)Me, C(O)OMe, C(O)NH2, CHCH2, NR'R”, R'NR”R”'; R2is no substitution, C1-C3alkyl, C1-C3alkenyl, NR'R", NHR'NR"R'", R'NR"R'", NHC(O)R'NR"R'", OR, CN, NO2, C(O)R, R'OR", R'NR"C(O)R"', C(O)OR, C(O)NR'R", C(O)NHR'NR"R'", P(O)R'R", R'NR"S(O)2R'", -O-R'NR"R'", halogen, CF3, A 1 , B 1 , -ORA 1 , -ORB 1 , -OA 1 , -OB 1 , ROA 1 , ROB 1 , NR'R"A 1 , NR'R"B 1 , N(R)B 1 , N(R)A 1 , NR'C(O)R"A 1 , NR'C(O)R"B 1 , N(R)C(O)A 1 , N(R)C(O)B 1 , RA 1 , RB 1 ; Y is CR'R", C(O), O, S or NR; W is CH2, O, S, NR or a single bond; R5is H2, C 1-6 alkyl, C 1-6 alkene, OR, NR'R", halogen or CN; R4is H, C 1-6 alkyl, OR, NR'R", halogen or CN; R3is A 3 , B 2 or a fused bicyclic aromatic ring system, wherein the fused bicyclic aromatic ring system optionally comprises one or more N, NR, O or S; A 1 and A 3 are each independently a 3- to 7-membered carbocyclic or heterocyclic ring; and B 1 and B 2 are each independently a 5- or 6-membered aromatic or heteroaromatic ring; wherein R4and / or R5are optional; wherein R, R', R" and R'" are each independently H, C 1-6 alkyl or C1-6 alkenyl; and, Where R, R', R”, R”', A 1 A 3 B 1 B 2 The fused bicyclic aromatic ring system is unsubstituted or substituted by one or more substituents selected from the following groups: CN, CF3, OR, =O, ROH, NR'R", C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Alkenes, halogens, and 3- to 7-membered carbon rings or heterocycles.

[0052] In some embodiments, the compound of the present invention, or its stereoisomer, or a pharmaceutically acceptable salt thereof, is shown as in formula (IIIa) or (IIIb): or , in: X1, X2, and X3 are each independently CH, C, or N; R2 is unsubstituted, or is a C1-C3 alkyl, C1-C3 alkenyl, NR'R", NHR'NR"R"', R'NR"R'", NHC(O)R'NR"R"', OR, CN, NO2, C(O)R, R'OR", R'NR"C(O)R"', C(O)OR, C(O)NR'R", C(O)NHR'NR"R"', P(O)R'R", R'NR"S(O)2R"', -O-R'NR"R"', halogen, CF3, A 1 B 1 -ORA 1 -ORB 1 -OA 1 -OB 1 ROA 1 ROB 1 ,NR'R”A 1 ,NR'R”B 1 N(R)B 1 N(R)A 1 ,NR'C(O)R”A 1 , NR'C(O)R”B 1 N(R)C(O)A 1 N(R)C(O)B 1 RA 1 RB 1 ; Y is CR'R", C(O), O, S or NR; R3 is A 3 B2 or a fused bicyclic aromatic ring system, wherein the fused bicyclic aromatic ring system optionally comprises one or more N, NR, O or S; A 1 and A 3 each independently is a 3- to 7-membered carbocyclic or heterocyclic ring; and B 1 and B 2 each independently is a 5- or 6-membered aromatic or heteroaromatic ring; wherein R, R', R" and R'" are each independently H, C 1-6 alkyl or C 1-6 alkenyl; and wherein R, R', R", R'", A 1 , A 3 , B 1 , B 2 and the fused bicyclic aromatic ring system is unsubstituted or substituted with one or more substituents selected from the group consisting of CN, CF3, OR, =0, ROH, NR'R", C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, halogen, and a 3- to 7-membered carbocyclic or heterocyclic ring.

[0053] In certain embodiments, the compounds of the present application are represented by formula (IIIa): .

[0054] In other embodiments, the compounds of the present application are represented by formula (IIIb): .

[0055] In certain embodiments, the compounds of the present application are represented by formula (IVa) or (IVb): or , wherein: X1, X2and X3are each independently CH, C or N; R2is unsubstituted or C 1- C3alkyl, C1-C3alkenyl, NR'R", NHR'NR"R'", R'NR"R'", NHC(O)R'NR"R'", OR, CN, NO2, C(O)R, R'OR", R'NR"C(O)R'", C(O)OR, C(O)NR'R", C(O)NHR'NR"R'", P(O)R'R", R'NR"S(O)2R'", -O-R'NR"R'", halogen, CF3, A 1 , B1 -ORA 1 -ORB 1 -OA 1 -OB 1 ROA 1 ROB 1 NR'R"A 1 NR'R"B 1 N(R)B 1 N(R)A 1 NR'C(O)R"A 1 NR'C(O)R"B 1 N(R)C(O)A 1 N(R)C(O)B 1 RA 1 RB 1 ; R3is A 3 , B 2 , or a fused bicyclic aromatic ring system, wherein the fused bicyclic aromatic ring system optionally comprises one or more N, NR, O, or S; A 1 and A 3 are each independently a 3- to 7-membered carbocyclic or heterocyclic ring; and, B 1 and B 2 are each independently a 5- or 6-membered aromatic or heteroaromatic ring; wherein R, R', R", and R'" are each independently H, C 1-6 alkyl, or C 1-6 alkenyl; and, wherein R, R', R", R'", A 1 , A 3 , B 1 , B 2 , and the fused bicyclic aromatic ring system are unsubstituted or substituted with one or more substituents selected from the group consisting of CN, CF3, OR, =O, ROH, NR'R", C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, halogen, and a 3- to 7-membered carbocyclic or heterocyclic ring.

[0056] In certain embodiments, the present application provides compounds of Formula (IVa) having the following structural formula: .

[0057] In other embodiments, the present application provides compounds of Formula (IVb) having the following structural formula: .

[0058] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, at least two of X1, X2, and X3are CH or N.

[0059] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R1is H, C 1-6 alkyl, or halogen. In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R2is unsubstituted, NR’R”, OR, CN, or a 5- or 6-membered heteroaromatic ring.

[0060] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R2is attached to X2or X3.

[0061] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, A 1 or B 1 is , , , , , , , , , or optionally substituted with one or two substituents selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, CN, OH, halogen, and NH2.

[0062] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, Y is CR’R” or CH2.

[0063] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, Y is NR in a compound of formula (IIIa), or Y is NR, O, or S in a compound of formula (IIIb).

[0064] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, Q is , , , , , or .

[0065] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R4is C 1-3 alkyl.

[0066] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, Z is a single bond.

[0067] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, the 3- to 7-membered carbocyclic or heterocyclic ring comprises one spirocyclic ring.

[0068] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, A in R3is 3 or B 2 substituted with one or more substituents selected from the group consisting of CN, CF3, OR, =0, ROH, NR’R”, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, halogen, and 3- to 7-membered carbocyclic or heterocyclic ring.

[0069] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R3is a 5- or 6-membered aromatic or heteroaromatic ring or a fused bicyclic aromatic ring system substituted with one or two substituents selected from the group consisting of CN, CF3, OR, =0, ROH, NR’R”, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, halogen, and 3- to 7-membered carbocyclic or heterocyclic ring.

[0070] In certain embodiments, for a compound of the present application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R3is , , , , , , , , , , , , , , , and the group is unsubstituted or has one, two or three substituents selected from the group consisting of CN, CF3, OR, =0, Ci-6alkyl, -0-Ci-6alkyl, Ci-6alkene, ROH, halogen, and a 3- to 7-membered carbocyclic or heterocyclic ring.

[0071] In certain embodiments, for a compound of the application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, A 2 one or two substituents selected from the group consisting of CN, CF3, OR, =0, ROH, NR’R”, Ci-6alkyl, -0-Ci-6alkyl, Ci-6alkene, F, Cl, Br, I, and a 3- to 7-membered carbocyclic or heterocyclic ring.

[0072] In certain embodiments, for a compound of the application, stereoisomer thereof, or pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0073] In other embodiments, the compound of the application, stereoisomer thereof, or pharmaceutically acceptable salt thereof is selected from the group consisting of: , , , , , , and .

[0074] In further embodiments, the compound of the application, stereoisomer thereof, or pharmaceutically acceptable salt thereof is: .

[0075] In further embodiments, the compound of the application, stereoisomer thereof, or pharmaceutically acceptable salt thereof is: .

[0076] In certain embodiments, the compound of the application, stereoisomer thereof, or pharmaceutically acceptable salt thereof is useful for medical use. Still further, the compound of the application, stereoisomer thereof, or pharmaceutically acceptable salt thereof is useful for the treatment of a disease responsive to OGG1 inhibition.

[0077] In certain embodiments, the compound of the application, stereoisomer thereof, or pharmaceutically acceptable salt thereof is used in the manufacture of a medicament for the treatment of a disease responsive to OGG1 inhibition. In certain aspects, the disease is selected from the group comprising cancer, cardiovascular disease, nervous system disease, inflammatory disease, autoimmune disease, and infectious disease.

[0078] Pharmaceutical compositions The compounds of Formulae I, II, Ilia, Illb, IVa, and IVb, their stereoisomers and pharmaceutically acceptable salts thereof can be used alone but will generally be administered in the form of a pharmaceutical composition in which the compound, its stereoisomers and pharmaceutically acceptable salts thereof is in association with a pharmaceutically acceptable excipient, diluent or carrier. For a review on conventional procedures for the selection and preparation of suitable pharmaceutical formulations see, for example, "Pharmaceutical Dosage Forms and Drug Delivery Systems," 7th Edition, Marcel Dekker, Inc., 2008, which is hereby incorporated by reference in its entirety.

[0079] The present application also provides a pharmaceutical composition comprising a compound of Formulae I, II, Ilia, Illb, IVa, or IVb, its stereoisomers and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0080] The present application also provides a compound for use in medicine comprising a compound of Formulae I, II, Ilia, Illb, IVa, or IVb, its stereoisomers and pharmaceutically acceptable salts thereof.

[0081] The present application also provides a pharmaceutical composition comprising a compound of Formulae I, II, Ilia, Illb, IVa, or IVb, its stereoisomers and pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0082] The present application still further provides a process for preparing a pharmaceutical composition of the present application comprising mixing a compound of Formulae I, II, Ilia, Illb, IVa, or IVb, its stereoisomers and pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0083] Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05% to about 99% (w / w), more specifically from about 0.05% to about 80% (w / w), more specifically from about 0.10% to about 70% (w / w), even more specifically from about 0.10% to about 50% (w / w), all w / w percentages being based on the total formulation, of the active ingredient.

[0084] The pharmaceutical composition can be administered in the form of a topical administration (e.g. application to the skin or administration via the lungs and / or respiratory tract), such as creams, solutions, suspensions, hydrofluoroalkane (HFA) aerosols and dry powder formulations, such as those used in the name Turbuhaler® ®The drug formulation is administered via an inhalation device; or via systemic administration, such as by oral administration, in the form of tablets, capsules, syrups, powders or granules; or via intravenous injection, such as via intravenous, subcutaneous, intramuscular, intravascular injection or infusion, as a sterile solution, suspension or emulsion; or via rectal administration in the form of a suppository.

[0085] The dry powder formulations and pressurized HFA aerosols of the compounds described in this invention (including their stereoisomers and pharmaceutically acceptable salts) can be administered orally or by nasal inhalation. When inhaled, the compounds are preferably in the form of a fine powder. Preferably, the fine powdered compound has a median diameter of less than 10 micrometers (μm) and can be suspended in the propellant mixture using a dispersant such as C8-C. 20 Fatty acids or their salts (e.g., oleic acid), bile salts, phospholipids, alkyl sugars, perfluorinated or polyethoxylated surfactants, or other pharmaceutically acceptable dispersants.

[0086] The compounds described in this invention can also be administered via a dry powder inhaler. The inhaler can be a single-dose or multiple-dose inhaler, and can be a breath-triggered dry powder inhaler.

[0087] An alternative method is to mix the finely dispersed compound of the present invention with a carrier substance, such as a monosaccharide, disaccharide, or polysaccharide, sugar alcohol, or another polyol. Suitable carriers include sugars such as lactose, glucose, raffinose, maltose, lactitol, maltitol, trehalose, sucrose, and mannitol; and starch. Furthermore, the finely powdered compound may be coated with another substance. The powder mixture may also be filled into hard capsules, each containing the desired dose of the active ingredient.

[0088] Another alternative method is to process the fine powder into spherical powder that breaks apart during inhalation. This spherical powder can then be filled into the drug reservoir of a multi-dose inhaler, such as the Turbuhaler. ® The inhaler measures the required dose through its metering unit, which is then inhaled by the patient. This system delivers the active ingredient into the patient's body regardless of whether it contains a carrier substance.

[0089] Another alternative approach is to formulate the compound as an amorphous dispersion in a polymer matrix, such as hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS). As the name suggests, spray-dried dispersions (SDDs) are produced by dissolving the drug and polymer in an organic solvent, atomizing the resulting solution into droplets, and then evaporating it into dry solid particles. Spray-dried dispersions are generally suitable for a variety of final oral formulations, including capsules and tablets.

[0090] For oral administration, the compounds described herein can be mixed with an excipient or carrier such as lactose, sucrose, sorbitol, mannitol, starch, such as potato starch, com starch or amylopectin; cellulose derivatives; binders such as gelatin or polyvinylpyrrolidone; and / or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets. If desired, the tablets can be coated with a suitable coating agent such as a concentrated sugar solution, which can contain gum arabic, gelatin, talc, and titanium dioxide. Similarly, the tablets can be coated with a suitable polymer dissolved in a readily evaporable organic solvent.

[0091] For preparation of a soft capsule, the compounds described herein can be mixed with, for example, vegetable oil or polyethylene glycol. Hard capsules can contain granules of the compounds described herein using excipients described above for tablets. Additionally, liquid or semisolid formulations of the compounds described herein can be filled into hard capsules.

[0092] Liquid preparations for oral administration can take the form of, for example, solutions or suspensions, which can contain the compounds described herein in the form of a solution, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations can contain colorants, flavoring agents, saccharine and / or carboxymethyl cellulose as a thickening agent or other excipients known to those skilled in the art.

[0093] Methods of treatment The terms "treat," "treating," or "treatment" and the like, as used herein, refer to any indicia of success in the amelioration of some disease (e.g., an injury, a disease pathology, or condition), including any objective or subjective parameter such as abatement of symptoms; slowing in the rate of progression; making the disease more tolerable; improving quality of life; or extending the survival period of the patient. Treatment of symptoms, including alleviation, can be considered a success in treatment, and can be based on objective or subjective parameters, including but not limited to, physical examination, neurologic examination, and / or psychiatric evaluations. Certain methods and uses described herein can treat cancer by, for example, causing the cancer to go into remission, slowing the rate of growth of cancer cells, slowing the rate of spread of cancer cells, reducing metastasis, or reducing growth of metastatic tumors, reducing the size of one or more tumors, reducing the number of one or more tumors, or any combination of the above.

[0094] The terms "administer," "administration," or "administering," as used herein, refer to the direct application or the application of a composition (including stereoisomers and pharmaceutically acceptable salts) to a subject (including an animal) in need of treatment by contacting or otherwise exposing the individual to the compound.

[0095] As used herein, the term "subject" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the application, the mammal is a human.

[0096] "Patient" refers to a mammal, for example, a human, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. "Patient" includes humans and animals.

[0097] As used herein, the term "inhibit" means to reduce the activity of a target or to completely inhibit the activity of a target. Reduction in activity can include reducing the activity of a component in a pathway to a level that is still detectable. Complete inhibition can include stopping all activity of a component in a pathway (e.g., stopping the activity of OGG1) or reducing the activity of a component in a pathway to a level that is not detectable. Inhibition of a component in a pathway can be measured directly or indirectly using any method known in the art.

[0098] As used herein, the term "disease" is used interchangeably with the terms "disorder" or "condition" unless otherwise indicated.

[0099] In certain embodiments, the compounds described herein are useful for treating one or more diseases associated with OGG1. As used herein, "responsive to OGG1 inhibition" refers to a disease that is expected to be ameliorated by administration of an inhibitory amount of a compound. Cancer is one disease that can be responsive to treatment by administration of the compounds. By analyzing the in vitro expression levels and aberrant activity of OGG1 in cancer cell lines, certain cancers that are responsive to treatment with the compounds can be identified. In addition, in vitro cell survival assays can be used to identify specific cancer cell lines that are responsive to treatment with the compounds. Cancer cell lines that are responsive to OGG1 inhibitor compounds in vitro are expected to be responsive to OGG1 inhibitor compounds in vivo, for example, in a xenograft model of mouse cancer growth. In addition, certain cancers can be indirectly responsive to OGG1 inhibitors by activating the patient's immune system rather than directly causing cancer cell death. Other methods can be used to identify cancers that are sensitive to OGG1, such as tumor-specific mutations of specific genes, tumor gene expression patterns, and biomarkers in the blood (such as circulating tumor DNA, RNA, or protein).

[0100] The compounds as described herein, such as those of Formula I, II, Ilia, Illb, IVa, or IVb, stereoisomers, and pharmaceutically acceptable salts thereof, have pharmacological activity.

[0101] The present application provides a compound as shown in Formula I, II, Ilia, Illb, IVa or IVb, stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, for use in treating a disease in a subject in need of treatment.

[0102] The present application provides a compound as shown in Formula I, II, Ilia, Illb, IVa or IVb, stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition for use in treating a disease in a subject in need of such treatment.

[0103] The present application provides a compound as shown in Formula I, II, Ilia, Illb, IVa or IVb, and stereoisomers and pharmaceutically acceptable salts of the compound, or a pharmaceutical composition of the compound, for use in treating a disease responsive to OGG1 inhibition.

[0104] The present application provides a compound as shown in Formula I, II, Ilia, Illb, IVa or IVb, stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, for use in treating a disease responsive to OGG1 inhibition.

[0105] The present application provides a compound as shown in Formula I, II, Ilia, Illb, IVa or IVb, stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating a disease responsive to OGG1 inhibition.

[0106] The present application also provides a method of treating a disease mediated by OGG1 in a subject in need of treatment, the method comprising administering to the subject a compound as shown in Formula I, II, Ilia, Illb, IVa or IVb, stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0107] In certain embodiments, the disease is selected from cancer, cardiovascular disease, nervous system disease, inflammatory disease, autoimmune disease, and infectious disease.

[0108] In certain embodiments, the disease is cancer. In certain embodiments, the cancer is of solid organ origin or of hematopoietic system origin.

[0109] In certain embodiments, the disease is cancer, the cancer is of solid organ origin, and the solid organ is selected from the group consisting of brain, breast, colon, endometrial, esophageal, head and neck, upper digestive tract, respiratory tract, lung, kidney, liver, lower digestive tract, small intestine, large intestine, ovary, pancreas, prostate, stomach, testicle, and urinary tract. In certain embodiments, the disease is cancer, and the cancer is adenocarcinoma. In certain embodiments, the disease is non-small cell lung cancer. In certain embodiments, the cancer is squamous cell lung cancer (SCCL).

[0110] In certain embodiments, the disease is cancer, and the cancer is leukemia or lymphoma. In certain embodiments, the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML). In certain embodiments, the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, or Burkitt's lymphoma.

[0111] In certain embodiments, the disease is cancer, and the cancer is selected from the group consisting of bladder cancer, bone cancer, cervical cancer, epithelial cancer, gall bladder cancer, rectal cancer, skin cancer, thyroid cancer, and uterine cancer.

[0112] In certain embodiments, the disease is an inflammatory disease, and the inflammatory disease is selected from the group consisting of inflammatory bowel disease (IBD), atherosclerosis, rheumatoid arthritis, fibrosis, Alzheimer's disease, and Parkinson's disease.

[0113] In certain embodiments, a compound of Formula I, II, Ilia, Illb, IVa, or IVb, stereoisomers and pharmaceutically acceptable salts thereof, is administered to a subject in need thereof to inhibit a component of the OGG1 pathway. In certain embodiments, the compound or stereoisomer or pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition as described herein.

[0114] In certain embodiments, the inhibition of a component of the OGG1 pathway can be measured directly, for example, by measuring a product of a reaction catalyzed by the component of the OGG1 pathway.

[0115] In certain embodiments, the inhibition of a component of the OGG1 pathway can be measured indirectly, for example, by measuring the expression level of one or more genes regulated by OGG1.

[0116] Examples General Synthetic Procedures In order that the application can be more fully understood, some examples are provided below. The synthetic and biological examples described in the present application are intended to illustrate the compounds, pharmaceutical compositions, and methods provided by the present application, but should not be construed to limit the scope thereof in any way.

[0117] The compounds provided by the present application can be prepared by modifications of the specific synthetic procedures described below, using readily available starting materials, as will be apparent to those skilled in the art. It should be noted that, when typical or preferred process conditions (e.g., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, they are intended to be only representative of the conditions that can be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[0118] In addition, as is well known to those skilled in the art, it can be necessary to use conventional protecting groups to prevent certain functional groups from undergoing undesirable reactions. The choice of a suitable protecting group for a particular functional group, and the appropriate conditions for protecting and deprotecting, are well known in the art. For example, a wide variety of protecting groups, and methods for their introduction and removal, are described in detail in Protecting Groups in Organic Synthesis, 2ndEdition, by Greene et al., Wiley, New York, 1991, and references cited therein.

[0119] Table 1 - Abbreviations

[0120] Routine1H NMR spectra were recorded at room temperature on a 400 MHz or 500 MHz nuclear magnetic resonance spectrometer (Agilent, Oxford or Bruker). The nuclear magnetic resonance solvents deuterated chloroform (CDCI3), deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated water (D2O) were used as received. d6) and deuterated methanol (CD3OD) were purchased from commercial suppliers and used without further purification. Spectra were processed by the software's automatic phase correction and polynomial baseline correction functions. When equal or unequal heights of two adjacent peaks were observed, the peaks could be labeled as multiplets or doublets. In the case of doublets, coupling constants could be assigned by the software. In any particular instance, one or more protons can not be observed due to obscuration by water and / or solvent peaks. Spectral data are reported as follows: chemical shift (multiplicity [singlet (s), broad singlet (bs), doublet (d), triplet (t), quartet (q), sextet (sex), multiplet (m), apparent (app), doublet of doublets (dd), doublet of doublets of doublets (ddd), triplet of doublets (dt)], coupling constant, integral). Chemical shifts are reported in ppm (δ) and coupling constants in Hz.1H resonance peaks were referenced to the solvent residual peak, specifically CDCl3(7.26 ppm), DMSO-d6(2.50 ppm), and CD3OD (3.30 ppm).

[0121] The HPLC-UV / MS instrument for product analysis included a Waters Alliance 2695 equipped with a column heater and a ZQ 4000 mass spectrometer. The mass spectrometer was equipped with an electrospray ionization (ESI) source in scan mode (100-1200 amu, source temperature: 150 °C) for positive and negative ionization. The HPLC was equipped with a Waters photodiode array detector (PDA) 2998 (detection range: 195-320 nm). The analytical method was developed on an XBridge C18 column (3.5 pm particle size, 4.6 x 30 mm) with a mobile phase of 10 mM buffer (ammonium formate pH 3.8 or ammonium bicarbonate pH 10) - A% and acetonitrile - B%. The flow rate was set to 3 mL / min, the temperature was 25 °C, and the following gradient program was used: 1) 5% B isocratic for 0.2 min, 5% to 100% B in 1.8 min linear ramp, 100% B for 1 min. Or 2) 5% B isocratic for 0.2 min, 5% to 100% B in 5.8 min linear ramp, 100% B for 1 min.

[0122] In other cases, the HPLC-UV / MS instrument used for product analysis includes an Agilent LCMS, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 pm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: from 90% [water + 10 mM ammonium bicarbonate] and 5% [acetonitrile] to 0% [water + 10 mM ammonium bicarbonate] and 100% [acetonitrile] over 6.0 minutes, followed by 2.0 minutes under these conditions, and finally a switch to 90% [water + 10 mM ammonium bicarbonate] and 5% [acetonitrile] over 0.1 minutes and 1 minute under this condition.

[0123] Preparative HPLC conditions The following describes the preparation HPLC conditions examples for purification of products. The purification process is not limited to the gradients shown in the following figures, the gradients are adjusted accordingly depending on the polarity of the resulting product.

[0124] 1.1 Chromatographic equipment Gilson pre-treatment HPLC system: GX-281 sample manager, 306 pump, 806 pressure measurement module, 811D dynamic mixer, UV / VIS-156.

[0125] 1.2 Chromatographic conditions Column: Waters X-Bridge TM Prep C18 5 pm OBD TM , 19 x 250 mm Flow rate: 20 mL / min Gradient: Table 2: Chromatographic gradient conditions

[0126] Wavelength: 214 nm and 254 nm.

[0127] The following synthesis examples are intended to illustrate the present content and should not be considered limiting of the present invention. In these examples, all fractions and percentages are by weight unless otherwise stated.

[0128] Example 1

[0129] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-(methoxymethyl)-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0130] Step 1

[0131] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-(methoxymethyl)-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a microwave tube was added (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin- 3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (50.0 mg, 84.3 µmol) and 1,4-dioxane (1.05 mL). The system was purged with nitrogen for 5 minutes, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene (9.64 mg, 16.9 µmol), bis(dibenzylideneacetone)palladium (4.85 mg, 8.43 µmol), and finally tributyl(methoxymethyl)tin (43.7 mg, 126 µmol). After the reaction was stirred at 80 °C for 16 hours, the reaction mixture was concentrated to give a crude product. The crude product was isolated and purified by C18 reverse phase column (eluent: acetonitrile / 10 mM ammonium formate solution 5% to 65%) and lyophilized to give a white powder (2.1 mg, 5.5% yield). LCMS ESI m / z 452.3 [M+H] + . 1 H NMR (400 MHz, dmso) δ 9.71 (s, 1H), 7.92 (s,1H), 7.29 (d, J = 1.7 Hz, 1H), 7.11 (dd, J = 8.0, 1.8 Hz, 1H), 7.00 (dd, J = 14.9, 7.9 Hz, 2H), 6.71 (d, J = 7.7 Hz, 1H), 4.41 (s, 2H), 4.24 (s, 2H), 4.23– 4.13 (m, 1H), 3.75 (s, 3H), 3.25 (s, 3H), 2.69 – 2.61 (m, 1H), 2.16 (s,3H), 2.15 – 2.10 (m, 2H), 2.08 (s, 3H), 2.06 – 1.95 (m, 2H), 1.73 – 1.60 (m,2H), 1.52 – 1.41 (m, 2H).

[0132] Example 2

[0133] (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0134] Step 1

[0135] ((1s,4s)-4-((3 - cyano - 4 - methoxyphenyl) carbamoyl) cyclohexyl) carbamic acid tert-butyl ester To cis-4-(Boc-amino)cyclohexanecarboxylic acid (1.02 g, 4.11 mmol) and 3-bromo-4-methoxyaniline (892 mg, 4.19 mmol) in N,N-dimethylformamide (8.22 mL) was added diisopropylethylamine (1.52 mL, 8.63 mmol), N,N-dimethylaminopyridine (10.2 mg, 82.2 µmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (644 mg, 1.64 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed sequentially with 1 M aqueous hydrochloric acid, saturated sodium bicarbonate solution and saturated brine. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by separation on a normal phase column (25 g, mobile phase: methanol / dichloromethane 0 to 15%) to give a white solid (0.717 g, 41% yield). LCMS ESI m / z 326.9, 328.9 [M+H] + .

[0136] Step 2

[0137] ((1s,4s)-4-((3 - cyano - 4 - methoxyphenyl) carbamoyl) cyclohexyl) carbamic acid tert-butyl ester [To a microwave tube was added 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (165 mg, 336 µmol), tris(dibenzylideneacetone)dipalladium(0) (154 mg, 168 µmol), zinc powder (11.0 mg, 168 µmol), zinc cyanide (207 mg, 1.76 mmol), tert-butyl ((1s,4s)-4-((3-bromo-4-methoxyphenyl)carbamoyl)cyclohexyl)carbamate (717 mg, 1.68 mmol) after sealing, the reaction system was replaced with nitrogen for 3 times. Meanwhile, N,N-dimethylacetamide (8.39 mL) was aerated with nitrogen flow in the solvent for 15 minutes before adding to the reaction, the reaction mixture was heated and stirred at 100 °C for 1.5 hours. The reaction mixture was cooled to room temperature, and filtered with diatomite. The filtrate was diluted with saturated sodium bicarbonate solution, and extracted with ethyl acetate for 3 times. The organic phase was combined, washed with water, saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated to give the crude product. The crude product was purified by silica gel column (50 g, mobile phase: ethyl acetate / n-hexane 40% to 100%) to give tert-butyl ((1s,4s)-4-((3-cyano-4-methoxyphenyl)carbamoyl)cyclohexyl)carbamate (515 mg, yield 82%) as a white solid. LCMS ESI m / z 274.0 [M+H] + .

[0138] Step 3

[0139] (1s,4s)-4-Amino-N-(3-cyano-4-methoxyphenyl)cyclohexanecarboxamide Tert-butyl ((1s,4s)-4-((3-cyano-4-methoxyphenyl)carbamoyl)cyclohexyl)carbamate (515 mg, 1.38 mmol) was dissolved in dichloromethane (500 μL), to which was added trifluoroacetic acid (500 μL, 6.52 mmol), the reaction mixture was stirred at room temperature for 3 hours, then the reaction mixture was concentrated, to which was added saturated sodium bicarbonate solution, extracted with ethyl acetate for 3 times, the combined organic phase was washed with saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to give (1s,4s)-4-amino-N-(3-cyano-4-methoxyphenyl)cyclohexanecarboxamide (244 mg, yield 65%) as a light orange solid. LCMS ESI m / z 274.0 [M+H] + .

[0140] Step 4

[0141] 3-methoxy-6-methyl-2-nitrobenzaldehyde Fuming nitric acid (5.40 mL, 106 mmol) and nitric acid (1.52 mL, 23.1 mmol) were added to a flask at 0 °C, after the internal temperature of the mixture was reduced to -10 °C, 5-methoxy-2-methylbenzaldehyde (2.00 g, 12.9 mmol) was slowly added to the mixture, keeping the reaction temperature no more than 0 °C during the process. After the reaction mixture was reacted at -10 to 0 °C for 30 minutes, ice was added to quench the reaction until the ice melted. The crude product was filtered and washed with cold water. The crude product was separated and purified using a normal phase column (25 g, mobile phase, ethyl acetate / heptane 0% to 20%) to obtain 3-methoxy-6-methyl-2-nitrobenzaldehyde (0.582 g, yield 23%) as a yellow powder.1H NMR (400 MHz, CDCl3) d 10.21 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H), 2.60 (s, 3H). J = 8.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H), 2.60 (s, 3H).

[0142] Step 5

[0143] (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-((3-methoxy-6-methyl-2-nitrobenzyl)amino)cyclohexanecarboxamide To a flask was added 3-methoxy-6-methyl-2-nitrobenzaldehyde (90.0 mg, 461 µmol), 1,2-dichloroethane (2.31 mL), (1s,4s)-4-amino-N-(3-cyano-4-methoxyphenyl)cyclohexanecarboxamide (126 mg, 461 µmol) and acetic acid (2.65 µL, 46.1 µmol). The reaction mixture was heated at 50 °C overnight, the reaction was cooled to 0 °C, sodium borohydride (21.9 mg, 576 µmol) was added to the reaction mixture at 0 °C, stirred for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction, extracted with ethyl acetate for 3 times, the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was separated and purified using a normal phase column (10 g, mobile phase: methanol / dichloromethane 0% to 15%) to obtain (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-((3-methoxy-6-methyl-2-nitrobenzyl)amino)cyclohexanecarboxamide (94.2 mg, yield 46%) as a white powder. LCMS ESI m / z 453.3 [M+H]+ .

[0144] Step 6

[0145] (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a solution of (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-((3-methoxy-6-methyl-2- nitrobenzyl)amino)cyclohexanecarboxamide (94.2 mg, 208 µmol) in methanol (2.22 mL) was added zinc powder (54.5 mg, 833 µmol) and ammonium chloride (44.5 mg, 833 µmol), the reaction mixture was heated at 60 ℃ for 2 hours, then the reaction mixture was cooled, filtered with celite and concentrated under reduced pressure to give a crude product. The crude product was dissolved in dichloromethane (2.22 mL), cooled to 0 ℃, then triethylamine (58.3 µL, 416 µmol), triphosgene (25.2 mg, 83.3 µmol) were added, the reaction was stirred at 0 ℃ for 1 hour, then the reaction was quenched with water and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by reverse phase column (C18, 10 g, eluent: acetonitrile / 10 mM aqueous ammonium formate 0% to 70%) to give a light yellow solid (15.2 mg, yield 16%). LCMS ESI m / z 449.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.99 (d, J = 2.6 Hz, 1H), 7.78(dd, J = 9.2, 2.6 Hz, 1H), 7.74 (s, 1H), 7.23 (d, J = 9.3 Hz, 1H), 6.78 – 6.65(m, 2H), 4.21 (s, 2H), 4.21 – 4.15 (m, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 2.72– 2.58 (m, 1H), 2.18 – 2.06 (m, 5H), 2.06 – 1.90 (m, 2H), 1.75 – 1.60 (m,2H), 1.52 – 1.41 (m, 2H).

[0146] Example 3

[0147] (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0148] Step 1

[0149] (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide Following the procedure described in Example 2, operating with the appropriate adaptations, using 3-chloro-4-methoxyaniline instead of 3-bromo-4- methoxyaniline, (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl- 2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide was obtained as a white solid (43 mg, yield 36%). LCMS ES Im / z: 458.4 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.74 (s, 1H), 7.45 (dd, J = 8.9, 2.3 Hz, 1H), 7.10 (d, J = 8.9 Hz,1H), 6.68 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.25 - 4.15 (m, 3H), 3.81 (s, 3H), 3.74 (s, 3H), 2.64 (s, 1H), 2.19 - 2.06 (m, 5H), 2.06 - 1.92 (m, 2H), 1.73 - 1.61 (m, 2H), 1.52 - 1.40 (m, 2H).

[0150] Example 4:

[0151] (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0152] Steps 1-5

[0153] (1s,4s)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide Proceeding as described in Example 2, and making appropriate adjustments as needed, replacing 3-bromo-4-methoxyaniline with 3-methyl-4-methoxyaniline, resulted in white solid ((1s,4s)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (23.4 mg, 14% yield). LCMS ESI m / z: 438.4 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.73(s, 1H), 7.42 – 7.31 (m, 2H), 6.89 – 6.81 (m, 1H), 6.79 – 6.65 (m, 2H), 4.21(s, 2H), 4.21 – 4.15 (m, 1H), 3.74 (d, J = 1.7 Hz, 6H), 2.66 – 2.57 (m, 1H),2.10 (d, J = 2.3 Hz, 8H), 2.07 – 1.91 (m, 2H), 1.74 – 1.56 (m, 2H), 1.53 –1.39 (m, 2H).

[0154] Example 5

[0155] (1s,4s)-4-(8-(dimethylphosphoryl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide

[0156] Step 1

[0157] (1s,4s)-4-(8-(dimethylphosphoryl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (50.0 mg, 84.3 µmol) and N,N-dimethylformamide (1.69 mL) were mixed and purged with nitrogen for 5 minutes. To the mixture was added palladium acetate (2.84 mg, 12.6 µmol), dimethylphosphine oxide (7.96 mg, 96.9 µmol), 1,3-bis(diphenylphosphino)propane (5.38 mg, 12.6 µmol) and diisopropylethylamine (73.4 µL, 421 µmol) sequentially. After the reaction mixture was heated and stirred at 100 °C for 16 hours, the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate three times, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was separated and purified by a reverse phase column (10 g, C18, mobile phase: 10 mM ammonium formate in water / acetonitrile 0 to 80%) to give a light yellow powder (8.49 mg, yield 21%) after lyophilization. LCMS ESI m / z: 484.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.12 (s, 1H), 9.71 (s, 1H), 8.32 (s, 1H), 7.31 – 7.22 (m,2H), 7.11 (dd, J = 8.1, 1.8 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 6.2Hz, 1H), 4.24 (s, 2H), 4.18 (ddd, J = 12.0, 7.6, 3.1 Hz, 1H), 3.75 (s, 3H),2.65 (s, 1H), 2.20 (s, 3H), 2.16 – 2.09 (m, 2H), 2.08 (s, 3H), 2.06 – 1.94(m, 2H), 1.78 – 1.68 (m, 6H), 1.68 – 1.60 (m, 1H), 1.51 – 1.41 (m, 2H).

[0158] Example 6 and Example 7

[0159] (1r,4r)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide and (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide

[0160] Step 1

[0161] (1s,4s)-Ethyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate Cis-4-(Boc-amino)cyclohexanecarboxylic acid (5.00 g, 20.1 mmol) was dissolved in N,N-dimethylformamide (50.3 mL), to which potassium carbonate (4.18 g, 30.2 mmol) and iodoethane (1.65 mL, 20.1 mmol) were added. After the reaction was stirred at room temperature for 16 hours, water was added thereto, and extracted with ethyl acetate 3 times, and the organic phase was combined, washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (70 g column, mobile phase: ethyl acetate / n-hexane 5% to 60%) to obtain (1s,4s)-ethyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (5.73 g, yield 105%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.62 – 4.51 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.70 – 3.58 (m, 1H), 2.43 (tt, J = 7.7, 4.0 Hz, 1H), 1.89 –1.78 (m, 2H), 1.76 – 1.63 (m, 4H), 1.60 – 1.56 (m, 1H), 1.43 (s, 9H), 1.25(t, J = 7.1 Hz, 3H)。

[0162] Step 2

[0163] Cis and trans ethyl 4-((tert-butoxycarbonyl)amino)-1-methylcyclohexanecarboxylate Diisopropylamine (389 μL, 2.78 mmol) was dissolved in tetrahydrofuran (2.4 mL) and cooled to 0 °C under nitrogen protection, then n-butyllithium (1.11 mL, 2.78 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 15 minutes, then cooled to -78 °C, and (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid ethyl ester dissolved in tetrahydrofuran (1.5 mL) was added dropwise. The reaction mixture was warmed to -30 °C and stirred for 30 minutes. Ethylene glycol dimethyl ether (2.5 mL) was added, and the reaction mixture was stirred at -60 °C for 45 minutes. Methyl iodide (76.8 μL, 1.22 mmol) dissolved in tetrahydrofuran (200 μL) was added dropwise, and the reaction mixture was stirred at -60 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution, the pH was adjusted to 6 with 1 N hydrochloric acid, and extracted twice with ethyl acetate (30 mL). The organic phase was washed with water (20 mL), saturated brine (15 mL) twice, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (25 g column, mobile phase: ethyl acetate / n-hexane 5% to 60%) to obtain 4-((tert-butoxycarbonyl)amino)-1-methylcyclohexanecarboxylic acid ethyl ester (265 mg, yield 84%) as a light yellow oil. The product was separated as an inseparable mixture of corresponding isomers. LCMS ESI m / z 186.2 [M+H-Boc] + .

[0164] Step 3

[0165] 4-amino-1-methylcyclohexanecarboxylic acid ethyl ester To a solution of 4-((tert-butoxycarbonyl)amino)-1-methylcyclohexanecarboxylic acid ethyl ester (2.54 g, 8.90 mmol) in dichloromethane (3 mL) was added hydrochloric acid (2.70 mL, 89.0 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was stirred in methyl tert-butyl ether for 30 minutes, and a white solid was filtered. The filtered solid was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain cis- and trans-4-amino-1-methylcyclohexanecarboxylic acid ethyl ester (1.12 g, yield 68%) as a colorless oil. LCMS ESI m / z 186.3 [M+H] + .

[0166] Step 4

[0167] 4-((3-methoxy-6-methyl-2-nitrobenzyl)amino)-1-methylcyclohexanecarboxylic acid ethyl ester To a solution of 3-methoxy-6-methyl-2-nitrobenzaldehyde (880 mg, 4.51 mmol) and 4-amino-1-methylcyclohexanecarboxylic acid ethyl ester (1.07 mL, 4.51 mmol) in 1,2-dichloroethane (15.0 mL) was added acetic acid (430 μL, 7.48 mmol) and the reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to 0 °C and sodium borohydride (266 mg, 6.76 mmol) was added portionwise followed by dropwise addition of 15 mL of methanol. The reaction mixture was allowed to warm to room temperature over 2 hours. Upon completion of the reaction, ammonium chloride solution was added and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (80 g column, eluent: (20% methanol in dichloromethane) / dichloromethane 0% to 40%) to give 4-((3-methoxy-6-methyl-2-nitrobenzyl)amino)-1-methylcyclohexanecarboxylic acid ethyl ester (1.34 g, 82% yield) as an orange oil. LCMS ESI m / z 365.3 [M+H] + .

[0168] Step 5

[0169] 4-((2-amino-3-methoxy-6-methylbenzyl)amino)-1-methylcyclohexanecarboxylic acid ethyl ester 4-((3-methoxy-6-methyl-2-nitrobenzyl)amino)-1-methylcyclohexanecarboxylic acid ethyl ester (1.30 g, 3.57 mmol) was dissolved in dichloromethane (43.7 mL) and methanol (43.7 mL) and the mixture was cooled to 0 °C. Nickel chloride hexahydrate (87.3 mg, 367 µmol) was added followed by slow portionwise addition of sodium borohydride (422 mg, 10.7 mmol). The reaction mixture was stirred at 0 °C for 0.5 hours and the reaction mixture turned black. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with dichloromethane three times. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 4-((2-amino-3-methoxy-6-methylbenzyl)amino)-1-methylcyclohexanecarboxylic acid ethyl ester (1.20 g, 100% yield). LCMS ESI m / z 335.1 [M+H] + .

[0170] Step 6

[0171] 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxylic acid ethyl ester Ethyl 4-((2-amino-3-methoxy-6-methylbenzyl)amino)-1- methylcyclohexanecarboxylate (1.15 g, 3.44 mmol) was dissolved in dichloromethane (160 mL), to which was added triphosgene (364 mg, 1.20 mmol), followed by slow addition of triethylamine (2.89 mL, 20.6 mmol) dissolved in 0.5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After the starting material was completely converted, the reaction mixture was concentrated to give a crude product, which was separated and purified by silica gel column (50 g column, eluent: (20% methanol in dichloromethane) / dichloromethane 1% to 60%) to give 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxylic acid ethyl ester (1.00 g, yield 81%) as a light brown solid. LCMS ESI m / z 361.3 [M+H] + .

[0172] Step 7

[0173] 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxylic acid To ethyl 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxylate (1.00 g, 2.77 mmol) dissolved in tetrahydrofuran was added lithium hydroxide (5.55 mL, 5.55 mmol), and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was transferred to a microwave tube and stirred at 170 °C for 30 minutes, and repeated 2 times. After the reaction solution was cooled to room temperature, the solution was acidified with 1 M hydrochloric acid, and the target product was extracted with ethyl acetate 3 times. The organic phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxylic acid (454 mg, yield 49%) as a light yellow solid. LCMS ESI m / z 333.1 [M+H] + .

[0174] Step 8

[0175] (1r,4r)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide and (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide To 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxylic acid (114 mg, 341 µmol) and 3-chloro-4- methoxyaniline (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.00 mL) was added diisopropylethylamine (180 µL, 1.02 mmol) followed by N,N,N',N'- tetramethyl-O-(7-azabenzotriazol-1-yl)urem hexafluorophosphate (159 mg, 410 µmol). After the reaction mixture was stirred for 64 h, the reaction was diluted with 1:1 saturated aqueous ammonium chloride and water and extracted with ethyl acetate 3 times. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product which was purified by C18 reverse phase column (120 g column, mobile phase: acetonitrile / 10 mM aqueous ammonium formate pH = 3.8) 0% to 60% and lyophilized to give (1r,4r)-N-(3-chloro-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide (Example 6) as a white solid (38.7 mg, 24% yield), LCMS ESI m / z 472.4 [M+H] + . 1 H NMR (400MHz, dmso-d6) δ 9.34 (s, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.71 (s, 1H), 7.51(dd, J = 8.9, 2.5 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H),6.64 (d, J = 8.5 Hz, 1H), 4.20 – 4.13 (m, 1H), 4.12 (s, 2H), 3.80 (s, 3H),3.71 (s, 3H), 2.34 (d, J =12.8 Hz, 2H), 2.03 (s, 3H), 1.75 – 1.60 (m, 2H),1.48 (d, J = 10.1 Hz, 2H), 1.31 (t, J = 12.2 Hz, 2H), 1.17 (s, 3H) and (Example 7) white solid (57.2 mg, yield 35 %), LCMS ESI m / z 472.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.25 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.73 (s, 1H), 7.53 (dd, J = 9.0, 2.5Hz, 1H), 7.07 (d, J = 9.1 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 8.3Hz, 1H), 4.30 (s, 2H), 4.17 – 4.06 (m, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 2.15(s, 3H), 1.95 – 1.82 (m, 2H), 1.81 – 1.74 (m, 4H), 1.49 (dd, J = 11.1, 2.5 Hz,2H), 1.29 (s, 3H). Subjectively isomer (1r,4r) assigned to Example 6 and (1s,4s) to Example 7.

[0176] Example 8 and Example 9:

[0177] (1r,4r)-N-(3-cyano-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxamide and (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide

[0178] Step 1

[0179] (1r,4r)-N-(3-cyano-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide and (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide To a solution of 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxylic acid (114 mg, 341 µmol) and 5-amino-2-methoxybenzonitrile (158 mg, 1.04 mmol) in N,N-dimethylformamide (2.00 mL) was added diisopropylethylamine (180 µL, 1.02 mmol) followed by N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (159 mg, 410 µmol). The reaction was stirred for 64 h, diluted with 1:1 saturated ammonium chloride solution and water and extracted with ethyl acetate 3 times. The organic phases were combined, washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by C18 reverse phase chromatography column (80 g column, mobile phase: acetonitrile / 10 mM ammonium formate in water (pH = 3.8) 0% to 60%) and lyophilized to give (1r,4r)-N-(3-cyano-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide (Example 8) as a white solid (30.7 mg, 19% yield). LCMS ESI m / z 463.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.36 (s, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.84 (dd, J = 9.2, 2.6 Hz, 1H), 7.72 (s, 1H), 7.22 (d, J = 9.2 Hz, 1H), 6.72 (d, J = 8.3 Hz,1H), 6.64 (d, J = 8.5 Hz, 1H), 4.20 – 4.13 (m, 1H), 4.12 (s, 2H), 3.87 (s,3H), 3.71 (s, 3H), 2.35 (d, J =12.9 Hz, 2H), 2.03 (s, 3H), 1.68 (q, J = 12.2Hz, 2H), 1.48 (d, J = 10.5 Hz, 2H), 1.32 (t, J = 12.0 Hz (2H), 1.17 (s, 3H) and white solid formate (1S,4S)-N-(3-cyano-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexaneformamide (Example 9) (85.4 mg, yield 54%) LCMS ESIm / z 463.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.85 (dd, J = 9.2, 2.6 Hz, 1H), 7.73 (s, 1H), 7.20 (d, J = 9.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 4.31 (s, 2H), 4.12 (tt, J = 11.8, 3.6 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 2.15 (s, 3H), 1.97 – 1.82 (m, 2H), 1.81 – 1.74 (m, 4H), 1.55 – 1.46 (m, 2H), 1.30 (s, 3H). (1r, 4r) was arbitrarily assigned to Example 8, and (1s, 4s) was arbitrarily assigned to Example 9.

[0180] Examples 10 and 11:

[0181] (1r,4r)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexaneformamide and (1s,4s)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexaneformamide

[0182] Step 1

[0183] (1r,4r)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide and (1s,4s)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide To 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1- methylcyclohexanecarboxylic acid (114 mg, 341 µmol) and 4-methoxy-3- methylbenzenamine (143 mg, 1.02 mmol) in N,N-dimethylformamide (2.00 mL) was added diisopropylethylamine (180 µL, 1.02 mmol) and finally N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urem hexafluorophosphate (159 mg, 410 µmol). After the reaction mixture was stirred for 64 h, the reaction was diluted with 1:1 saturated NH4Cl and water and extracted with ethyl acetate 3 times. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by C18 reverse phase chromatography column (80 g column, mobile phase: acetonitrile / 10 mM ammonium formate in water (pH = 3.8) 0% to 60%) and lyophilized to give (1r,4r)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide (Example 10) as a white solid (52.4 mg, 34% yield); off-white solid LCMS ESI m / z 452.4 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 7.72 (s, 1H), 7.41 – 7.34 (m,2H), 6.82 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.67 (d, J =8.3 Hz,1H), 4.30 (s, 2H), 4.17 – 4.06 (m, 1H), 3.72 (s, 6H), 2.14 (s, 3H), 2.10 (s,3H), 1.95 – 1.81 (m, 2H), 1.81 – 1.74 (m, 4H), 1.49 (d, J = 8.9 Hz (2H), 1.28 s (3H); and (1s,4s)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexaneformamide (Example 11) (29.9 mg, yield 19%) LCMS ESI m / z 452.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.14 (s, 1H), 7.71 (s, 1H), 7.38 –7.31 (m, 2H), 6.85 (d, J = 9.4 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.22 – 4.13 (m, 1H), 4.12 (s, 2H), 3.73 (s, 3H), 3.71 (s, 3H), 2.35 (d, J = 12.8 Hz, 2H), 2.11 (s, 3H), 2.03 (s, 3H), 1.76 – 1.61 (m, 2H), 1.47 (d, J = 10.2 Hz (2H), 1.35 – 1.22 (m, 2H), 1.16 (s, 3H). (1r, 4r) is arbitrarily assigned to Example 10, and (1s, 4s) is arbitrarily assigned to Example 11.

[0184] Examples 12 and 13:

[0185] (1r,4r)-N-(3-methoxy-4-methylphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide and (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide

[0186] Step 1

[0187] (1r,4r)-N-(3-methoxy-4-methylphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide and (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-methoxy-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide To a solution of 4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)- 1-methylcyclohexanecarboxylic acid (114 mg, 341 µmol) and 4-methyl-3- methoxyaniline (143 mg, 1.02 mmol) in N,N-dimethylformamide (2.00 mL) was added diisopropylethylamine (180 µL, 1.02 mmol) followed by N,N,N',N'- tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (159 mg, 410 µmol). The reaction mixture was stirred for 64 h. The reaction mixture was diluted with 1:1 saturated ammonium chloride and water and extracted with ethyl acetate 3 times. The organic phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by C18 reverse phase column (80 g column, mobile phase: acetonitrile / 10 mM aqueous ammonium formate (pH = 3.8) 0% to 60%) and the purified fractions were directly lyophilized to give (1r,4r)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide (Example 12) as a off-white solid (20.8 mg, 13% yield). LCMS ESI m / z 452.4 [M+H] + ;1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.73 (s, 1H), 7.33 (d, J =1.7 Hz,1H), 7.17 (dd, J = 8.1, 1.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.3Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.31 (s, 2H), 4.13 (tt, J = 12.0, 3.7 Hz,1H), 3.73 (s, 3H), 3.72 (s, 3H), 2.15 (s, 3H), 2.06 (s, 3H), 1.95 – 1.83 (m,2H), 1.82 – 1.75 (m, 4H), 1.50 (dd, J = 11.8, 2.9 Hz, 2H), 1.30 (s, 3H); white solid (1s,4s)-N-(3-methyl-4-methoxyphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-1-methylcyclohexanecarboxamide (Example 13) (33.1 mg, yield 21 %) LCMS ESI m / z 452.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.72 (s, 1H), 7.29 (d, J = 1.7Hz, 1H), 7.17 (dd, J = 8.0, 1.8 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 4.17 (tt, J = 12.3, 3.3 Hz, 1H), 4.12(s, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 2.37 (d, J = 12.7 Hz, 2H), 2.07 (s, 3H),2.02 (s, 3H), 1.68 (qd, J = 13.1, 2.0 Hz, 2H), 1.48 (dd, J = 11.4, 1.8 Hz, 2H),1.35 – 1.26 (m, 2H), 1.18 (s, 3H).

[0188] Example 14 and Example 15:

[0189] (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide and (1s,4s)-N-(4-methoxyphenyl)-4-(5- methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide

[0190] Step 1

[0191] Methyl 2,6-dichloro-4-methylnicotinate Methyl 2,6-dichloro-4-methylnicotinate (2.00 g, 9.71 mmol) was dissolved in N,N- dimethylformamide (24.3 mL), to which potassium carbonate (2.01 g, 14.6 mmol) and iodomethane (610 μL, 9.71 mmol) were added. The reaction was stirred at room temperature for 1 hour, to which water was added and extracted with ethyl acetate three times. The organic phases were combined, washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (70 g column, mobile phase, ethyl acetate / n-hexane 5% to 60%) to give methyl 2,6-dichloro-4-methylnicotinate (2.13 g, yield 100%) as a white solid. LCMS ES Im / z 220.0 [M+H] + .

[0192] Step 2

[0193] Methyl 6-chloro-2-((4-methoxybenzyl)amino)-4-methylnicotinate Methyl 2,6-dichloro-4-methylnicotinate (825 mg, 3.75 mmol) was added to acetonitrile (7.50 mL), the reaction was cooled to 0 °C, then diisopropylethylamine (1.90 mL, 10.8 mmol) and 4-methoxyphenethylamine (500 μL, 3.75 mmol) were added, the reaction was stirred at 0 °C for 10 min, then the temperature was raised to 90 °C and stirring was continued for 16 h. After the reaction was terminated, the reaction was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column (50 g column, mobile phase, ethyl acetate / n-hexane 0% to 45%) to give methyl 6-chloro-2-((4-methoxybenzyl)amino)-4-methylnicotinate (1.01 g, 84% yield) as a white solid. LCMS ESI m / z 320.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H),7.29 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.40 (s, 1H), 4.59 (s, 2H),3.84 (s, 3H), 3.79 (s, 3H), 2.42 (s, 3H)。

[0194] Step 3

[0195] (6-chloro-2-((4-methoxybenzyl)amino)-4-methylpyridin-3-yl)methanol A solution of methyl 6-chloro-2-((4-methoxybenzyl)amino)-4-methylnicotinate (641 mg, 2.00 mmol) in dichloromethane (9.99 mL) was cooled to -78 °C, then a 1M solution of diisobutylaluminum hydride (4.00 mL, 4.00 mmol) was added slowly dropwise under nitrogen protection. The reaction was stirred at -78 °C for 2 h. To the reaction was added 1M hydrochloric acid at -78 °C, then the reaction mixture was allowed to warm up to room temperature slowly. The reaction was extracted with dichloromethane twice, then extracted with a chloroform solution containing 20% isopropanol once. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by silica gel column (50 g column, eluent: ethyl acetate / n-hexane 30% to 80%) to give (6-chloro-2-((4-methoxybenzyl)amino)-4-methylpyridin-3-yl)methanol (451 mg, 80% yield) as a white solid. LCMS ESI m / z 292.9 [M+H] + .

[0196] Step 4

[0197] 6-chloro-2-((4-methoxybenzyl)amino)-4-methylnicotinaldehyde (6-chloro-2-((4-methoxybenzyl)amino)-4-methylpyridin-3-yl)methanol (430 mg, 1.47 mmol) was dissolved in dichloromethane (7.34 mL), to which activated manganese dioxide (709 mg, 7.34 mmol) was added, after the reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was filtered with diatomite, the filter cake was rinsed with dichloromethane, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (50 g column, mobile phase, ethyl acetate / n-hexane 5% to 60%) to obtain 6-chloro-2-((4-methoxybenzyl)amino)-4-methylnicotinaldehyde (293 mg, yield 69%) as a light yellow solid. LCMS ESI m / z 290.9 [M+H] + .

[0198] Step 5

[0199] (1s,4s)-4-(((6-chloro-2-((4-methoxybenzyl)amino)-4-methylpyridin-3-yl)methyl)amino)-N-(3-chloro-4-methoxyphenyl)cyclohexanecarboxamide 6-chloro-2-((4-methoxybenzyl)amino)-4-methylnicotinaldehyde (225 mg, 774 µmol) and (1s,4s)-4-amino-N-(3-chloro-4-methoxyphenyl)cyclohexanecarboxamide (225 mg, 797 µmol) were placed in a flask, to which 1,2-dichloroethane (5.16 mL) was added, followed by the addition of one drop of acetic acid. After the reaction solution was stirred at 50 °C for 16 hours, sodium triacetoxyborohydride (490 mg, 2.32 mmol) was added at once. The reaction solution was stirred at 50 °C for 16 hours. After methanol was added to the reaction solution, stirring was continued at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (mobile phase: (20% methanol in dichloromethane) / dichloromethane 1% to 60%) to obtain (1s,4s)-4-(((6-chloro-2-((4-methoxybenzyl)amino)-4-methylpyridin-3-yl)methyl)amino)-N-(3-chloro-4-methoxyphenyl)cyclohexanecarboxamide (255 mg, yield 59%) as a light yellow solid. LCMS ESI m / z 556.9, 558.8 [M+H] + .

[0200] Step 6

[0201] (1s,4s)-4-(((2-amino-6-chloro-4-methylpyridin-3-yl)methyl)amino)-N-(3-chloro-4- methoxyphenyl)cyclohexanecarboxamide To a reaction flask containing (1s,4s)-4-(((6-chloro-2-((4-methoxybenzyl)amino)-4- methylpyridin-3-yl)methyl)amino)-N-(3-chloro-4-methoxyphenyl)cyclohexanecarboxamide (160 mg, 287 µmol) was added trifluoroacetic acid (220 uL, 2.87 mmol) and the reaction mixture was stirred at 90 °C for 1 hour. The reaction was concentrated under reduced pressure and to this was added saturated sodium bicarbonate solution and extracted with dichloromethane 3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1s,4s)-4-(((2-amino-6-chloro-4-methylpyridin-3-yl)methyl)amino)-N-(3-chloro-4- methoxyphenyl)cyclohexanecarboxamide (121 mg, 96 % yield) as a brown solid. LCMS ESI m / z 436.8, 438.8 [M+H] + .

[0202] Step 7

[0203] (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(7-chloro-5-methyl-2-oxo-1,2-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide To a solution of (1s,4s)-4-(((2-amino-6-chloro-4-methylpyridin-3-yl)methyl)amino)-N-(3-chloro-4-methoxyphenyl)cyclohexaneformamide (121 mg, 277 µmol) in dichloromethane (12.9 mL), triphosgene (29.3 mg, 96.8 µmol) was added sequentially, followed by the slow dropwise addition of triethylamine (233 µL, 1.66 mmol) dissolved in 0.5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After complete conversion of the starting materials, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (25 g column, mobile phase: (20% methanol in dichlorohexane) / dichlorohexane 1% to 60%) to obtain a brown solid (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(7-chloro-5-methyl-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)cyclohexaneformamide (77.1 mg, 60% yield). LCMS ESI m / z 462.9, 464.9 [M+H] + .

[0204] Step 8

[0205] (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridino[2,3-d]pyrimidin-3(4H)-yl)cyclohexaneformamide and (1s,4s)-N-(4-methoxyphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridino[2,3-d]pyrimidin-3(4H)-yl)cyclohexaneformamide (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(7-chloro-5-methyl-2-oxo- 1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide (77.1 mg, 166 µmol) was dissolved in methanol (7.74 mL), purged with nitrogen, and then 10% palladium on carbon (17.7 mg, 16.6 µmol) was added. The reaction flask was purged with hydrogen and stirred at room temperature for 16 hours. The reaction mixture was purged with nitrogen, filtered through celite, and concentrated under reduced pressure to give a crude product. The crude product was purified by separation on a C18 column (30 g column, mobile phase: acetonitrile / 10 mM aqueous ammonium formate, 2% to 60%, pH = 3.8) and directly lyophilized to give (1s,4s)-N-(3-chloro-4-methoxyphenyl)-4-(5-methyl-2-oxo- 1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide (Example 14) as a white solid (11.7 mg, 16% yield). LCMS ESI m / z 429.4 [M+H] + . 1 HNMR (400 MHz, dmso-d6) δ 9.78 (s, 1H), 9.43 (s, 1H), 7.88 (d, J = 4.8 Hz, 1H),7.83 – 7.77 (m, 1H), 7.43 (dt, J = 8.9, 2.2 Hz, 1H), 7.08 (dd, J = 9.1, 1.9 Hz,1H), 6.73 (d, J = 5.0 Hz, 1H), 4.25 (s, 2H), 4.23 – 4.13 (m, 1H), 3.79 (s,3H), 2.64 – 2.59 (m, 1H), 2.16 (s, 3H), 2.14 – 2.04 (m, 2H), 1.98 (q, J = 11.3Hz, 2H), 1.65 (t, J = 12.9 Hz, 2H), 1.45 (d, J = 10.9 Hz, 2H); white solid (1s,4s)-N-(4-methoxyphenyl)-4-(5-methyl-2-oxo- 1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide (Example 15) (15.3 mg, 23% yield). LCMS ESI m / z 395.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d 6) δ 9.62 (s, 1H), 9.43 (s, 1H), 7.88 (d, J = 5.1 Hz, 1H), 7.50 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 6.73 (d, J = 5.2 Hz, 1H), 4.24 (s, 2H),4.18 (tt, J = 11.9, 3.5 Hz, 1H), 3.69 (s, 3H), 2.64 – 2.58 (m, 1H), 2.15 (s,3H), 2.10 (d, J = 13.2 Hz, 2H), 2.05 – 1.93 (m, 2H), 1.69 – 1.58 (m, 2H), 1.44(d, J = 9.5 Hz, 2H)。

[0206] Preparation of common intermediate (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide

[0207] (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide

[0208] Step 1

[0209] (1s,4s)-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid Dissolve 4-aminocyclohexanecarboxylic acid (90 g, 630 mmol) in acetonitrile (900 mL) and water (900 mL), to which tert-butyloxycarbonyl tert-butyl carbonate (137 g, 629 mmol) and triethylamine (64 g, 630 mmol, 88 mL) are added, and the reaction solution is stirred at 25 °C for 16 hours. The reaction solution is concentrated under reduced pressure, acidified with 1M aqueous hydrochloric acid solution to pH 5-6, and then extracted with dichloromethane (200 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain (1s,4s)-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (120 g, 493 mmol) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (s,1H), 6.72 (d, J= 6.2 Hz, 1H), 3.33 - 3.08 (m, 1H), 2.38 - 2.36 (m, 1H), 1.88- 1.83 (m, 2H), 1.58 - 1.39 (m, 6H), 1.37 (s, 9H).

[0210] Step 2

[0211] (1s,4s)-4-(3-methoxy-4-methylphenylcarbamoyl)cyclohexylcarbamate tert-butyl ester 4-(tert-Butoxycarbonylamino)cyclohexanecarboxylic acid (40 g, 160 mmol) was dissolved in N,N-dimethylformamide (200 mL), and diisopropylethylamine (63.7 g, 493 mmol, 85.9 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (75.4 g, 197 mmol) and 3-methoxy-4-methylaniline (27.1 g, 197 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ethyl acetate (300 mL), the organic phase was washed three times with water (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (mobile phase: ethyl acetate / n-hexane 5–10%) to give a white solid (1s,4s)-4-(3-methoxy-4-methylphenylcarbamoyl)cyclohexylcarbamate tert-butyl ester (53.3 g, 147 mmol). LCMS ESI m / z: 307.2 [M+H-56] + .

[0212] Step 3

[0213] (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(3-methoxy-4-methylphenylcarbamoyl)cyclohexylcarbamate tert-butyl ester (80 g, 220 mmol) was dissolved in dichloromethane (78 mL), and trifluoroacetic acid (33.8 g, 297 mmol, 22.9 mL) was added. The resulting mixture was stirred at 25 °C for 16 hours. The reaction was adjusted to pH 7–8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (100 mL × 3). The organic extract was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (50 g, 190 mmol) as a pale yellow solid. LCMS ESI m / z: 263.2 [M+H] + The product was used directly in subsequent steps without further purification. 1 HNMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.14 – 6.94(m, 2H), 3.74 (s, 3H), 3.28 – 3.08 (m, 1H), 2.54 – 2.52 (m, 1H), 2.08 (s, 3H), 1.98 – 1.88 (m, 2H), 1.86 – 1.56 (m, 6H).

[0214] Example 16:

[0215] (1s,4s)-N-(4-methoxy-3-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridino[2,3-d]pyrimidin-3(4H)-yl)cyclohexaneformamide

[0216] Step 1

[0217] (1s,4s)-4-(((6-chloro-2-((4-methoxybenzyl)amino)-4-methylpyridin-3-yl)methyl)amino)-N-(4-methoxy-3-methylphenyl)cyclohexaneformamide (1s,4s)-4-( ((6-chloro-2-((4-methoxybenzyl)amino)-4-methylpyridin-3-yl)methyl)amino)-N-(4-methoxy-3-methylphenyl)cyclohexanecarboxamide (114 mg, yield 62%) was obtained as a purple solid. LCMS ESI m / z 537.2 [M+H] + .

[0218] Step 2

[0219] (1s,4s)-4-(7-chloro-1-(4-methoxybenzyl)-5-methyl-2-oxo-1,2-dihydropyridino[2,3-d]pyrimidin-3(4H)-yl)-N-(4-methoxy-3-methylphenyl)cyclohexanecarboxamide (1s,4s)-4-( ((6-chloro-2-((4-methoxybenzyl)amino)-4-methylpyridin-3-yl)methyl)amino)-N-(4-methoxy-3-methylphenyl)cyclohexanecarboxamide (114 mg, yield 62%) was obtained as a purple solid. LCMS ESI m / z 537.2 [M+H] + .

[0220] Step 3

[0221] (1s,4s)-N-(4-methoxy-3-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyrido[2,3- d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide To a solution of (1s,4s)-4-(7-chloro-1-(4-methoxybenzyl)-5-methyl-2-oxo-1,2- dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)-N-(4-methoxy-3-methylphenyl)cyclohexanecarboxamide (35.0 mg, 62.2 µmol) in methanol (3.5 mL) under nitrogen atmosphere was added palladium on carbon (7.01 mg, 6.59 µmol) (Pd 10% wt / C) followed by hydrogenation of the reaction vessel and stirring under hydrogen atmosphere (1 atm) at room temperature for 1 day. After purging the reaction with nitrogen, it was filtered through celite. The crude was concentrated under reduced pressure. The crude was separated and purified by reverse phase C18 column (30 g column, mobile phase: acetonitrile / 10 mM ammonium formate in water, 2% to 60%, pH=3.8) and directly lyophilized to give (1s,4s)-N-(4-methoxy-3-methylphenyl)-4-(5-methyl-2-oxo-1,2- dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide as a white solid (2.89 mg, yield 11%). LCMS ESI m / z 409.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.54(s, 1H), 9.44 (s, 1H), 7.88 (d, J = 5.1 Hz, 1H), 7.36 (s, 1H), 7.37 – 7.33 (m,1H), 6.83 (d, J = 9.1 Hz, 1H), 6.73 (d, J = 5.3 Hz, 1H), 4.24 (s, 2H), 4.22 –4.14 (m, 1H), 3.72 (s, 3H), 2.63 – 2.57 (m, 1H), 2.15 (s, 3H), 2.10 (s, 3H),2.08 – 2.06 (m, 2H), 2.00 (q, J = 11.8 Hz, 2H), 1.70 – 1.55 (m, 2H), 1.43 (dd, J =11.8, 2.4 Hz, 2H).

[0222] Example 17:

[0223] (1s,4s)-4-(8-(Ethoxycarbonyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0224] Step 1

[0225] (1s,4s)-4-(8-(Ethoxycarbonyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (1s,4s)-4-(8-(Ethoxycarbonyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (64.1 mg, 103 µmol) prepared in Example 58 was dissolved in a mixture of dichloromethane (1.03 mL) and triethylamine (14.3 µL, 103 µmol) and acetyl chloride (7.46 µL, 103 µmol) was added to it at 0 °C. After the reaction mixture was reacted at 0 °C for 30 minutes, the crude reaction mixture was concentrated under reduced pressure and purified by reverse phase column (10 g, C18 column, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, 0% to 80%). The target isolated fraction was directly lyophilized to obtain the target product (12.4 mg, yield 25%) as a white powder. LCMS ESI m / z 479.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.58 (s, 1H), 8.44 (t, J = 6.2 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.08 (dd, J = 8.0, 1.7 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.92(d, J = 7.7 Hz, 1H), 6.66 (d, J =7.8 Hz, 1H), 4.17 (s, 2H), 4.16 – 4.11 (m, 1H), 4.09 (d, J = 6.2 Hz, 2H), 3.72 (s, 3H), 2.62 (s, 1H), 2.12 (s, 4H), 2.06(d, J = 6.3 Hz, 4H), 2.04 – 1.91 (m, 2H), 1.81 (s, 3H), 1.63 (t, J = 13.2 Hz,2H), 1.43 (d, J = 9.3 Hz, 2H)。

[0226] Example 18:

[0227] (1s,4s)-N-(3-ethoxy-4-methyIphenyl)-4-(5-methyl-8-(methylsulfonamidomethyl)- 2-oxo- 1,2-dihydropyrido [3,4-d] pyrimidin-3(4H)-yl)cyclohexanecarboxamide oxamide

[0228] Step 1

[0229] (1s,4s)-N-(3-ethoxy-4-methyIphenyl)-4-(5-methyl-8-(methylsulfonamidomethyl)- 2-oxo- 1,2-dihydropyrido [3,4-d] pyrimidin-3(4H)-yl)cyclohexanecarboxamide oxamide (1s,4s)-4-(8-(Aminomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4- d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 20 (26.0 mg, 59.4 µmol) was dissolved in dichloromethane (432 uL) to which was added triethylamine (9.06 uL, 178 µmol) and methanesulfonyl chloride (4.69 uL, 59.4 µmol) and the reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and directly loaded onto a C18 column for reverse phase chromatography (30 g, mobile phase: acetonitrile / 10 mM ammonium formate in water, 2% to 60%, pH = 3.8. After purification, the fractions were directly lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-8-(methylsulfonamidomethyl)-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide oxime as a white solid (3.78 mg, 12% yield). LCMS ESI m / z 516.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6)δ 9.69 (s, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.32 (t, J = 5.9 Hz,1H), 7.26 (d, J = 1.7 Hz, 1H), 7.08 (dd, J = 8.0, 1.8 Hz, 1H), 6.99 (d, J = 8.2Hz, 1H), 4.26 (s, 2H), 4.20 (d, J = 6.1 Hz, 2H), 4.17 – 4.13 (m, 1H), 3.72 (s,3H), 2.88 (s, 3H), 2.65 – 2.60 (m, 1H), 2.13 (s, 3H), 2.11 – 2.06 (m, 2H),2.05 (s, 3H), 2.03 – 1.91 (m, 2H), 1.70 – 1.57 (m, 2H), 1.44 (dd, J = 11.6,1.7 Hz, 2H)。

[0230] Example 19:

[0231] 1s,4s)-4-(8-(acetamidomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0232] Step 1

[0233] (1s,4s)-4-(8-(acetamidomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide The (1s,4s)-4-(8-(aminomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (26.0 mg, 59.4 µmol) prepared in Example 20 was dissolved in dichloromethane (432 μL), and triethylamine (9.06 μL, 178 µmol) and acetic anhydride (6.29 μL, 66.6 µmol) were added to it. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and then directly loaded onto a C18 column. Separation was performed by reversed-phase chromatography (30 g, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, 2% to 60%, pH=3.8). The purified fraction was directly lyophilized to give a white solid (1S,4S)-4-(8-(acetamidomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (8.27 mg, yield 29%). LCMS ESI m / z 480.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.68(s, 1H), 8.82 (s, 1H), 8.68 (t, J = 6.2 Hz, 1H), 7.84 (s, 1H), 7.26 (d, J = 1.6Hz, 1H), 7.08 (dd, J = 8.1, 1.7 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 4.23 (s,2H), 4.22 (d, J =6.6 Hz, 2H), 4.19 – 4.10 (m, 1H), 3.72 (s, 3H), 2.65 – 2.59 (m, 1H), 2.11 (s, 3H), 2.10 – 2.06 (m, 2H), 2.05 (s, 3H), 2.02 – 1.89 (m, 2H), 1.82 (s, 3H), 1.69 – 1.56 (m, 2H), 1.47 – 1.37 (m, 2H).

[0234] Example 20:

[0235] (1s,4s)-4-(8-(Aminomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide

[0236] Step 1

[0237] (2-Chloro-5-methylpyridin-3-yl)carbamic acid tert-butyl ester To a solution of 3-amino-2-chloro-5-methylpyridine (1.50 g, 10.3 mmol) in tetrahydrofuran (25.9 mL) was cooled to -10 °C, then lithium bis(trimethylsilyl)amide in tetrahydrofuran (22.8 mL, 22.8 mmol) was added slowly dropwise. The reaction mixture was stirred at -10 °C for 30 minutes, then di-tert-butyl dicarbonate (2.61 mL, 11.4 mmol) in tetrahydrofuran (25.9 mL) was added. The reaction mixture was stirred at -10 °C for another 30 minutes, then was allowed to warm to room temperature. After the reaction was completed, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate for 3 times. The organic phase was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel column (40 g column, mobile phase: ethyl acetate / n-hexane, 0% to 60%) to give (2-chloro-5-methylpyridin-3-yl)carbamic acid tert-butyl ester (200 mg, yield 8%) as a yellow oil. LCMS ESI m / z 242.9 [M+H] + .

[0238] Step 2

[0239] tert-Butyl (2-chloro-4-formyl-5-methylpyridin-3-yl)carbamate tert-Butyl (2-chloro-5-methylpyridin-3-yl)carbamate (400 mg, 1.65 mmol) was dissolved in tetrahydrofuran (8.24 mL), to which N,N,N',N'-tetramethyl ethylenediamine (546 μL, 3.63 mmol) was added. The reaction was purged with nitrogen and cooled to -78 °C, and n-butyllithium (1.44 mL, 3.61 mmol) was added slowly dropwise. The reaction was stirred at -35 °C for 30 minutes. Cooling was continued to -78 °C, and dimethylformamide (320 μL, 4.12 mmol) was added slowly dropwise with stirring. The reaction was stirred at -35 °C for 30 minutes and slowly warmed to room temperature. Ammonium chloride saturated solution was added to the reaction mixture, which was extracted with ethyl acetate three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column (30 g column, mobile phase: ethyl acetate / n-hexane, 0% to 70%) to give tert-butyl (2-chloro-4-formyl-5-methylpyridin-3-yl)carbamate (163 mg, 37% yield) as a yellow solid. LCMS ESI m / z 214.0 [M-tBu] + .

[0240] Step 3

[0241] tert-Butyl (2-chloro-4-((((ls,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)amino)methyl)-5-methylpyridin-3-yl)carbamate tert-Butyl (2-chloro-4-formyl-5-methylpyridin-3-yl)carbamate (163 mg, 602 µmol) and (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (160 mg, 608 µmol) were dissolved in a flask with dichloroethane (4.01 mL) and one drop of acetic acid. The reaction was stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature and sodium triacetoxyborohydride (381 mg, 1.81 mmol) was added in one portion. The reaction mixture was stirred at 23 °C for 3 hours. Methanol was added to the reaction mixture and the resulting solution was stirred at room temperature for 30 minutes and concentrated to dryness. The crude product was purified by silica gel column (25 g column, eluent: (20% methanol in dichloromethane) / dichloromethane, 1% to 60%) to give (2-chloro-4-((((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)amino)methyl)-5-methylpyridin-3-yl)carbamate as a light brown solid (270 mg, 87% yield). LCMS ESI m / z 517.0 [M+H] + .

[0242] Step 4

[0243] (1s,4s)-4-(((3-amino-2-chloro-5-methylpyridin-4-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide To (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(((3-((4-methoxybenzyl)amino)-5-methylpyridin-4-yl)methyl)amino)cyclohexanecarboxamide (250 mg, 484 µmol) in dichloromethane was added trifluoroacetic acid (37.0 uL, 484 µmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give a crude product, which was added to saturated sodium bicarbonate solution and extracted with ethyl acetate for 3 times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give (1s,4s)-4-(((3-amino-2-chloro-5-methylpyridin-4-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide as a white solid (224 mg). LCMS ESI m / z 417.2 [M+H] + .

[0244] Step 5

[0245] (1s,4s)-4-(8-chloro-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (1s,4s)-4-(((3-amino-2-chloro-5-methylpyridin-4-yl)methyl)amino)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (201 mg, 482 µmol) was dissolved in dichloromethane (22.4 mL), to which was added triphosgene (51.1 mg, 169 µmol) followed by slow dropwise addition of triethylamine (405 uL, 2.89mmol) dissolved in 0.5mL dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After complete conversion of the starting material, the reaction was concentrated to dryness under reduced pressure, and the crude product was isolated by C18 column chromatography (30 g column, mobile phase: acetonitrile / 10 mM ammonium formate in water, 2% to 60%, pH=3.8), and the purified fractions were directly lyophilized to give (1s,4s)-4-(8-chloro-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide as a white solid (198 mg, 93% yield). LCMS ESI m / z 443.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.60 (s, 1H),7.76 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.0, 1.7 Hz, 1H), 7.00(d, J = 8.3 Hz, 1H), 4.31 (s, 2H), 4.19 (tt, J = 11.9, 3.6 Hz, 1H), 3.73 (s,3H), 2.68 – 2.59 (m, 1H), 2.14 (s, 3H), 2.13 – 2.08 (m, 2H), 2.06 (s, 3H),1.99 (qd, J = 12.5, 3.3 Hz, 2H), 1.73 – 1.60 (m, 2H), 1.51 – 1.41 (m, 2H).

[0246] Step 6

[0247] (3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-d]pyrimidin-8-yl)methyl)tert-butyl carbamate Potassium (((tert-Butoxycarbonyl)amino)methyl)trifluoroborate (13.2 mg, 54.2 µmol), (1s,4s)-4-(8-chloro-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (20.0 mg, 45.2 µmol), cesium carbonate (44.1 mg, 135 µmol), water (75.3 μL), and 1,4-dioxane (376 μL) were added to the microwave tube. The microwave tube was then sealed and degassed with a nitrogen stream for 10 minutes. Finally, palladium(II) acetate (1.01 mg, 4.52 µmol) and n-butyldi(1-adamantyl)phosphine (3.41 mg, 9.03 µmol) were added to a microwave tube under a nitrogen atmosphere. The reaction mixture was sealed and stirred at 90 °C for 16 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure to obtain a white, crude solid (tert-butyl 3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-d]pyrimidin-8-yl)methyl)carbamate (24.5 mg, 101% yield) for direct use in the next reaction. LCMS ESI m / z 538.4 [M+H] + .

[0248] Step 7

[0249] (1s,4s)-4-(8-(aminomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide To a solution of (1s,4s)-4-(8-(aminomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4- d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (20.0 mg, 37.2 µmol) in dichloromethane (200 µL) was added trifluoroacetic acid (200.0 µL, 2.61 mmol), the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated to dryness under reduced pressure and directly separated by reverse phase C18 column (30 g column, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, 2% to 60%, pH=3.8), the purified component was directly lyophilized to give (1s,4s)-4-(8-(aminomethyl)-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide as a white solid (13.1 mg, yield 80%). LCMS ESI m / z 438.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.72(s, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 7.29 (d, J = 1.7 Hz, 1H), 7.12 (dd, J = 8.0, 1.9 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 4.29 (s, 2H), 4.26 – 4.16 (m, 1H),3.94 (s, 2H), 3.75 (s, 3H), 2.66 – 2.61 (m, 1H), 2.15 (s, 3H), 2.14 – 2.08(m, 2H), 2.08 (s, 3H), 2.06 – 1.94 (m, 2H), 1.72 – 1.60 (m, 2H), 1.50 – 1.41(m, 2H).

[0250] Example 21

[0251] (1s,4s)-4-(8-(2-(dimethylamino)ethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0252] Step 1

[0253] (1s,4s)-4-(8-(2-(dimethylamino)ethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide To the reaction flask containing (1s,4s)-4-(8-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 61 (25.0 mg, 44.9 µmol) was added N,N-dimethylformamide (4.49 mL) and cesium carbonate (29.5 mg, 89.7 µmol), the reaction mixture was stirred at room temperature for 2 minutes, then 2-bromo-N,N-dimethylethanamine hydrobromide (31.4 mg, 135 µmol) was added, and the reaction mixture was heated to 100 °C for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate for 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, which was separated and purified by reverse phase separation column (10 g, C18, mobile phase: acetonitrile / 10 mM aqueous ammonium formate, 2% to 60%, pH=3.8) and directly freeze-dried to obtain a light yellow solid (11.7 mg, yield 52%). LCMS ESI m / z 495.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.38 – 8.27 (m, 1H), 7.29 (s, 1H), 7.12 (d, J = 8.0 Hz,1H), 7.02 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.3 Hz,1H), 4.23 (s, 2H), 4.23 – 4.15 (m, 1H), 3.97 (t, J = 5.4 Hz, 2H), 3.75 (s,3H), 2.65 (s, J = 0.8 Hz, 1H), 2.59 (t, J =5.4 Hz, 2H), 2.26 – 2.19 (m, 6H),2.17 – 2.07 (m, 8H), 2.06 – 1.93 (m, 2H), 1.75 – 1.59 (m, 2H), 1.52 – 1.39(m, 2H).

[0254] Example 22

[0255] (1s,4s)-4-(8-cyano-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N- (3-methoxy-4-methylphenyl)cyclohexanecarboxamide

[0256] Step 1

[0257] (1s,4s)-4-(8-cyano-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N- (3-methoxy-4-methylphenyl)cyclohexanecarboxamide Into a microwave tube was added 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (22.2 mg, 45.2 µmol), tris(dibenzylideneacetone)dipalladium(0) (20.7 mg, 22.6 µmol), zinc (1.48 mg, 22.6 µmol), zinc cyanide (27.8 mg, 237 µmol), (1s,4s)-4-(8-chloro-5-methyl-2-oxo-1,2- dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (100 mg, 226 µmol), capped and purged with nitrogen, N,N-dimethylacetamide (4.52 mL) was added to the microwave tube and degassed with a stream of nitrogen for 15 minutes. The reaction was heated to 100 °C for 90 minutes, then cooled to room temperature and filtered through celite. The filtrate was diluted with saturated sodium bicarbonate solution and extracted 3 times with ethyl acetate. The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by silica gel column (25 g column, ethyl acetate / methylene chloride, 20% to 80%) to give (1s,4s)-4-(8-cyano-5-methyl-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (64.8 mg, 66% yield) as a white solid. LCMS ESI m / z 434.1 [M+H]+ . 1 H NMR (400MHz, DMSO-D6) δ 9.70 (s, 1H), 9.51 (s, 1H), 8.07 (s, 1H), 7.28 (d, J = 1.6 Hz,1H), 7.09 (dd, J = 8.1, 1.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H),4.16 (tt, J = 12.2, 3.9 Hz, 1H), 3.73 (s, 3H), 2.67 – 2.62 (m, 1H), 2.22 (s,3H), 2.11 (d, J = 13.3 Hz, 2H), 2.06 (s, 3H), 1.98 (qd, J = 12.5, 1.7 Hz, 2H),1.71 – 1.59 (m, J = 13.0 Hz, 2H), 1.46 (dd, J = 11.9, 2.6 Hz, 2H)。

[0258] Example 23

[0259] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-8-((3-methoxyethan-3-yl)methoxy)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0260] Step 1 (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-8-((3-methoxyethan-3-yl)methoxy)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a flask containing (1s,4s)-4-(8-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 61 (25.0 mg, 44.9 µmol), cesium carbonate (29.5 mg, 89.7 µmol) and N,N-dimethylformamide (449 µL) was added and stirred at room temperature for 2 minutes, then 3-(iodomethyl)-3-methyloxetane (28.5 mg, 135 µmol) was added. The reaction was stirred at 100 °C for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate for 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by reverse phase separation column (10 g C18, mobile phase: acetonitrile / 10 mM aqueous ammonium formate, 0% to 80%). The product was further separated and purified by normal phase column (10 g, mobile phase: methanol / dichloromethane, 0% to 20%) after lyophilization. Lyophilization gave a white solid powder (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-8-((3-methoxyethan-3-yl)methoxy)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (0.9 mg, yield 4%). LCMS ESI m / z 434.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.71 (s, 1H),7.79 (s, 1H), 7.29 (s, 1H), 7.10 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.79 (s,1H), 6.69 (d, J = 7.4 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 4.32 (d, J = 5.2 Hz,2H), 4.23 (s, 2H), 4.03 (s, 2H), 3.75 (s, 3H), 2.12 (s, 5H), 2.08 (s, 4H),2.04 – 1.98 (m, 2H), 1.67 (s, 2H), 1.48 (s, 2H), 1.37 (s, 3H), 1.23 (s, 2H).

[0261] Example 24

[0262] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-8-(methylsulfonamidomethyl)- 2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0263] Step 1

[0264] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-8-(methylsulfonamidomethyl)- 2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a flask containing (1s,4s)-4-(8-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin- 3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 58 (30.0 mg, 68.7 µmol) was added dichloromethane (687 µL) and triethylamine (19.3 µL, 137 µmol). The mixture was cooled to 0 °C, then methanesulfonyl chloride (6.78 µL, 85.9 µmol) was added slowly and stirred for 15 min, the reaction mixture was stirred at room temperature for 1 h. To the reaction mixture was added saturated sodium bicarbonate solution, extracted with ethyl acetate for 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude product was separated and purified by reverse phase column (10 g, C18, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, 0% to 100%), concentrated and lyophilized, further separated and purified by normal phase column (10 g, mobile phase: methanol / dichloromethane 0% to 20%), concentrated and lyophilized to give the product (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-8- (methylsulfonamidomethyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (2.91 mg, yield 8.2%). LCMS ESI m / z 515.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.09 (s, 1H), 7.38 (t, J = 6.3Hz, 1H), 7.28 (s, 1H), 7.09 (s, 1H), 7.01 (d, J = 7.9 Hz, 2H), 6.72 (d, J =8.0 Hz, 1H), 4.22 (s, 2H), 4.21 - 4.14 (m, 1H), 4.12 - 4.03 (m, 2H), 3.74 (s, 3H), 2.90 (s, 2H), 2.18 - 2.12 (m, 4H), 2.12 - 2.06 (m, 5H), 2.06 - 1.96 (m, 3H), 1.73 - 1.60 (m, 2H), 1.50 - 1.41 (m, 2H).

[0265] Example 25

[0266] (1s,4s)-4-(5,8-Dimethyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide

[0267] Step 1

[0268] (1s,4s)-4-(5,8-Dimethyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide To a flask containing (1s,4s)-4-(8-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)- N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 59 (18.2 mg, 42.1 pmol) and 10% palladium on carbon (896 mg) was first purged with nitrogen for 15 minutes, then methanol (553 pL) and water (111 pL) were added under nitrogen protection. The reaction mixture was purged with hydrogen atmosphere (balloon) for 5 minutes, then left overnight under hydrogen atmosphere. After stirring overnight, the reaction was purged with nitrogen, and diluted with ethyl acetate and methanol, filtered over celite and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase column chromatography (C18 column, 10 g, mobile phase: acetonitrile / 10 mM ammonium formate in water, 0% to 80%) to give (1s,4s)-4-(5,8-dimethyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide as a light yellow solid (5.93 mg, 33% yield). LCMS ESI m / z 422.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.27 (s, 1H), 7.29 (s, 1H), 7.17 - 7.08 (m, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 4.26 - 4.21 (m, 1H), 4.20 (s, 2H), 3.75 (s, 3H), 2.69 - 2.61 (m, 1H), 2.18 - 2.07 (m, 11H), 2.07 - 1.92 (m, 2H), 1.75 - 1.59 (m, 2H), 1.53 - 1.40 (m, 2H).

[0269] Example 26

[0270] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(methylsulfonamidomethyl)-2- oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0271] Step 1

[0272] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(methylsulfonamidomethyl)-2- oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide ((1s,4s)-4-(7-(Aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (30.0 mg, 68.7 µmol) prepared in example 28 was dissolved in dichloromethane (500 uL), triethylamine (28.9 µL, 206 µmol) and methanesulfonyl chloride (5.97 µL, 75.6 µmol) were added, the reaction mixture was stirred at room temperature for 3 hours, concentrated to dryness under reduced pressure and directly loaded onto a C18 column, purified by reverse phase chromatography (30 g column, mobile phase: acetonitrile / 10 mM ammonium formate in water, 2% to 60%) and lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(methylsulfonamidomethyl)-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (6.15 mg, 17% yield) as a white solid. LCMS ESI m / z 515.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.66 (s, 1H), 9.10 (s, 1H), 7.43 (t, J = 6.3 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.09 (dd, J = 8.1, 1.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.64 (s,1H), 6.55 (s, 1H), 4.18 (s, 2H), 4.24 – 4.11 (m, 1H), 3.96 (d, J = 6.2 Hz,2H), 3.73 (s, 3H), 2.83 (s, 3H), 2.64 – 2.60 (m, 1H), 2.13 (s, 3H), 2.11 –2.07 (m, 2H), 2.06 (s, 3H), 1.98 (qd, J = 12.5, 3.2 Hz, 2H), 1.69 – 1.57 (m,2H), 1.43 (dd, J = 11.6, 2.4 Hz, 2H)。

[0273] Example 27

[0274] (1s,4s)-4-(7-(acetamidomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0275] Step 1

[0276] (1s,4s)-4-(7-(acetamidomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide ((1s,4s)-4-(7-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (30.0 mg, 68.7 µmol) prepared in Example 28 was dissolved in dichloromethane (500 uL), triethylamine (28.9 µL, 206 µmol) and acetyl chloride (5.48 µL, 75.6 µmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and directly loaded onto a C18 column and purified by reverse phase chromatography (30 g column, mobile phase: acetonitrile / 10 mM ammonium formate in water, 2% to 60%) to give (1s,4s)-4-(7-(acetamidomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (8.28 mg, 25% yield) as a white solid. LCMS ESI m / z 479.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.03 (s, 1H), 8.21 (t, J = 5.8 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.09 (dd, J = 8.0, 1.8 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.56 (s,1H), 6.46 (s, 1H), 4.22 – 4.13 (m, 1H), 4.17 (s, 2H), 4.05 (d, J =5.9 Hz,2H), 3.73 (s, 3H), 2.66 – 2.59 (m, 1H), 2.11 (s, 3H), 2.10 – 2.07 (m, 2H),2.06 (s, 3H), 1.98 (qd, J = 12.7, 3.5 Hz, 2H), 1.81 (s, 3H), 1.69 – 1.57 (m, 2H), 1.47 – 1.37 (m, 2H).

[0277] Example 28

[0278] (1s,4s)-4-(7-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0279] Step 1

[0280] (1s,4s)-4-(7-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide The (1s,4s)-4-(7-cyano-5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (20.0 mg, 46.2 µmol) prepared in Example 31 was dissolved in a 1:1 mixture of dichloromethane (567 µL) and methanol (567 µL). Nickel chloride hexahydrate (1.13 mg, 4.76 µmol) was added at 0 °C, followed by the slow, fractional addition of sodium borohydride (5.28 µL, 139 µmol). The reaction mixture was stirred at 0 °C for 1 hour and gradually turned black. A saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by C18 reversed-phase chromatography (30g column, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, 2% to 60%). The product was directly lyophilized to give a white solid (1S,4S)-4-(7-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (8.52 mg, yield 42%). LCMS ESI m / z 437.4 [M+H]+ . 1 H NMR (400MHz, DMSO- d 6) δ 9.70 (s, 1H), 9.13 (s, 1H), 8.32 (s, 1H), 7.29 (s, 1H), 7.12(d, J = 7.3 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 4.21(s, 2H), 4.24 – 4.16 (m, 1H), 3.75 (s, 3H), 3.67 (s, 2H), 2.68 – 2.65 (m,1H), 2.15 (s, 3H), 2.13 – 2.09 (m, 2H), 2.08 (s, 3H), 2.01 (dd, J = 23.5, 12.3Hz, 2H), 1.71 – 1.59 (m, 2H), 1.45 (d, J = 10.0 Hz, 2H).

[0281] Example 29

[0282] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(7-(3-methoxyazacyclobutane-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0283] Step 1

[0284] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(7-(3-methoxyazacyclobutane-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (50.0 mg, 103 pmol) was added into a microwave tube, followed by adding methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8.97 mg, 10.3 pmol), cesium carbonate (76.9 mg, 231 pmol), 3-methoxyazetidine hydrochloride (50.8 mg, 411 pmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (2.53 mg, 5.14 pmol) into the microwave tube. The microwave tube was sealed and purged with nitrogen by vacuum evacuation and nitrogen backfilling (3 times). Meanwhile, 1,4-dioxane was purged with a stream of nitrogen for 15 minutes, followed by adding degassed 1,4-dioxane (1.00 mL) into the microwave tube, the reaction was stirred at 100 °C for 3 hours. After the reaction was cooled to room temperature, the solvent was evaporated to dryness. The crude product was isolated and purified by C18 reverse phase chromatography (30 g, mobile phase: acetonitrile / 10 mM aqueous ammonium formate (pH = 3.8), 2% to 60%). The pure fractions were lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(7-(3-methoxyazetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (8.91 mg, 18% yield) as a light yellow solid. LCMS ESI m / z 493.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.83 (s, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.1, 1.7 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 5.81(d, J = 1.7 Hz, 1H), 5.68 (d, J = 2.0 Hz, 1H), 4.28 – 4.22 (m, 1H), 4.22 – 4.12(m, 1H), 4.09 (s, 2H), 3.92 (t, J = 7.0 Hz, 2H), 3.73 (s, 3H), 3.45 (dd, J =7.9, 4.4 Hz, 2H), 3.20 (s, 3H), 2.64 – 2.59 (m, 1H), 2.15 – 2.08 (m, 2H),2.06 (s, 3H), 2.05 (s, 3H), 2.02 – 1.90 (m, 2H), 1.67 – 1.56 (m, 2H), 1.45 –1.37 (m, 2H).

[0285] Example 30

[0286] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0287] Step 1

[0288] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (50.0 mg, 103 pmol), 2-oxa-6- azaspiro[3.3]heptane (40.8 mg, 411 pmol), cesium carbonate (85.4 mg, 257 pmol), (2-dicylohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'- biphenyl-2-yl)palladium (22.4 mg, 25.7 pmol) and 2-dicylohexylphosphino-2',4',6'- triisopropylbiphenyl (5.05 mg, 10.3 pmol) were added to a microwave tube. The microwave tube was sealed and purged with nitrogen by vacuum and nitrogen backfilling (3 times). Meanwhile, 1,4-dioxane was degassed with a nitrogen stream for 15 minutes, then degassed 1,4-dioxane (514 uL) was added to the microwave tube, and the reaction was heated at 100 °C for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by C18 reverse phase chromatography (30 g column, mobile phase: acetonitrile / 10 mM aqueous ammonium formate, 2% to 60%) to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-7-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide as a light yellow solid (29.2 mg, 56%). LCMS ESI m / z 505.4 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ9.66 (s, 1H), 8.84 (s, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.0, 1.8Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 5.80 (d, J = 1.7 Hz, 1H), 5.68 (d, J = 1.9Hz, 1H), 4.67 (s, 4H), 4.15 (tt, J =11.9, 3.3 Hz, 1H), 4.08 (s, 2H), 3.83 (s,4H), 3.73 (s, 3H), 2.66 – 2.57 (m, 1H), 2.13 – 2.07 (m, 2H), 2.06 (s, 3H),2.05 (s, 3H), 1.96 (qd, J = 12.5, 2.8 Hz, 2H), 1.69 – 1.56 (m, 2H), 1.46 –1.35 (m, 2H)。

[0289] Example 31

[0290] (1s,4s)-4-(7-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0291] Step 1

[0292] (1s,4s)-4-(7-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (9.41 mg, 10.3 µmol), zinc (673 µg, 10.3 µmol), zinc cyanide (12.7 mg, 108 µmol), (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (Example 74) (50.0 mg, 103 µmol) were added into a microwave tube and capped after purging with nitrogen for 3 times. Meanwhile, N,N-dimethylacetamide was degassed by purging with a stream of nitrogen for 15 minutes. Degassed N,N-dimethylacetamide (2.06 mL) was added into the reaction system. The reaction was heated at 100 °C with stirring for 1 hour. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was directly separated and purified by C18 reverse phase column (mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution (pH = 3.8), 2% to 70%). The pure fractions were directly lyophilized to give (1s,4s)-4-(7-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (17.7 mg, 40% yield) as a white solid. LCMS ESI m / z 433.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.67 (s, 1H), 9.38(s, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.16 (s, 1H), 7.09 (dd, J = 8.0, 1.8 Hz,1H), 7.00 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 4.28 (s, 2H), 4.22 – 4.12 (m,1H), 3.73 (s, 3H), 2.67 – 2.58 (m, 1H), 2.19 (s, 3H), 2.10 (d, J = 13.4 Hz,2H), 2.06 (s, 3H), 1.99 (qd, J = 12.7, 3.2 Hz, 2H), 1.69 – 1.57 (m, 2H), 1.49– 1.39 (m, 2H).

[0293] Example 32

[0294] (1s,4s)-4-(8-chloro-5-methyl-2-oxo-1,2-dihydropyridin[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(8-chloro-5-methyl-2-oxo-1,2-dihydropyridin[3,4-d]pyrimidin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide was synthesized according to the steps described in Example 20, and the product was a white solid (198 mg, 93% yield). LCMS ESI m / z 443.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.67(s, 1H), 8.60 (s, 1H), 7.76 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.0, 1.7 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 4.31 (s, 2H), 4.19 (tt, J = 11.9,3.6 Hz, 1H), 3.73 (s, 3H), 2.68 – 2.59 (m, 1H), 2.14 (s, 3H), 2.13 – 2.08 (m,2H), 2.06 (s, 3H), 1.99 (qd, J = 12.5, 3.3 Hz, 2H), 1.73 – 1.60 (m, 2H), 1.51 – 1.41 (m, 2H).

[0295] Example 33

[0296] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(oxetane-3-yl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0297] Step 1

[0298] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(oxetan-3-yl)-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a microwave tube was added 4,4,5,5-tetramethyl-2-(oxetan-3-yl)-1,3,2- dioxaborolane (21.9 mg, 113 µmol), cesium carbonate (67.0 mg, 206 µmol), (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (Example 74) (50.0 mg, 103 µmol) and 1,4- dioxane (467 µL) and water (93.5 µL). The vial was capped and purged with nitrogen for 15 minutes, then palladium (7.68 mg, 10.3 µmol) of 1,1-bis(diphenylphosphino) ferrocene dichloride was added and purged for a further minute and the reaction stirred at 85 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction was purified by flash column chromatography (dry loading, 25g, eluting with dichloromethane (20% methanol in dichloromethane) from 1% to 60% gradient) to give 10 mg of crude material which was further purified by C18 reverse phase flash column chromatography (30g column, eluting with 10mM ammonium bicarbonate (pH=10) in water with acetonitrile from 2% to 60% gradient) and lyophilised to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(oxetan-3-yl)-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide as a white solid (3.27 mg, 6.9% ). LCMS ESI m / z 464.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.67 (s, 1H), 9.03 (s, 1H), 7.27 (s, 1H), 7.10 (dd, J = 8.1, 1.8Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.60 (s, 1H), 6.36 (d, J = 15.9 Hz, 1H), 6.18 (dt, J = 15.9, 5.1 Hz, 1H), 4.80 (t, J =5.6 Hz, 1H), 4.26 –4.12 (m, 2H), 4.19 (s, 2H), 4.06 (t, J = 4.6 Hz, 1H), 3.74 (s, 3H), 2.64 –2.60 (m, 1H), 2.13 (s, 3H), 2.12 – 2.08 (m, 2H), 2.06 (s, 3H), 2.02 – 1.91(m, 2H), 1.70 – 1.58 (m, 2H), 1.48 – 1.39 (m, 2H)。

[0299] Example 33

[0300] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(oxetan-3-yl)-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0301] Step 1

[0302] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(oxetan-3-yl)-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a microwave tube was added 4,4,5,5-tetramethyl-2-(oxetan-3-yl)-1,3,2- dioxaborolane (21.9 mg, 113 µmol), cesium carbonate (67.0 mg, 206 µmol), (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (Example 74) (50.0 mg, 103 µmol) and 1,4- dioxane (467 µL) and water (93.5 µL). The tube was capped and purged with nitrogen for 15 minutes, then palladium (7.68 mg, 10.3 µmol) of 1,1-bis(diphenylphosphino)ferrocene dichloride was added and purged for a further minute, the reaction was stirred at 85 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction was purified by flash column chromatography (dry loading, 25 g, elution system 20% methanol in dichloromethane / dichloromethane, gradient from 1% to 60%) to give 10 mg of crude which was further purified by C18 reverse phase flash column chromatography (30 g column, elution system 10 mM ammonium bicarbonate (pH=10) in water / acetonitrile, gradient from 2% to 60%) and lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-7-(oxetan-3-yl)-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (3.27 mg, 6.9% yield) as a white solid. LCMS ESI m / z 464.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ9.67 (s, 1H), 9.03 (s, 1H), 7.27 (s, 1H), 7.10 (dd, J = 8.1, 1.8 Hz, 1H), 7.00(d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.60 (s, 1H), 6.36 (d, J = 15.9 Hz, 1H),6.18 (dt, J = 15.9, 5.1 Hz, 1H), 4.80 (t, J = 5.6 Hz, 1H), 4.26 – 4.12 (m, 2H),4.19 (s, 2H), 4.06 (t, J =4.6 Hz, 1H), 3.74 (s, 3H), 2.64 – 2.60 (m, 1H),2.13 (s, 3H), 2.12 – 2.08 (m, 2H), 2.06 (s, 3H), 2.02 – 1.91 (m, 2H), 1.70 –1.58 (m, 2H), 1.48 – 1.39 (m, 2H).

[0303] Example 34

[0304] (1s,4s)-4-(8-(3-cyano-3-methylazetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide

[0305] Step 1

[0306] (E)-N-(2-bromo-5-methylphenyl)-2-(hydroxyimino)acetamide Sodium sulfate (122 g, 860 mmol) was dissolved in water (726 mL) and added to a 2000 mL flask. Subsequently, hydroxylamine hydrochloride (27.4 g, 387 mmol), 2-bromo-5-methylaniline (14.4 mL, 107 mmol) and 2 M hydrochloric acid (36.0 mL, 72.0 mmol) were added (forming a white precipitate of aniline sulfate sulfate). The mixture was warmed to 55 °C and chloral hydrate (21.3 g, 129 mmol) was added. The reaction was stirred vigorously at 55 °C overnight. A resinous precipitate formed in the solution which was filtered through a Buchner funnel and the filter cake was washed with water (500 mL) and heptane (4 x 400 mL). The solid was dried under vacuum overnight to give the crude (E)-N-(2-bromo-5-methylphenyl)-2-(hydroxyimino)acetamide (27.6 g, 100% yield, purity 85%) which was used directly in the next step. 1 H NMR (400 MHz, DMSO- d 6) δ 12.42 (s, 1H), 9.39 (s, 1H), 7.72 (d, J = 1.1 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 6.96 (dd, J =8.3, 1.8Hz, 1H), 2.27 (s, 3H).

[0307] Step 2

[0308] 7-bromo-4-methylindoline-2,3-dione The crude (E)-N-(2-bromo-5-methylphenyl)-2-(hydroxyimino)acetamide (28.0 g, 109 mmol) was added portionwise to a rapidly stirred solution of concentrated sulfuric acid (80 mL, 109 mmol) preheated to 55 °C (the addition rate was controlled to keep the reaction temperature between 55-70 °C). The resulting solution was warmed to 70 °C and stirred for 20 minutes, then cooled to room temperature. The purple-red mixture was carefully poured onto crushed ice (~1000 g) and the mixture was allowed to stand for 1 hour. The purple solid precipitate was filtered, the filter cake was washed with water (200 mL x 3) and then dried under vacuum to give the crude brown solid 7-bromo-4-methylindoline-2,3-dione (26.1 g, yield 100%) and used directly in the next reaction. 1 H NMR (400 MHz, DMSO- d 6) δ 11.23 (s, 1H),7.62 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H).

[0309] Step 3

[0310] 2-amino-3-bromo-6-methylbenzoic acid 7-bromo-4-methylindoline-2,3-dione (27.0 g, 112 mmol) was dissolved in a ice-bath cooled solution of 2 M sodium hydroxide solution (112 mL, 225 mmol), then hydrogen peroxide (35 mL, 337 mmol) was added slowly dropwise. The mixture was warmed to room temperature and stirred for 2 hours, then acidified carefully by dropwise addition of saturated citric acid solution. The solid precipitate was collected by filtration, washed with water and dried under vacuum to give the dark brown solid 2-amino-3-bromo-6-methylbenzoic acid (10.5 g, 41% overall yield over 3 steps) which was used directly in the next reaction. 1 H NMR (400 MHz, DMSO- d 6) δ 7.37 (d, J = 8.1 Hz, 1H), 6.40 (d, J =8.1 Hz, 1H), 2.28 (s, 3H).

[0311] Step 4

[0312] 2-Amino-3-bromo-6-methylbenzyl alcohol To a dry, nitrogen purged 100 mL round bottom flask was added 2-amino-3-bromo-6- methylbenzoic acid (1.85 g, 8.06 mmol) and dissolved in anhydrous tetrahydrofuran (40.3 mL) and then cooled to 0 °C with an ice bath, borane dimethyl sulfide complex dissolved in tetrahydrofuran (8.06 mL, 16.1 mmol) was added dropwise, gas evolution was observed during the addition, after the gas evolution had ceased the reaction was heated to reflux at 70 °C with stirring for 16 hours. After the reaction was complete, the system was cooled to room temperature and methanol (10 mL) was added dropwise to quench the reaction, after stirring at room temperature for 1 hour, the reaction was concentrated under reduced pressure to yield a yellow solid (2-amino-3-bromo-6-methylbenzyl alcohol (1.74 g, 100% yield) and used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 1H), 4.83 (s, 2H), 3.47 (d, J = 11.7 Hz, 1H), 2.29 (s, 3H). J =

[0313] Step 5

[0314] 2-Amino-3-bromo-6-methylbenzaldehyde To a 100 mL round bottom flask was added 2-amino-3-bromo-6-methylbenzyl alcohol (1.63 g, 7.56 mmol) and diluted with dichloromethane (37.8 mL), then the reaction was initiated by the addition of activated manganese dioxide (3.65 g, 37.8 mmol), the reaction was stirred at room temperature until completion. After 4 hours, the mixture was filtered through celite, the filtrate was concentrated to dryness to yield a clear yellow oil that gradually solidified to a light green solid 2-amino-3-bromo-6-methylbenzaldehyde (1.40 g, 85% yield), the product was used directly in the next step without purification. 1 H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H),7.47 (d, J = 7.9 Hz, 1H), 6.37 (d, J = ​7.9 Hz, 1H), 2.55 (s, 3H).

[0315] Step 6

[0316] (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide To a 100 mL round bottom flask was added 2-amino-3-bromo-6-methylbenzaldehyde (1.40 g, 6.54 mmol) to which was added anhydrous 1,2-dichloroethane (32.7 mL). To this was then added (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (2.57 g, 9.81 mmol) and acetic acid (112 μL, 1.96 mmol). The reaction was stirred at 50 °C for 2 hours after which time sodium triacetoxyborohydride (3.56 g, 16.4 mmol) was added in one portion and the reaction heated to 50 °C. Once the reaction had cooled to room temperature it was concentrated to give a black, viscous solid crude product. The crude product was purified by reverse phase C18 column chromatography (elution gradient 100% AMF to 60% acetonitrile (40% AMF). Fractions containing the desired product were combined and evaporated to dryness to give (1s,4s)-4-((2-amino-3-bromo-6-methylbenzyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide as a white solid (1.17 g, 39%). The product was used directly in the next reaction. LCMS ESI m / z 458.4, 460.4 [M+H] + .

[0317] Step 7

[0318] (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (1s,4s)-4-((2-amino-3-bromo-6-methylbenzyl)amino)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (140 mg, 304 µmol) was charged into a 250 mL round bottom flask and diluted with dichloromethane (12.7 mL). To this was added portionwise, triphosgene (846 mg, 2.80 mmol) and triethylamine (712 μL, 5.08 mmol). The reaction was slightly exothermic and reaction completion was observed after 3 hours, the reaction was terminated by evaporation to dryness, resulting in a white solid. Purification using an elution gradient of 40% ethyl acetate in heptane to 100% ethyl acetate resulted in a white solid (1s,4s)-4-(8 -bromo -5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (960 mg, 78% yield). LCMS ESI m / z 486.0, 488.0 [M+H] + (see Example 62 for details) Step 8

[0319] (1s,4s)-4-(8-(3-cyano-3-methylazetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide To a dry, nitrogen purged 0.5-2.0 mL Biotage vial was added (1s,4s)-4-(8-bromo-5- methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (25.0 mg, 51.4 µmol), diluted with 1,4-dioxane (0.257 mL), and purged with nitrogen for 5 minutes. Subsequently, methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8.97 mg, 10.3 µmol), cesium carbonate (76.9 mg, 231 µmol), 3-methylazetidine-3-carbonitrile hydrochloride (35.1 mg, 257 µmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (2.53 mg, 5.14 µmol) were added. The vial was sealed with a microwave cap and stirred at 100 °C for 1.5 hours. After which the reaction was cooled to room temperature and exposed to air. The solvent was evaporated to dryness and the crude product was purified by silica gel column chromatography using an elution gradient of 60% heptane with 40% ethyl acetate to 100% ethyl acetate and 80% ethyl acetate with 20% methanol. The pure fractions were evaporated to dryness to yield (1s,4s)-4-(8-(3-cyano-3-methylazetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (7.90 mg, 29% yield) as a yellow solid. LCMS ESI m / z 502.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.67(s, 1H), 7.68 (s, 1H), 7.27 (s, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 8.1Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 4.22 – 4.11 (m,1H), 4.17 (s, 2H), 4.00 (d, J = 7.0 Hz, 2H), 3.72 (d, J =8.3 Hz, 2H), 3.73 (s,3H), 2.67-2.60 (m, 1H), 2.14 – 2.03 (m, 2H), 2.09 (s, 3H), 2.06 (s, 3H),2.04-1.97 (m, 2H), 1.73 – 1.59 (m, 2H), 1.66 (s, 3H), 1.52 – 1.38 (m, 2H)。

[0320] Example 35

[0321] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0322] Step 1

[0323] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a dry, nitrogen purged 0.5-2.0 mL Biotage vial was added (1s,4s)-4-(8-bromo-5- methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 62 (25.0 mg, 51.4 µmol) and diluted with 1,4-dioxane (257 µL). After purging the solvent with nitrogen for 5 minutes, methanesulfonic acid (2-dicylohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8.97 mg, 10.3 µmol), cesium carbonate (76.9 mg, 231 µmol), 2-oxa-6-azaspiro[3.3]heptane (20.4 mg, 206 µmol), and 2-dicylohexylphosphino-2',4',6'-triisopropylbiphenyl (2.53 mg, 5.14 µmol) were added in order. The vial was sealed with a microwave vial cap and heated at 100 °C overnight after which the reaction was cooled to room temperature and exposed to air. The solvent was evaporated to dryness. Purification by silica gel column chromatography (elution gradient 100% ethyl acetate to 80% ethyl acetate with 20% methanol) and lyophilization of the pure fractions after solvent evaporation gave (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-8-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (10.5 mg, 37% yield) as a yellow solid. LCMS ESI m / z 505.3 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 9.67 (s, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 7.08 (s,1H), 7.00 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.46 (d, J =7.7 Hz, 1H), 4.67 (s, 4H), 4.20 - 4.11 (m, 1H), 4.16 (s, 2H), 3.86 (s, 4H), 3.73 (s, 3H), 2.67-2.61 (m, 1H), 2.14-2.06 (m, 2H), 2.07 (s, 3H), 2.06 (s, 3H) 2.01-1.92 (m, 2H), 1.71 - 1.58 (m, 2H), 1.48-1.39 (m, 2H).

[0324] Example 36

[0325] (1R,3R)-3-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclopentanecarboxamide

[0326] Step 1

[0327] 4-bromo-2-methyl-6-nitrobenzaldehyde To a stirred solution of 5-bromo-l,2-dimethyl-3-nitrobenzene (1.00 g, 4.26 mmol) in N,N-dimethylformamide (10.6 mL) was added N,N-dimethylformamide dimethyl acetal (1.70 mL, 12.8 mmol) and the reaction was heated at 140 °C for 24 h. The dark red solution was cooled to room temperature and added to a solution of sodium metaperiodate (2.99 g, 13.8 mmol) in N,N-dimethylformamide (2.5 mL) and water (7.5 mL) with stirring at 0 °C. The reaction flask was washed with N,N-dimethylformamide (2 mL) and added to the stirring mixture. The reaction was stirred at 0 °C for 3 h and allowed to warm to room temperature slowly. The orange solution was filtered and rinsed with ethyl acetate (80 mL). The filtrate was washed with water (25 mL x 3) and saturated brine (25 mL x 3), dried over sodium sulfate and concentrated under reduced pressure to give the crude product as a dark orange oil. The crude product was purified by silica gel column chromatography using 10-70% ethyl acetate in hexanes as eluent to give 4-bromo-2-methyl-6-nitrobenzaldehyde (228 mg, 22% yield) as a light orange solid. LCMS ESI m / z 244.0 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H),8.11 (d, J = 1.5 Hz, 1H), 7.74 (s, 1H), 2.50 (s, 3H)。

[0328] Step 2

[0329] tert-butyl ((1r,3r)-3-((3-methoxy-4-methylphenyl)carbamoyl)cyclopentyl)carbamate To a solution of (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclopentane carboxylic acid (500 mg, 2.14 mmol) in N,N-dimethylformamide (10.7 mL) was added HATU (995 mg, 2.56 mmol) and diisopropylethylamine (931 uL, 5.34 mmol), the reaction mixture was stirred for 30 minutes before 3-methoxy-4-methylaniline (299 mg, 2.14 mmol) was added, the reaction was continued to stir for 8 hours. After complete conversion, 1:1 volume ratio of brine and ethyl acetate was added to the reaction mixture, extracted with ethyl acetate for 3 times, combined the organic phase and washed with brine, concentrated under reduced pressure to give tert-butyl ((1R,3R)-3-((3-methoxy-4-methylphenyl)carbamoyl)cyclopentyl)carbamate (745 mg, yield 100%) as a light white powder. LCMS ESI m / z 293.3 [M-tBu] + .

[0330] Step 3

[0331] (1r,3r)-3-amino-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide Tert-butyl ((1r,3r)-3-((3-methoxy-4-methylphenyl)carbamoyl)cyclopentyl)carbamate (745 mg, 2.14 mmol) was dissolved in dichloromethane (4.28 mL), hydrochloric acid (3.74 mL, 15.0 mmol) was added to the solution. The solution was stirred until the starting material was consumed, the reaction mixture was concentrated under reduced pressure, the crude product was isolated and purified by C18 reverse phase column chromatography (elution gradient from 100% ammonium formate solution to 100% acetonitrile), the pure fractions containing the target product were concentrated under reduced pressure to give (1r,3r)-3-amino-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide (160 mg, yield 30%) as a white solid. LCMS ESI m / z 249.3 [M+H] +.

[0332] Step 4

[0333] (1r,3r)-3-((4-bromo-2-methyl-6-nitrobenzyl)amino)-N-(3-methoxy-4- methylphenyl)cyclopentanecarboxamide (1r,3r)-3-amino-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide (155 mg, 527 µmol) was dissolved in dichloroethane (2.93 mL) to which was added 4-bromo-2-methyl-6-nitrobenzaldehyde (143 mg, 585 µmol). After stirring for 2 hours, sodium triacetoxyborohydride (127 mg, 585 µmol) was added rapidly and the solution was stirred until the amine was consumed. The reaction was quenched with water and extracted 3 times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give a yellow crude product. The crude product was dissolved in dimethyl sulfoxide and purified by reverse phase column chromatography (elution gradient: formic acid in water / acetonitrile (5%-95%)) to give (1r,3r)-3-((4-bromo-2-methyl-6-nitrobenzyl)amino)-N-(3-methoxy-4- methylphenyl)cyclopentanecarboxamide (140 mg, 50% yield) as a yellow powder. LCMS ESI m / z 478.3 [M+H] + .

[0334] Step 5

[0335] (1r,3r)-3-((2-amino-4-bromo-6-methylphenyl)amino)-N-(3-methoxy-4- methylphenyl)cyclopentanecarboxamide To a solution of (1r,3r)-3-((4-bromo-2-methyl-6-nitrobenzyl)amino)-N-(3-methoxy-4- methylphenyl)cyclopentanecarboxamide (30.0 mg, 63.0 µmol) in methanol (500 µL) was added ammonium chloride (13.5 mg, 252 µmol) and zinc (2.36 µL, 252 µmol). After stirring at 60 °C for 2 hours, the reaction was filtered through a 0.45 µm syringe filter. To the resulting filtrate was added saturated sodium bicarbonate solution and extracted 3 times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give (1r,3r)-3-((2-amino-4-bromo-6-methylphenyl)amino)-N-(3-methoxy-4- methylphenyl)cyclopentanecarboxamide (28.1 mg, 100% yield) as a white solid. This product was used without purification in the next step. LCMS ESI m / z 446.3 [M+H]+ .

[0336] Step 6

[0337] (1r,3r)-3-(7-Bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclopentanecarboxamide (1r,3r)-3-((2-Amino-4-bromo-6-methylphenyl)amino)-N-(3-methoxy-4- methylphenyl)cyclopentanecarboxamide (28.1 mg, 63.0 µmol) was dissolved in tetrahydrofuran (420 μL), the mixture was cooled to 0 °C, then triethylamine (8.83 μL, 63.0 µmol), triphosgene (9.35 mg, 31.5 µmol) was added. After the starting material was reacted completely, water was added, and extracted with ethyl acetate for 3 times. The organic phase was combined and concentrated under reduced pressure to obtain a yellow solid crude product. The crude product was dissolved in a small amount of dimethyl sulfoxide and separated and purified by reverse phase column chromatography (elution system: ammonium formate solution: acetonitrile, 30%-95%) to obtain (1r,3R)-3-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide (1.49 mg, yield 5%) as a light yellow solid. LCMS ESIm / z 474.1 [M+H] + .1H NMR (400 MHz, DMSO- d 6) δ 9.83 (s, 1H), 9.25 (s, 1H), 7.36(s, 1H), 7.07 – 6.99 (m, 2H), 6.93 (d, J = 1.2 Hz, 1H), 6.78 (d, J = 1.6 Hz,1H), 4.80 (dd, J = 16.8, 8.4 Hz, 1H), 4.26 (s, 2H), 3.75 (s, 3H), 3.06 – 2.96(m, 1H), 2.21 (s, 3H), 2.08 (s, 3H), 2.05 – 2.00 (m, 1H), 1.99 – 1.92 (m,2H), 1.86 – 1.79 (m, 2H), 1.73 (m, 1H).

[0338] Example 37

[0339] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridine[3,4- d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide

[0340] Step 1

[0341] Methyl 3-bromo-5-fluoroisonicotinate Methyl 3-bromo-5-fluoroisonicotinate was prepared according to the procedure described in WO2016 / 175 1 1 1. To a solution of methyl 3-bromo-5-fluoroisonicotinate (1.88 g, 6.87 mmol) in N,N-dimethylformamide (6.8 mL) was added potassium carbonate (1.89 g, 13.7 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate for three times. The organic phase was combined, washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (70 g column, elution system: 5% to 60% ethyl acetate in n-hexane) to give methyl 3-bromo-5-fluoroisonicotinate (1.88 g, yield 85%) as a clear oil. LCMS ESI m / z 274.9 [M+H] + .

[0342] Step 2

[0343] Methyl 3-fluoro-5-methylisonicotinate Methyl 3-fluoro-5-methylisonicotinate was prepared according to the procedure described in WO2016 / 175 1 1 1. To a solution of methyl 3-bromo-5-fluoroisonicotinate (1.88 g, 6.87 mmol) in N,N-dimethylformamide (6.8 mL) was added potassium carbonate (1.89 g, 13.7 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate for three times. The organic phase was combined, washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (70 g column, elution system: 5% to 60% ethyl acetate in n-hexane) to give methyl 3-bromo-5-fluoroisonicotinate (1.88 g, yield 85%) as a clear oil. LCMS ESI m / z 274.9 [M+H] + .

[0344] Step 3

[0345] 3-((4-methoxybenzyl)amino)-5-methylisonicotinic acid methyl ester Methyl 3-fluoro-5-methylnicotinate (217 mg, 1.28 mmol) was dissolved in N-methylpyrrolidine (6.41 mL), to which diisopropylethylamine (677 μL, 3.85 mmol) and 4-methoxybenzylamine (171 μL, 1.28 mmol) were added, the reaction mixture was stirred at 80 °C for 16 hours. To the reaction mixture was added saturated sodium bicarbonate solution, extracted with ethyl acetate 3 times. The organic phase was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was separated and purified by silica gel column chromatography (50 g column, ethyl acetate in n-hexane 5% to 60%), to give 3-((4-methoxybenzyl)amino)-5-methylisonicotinic acid methyl ester (12.6 mg, yield 3.4%) as a yellow oil. LCMS ESI m / z 287.0 [M+H] + .

[0346] Step 4

[0347] (3-((4-methoxybenzyl)amino)-5-methylpyridin-4-yl)methanol To a solution of methyl 3-((4-methoxybenzyl)amino)-5-methylisonicotinate (132 mg, 461 µmol) in tetrahydrofuran (2.31 mL) was added 2M lithium borohydride solution (692 uL, 1.38 mmol), the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added methanol and stirred for 1 hour, concentrated to dryness under reduced pressure, to give (3-((4-methoxybenzyl)amino)-5-methylpyridin-4-yl)methanol (119 mg, yield 100%) as a white solid, the product was directly used in the next step without purification. LCMS ESI m / z 259.1 [M+H] + .

[0348] Step 5

[0349] 3-((4-methoxybenzyl)amino)-5-methylisonicotinaldehyde (3-((4-methoxybenzyl)amino)-5-methylpyridin-4-yl)methanol (119 mg, 461 µmol) was dissolved in dichloromethane (2.30 mL), and activated manganese dioxide (222 mg, 2.30 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography (25 g column, ethyl acetate in n-hexane 10% to 80%) to give 3-((4-methoxybenzyl)amino)-5-methylisoniazol (65.3 mg, 55% yield) as a yellow solid. LCMS ESI m / z 257.2 [M+H] + .

[0350] Step 6

[0351] (1s,4s)-4-(((3-amino-5-methylpyridin-4-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide 3-((4-methoxybenzyl)amino)-5-methylisononaldehyde (65.0 mg, 254 µmol) and (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (67.2 mg, 256 µmol) were added to the same flask, followed by 1,2-dichloroethane (1.69 mL) and one drop of acetic acid. The reaction mixture was stirred at 50 °C for 16 hours, then cooled to room temperature. Sodium triacetoxyborohydride (160 mg, 761 µmol) was added in a single batch, and the mixture was stirred at 23 °C for 48 hours. Methanol was then added to the reaction mixture, and the resulting solution was concentrated to dryness after stirring at room temperature for 1 hour. The crude product was purified by silica gel chromatography (dichloromethane / dichloromethane containing 20% ​​methanol, gradient from 1% to 60%) to give (1S,4S)-4-((3-amino-5-methylpyridin-4-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (54.7 mg, yield 43%), as a pale yellow solid. LCMS ESI m / z 503.2 [M+H] + .

[0352] Step 7

[0353] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(1-(4-methoxybenzyl)-5-methyl-2-oxo- 1,2-dihydropyridine[3,4-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide To a solution of (1s,4s)-4-(((3-amino-5-methylpyridin-4-yl)methyl)amino)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (55.0 mg, 109 µmol) in dichloromethane (547 uL) was added triphosgene (11.6 mg, 38.3 µmol) followed by triethylamine (30.7 uL, 219 µmol) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness and the crude product was purified by silica gel chromatography (25 g column, 20% methanol in dichloromethane / dichloromethane, gradient from 1% to 60%) to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(1-(4-methoxybenzyl)-5-methyl-2-oxo- 1,2-dihydropyridine[3,4-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide (13.7 mg, 24%) as a colorless gum. LCMS ESI m / z 529.2 [M+H] + .

[0354] Step 8

[0355] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridine[3,4- d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide To a solution of (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(1-(4-methoxybenzyl)-5- methyl-2-oxo-1,2-dihydropyridine[3,4-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide (13.7 mg, 25.9 µmol) in dichloromethane (0.2 mL) was added trifluoroacetic acid (0.2 mL, 2.61 mmol). The reaction mixture was heated at 55 °C with stirring for 4 hours and the reaction mixture was concentrated under reduced pressure to give the crude product which was purified by C18 reverse phase column chromatography (30 g column, elution gradient 0% to 60% acetonitrile in 10 mM aqueous ammonium formate (pH=3.8)). The pure fractions were directly lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2- dihydropyridine[3,4-d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide (1.58 mg, 15% yield) as a white solid. LCMS ESI m / z 409.9 [M+H]+ . 1 H NMR (400 MHz, DMSO- d 6) δ 9.67 (s, 1H), 9.27 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.10 (dd, J = 8.1, 1.7 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 4.27(s, 2H), 4.19 (tt, J = 12.2, 3.6 Hz, 1H), 3.74 (s, 3H), 2.66 – 2.60 (m, 1H),2.13 (s, 3H), 2.16 – 2.08 (m, 2H), 2.06 (s, 3H), 2.04 – 1.94 (m, 2H), 1.70 –1.57 (m, 2H), 1.44 (dd, J = 12.2, 3.1 Hz, 2H)。

[0356] Example 38

[0357] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-(3-methoxyazetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0358] Step 1

[0359] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-(3-methoxyazetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide Into a dry, nitrogen purged 0.5-2.0 mL Biotage reaction vial, (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 34 (25.0 mg, 51.4 µmol) was added diluted with 1,4-dioxane (257 mL) and the solvent was purged with nitrogen for 5 minutes before adding to it, in order, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8.97 mg, 10.3 µmol), cesium carbonate (76.9 mg, 231 µmol), 3-methoxyazetidine hydrochloride (32.4 mg, 262 µmol) and 2-dicyclohexylphosphoroxy-2',4',6'-triisopropylbiphenyl (2.53 mg, 5.14 µmol). Sealed with a microwave cap and heated at 100 °C overnight. The reaction was left to cool to room temperature before unsealing and allowing the solvent to evaporate to dryness to give a crude product. The crude product was purified by Biotage purification system (12 g column, 100% ammonium formate in water (pH=3.8) to 70% acetonitrile) and lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-(3-methoxyazetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (3.30 mg, 12% yield) as a white solid. LCMS ESI m / z 493.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s,1H), 7.27 (s, 1H), 7.23 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.1 Hz,1H), 6.65 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 8.3 Hz, 1H), 4.23 – 4.09 (m, 2H),4.18 (s, 2H), 4.02 (dd, J = 7.7, 6.2 Hz, 2H), 3.73 (s, 3H), 3.40 (dd, J =7.8,5.4 Hz, 2H), 3.19 (s, 3H), 2.64-2.61 (m, 1H), 2.09-2.02 (m, 2H), 2.06 (s,3H), 2.03 (s, 3H), 2.02-1.91 (m, 2H), 1.71-1.59 (m, 2H), 1.49-1.41 (m, 2H).

[0360] Example 39

[0361] (1s,4s)-4-(8-cyclopropyl-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0362] Step 1

[0363] (1s,4s)-4-(8-cyclopropyl-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide Add (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (30.0 mg, 61.7 µmol) prepared in Example 34 to a dry, nitrogen-purged 0.5–2.0 mL Biotage reaction flask, and dilute with 1,4-dioxane (308 μL) and water (308 μL). After purging the solvent with nitrogen for 5 min, add chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (8.41 mg, 12.3 µmol), cesium carbonate (61.5 mg, 185 µmol), and potassium cyclopropyltrifluoroborate (45.6 mg, 308 µmol). The reaction flask was sealed with a microwave-safe cap. After stirring at 100 °C for 4 hours, the flask was cooled to room temperature and exposed to air until the solvent evaporated, yielding a black crude product. The crude product was purified by C18 reversed-phase column chromatography (elution gradient: 100% ammonium formate aqueous solution (pH=3.8) to 90% acetonitrile), and then directly lyophilized to obtain (1s,4s)-4-(8-cyclopropyl-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (10.5 mg, yield 37%), a white solid. LCMS ESI m / z 448.3 [M+H]+ . 1 H NMR (400 MHz, DMSO- d 6) δ 9.67 (s, 1H), 8.06(s, 1H), 7.27 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.72(d, J = 7.8 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 4.26 – 4.14 (m, 1H), 4.20 (s,2H), 3.74 (s, 3H), 2.68-2.59 (m, 1H), 2.17-2.04 (m, 2H), 2.11 (s, 3H), 2.07(s, 3H), 2.04-1.95 (m, 2H), 1.90 – 1.81 (m, 1H), 1.73-1.61(m, 2H), 1.50-1.42(m, 2H), 0.88-0.81 (m, 2H), 0.49-0.43 (m, 2H)。

[0364] Example 40

[0365] (1s,4s)-4-(6-(2-(dimethylamino)ethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide

[0366] Step 1

[0367] (1s,4s)-4-(6-(2-(dimethylamino)ethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide To a dry, nitrogen purged reaction vial was added (1s,4s)-4-(6-bromo-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 63 (20.0 mg, 41.1 pmol) and diluted with anhydrous 1,4-dioxane (206 pL) and the solvent was purged with nitrogen for 5 minutes. 2-Dimethylaminoethanol (12.5 pL, 123 pmol), cesium carbonate (41.0 mg, 123 pmol), and 2-(adamantylcyclohexylphosphine)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'- biphenyl (2.42 mg, 4.11 pmol), and tris(dibenzylideneacetone)dipalladium (1.92 mg, 2.06 pmol) were added sequentially. The reaction vial was sealed with a microwave vial cap and stirred at 100 °C for 3 hours. After the reaction was complete, the reaction vial was cooled to room temperature and exposed to air open to the atmosphere, extracted with ethyl acetate, washed with saturated brine (20 mL x 3), dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by C18 reverse phase column chromatography (elution gradient 100% ammonium formate in water (pH = 3.8) to 70% acetonitrile) and concentrated. The most pure fractions were lyophilized to afford (1s,4s)-4-(6-(2-(dimethylamino)ethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (3.60 mg, 6.9% yield) as a white solid. LCMS ESI m / z 495.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ9.68 (s, 1H), 8.89 (s, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.10 (dd, J = 8.2, 1.8Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 8.8Hz, 1H), 4.23-4.14 (m, 1H), 4.19 (s, 2H), 3.91 (t, J = 5.6 Hz, 2H), 3.73 (s,3H), 2.64-2.61 (m, 1H), 2.57 (t, J =5.6 Hz, 2H), 2.18 (s, 6H), 2.14 – 2.02(m, 2H), 2.06 (s, 3H), 2.02-1.92 (m, 2H), 2.00 (s, 3H), 1.69 – 1.57 (m, 2H),1.48-1.39 (m, 2H)。

[0368] Example 41

[0369] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridine[2,3- d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide

[0370] Step 1

[0371] Methyl 2-chloro-4-methylnicotinate To a microwave reaction vial was added potassium carbonate (344 mg, 2.49 mmol), ethyl-2-chloro-4-iodonicotinate (388 mg, 1.25 mmol) and trimethylboroxine (79.1 μL, 561 µmol), followed by water (2.08 mL) and 1,4-dioxane (10.4 mL), the reaction vial was purged with nitrogen for 10 minutes before palladium (93.0 mg, 125 µmol) of 1,1-bis(diphenylphosphino)ferrocene dichloride palladium was added to the reaction vial under nitrogen protection, the reaction vial was sealed and stirred at 100 °C for 24 hours. The reaction mixture was cooled to room temperature before direct addition of silica gel, the silica gel loaded with crude mixture was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / n-hexane, 0% to 60%) to give methyl 2-chloro-4-methylnicotinate (186 mg, yield 75%) as a light yellow oil. LCMS ESI m / z 200.0 [M+H] + .

[0372] Step 2

[0373] Methyl 2-((tert-butoxycarbonyl)amino)-4-methylnicotinate tert-Butyl carbamate (168 mg, 1.40 mmol), tris(dibenzylideneacetone)dipalladium (38.5 mg, 42.1 µmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37.3 mg, 63.1 µmol), cesium carbonate (457 mg, 1.40 mmol) and ethyl-2-chloro-4-methylnicotinate (140 mg, 701 µmol) were added to a microwave tube, which was flushed with nitrogen. Meanwhile, toluene was purged with nitrogen for 10 minutes. Then, nitrogen-purged toluene (4.68 mL) was added to the microwave tube, which was stirred at 100 °C for 5 hours under nitrogen protection. After the reaction mixture was cooled to room temperature, it was directly loaded onto a silica gel column and purified by elution with the mobile phase: ethyl acetate / n-hexane, 0% to 50% to give methyl 2-((tert-butoxycarbonyl)amino)-4-methylnicotinate (105 mg, yield 53%) as a yellow solid. LCMS ESI m / z 222.0 [M+H] + .

[0374] Step 3

[0375] 2-(tert-Butoxycarbonylamino)-4-methylpyridine-3-methanol Methyl 2-((tert-butoxycarbonyl)amino)-4-methylnicotinate (79.4 mg, 478 µmol) was dissolved in tetrahydrofuran (2.39 mL), to which was added 2M lithium borohydride in tetrahydrofuran (717 µL, 1.43 mmol), and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added saturated sodium bicarbonate solution, which was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(tert-butoxycarbonylamino)-4-methylpyridine-3-methanol (46.4 mg, yield 70%) as a brown gum, which was used directly in the next reaction without purification. LCMS ESI m / z 238.9 [M+H] + .

[0376] Step 4

[0377] 2-(tert-Butoxycarbonylamino)-4-methylpyridine-3-carbaldehyde 2-(tert-Butoxycarbonylamino)-4-methylpyridine-3-methanol (99.6 mg, 418 µmol) was dissolved in dichloromethane (2.09 mL), and activated manganese dioxide (202 mg, 2.09 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated to dryness to give 2-(tert-Butoxycarbonylamino)-4-methylpyridine-3-carboxaldehyde (70.5 mg, 71% yield) as a pale yellow solid, which was used directly in the next step without purification. LCMSESI m / z 236.8 [M+H] + .

[0378] Step 5 (1s,4s)-4-(((2-amino-4-methylpyridin-3-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide 2-(tert-Butoxycarbonylamino)-4-methylpyridine-3-carboxaldehyde (70.5 mg, 298 µmol) and (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (78.3 mg, 298 µmol) were placed in a flask, and 1,2-dichloroethane (1.99 mL) was added, followed by one drop of acetic acid. The reaction mixture was stirred at 50°C for 16 hours. The mixture was cooled to room temperature, and sodium triacetoxyborohydride (189 mg, 895 µmol) was added in a single batch. The mixture was stirred at 23°C for 1 hour, then cooled to room temperature. Methanol was added, and the reaction mixture was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (25 g column, elution gradient: 1% to 60% of dichloromethane in 20% methanol / dichloromethane) to obtain (1s,4s)-4-(((2-amino-4-methylpyridin-3-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (74.3 mg, 65% yield), a pale yellow gel. LCMS ESI m / z 383.2 [M+H] + .

[0379] Step 6

[0380] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridin[2,3-d]pyrimidin-3(4H)-yl)cyclohexaneformamide Triphosgene (2.77 mg, 9.15 µmol) and triethylamine (7.32 µmol) were added to a solution of (1s,4s)-4-(((2-amino-4-methylpyridin-3-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (10.0 mg, 26.1 µmol) in dichloromethane (131 µL), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to obtain a crude product, which was then purified by C18 reversed-phase column chromatography (30 g column, elution gradient: acetonitrile / 10 mM ammonium formate aqueous solution, 0% to 60%, pH=3.8). The pure fraction was directly lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridin[2,3-d]pyrimidin-3(4H)-yl)cyclohexaneformamide (10.7 mg, 100% yield) as a white solid. LCMS ESI m / z 409.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69(s, 1H), 9.43 (s, 1H), 7.88 (d, J = 5.0 Hz, 1H), 7.27 (s, 1H), 7.10 (d, J = 8.7Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 5.1 Hz, 1H), 4.25 (s, 2H), 4.23– 4.14 (m, 1H), 3.73 (s, 3H), 2.67 – 2.60 (m, 1H), 2.15 (s, 3H), 2.11 (d, J = 14.2 Hz, 2H), 2.06 (s, 3H), 2.02 – 1.92 (m, 2H), 1.70 – 1.58 (m, 2H), 1.45(d, J = 9.7 Hz, 2H).

[0381] Example 42

[0382] (1s,4s)-4-(6-(azacyclobutan-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0383] Step 1

[0384] (1s,4s)-4-(6-(azetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide To a dry, nitrogen purged 0.5-2.0 mL Biotage vial was added (1s,4s)-4-(6-bromo-5- methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 63 (25.0 mg, 51.4 µmol) and diluted with 1,4-dioxane (257 mL). After purging the solvent with nitrogen for 5 minutes, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8.97 mg, 10.3 µmol), cesium carbonate (76.9 mg, 231 µmol), azetidine hydrochloride (15.2 mg, 154 µmol), and 2- dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (2.53 mg, 5.14 µmol) were added. The vial was sealed with a microwave vial cap and heated at 100 °C overnight. After the reaction was complete, the reaction was cooled to room temperature and exposed to air open to the atmosphere until the solvent was evaporated to dryness to give the crude product. Purification of the crude product by gradient elution from 100% ammonium formate in water (pH = 3.8) to 70% acetonitrile in ammonium formate in water) gave (1s,4s)-4-(6-(azetidin-1-yl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (2.60 mg, 10% yield) as a white solid. LCMS ESI m / z 463.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 8.81 (s, 1H), 7.27 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H),7.00 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H), 6.36 (d, J =8.4 Hz, 1H),4.22 – 4.11 (m, 1H), 4.17 (s, 2H), 3.73 (s, 3H), 3.65 (t, J = 7.0 Hz, 4H),2.65-2.60 (m, 1H), 2.15 – 2.08 (m, 4H), 2.03 (s, 3H), 2.04 – 1.94 (m, 2H),1.94 (s, 3H), 1.69 – 1.56 (m, 2H), 1.46 – 1.37 (m, 2H)。

[0385] Example 43

[0386] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridine[4,3- d]pyrimidin-3(4H)-yl)cyclohexanecarboxamide

[0387] Step 1

[0388] 4-azido-2-chloronicotinic acid methyl ester Methyl 2-chloro-4-iodonicotinate (448 mg, 1.51 mmol) was dissolved in N- methylpyrrolidine (7.53 mL) to which was added potassium carbonate (312 mg, 2.26 mmol) and sodium azide (108 μL, 1.66 mmol) and the reaction mixture was stirred at 100 °C for 20 minutes. The reaction mixture was added to saturated sodium bicarbonate solution and extracted 3 times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography (50 g column, eluent: ethyl acetate / n-hexane 2% to 60%) to give 4-azido-2-chloronicotinic acid methyl ester (149 mg, 47%) as a white solid. LCMS ESI m / z 185.0 [M-N2] + . 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 5.6Hz, 1H), 7.07 (d, J = 5.6 Hz, 1H), 3.97 (s, 3H)。

[0389] Step 2

[0390] 4-amino-2-methylnicotinic acid methyl ester To a microwave tube was added potassium carbonate (194 mg, 1.40 mmol), methyl-4-azido-2-chloronicotinate (149 mg, 701 µmol) and trimethylboroxine (148 uL, 1.05 mmol), followed by 1,4-dioxane (5.84 mL) and water (1.17 mL), purged with nitrogen for 15 minutes before adding palladium (1,1-bis(diphenylphosphino)ferrocene dichloride (52.3 mg, 70.1 µmol) under a nitrogen atmosphere, sealing the microwave tube and stirring at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and directly loaded onto a silica gel dry column before purification by silica gel column chromatography (eluent: (20% methanol in dichloromethane) / dichloromethane 0% to 60%) to give 4-amino-2-chloronicotinic acid methyl ester (104 mg, 79% yield) as a brown solid. LCMS ESIm / z 186.9 [M+H] + .

[0391] Step 3

[0392] 4-amino-2-methylnicotinic acid methyl ester To a microwave tube was added potassium carbonate (148 mg, 1.07 mmol), methyl-4-amino-2-chloronicotinate (100 mg, 536 µmol) and trimethylboroxine (114 uL, 804 µmol), followed by 1,4-dioxane (4.47 mL) and water (893 µL), purged with nitrogen for 15 minutes before adding palladium (1,1-bis(diphenylphosphino)ferrocene dichloride (40.0 mg, 53.6 µmol) under a nitrogen atmosphere, sealing the microwave tube and stirring at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and directly loaded onto a silica gel dry column before purification by silica gel column chromatography (eluent: (20% methanol in dichloromethane) / dichloromethane, 0% to 60%) to give 4-amino-2-methylnicotinic acid methyl ester (79.4 mg, 89% yield) as a brown solid. LCMS ESI m / z 167.1 [M+H] + .

[0393] Step 4

[0394] (4-amino-2-methylpyridin-3-yl)methanol Methyl 4-amino-2-methylnicotinate (79.4 mg, 478 µmol) was dissolved in tetrahydrofuran (2.39 mL), to which was added 2M lithium borohydride tetrahydrofuran solution (717 uL, 1.43 mmol), the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added saturated sodium bicarbonate solution, extracted with ethyl acetate 3 times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude (4-amino-2-methylpyridin-3-yl)methanol (46.4 mg, yield 70%) as a brown oil, which was used in the next step without purification. LCMS ESI m / z 138.9 [M+H] + .

[0395] Step 5

[0396] 4-amino-2-methylnicotinaldehyde (4-amino-2-methylpyridin-3-yl)methanol (46.4 mg, 336 µmol) was dissolved in dichloromethane (1.68 mL), to which was added activated manganese dioxide (162 mg, 1.68 mmol), the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, eluted with dichloromethane. The filtrate was concentrated to dryness to give 4-amino-2-methylnicotinaldehyde (16.1 mg, yield 35%) as a light brown oil, which was used in the next step without purification. LCMS ESI m / z 137.0 [M+H] + .

[0397] Step 6

[0398] (1s,4s)-4-(((4-amino-2-methylpyridin-3-yl)methyl)amino)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide 4-Amino-2-methylnicotinaldehyde (16.0 mg, 118 µmol) and (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (30.8 mg, 118 µmol) were added to a flask, followed by the addition of 1,2-dichloroethane (783 µL) and then acetic acid. The reaction mixture was stirred at 50°C for 16 hours, and then sodium triacetoxyborohydride (74.4 mg, 353 µmol) was added in a single batch. The reaction mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, methanol was added, and the solution was concentrated to dryness to obtain the crude product. The crude product was purified by C18 reversed-phase column chromatography (30 g column, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, pH=3.8, 0% to 60%). The pure fraction was directly lyophilized to give (1s,4s)-4-(((4-amino-2-methylpyridin-3-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (20.7 mg, yield 46%), as a white solid. LCMS ESI m / z 383.1 [M+H] + .

[0399] Step 7

[0400] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridin[4,3-d]pyrimidin-3(4H)-yl)cyclohexaneformamide (1s,4s)-4-(((4-amino-2-methylpyridin-3-yl)methyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (20.7 mg, 54.1 µmol) was suspended in dichloromethane (1 mL), and triphosgene (5.74 mg, 18.9 µmol) was added, followed by the slow dropwise addition of triethylamine (15.2 μL, 108 µmol) dissolved in 0.5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours until the starting material was completely converted. The reaction mixture was then concentrated to dryness, and the crude product was purified by C18 reversed-phase column chromatography (30 g column, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, pH=3.8, 2% to 60%). The purest fraction was directly lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydropyridin[4,3-d]pyrimidin-3(4H)-yl)cyclohexaneformamide (10.7 mg, 48% yield), as a white solid. LCMS ESI m / z 409.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ 9.69 (s, 1H), 9.47 (s, 1H), 8.18 (s, 1H), 8.02 (d, J = 5.4 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.10 (dd, J = 8.1, 1.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 5.4 Hz, 1H), 4.26 (s, 2H), 4.23 – 4.13 (m, 1H), 3.73 (s, 3H), 2.62 – 2.57 (m, 1H), 2.27 (s, 3H), 2.11(d, J = 13.2 Hz, 2H), 2.06 (s, 3H), 2.03 – 1.93 (m, 2H), 1.70 – 1.58 (m, 2H), 1.45 (dd, J = 12.1, 3.2 Hz, 2H).

[0401] Example 44

[0402] (1s,4s)-4-(8-(azacyclobutane-3-ylmethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0403] Step 1

[0404] 1-tert-butyl3-(((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)oxy)methyl)azacyclobutane To a dry, nitrogen purged 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(8-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide prepared in Example 61 (15.0 mg, 17.7 µmol) and anhydrous N,N-dimethylformamide (177 µL), purged with nitrogen for 5 minutes before the addition of tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (7.00 μL, 53.7 µmol) and cesium carbonate (6.48 mg, 19.5 µmol) were added sequentially. The microwave tube was sealed and stirred at 80 °C for 2 hours, after which time the reaction was cooled to room temperature and exposed to air open to the atmosphere to give a black crude product which was purified by C18 reverse phase column chromatography (12g SNAP Ultra, mobile phase: acetonitrile / 10 mM aqueous ammonium formate, pH = 3.8, 0% to 90%) to give 1-tert-butyl 3-(((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)oxy)methyl)azetidine (6.50 mg, 62%) as a light brown solid. LCMS ESI m / z 593.2 [M+H] + .

[0405] Step 2

[0406] (1s,4s)-4-(8-(azetidin-3-ylmethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide To a 20 mL reaction vial was added 1-tert-butyl 3-( ((3-((1s,4s)-4-((3-methoxy-4- methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)oxy) methyl)azetidine (6.50 mg, 11.0 µmol) to which was added slowly dropwise a solution containing 5% trifluoroacetic acid in hexafluoroisopropanol (2 mL) and the reaction stirred for 1 hour. The reaction was concentrated to give a translucent oil. The crude product was purified by Bitoage purification system (12 g C18 column, mobile phase: acetonitrile / 10 mM ammonium formate in water, pH=3.8, 0% to 70%) and directly lyophilized to give (1s,4s)-4-(8-(azetidin-3-ylmethoxy)-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide formate salt (5.20 mg, 82% yield) as a white solid. LCMS ESI m / z 493.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.39 (s, 1H), 8.23 (s,1H), 7.27 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 4.29 – 4.13 (m, 1H), 4.21 (s, 2H),4.02 (d, J = 4.2 Hz, 2H), 3.91 (t, J = 9.1 Hz, 2H), 3.79-3.69 (m, 2H), 3.73 (s,3H), 3.16-3.08 (m, 1H), 2.67-2.60 (m, 1H), 2.16 – 2.03 (m, 2H), 2.10 (s, 3H),2.06 (s, 3H), 2.01-1.93 (m, 2H), 1.72-1.60 (m, 2H), 1.48 – 1.40 (m, 2H).

[0407] Example 45

[0408] ((1s,4s)-4-(8-(azetidin-3-yloxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0409] Step 1

[0410] 1-tert-butyl 3-((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5- methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)oxy)azetidine-1-carboxylate To a dry, nitrogen purged 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(8-hydroxy-5- methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 61 (15.0 mg, 35.4 µmol), N,N-dimethylformamide (177 µL) was added for dilution, purged with nitrogen for 5 minutes, 1-tert-butoxycarbonyl-3-iodoazetidine (13.3 μL, 107 µmol) and cesium carbonate (13.0 mg, 39.0 µmol) were added sequentially. The reaction vial was sealed with a microwave cap and stirred at 100 °C overnight. Additional cesium carbonate (13.0 mg, 39.0 µmol) was added and stirring was continued for 30 minutes, the reaction was then cooled to room temperature and exposed to air open to the atmosphere to give a black residue crude product which was isolated and purified by C18 reverse phase column chromatography (12 g column, mobile phase: acetonitrile / 10 mM ammonium formate in water pH = 3.8, 0% to 70%). Fractions containing the desired compound were combined and the solvent was evaporated to give tert-butyl 3-((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5- methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)oxy)azetidine-1-carboxylate (13.5 mg, 66% yield) as a light brown solid which was used directly in the next step (deprotection). LCMS ESI m / z 479.2 [M-Boc] + .

[0411] Step 2

[0412] ((1s,4s)-4-(8-(azetidin-3-yloxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide To a 20 mL reaction vial was added 1-tert-butyl 3-((3-((1s,4s)-4-((3-methoxy-4- methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-8-yl)oxy) azetidine (13.5 mg, 23.3 pmol) and to this was slowly added a solution of 5% trifluoroacetic acid in hexafluoroisopropanol (2 mL). After stirring for 1 hour, the reaction was concentrated to give a translucent oil. The crude product was lyophilized from a mobile phase of acetonitrile / 10 mM ammonium formate in water, pH = 3.8, 0% to 70% gradient elution to give ((1s,4s)-4-(8-(azetidin-3-yloxy)-5-methyl-2-oxo-1,2-dihydroquinolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (6.50 mg, 51% yield) as a white solid as the formate salt. LCMS ESI m / z 479.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.70(s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.10 (dd, J = 8.1, 1.8 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H), 4.98-4.86 (m, 1H), 4.28-4.15 (m, 1H), 4.21 (s, 2H), 3.98-3.86(m, 2H), 3.79-3.67 (m, 2H), 3.73 (s, 3H), 3.55-3.19 (m, 1H), 2.67-2.60 (m,1H), 2.15 – 2.03 (m, 2H), 2.09 (s, 3H), 2.06 (s, 3H), 2.02-1.93 (m, 2H),1.71-1.59 (m, 2H), 1.49-1.40 (m, 2H).

[0413] Example 46

[0414] (1s,4s)-4-(6-amino-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0415] Step 1

[0416] (1s,4s)-4-(6-amino-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide To a dry, nitrogen purged 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(6-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide prepared in Example 63 (50.0 mg, 103 µmol) and diluted with 1,4-dioxane (514 mL). After purging the solvent with nitrogen for 5 minutes, to this was added tert-butyl carbamate (24.6 mg, 206 µmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.05 mg, 10.3 µmol), cesium carbonate (37.6 mg, 113 µmol) and methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium (8.97 mg, 10.3 µmol). The vial was sealed with a microwave cap and heated at 100 °C overnight. After the reaction was cooled to room temperature, the resulting crude suspension was directly subjected to deprotection reaction. LCMS ESI m / z 523.3 [M+H] + .

[0417] Step 2

[0418] (1s,4s)-4-(6-amino-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide Dioxane hydrochloride (257 µL, 1.03 mmol) was added directly to crude (3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-yl)carbamate (53.7 mg, 103 µmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to obtain crude product, which was purified by gradient elution with acetonitrile / ammonium bicarbonate aqueous solution, pH=10, 0% to 80%, and directly lyophilized to give (1s,4s)-4-(6-amino-5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (26.0 mg, two-step yield 59%) as a white solid. LCMS ESI m / z 423.3 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 8.64 (s, 1H), 7.28 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 8.5 Hz, 1H), 4.41 (s, 2H), 4.24-4.13 (m, 1H), 4.16 (s, 2H), 3.74 (s, 3H), 2.66-2.60 (m, 1H), 2.16 – 1.96 (m, 4H), 2.07 (s, 3H), 1.88 (s, 3H), 1.68-1.56 (m, 2H), 1.43-1.40 (m, 2H).

[0419] Example 47

[0420] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0421] Step 1

[0422] To a dry, nitrogen purged 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(8- hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 61 (15.0 mg, 35.4 µmol) and diluted with anhydrous N,N-dimethylformamide (177 uL), the solvent was purged with nitrogen for 5 minutes before iodomethane (6.68 μL, 106 µmol) and cesium carbonate (13.0 mg, 39.0 µmol) were added sequentially. The reaction vial was sealed with a microwave cap and heated at 80 °C for 2 hours. After the reaction had cooled to room temperature the cap was removed and evaporated to give a brown crude product which was isolated and purified by C18 reverse phase column chromatography (12g column, mobile phase: acetonitrile / 10 mM ammonium formate in water pH = 3.8, 0% to 70%) and the fractions containing the desired compound were combined and lyophilized overnight to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(8-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (6.30 mg, 38% yield) as a white solid. LCMS ESI m / z 438.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69(s, 1H), 7.73 (s, 1H), 7.27 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.1Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 4.27 – 4.07 (m,1H), 4.20 (s, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 2.67-2.61 (m, 1H), 2.15-2.03(m, 2H), 2.09 (s, 3H), 2.06 (s, 3H), 2.03-1.93 (m, 2H), 1.71-1.59 (m, 2H),1.49-1.39 (m, 2H).

[0423] Example 48

[0424] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(6-(methoxymethyl)-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0425] Step 1

[0426] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(6-(methoxymethyl)-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a dry, nitrogen filled 0.5-2.0 mL Biotage vial was added (1s,4s)-4-(6-bromo-5- methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl) cyclohexanecarboxamide prepared in Example 63 (200 mg, 411 µmol), 1,4- dioxane (2.05 mL) and water (205 µL). After purging the solvents with nitrogen for 5 minutes, methoxymethylpotassium trifluoroborate (375 mg, 1.23 mmol) and 2- dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (29.4 mg, 61.7 µmol), (2- dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (54.3 mg, 61.7 µmol) and cesium carbonate (402 mg, 1.23 mmol) were added sequentially. The reaction vial was sealed with a microwave cap and after stirring at 100 °C overnight, the reaction was allowed to cool to room temperature before venting to allow the solvents to evaporate to give a crude product. The crude product was purified by HPLC eluting with a mobile phase of acetonitrile / 10 mM aqueous ammonium formate, pH = 3.8, 0% to 70% gradient, the product eluting at 40% of the gradient, and lyophilized to give (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(6-(methoxymethyl)-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (8.50 mg, 4.2% yield) as a white solid. LCMS ESI m / z 452.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.09 (s,1H), 7.27 (s, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.01 (d, J =8.1 Hz, 2H), 6.53 (d, J = 7.0 Hz, 1H), 4.27 (s, 2H), 4.23-4.13 (m, 1H), 4.23 (s, 2H), 3.74 (s, 3H),3.21 (s, 3H), 2.63 – 2.61 (m, 1H), 2.15-2.04 (m, 2H), 2.08 (s, 3H), 2.07 (s,3H), 2.03-1.92 (m, 2H), 1.69-1.60 (m, 2H), 1.48-1.40 (m, 2H)。

[0427] Example 49

[0428] (1s,4s)-4-(6-(azetidin-3-yloxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0429] Step 1

[0430] 1-tert-butoxycarbonyl 3-((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5- methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)oxy)azetidine Add (1s,4s)-4-(6-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (15.0 mg, 35.4 µmol) prepared in Example 60 to a dry, nitrogen-filled 0.5–2.0 mL Biotage reaction flask, and dilute with anhydrous N,N-dimethylformamide (177 µL). After purging the solvent with nitrogen for 5 min, add cesium carbonate (17.7 mg, 53.1 µmol) and 1-Boc-3-iodozacyclobutane (30.1 mg, 106 µmol) sequentially. Seal the reaction flask with a microwave-safe cap and heat with stirring at 80 °C for 4 h. After the reaction was cooled to room temperature, the container was opened and ventilation was provided to allow the solvent to evaporate, yielding the crude product. The crude product was purified by C18 reversed-phase column chromatography (mobile phase: acetonitrile / 10mM ammonium formate aqueous solution, pH=3.8, 0% to 70%), and evaporated to dryness to give 1-tert-butyl3-((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)oxo)azacyclobutane (18.0 mg, yield 87%), as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 8.92 (s, 1H), 7.27 (s, 1H), 7.09 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.50 (dd, J = 17.5, 8.7 Hz, 2H), 4.86 – 4.76 (m, 1H), 4.26-4.13 (m, 4H), 3.77-3.69(m, 4H), 2.70-2.51 (m, 3H), 2.14-1.92 (m, 4H), 2.06 (s, 3H), 2.02 (s, 3H), 1.70-1.58 (m, 2H), 1.47-1.32 (m, 2H), 1.36 (s, 9H).

[0431] Step 2

[0432] (1s,4s)-4-(6-(azacyclobutane-3-yloxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide To a 20 mL reaction vial was added 1-tert-butyl 3-((3-((1s,4s)-4-((3-methoxy-4- methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)oxy)azetidine (18.0 mg, 31.1 µmol), to which was added 5% trifluoroacetic acid in hexafluoroisopropanol (2 mL) slowly, after the reaction was stirred for 1 hour, the solvent was evaporated to give a translucent oil crude, the crude was separated and purified by gradient elution with mobile phase: acetonitrile / 10 mM ammonium formate in water pH=3.8, 0% to 70% and the purified fractions were lyophilized to give (1s,4s)-4-(6-(azetidin-3-yloxy)-5-methyl-2-oxo-1,2-dihydroquinolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (4.50 mg, 28% yield) as a white solid as a formate salt. LCMS ESI m / z 479.4 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6)δ 9.69 (s, 1H), 8.91 (s, 1H), 8.26 (s, 1H), 7.26 (d, J = 1.3 Hz, 1H), 7.09(dd, J = 8.0, 1.5 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.47 (q, J = 8.7 Hz, 2H),4.82 (p, J = 6.6 Hz, 1H), 4.26 –4.10 (m, 1H), 4.19 (s, 2H), 3.86 (t, J = 7.6Hz, 2H), 3.73 (s, 3H), 3.58 (dd, J = 8.2, 6.7 Hz, 2H), 2.67-2.59 (m, 1H),2.14-2.04 (m, 2H), 2.06 (s, 3H), 2.04-1.91 (m, 2H), 2.02 (s, 3H), 1.69-1.56(m, 2H), 1.46-1.36 (m, 2H).

[0433] Example 50

[0434] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-6-(2-morpholinoethoxy)-2- oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0435] Step 1

[0436] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-6-(2-morpholinoethoxy)-2- oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a dry, nitrogen-purged 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(6- hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide prepared in Example 60 (15.0 mg, 35.4 µmol) and anhydrous N,N-dimethylformamide (177 uL). After purging the solvent with nitrogen for 5 minutes, 4-(2-bromoethyl)morpholine hydrobromide (29.2 mg, 106 µmol) and cesium carbonate (35.3 mg, 106 µmol) were added sequentially. The reaction vial was sealed with a microwave cap and heated to 80 °C for 4 hours with stirring before being terminated. The crude product was isolated and purified by C18 reverse phase column chromatography (mobile phase: acetonitrile / 10 mM aqueous ammonium formate pH = 3.8, 0% to 70%) followed by rotary evaporation to give a solid powder, which was further purified by 12 g C18 reverse phase column chromatography (mobile phase: acetonitrile / 10 mM aqueous ammonium bicarbonate pH = 10, 20% to 90%). Lyophilization gave (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-6-(2-morpholinoethoxy)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (1.70 mg, 8.0% yield) as a white solid. LCMS ESI m / z 537.5 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6+D2O) δ 9.73 (s, 1H), 8.84 (s, 1H), 8.38 (s,1H), 7.23 (s, 1H), 7.05-6.98 (m, 2H), 6.73 (d, J = 8.8 Hz, 2H), 6.51 (d, J= 8.9 Hz, 2H), 4.21 (s, 2H), 4.21-4.09 (m, 1H), 3.94 (t, J = 5.7 Hz, 2H), 3.71(s, 3H), 3.54 – 3.50 (m, 4H), 2.63-2.59 (m, 3H), 2.42-2.40 (m, 2H), 2.11-1.88(m, 10H), 1.67-1.55 (m, 2H), 1.45-1.38 (m, 2H)。

[0437] Example 51

[0438] (1s,4s)-N-(3-ethoxy-4-methoxyphenyl)-4-(6-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0439] Step 1

[0440] (1s,4s)-N-(3-ethoxy-4-methoxyphenyl)-4-(6-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a dry, nitrogen-purged 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(6-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 60 (10.0 mg, 23.6 µmol) and anhydrous N,N-dimethylformamide (118 uL). After purging the solvent with nitrogen for 5 minutes, iodomethane (2.97 μL, 47.2 µmol) and cesium carbonate (7.85 mg, 23.6 µmol) were added sequentially. The microwave tube was sealed with a microwave cap, stirred at 50 °C for 1 hour and monitored by LCMS for completion of the reaction. After cooling the reaction to room temperature and exposing to air, the crude product was isolated and purified by C18 reverse phase column chromatography (12 g column, mobile phase: acetonitrile / ammonium bicarbonate in water pH=10, 0% to 80%). Lyophilization afforded (1s,4s)-N-(3-ethoxy-4-methoxyphenyl)-4-(6-methoxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (6.50 mg, 63% yield) as a white solid. LCMS ESI m / z 438.3 [M+H]+ 1H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 8.89 (s, 1H),7.27 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H), 4.23-4.13 (m, 2H), 3.73 (s, 3H), 3.67(s, 3H), 2.62-2.57 (m, 1H), 2.12-2.03 (m, 2H), 2.06 (s, 3H), 2.02 – 1.92 (m,2H), 1.99 (s, 3H), 1.68-1.57 (m, 2H), 1.46-1.38 (m, 2H).

[0441] Example 52

[0442] (1s,4s)-4-(8-((dimethylamino)methyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide

[0443] Step 1

[0444] (1s,4s)-4-(8-formyl-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide To a 20 mL scintillation vial was added (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-8-vinyl-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide prepared in Example 55 (30.0 mg, 69.2 µmol) and sodium periodate (44.9 mg, 208 µmol), followed by acetonitrile (346 uL), followed by ruthenium trichloride hydrate (144 ug, 0.69 µmol) dissolved in 346 uL water. The mixture was stirred at room temperature overnight, followed by addition of ruthenium trichloride hydrate (144 ug, 0.69 µmol) and stirring for an additional 3 hours. The reaction was diluted with ethyl acetate (20 mL) and water (10 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give crude (1s,4s)-4-(8-formyl-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (30.1 mg, 100% yield) as a green oil which was used directly in the next step without purification. LCMS ESI m / z 436.5 [M+H] + .

[0445] Step 2

[0446] (1s,4s)-4-(8-((dimethylamino)methyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide To a 20 mL scintillation vial was added crude (ls,4s)-4-(8-formyl-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (30.1 mg, 69.2 µmol), 1,2-dichloroethane (692 µL), followed by dimethylamine ethanol solution (61.8 µL, 346 µmol, 5.8 M) and acetic acid (0.795 µL, 13.8 µmol), the reaction was sealed and heated to 50 °C for 30 minutes with stirring, then sodium triacetoxyborohydride (75.2 mg, 346 µmol) was added, and stirring was continued at 50 °C for 3 hours. The reaction was then quenched by solvent evaporation, the resulting crude was directly loaded onto a C18 reverse phase column for separation and purification (mobile phase: acetonitrile / ammonium bicarbonate aqueous solution pH=10, 0% to 80%). The pure fractions were lyophilized to give (ls,4s)-4-(8-(dimethylaminomethyl)-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (3.90 mg, 12% yield) as a white solid. LCMS ESI m / z 465.4 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 8.75 (s,1H), 7.27 (d, J = 1.7 Hz, 1H), 7.09 (dd, J = 7.9, 1.8 Hz, 1H), 7.00 (d, J = 8.2Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 4.26 – 3.98 (m,3H), 3.73 (s, 3H), 3.38 (s, 2H), 2.62-2.56 (m, 1H), 2.16 (s, 3H), 2.13 (s,6H), 2.16-2.04 (m, 2H), 2.06 (s, 3H), 2.02-1.94 (m, 2H), 1.70-1.59 (m, 2H),1.47-1.41 (m, 2H).

[0447] Example 53

[0448] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-6-vinyl-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0449] Step 1

[0450] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-6-vinyl-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a dry, nitrogen filled 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(6-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (100 mg, 206 µmol) and N,N- dimethylformamide (1.03 mL). After purging the solvent with nitrogen for 5 minutes, 97% tributylvinyltin (92.9 µL, 308 µmol) and tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 20.6 µmol) were added sequentially. The microwave tube was sealed with a microwave cap and stirred at 100 °C for 3 hours. After the reaction was cooled to room temperature, the cap was opened and vented to obtain a black residue crude. The crude was isolated and purified by C18 reverse phase column chromatography (30 g SNAP Ultra, mobile phase: 10 mM ammonium formate in water, pH = 10 / acetonitrile, 100% to 70%) to collect the target product, but the product contained triphenylphosphine oxide impurity. The further separation and purification was continued with C18 column (10 mM ammonium formate in water, pH = 10 / acetonitrile, 70% to 20%) to dry the pure component to obtain (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-6-vinyl-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (42.0 mg, 47% yield) as a white solid. LCMS ESI m / z 434.4 [M+H] + LCMS ESI m / z 434.4 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 9.12 (s, 1H), 7.27-7.25(m, 2H), 7.09 (d, J = 7.7 Hz, 1H), 7.00 (d, J =7.9 Hz, 1H), 6.89 (dd, J = 17.4,11.0 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 5.48 (d, J = 16.9 Hz, 1H), 5.13 (d, J = 11.1 Hz, 1H), 4.30 – 4.10 (m, 3H), 3.73 (s, 3H), 2.66-2.60 (m, 1H), 2.14-2.06(m, 2H), 2.14 (s, 3H), 2.06 (s, 3H), 2.03 – 1.93 (m, 2H), 1.69-1.57 (m, 2H),1.47-1.38 (m, 2H).

[0451] Example 54

[0452] (1s,4s)-4-(8-(hydroxymethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0453] Step 1

[0454] (1s,4s)-4-(8-(hydroxymethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide To a 100 mL round bottom flask was added crude (1s,4s)-4-(8-formyl-5-methyl-2-oxo- 1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in example 52 (26.9 mg, 61.7 µmol) and dissolved in methanol (617 uL). To this was added sodium borohydride (11.7 uL, 308 µmol) and stirred at room temperature for 5 minutes until the reaction was fully converted. The solvent was evaporated to give a crude product which was isolated and purified by C18 reverse phase column chromatography (30g SNAP Ultra column, mobile phase: acetonitrile / 10 mM ammonium formate in water pH=3.8, 0% to 70%) and the fractions were combined and evaporated to give a white solid which was purified twice, first by C18 column (30g SNAP Ultra column, mobile phase: acetonitrile / ammonium bicarbonate in water pH=10, 0% to 70%) and then by silica gel column chromatography (mobile phase: ethyl acetate / n-hexane, 50% to 100%) to give (1s,4s)-4-(8-(hydroxymethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (5.1 mg, 19% yield). LCMS ESI m / z 438.4 [M+H] + .1H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 8.02 (s, 1H), 7.27 (d, J = 1.5 Hz,1H), 7.09 (dd, J = 7.7, 1.7 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 7.8Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 5.28 (t, J = 5.4 Hz, 1H), 4.44 (d, J = 5.2Hz, 2H), 4.26 – 4.12 (m, 3H), 3.73 (s, 3H), 2.64 – 2.60 (m, 1H), 2.17-2.02(m, 2H), 2.13 (s, 3H), 2.06 (s, 3H), 2.02-1.93 (m, 2H), 1.70-1.58 (m, 2H),1.49-1.41 (m, 2H).

[0455] Example 55

[0456] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-8-vinyl-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide

[0457] Step 1

[0458] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-8-vinyl-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide To a dry, nitrogen filled 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide prepared in Example 34 (100 mg, 206 µmol) and N,N-dimethylformamide (1.03 mL). After purging the solvent with nitrogen for 5 minutes, tributyl(vinyl)tin, 97% (92.9 µL, 308 µmol) and tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 20.6 µmol) were added sequentially. The microwave tube was sealed with a microwave cap and heated to 100 °C for 3 hours with stirring. After the reaction was cooled to room temperature, the cap was removed and the mixture was vented to yield a black residue crude product. The crude product was isolated and purified by C18 reverse phase column chromatography (30 g SNAP Ultra column, mobile phase: acetonitrile / 10 mM ammonium formate in water, 0% to 70%) but the resulting product contained triphenylphosphine oxide impurities. The isolation and purification was repeated using an elution gradient (mobile phase: acetonitrile / 10 mM ammonium formate in water, 30% to 80%). The resulting fractions were evaporated to dryness to yield (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-8-vinyl-1,2- dihydroquinazolin-3(4H)-yl)cyclohexanecarboxamide (39.0 mg, 44% yield) as a white solid. LCMS ESI m / z 434.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 9.70 (s, 1H), 8.64 (s, 1H), 8.35 (s, 1H), 7.28-7.25(m, 2H), 7.16-7.08 (m,2H), 7.00 (d, J =8.5 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H),5.61 (d, J = 16.9 Hz, 1H), 5.16 (d, J = 12.2 Hz, 1H), 4.21-4.13 (m, 3H), 3.73(s, 3H), 2.68-2.61 (m, 1H), 2.19 – 2.02 (m, 8H), 2.01-1.94 (m, 2H), 1.70-1.60(m, 2H), 1.49-1.41 (m, 2H).

[0459] Example 56

[0460] (1s,4s)-4-(6-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide

[0461] Step 1

[0462] (1s,4s)-4-(6-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide To a dry, nitrogen-purged 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(6-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide prepared in Example 63 (20.0 mg, 41.1 pmol) and N,N- dimethylacetamide (548 pL). After purging the solvent with nitrogen for 5 minutes, tris(dibenzylideneacetone)dipalladium(0) (7.53 mg, 8.22 pmol) and zinc (0.54 mg, 8.22 pmol), zinc cyanide (9.66 mg, 82.2 pmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (8.08 mg, 16.4 pmol) were added. The reaction vial was sealed with a microwave cap and microwaved at 130 °C for 30 minutes. After the reaction was cooled to room temperature, the cap was opened and vented, and directly separated and purified by a C18 reverse-phase separation column (12 g SNAP Ultra column, mobile phase: acetonitrile / ammonium bicarbonate in water pH = 10, 0% to 70%) and the fractions containing the desired product were combined and lyophilized to dryness to give (1s,4s)-4-(6-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (26.0 mg, 66% yield) as a white solid. LCMS ESI m / z 433.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 9.60 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.10 (dd, J = 7.9, 1.8 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 4.28 (s, 2H), 4.20-4.13 (m, 1H), 3.73 (s, 3H), 2.63 (br s,1H), 2.30 (s, 3H), 2.15 – 2.03 (m, 2H), 2.06 (s, 3H), 2.02-1.95 (m, 2H),1.68-1.60 (m, 2H), 1.45-1.43 (m, 2H).

[0463] Example 57

[0464] (1s,4s)-4-(6-(Aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0465] Step 1

[0466] ((3-((1s,4s)-4-((3-Methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2- oxo-1,2,3,4-tetrahydroquinazolin-6-yl)methyl)carbamic acid tert-butyl ester To a dry, nitrogen-purged microwave tube was added (1s,4s)-4-(6-bromo-5-methyl-2- oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 63 (40.0 mg, 82.2 µmol), 1,4-dioxane (411 uL) and ethylene glycol (411 uL). After purging the solvents with nitrogen for 5 minutes, chloro[(n- butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (5.61 mg, 8.22 µmol) and DIPEA (31.8 µL, 181 µmol) and potassium N-aminomethyltrifluoroborate (40.2 mg, 164 µmol) were added sequentially. The microwave tube was sealed with a microwave cap and stirred at 100 °C for 1 hour after which the reaction was cooled to room temperature and unsealed to give a black residue which was extracted with ethyl acetate (30 mL) and transferred to a 60 mL separatory funnel, partitioned with saturated brine, the ethyl acetate phase was washed with saturated brine (30 mL x 2), dried over sodium sulfate, filtered and concentrated to dryness to give a black residue crude ((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2- oxo-1,2,3,4-tetrahydroquinazolin-6-yl)methyl)carbamic acid tert-butyl ester (44.1 mg, 100% yield). LCMS ESI m / z 537.2 [M+H] + The crude product was used directly in the next step without purification.

[0467] Step 2

[0468] (1s,4s)-4-(6-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide To a 20 mL reaction vial was added ((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)methyl)carbamic acid tert-butyl ester (44.1 mg, 82.2 µmol) and a solution of hydrochloric acid in dioxane (20.6 µL, 82.2 µmol). After stirring at room temperature for 30 minutes, the reaction was complete and concentrated to give a crude product. The crude product was purified by HPLC with mobile phase: acetonitrile / 10 mM ammonium formate pH=3.8, 0% to 70% gradient elution, the product eluted at a ratio of 40%, and lyophilized to give (1s,4s)-4-(6-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (13.0 mg, 36% yield over two steps) as a white solid. LCMS ESI m / z 537.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.71 (s,1H), 9.10 (s, 1H), 8.34 (s, 1H), 7.28 (s, 1H), 7.09 (t, J = 7.5 Hz, 2H), 7.01(d, J = 8.0 Hz, 1H), 6.57 (d, J = 7.7 Hz, 1H), 4.23 (s, 2H), 4.23-4.19 (m, 1H),3.78-3.74 (m, 2H), 3.74 (s, 3H), 2.64 (br s, 1H), 2.12 (s, 3H), 2.07 (s, 3H),2.12-2.04 (m, 2H), 2.04-1.92 (m, 2H), 1.70-1.57 (m, 2H), 1.48-1.38 (m, 2H).

[0469] Example 58

[0470] (1s,4s)-4-(8-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0471] Step 1

[0472] ((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2- oxo-1,2,3,4-tetrahydroquinazolin-8-yl)methyl)carbamic acid tert-butyl ester To a dry, nitrogen-purged 0.5-2.0 mL Biotage reaction vial was added (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide prepared in Example 62 (40.0 mg, 82.2 µmol) diluted with 1,4-dioxane (411 uL) and ethylene glycol (411 uL). After purging the solvents with nitrogen for 5 minutes, chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2- aminobiphenyl)]palladium(II) (5.61 mg, 8.22 µmol) and diisopropylethylamine (31.8 µL, 181 µmol) and potassium N-amino methyltrifluoroborate (40.2 mg, 164 µmol) were added sequentially. After stirring at 100 °C for 1 hour with a microwave cap, the microwave tube was cooled to room temperature and vented to air to give a black residue crude. Extraction with ethyl acetate (30 mL) and transfer to a 60 mL separatory funnel, partitioned with saturated brine, the ethyl acetate phase was washed with saturated brine (30 mL x 2), dried over sodium sulfate, filtered and concentrated to dryness to give a black residue crude ((3-((1s,4s)-4-((3-methoxy-4-methylphenyl)carbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4- tetrahydroquinazolin-8-yl)methyl)carbamic acid tert-butyl ester (44.1 mg, 100% yield) which was used directly for the next step and purification.

[0473] Step 2

[0474] (1s,4s)-4-(8-(Aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide Add tert-butyl carbamate (22.1 mg, 41.1 µmol) and 4M dioxane hydrochloride solution (10.3 µL, 41.1 µmol) to a 20 mL reaction flask. The reaction was stopped after stirring at room temperature for 30 minutes. The crude target product was obtained after concentration and drying. It was then purified using a Biotage purification system (C18 column, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, pH 3.8, 0% to 70%). The product was eluted at 40% concentration and lyophilized to give (1s,4s)-4-(8-(aminomethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (5.00 mg, two-step yield 25%) as a white solid. LCMS ESI m / z 437.2 [M+H] + , 1 H NMR (400 MHz, DMSO- d 6)δ 9.70 (s, 1H), 9.15 (s, 1H), 8.26 (s, 3H), 7.27 (d, J = 1.6 Hz, 1H), 7.10 (dd, J = 8.1, 1.7 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 4.25 –4.14 (m, 3H), 3.82 (s, 2H), 3.73 (s, 3H), 2.64(br s, 1H), 2.17-2.08 (m, 2H), 2.14 (s, 3H), 2.02 (s, 3H), 2.02-1.94 (m, 2H), 1.71-1.60 (m, 2H), 1.47-1.41 (m, 2H).

[0475] Example 59

[0476] (1s,4s)-4-(8-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0477] Step 1

[0478] (1s,4s)-4-(8-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide To a dry, nitrogen-purged 0.5 mL-2 mL Biotage reaction vial prepared in Example 62 (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (30.0 mg, 61.7 µmol), cuprous cyanide (27.9 mg, 308 µmol) and anhydrous N,N-dimethylformamide (206 µL) were added, the mixture was purged with nitrogen for 5 minutes, then the vial was sealed and stirred at 150 °C for 6 hours. After the reaction was completed, the reaction was cooled to room temperature and directly separated and purified by C18 reverse phase column chromatography (30 g column, mobile phase: acetonitrile / ammonium bicarbonate aqueous solution pH=10, 0% to 70%). After lyophilizing to remove the solvent, (1s,4s)-4-(8-cyano-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide (5.40 mg, yield 19%) was obtained as a yellow powder. LCMS ESI m / z 433.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H),8.97 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.1, 1.8 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 4.25 (s,2H), 4.18-4.12 (m, 1H), 3.73 (s, 3H), 2.63 (br s, 1H), 2.22 (s, 3H), 2.13 –2.05 (m, 2H), 2.01 (s, 3H), 2.01-1.95 (m, 2H), 1.68-1.61 (m, 2H), 1.46 (br d, J =9.4 Hz, 2H).

[0479] Example 60

[0480] (1s,4s)-4-(6-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0481] Step 1

[0482] (1s,4s)-4-(6-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide Add (1s,4s)-4-(6-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (20.0 mg, 41.1 µmol) and 1,4-dioxane (411 µL) prepared in Example 63 to a dry, nitrogen-filled 0.5–2.0 mL Biotage reaction tube. After purging the solvent with nitrogen for 5 min, add 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (3.07 mg, 4.11 µmol), potassium acetate (12.4 mg, 123 µmol), and bis-pinacolborate (16.1 mg, 61.7 µmol) sequentially. Seal the reaction tube with a microwave-safe cap and stir overnight at 100 °C. After the reaction has cooled to room temperature, open the cap for ventilation. Methanol (1 mL) and urea peroxide (12.0 mg, 123 µmol) were added sequentially to a microwave tube, and the reaction was stirred for 30 minutes until completion. The reaction was then extracted with ethyl acetate (20 mL) and transferred to a 60 mL separatory funnel. The mixture was washed with water and the layers separated. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a black crude residue. The crude residue was purified by C18 reversed-phase column chromatography (12 g SNAP Ultra column, mobile phase: acetonitrile / 10 mM ammonium formate aqueous solution, pH=3.8, 0% to 70%). The fractions containing the target product were combined and lyophilized overnight to obtain (1s,4s)-4-(6-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (3.20 mg, yield 18%), a light brown solid. LCMS ESI m / z 424.1 [M+H] + . 1H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 8.82 (s, 1H), 8.76 (s, 1H), 7.27 (d, J = 1.3 Hz, 1H), 7.10 (dd, J = 8.0, 1.6 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 4.22-4.12 (m, 1H), 4.15 (s, 2H), 3.74 (s, 3H), 2.66-2.61 (m, 1H), 2.14-2.02 (m, 2H), 2.07 (s, 3H), 2.01-1.91 (m, 2H), 1.96 (s, 3H), 1.69-1.57 (m, 2H), 1.46-1.36 (m, 2H).

[0483] Example 61

[0484] (1s,4s)-4-(8-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0485] Step 1

[0486] (1s,4s)-4-(8-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide To a dry, nitrogen filled 0.5-2.0 mL Biotage reaction tube was added (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide prepared in Example 62 (30.0 mg, 61.7 µmol) and 1,4-dioxane (617 µL). After purging the solvent with nitrogen for 5 minutes, 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (4.61 mg, 6.17 µmol), potassium acetate (18.5 mg, 185 µmol) and bis(pinacolato)diboron (24.2 mg, 92.5 µmol) were added sequentially. The microwave tube was sealed with a microwave cap and stirred at 90 °C overnight. After the reaction was complete, the microwave tube was cooled to room temperature and vented. To the microwave tube was added methanol (1 mL) and urea hydrogen peroxide (17.9 mg, 185 µmol) sequentially and the reaction was complete after stirring for 30 minutes. The reaction was quenched with ethyl acetate (20 mL) and transferred to a 60 mL separatory funnel, washed with water and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a black residue crude which was purified by C18 reverse phase column chromatography (12 g SNAP Ultra column, mobile phase: acetonitrile / 10 mM ammonium formate in water pH = 3.8, 0% to 70%) and the fractions containing the desired product were combined and lyophilized overnight to give (1S,4S)-4-(8-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (6.20 mg, 23% yield) as a light brown solid. LCMS ESI m / z 424.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 9.36 (br s, 1H), 7.49 (s, 1H),7.27 (s, 1H), 7.10 (dd, J = 1.5, 7.5 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.60 –6.45 (m, 2H), 4.24 – 4.11 (m, 3H), 3.73 (s, 3H), 2.63 (br s, 1H), 2.06-2.00(m, 8H), 2.02 – 1.89 (m, 2H), 1.67-1.61 (m, 2H), 1.45-1.42 (m, 2H).

[0487] Example 62

[0488] (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0489] Step 1-7

[0490] (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide The synthesis of Example 62 has been described in the scheme and steps of Example 34. Following the described procedure (1s,4s)-4-(8-bromo-5-methyl-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (960 mg, yield 78%) was obtained as a white solid. LCMS ESI m / z 486.0, 488.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 7.74 (s, 1H), 7.29 (dd, J = 11.2, 4.8 Hz,2H), 7.09 (dd, J = 8.0, 1.7 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.3Hz, 1H), 4.25 (s, 2H), 4.17 (tt, J = 12.3, 4.2 Hz, 1H), 3.73 (s, 3H), 2.67-2.60 (m, 1H), 2.16 – 2.04 (m, 8H), 2.02 – 1.93 (m, 2H), 1.70-1.59 (m, 2H),1.48-1.42 (m, 2H).

[0491] Example 63

[0492] (1s,4s)-4-(6-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide

[0493] Step 1

[0494] 6-amino-3-bromo-2-methylbenzoic acid methyl ester A solution of methyl 2-amino-6-methylbenzoate (300 mg, 1.82 mmol) in N,N- dimethylformamide (3.63 mL) was cooled with an ice bath under stirring, to which a solution of N-bromosuccinimide (323 mg, 1.82 mmol) dissolved in N,N- dimethylformamide (3.63 mL) was added dropwise slowly. It was continued for about 30 minutes while keeping the reaction temperature between 0-5ºC, after the addition was completed, the reaction mixture was stirred at room temperature for about 20 hours, the reaction mixture was poured into 12 mL of sodium bicarbonate solution, ethyl acetate was added and transferred to a 125 mL separatory funnel, the phases were separated and the aqueous phase layer was extracted with ethyl acetate (20 mL x 3), the combined organic phase layers were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give crude methyl 6-amino-3-bromo-2-methylbenzoate (412 mg, yield 93%) as a transparent orange oil, which was used directly for the subsequent reaction. LCMS ESI m / z 244.0, 246.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.36(d, J = 8.7 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 2.43 (s, 3H).

[0495] Step 2

[0496] (6-amino-3-bromo-2-methylphenyl)methanol Methyl 6-amino-3-bromo-2-methylbenzoate (12.0 g, 49.2 mmol) was charged to a dry, nitrogen-filled round bottom flask to which was added anhydrous tetrahydrofuran (197 mL). Lithium aluminum hydride (2.80 g, 73.7 mmol) was added at 0 °C. The reaction was allowed to warm to room temperature and stirred for 20 hours. Sodium sulfate decahydrate was added portionwise until no gas evolution, followed by the addition of 2M aqueous sodium hydroxide and solid sodium sulfate. The suspension was stirred overnight to quench the aluminum salt and filtered through celite, the filter cake was rinsed with tetrahydrofuran (300 mL) and the filtrate was concentrated under reduced pressure to yield (6-amino-3-bromo-2-methylphenyl)methanol (8.30 g, 78% yield) as a yellow solid. LCMS ESI m / z 216.0, 218.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 7.13 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 8.6 Hz, 1H), 5.06 (s, 2H),4.80 (t, J = 5.4 Hz, 1H), 4.43 (d, J = 5.4 Hz, 2H), 2.30 (s, 3H)。

[0497] Step 3

[0498] 6-amino-3-bromo-2-methylbenzaldehyde (6-amino-3-bromo-2-methylphenyl)methanol (2.00 g, 9.26 mmol) and dichloromethane (46.3 mL) were charged to a 100 mL round bottom flask to which was added activated manganese dioxide (3.58 g, 37.0 mmol). The reaction was stirred vigorously at room temperature for 12 hours after which the black suspension was filtered through celite to complete the reaction. The filter cake was rinsed with dichloromethane (40 mL) and the filtrate was concentrated under reduced pressure to yield 6-amino-3-bromo-2-methylbenzaldehyde (1.90 g, 96% yield) as a yellow solid which was used directly in the next reaction without purification. 1 H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.41 (d, J = 8.9 Hz, 1H), 6.42 (d, J = 8.9 Hz, 1H), 2.66 (s, 3H)。

[0499] Step 4

[0500] (1s,4s)-4-((6-amino-3-bromo-2-methylbenzyl)amino)-N-(3-methoxy-4- methylphenyl)cyclohexanecarboxamide In a 20 mL scintillation vial, 6-amino-3-bromo-2-methylbenzaldehyde (16.0 mg, 74.7 µmol) was dissolved in anhydrous 1,2-dichloroethane (374 uL), followed by the addition of (1s,4s)-4-amino-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (29.4 mg, 112 µmol) and 1 drop of acetic acid. After the reaction solution was stirred for 30 min, sodium triacetoxyborohydride (48.8 mg, 224 µmol) was added in one portion and stirred at room temperature for 24 h. The reaction was worked up by concentration under reduced pressure to give an orange gum-like crude product, which was separated and purified by C18 reverse phase column (mobile phase: acetonitrile / 10 mM aqueous ammonium formate, 0% to 60%) and the separated fractions containing the target product were combined and evaporated to dryness to give (1s,4s)-4-((6-amino-3-bromo-2-methylbenzyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexanecarboxamide (19.0 mg, 55% yield) as a white solid. LCMS ESI ​ 460.0, 462.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 7.95 (d, J = 13.6 Hz, 1H), 7.33 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 9.0 Hz,2H), 6.45 (d, J = 8.4 Hz, 1H), 3.71 (s, 3H), 3.61 (s, 2H), 2.75 (s, 1H), 2.32(s, 3H), 2.05 (s, 3H), 1.96-1.50 (m, 4H), 1.55-1.30 (m, 4H).

[0501] Step 5

[0502] (1s,4s)-4-(6-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide In a 20 mL scintillation vial, (1s,4s)-4-((6-amino-3-bromo-2-methylphenyl)amino)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (19.0 mg, 41.3 µmol) was dissolved in dichloromethane (206 µL) at 0 °C, to which was added dropwise, batchwise, triphosgene (13.7 mg, 45.4 µmol) and triethylamine (11.6 µL, 82.5 µmol). The reaction was slightly exothermic, after the reaction was stirred for 30 minutes, the reaction was concentrated under reduced pressure to end the reaction, to give a white solid crude, which was separated and purified by silica gel column chromatography (10 g silica gel, mobile phase: ethyl acetate / n-hexane, 50% to 100%), concentrated under reduced pressure to give (1s,4s)-4-(6-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3- methoxy-4-methylphenyl)cyclohexanecarboxamide (7.00 mg, yield 35%) as a white solid. LCMS ESI ​ 486.1, 488.1 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 9.21 (s, 1H), 7.32 (d, J = 6.2 Hz, 1H),7.27 (s, 1H), 7.10 (d, J = 7.3 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H), 4.27 (s, 2H), 4.17 (t, J = 11.8 Hz, 1H), 3.74 (s, 3H), 2.63 –2.58 (m, 1H), 2.21 (s, 3H), 2.15 – 1.92 (m, 7H), 1.67-1.59 (m, 2H), 1.47-1.38(m, 2H).

[0503] Example 64

[0504] N-(3-methoxy-4-methylphenyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1- carboxamide

[0505] Step 1

[0506] tert-Butyl 4-[(2-aminobenzyl)amino]piperidine-1-carboxylate tert-Butyl 4-[(2-aminobenzyl)amino]piperidine-1-carboxylate (2.0 g, 6.6 mmol) was dissolved in acetonitrile (5 mL), to which was added dicarbonylimidazole (1.13 g, 7.86 mmol). The reaction mixture was stirred at 90 °C for 3 hours, after which the mixture was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude oil. The crude product was purified by silica gel column chromatography to obtain tert-butyl 4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylate (2.0 g, 6.0 mmol, yield 92%) as a yellow solid. LCMS ESI m / z: 275.9 [M+H] + .

[0507] Step 2

[0508] tert-Butyl 4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate tert-Butyl 4-[(2-aminobenzyl)amino]piperidine-1-carboxylate (2.0 g, 6.6 mmol) was dissolved in acetonitrile (5 mL), to which was added dicarbonylimidazole (1.13 g, 7.86 mmol). The reaction mixture was stirred at 90 °C for 3 hours, after which the mixture was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude oil. The crude product was purified by silica gel column chromatography to obtain tert-butyl 4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylate (2.0 g, 6.0 mmol, yield 92%) as a yellow solid. LCMS ESI m / z: 275.9 [M+H] + .

[0509] Step 3

[0510] 3-(Piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one Tert-butyl 4-(2-oxo-l,4-dihydroquinazolin-3-yl)piperidine-l-carboxylate (2.1 g, 6.3 mmol) was dissolved in dichloromethane (28 mL) and trifluoroacetic acid (12 mL, 160 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, concentrated, diluted with water and the pH adjusted to 9 with sodium bicarbonate and extracted with dichloromethane. The organic phases were combined, dried and concentrated to give 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(lH)-one (1.3 g, 5.6 mmol, 89% yield) as a yellow oil. LCMS ESI m / z: 232.0 [M+H] + .

[0511] Step 4

[0512] N-(3-methoxy-4-methylphenyl)-4-(2-oxo-l,2-dihydroquinazolin-3(4H)-yl)piperidine-l- carboxamide Trichloromethyl chloroformate (433 mg, 2.19 mmol, 264 μL) and triethylamine (221 mg, 2.19 mmol, 305 μL) were added to dichloromethane (8 mL) and 3-methoxy-4- methylphenylamine (300 mg, 2.19 mmol) was added at 0 °C and stirred for 2 hours. A solution of 3-(4-piperidinyl)-l,4-dihydroquinazolin-2-one (290 mg, 1.25 mmol) and triethylamine (380 mg, 3.76 mmol, 524 μL) in 10 mL of dichloromethane was added slowly dropwise to the reaction mixture at 0 °C. The reaction was stirred at 0 °C for 1 hour after which the mixture was poured into water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude oil. The crude was purified by preparative HPLC to give N-(3-methoxy-4-methylphenyl)-4-(2-oxo-l,4-dihydroquinazolin-3-yl)piperidine-l- carboxamide (39 mg, 99 μmol, 7.9% yield) as a white solid. LCMS ESI m / z: 394.9 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.21(s, 1H), 8.43 (s, 1H), 7.18 (d, J = 1.7 Hz, 1H), 7.11 (t, J= 7.3 Hz, 2H), 7.02– 6.96 (m, 2H), 6.88 – 6.82 (m, 1H), 6.77 (d, J = 7.4 Hz, 1H), 4.39 – 4.33 (m,1H), 4.31 (s, 2H), 4.28 – 4.24 (m, 2H), 3.73 (s, 3H), 2.84 (t, J = 11.9 Hz, 2H), 2.06 (s, 3H), 1.79 – 1.68 (m, 2H), 1.61 – 1.56 (m, 2H).

[0513] Example 65

[0514] (1R,3S)-N-(3-methoxy-4-methylphenyl)-3-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclopentanecarboxamide

[0515] Step 1

[0516] tert-Butyl(1S,3R)-3-(3-methoxy-4-methylphenylurea)cyclopentylurea carbamate (1R,3S)-3-(tert-Butoxycarbonylamino)cyclopentanecarboxylic acid (500 mg, 2.18 mmol) was dissolved in N,N-dimethylformamide (8 mL), and HATU (1.24 g, 3.27 mmol), diisopropylethylamine (846 mg, 6.54 mmol, 1.14 mL), and 3-methoxy-4-methylaniline (329 mg, 2.40 mmol) were added. The reaction mixture was reacted at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography to give tert-butyl(1S,3R)-3-(3-methoxy-4-methylphenylurea)cyclopentylurea (700 mg, 2.01 mmol, yield 92.1%) as a white solid. LCMS (ESI) m / z: 249.0 [M-100+H] + .

[0517] Step 2

[0518] (1R,3S)-3-amino-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide hydrochloride (1R,3S)-3-amino-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide hydrochloride (700 mg, crude) was obtained as a white solid after stirring the tert-butyl (1S,3R)-3-(3-methoxy-4-methylphenylureido)cyclopentyl urethane (700 mg, 2.01 mmol) in methanolic hydrochloric acid solution (10 mL, 4M) at 25 °C for 3 hours, and then concentrating the mixture. LCMS (ESI) m / z: 249.0 [M+H] + .

[0519] Step 3

[0520] (1R,3S)-N-(3-methoxy-4-methylphenyl)-3-(2-nitrobenzylamino)cyclopentanecarboxamide (1R,3S)-N-(3-methoxy-4-methylphenyl)-3-(2-nitrobenzylamino)cyclopentanecarboxamide (300 mg, 38.9% yield) was obtained as a yellow solid after purifying the crude product by silica gel column chromatography after stirring the (1R,3S)-3-amino-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide hydrochloride (500 mg, 2.01 mmol) in a solution of dichloromethane (3 mL) and methanol (1 mL), adding 2-nitrobenzaldehyde (609 mg, 4.03 mmol) thereto, stirring at room temperature for 30 minutes, and then adding sodium triacetoxyborohydride (854 mg, 4.03 mmol) to the reaction mixture. The reaction solution was stirred at 40 °C for 16 hours, and then the mixture was concentrated under reduced pressure. LCMS (ESI) m / z: 383.9 [M+H] + .

[0521] Step 4

[0522] (1R,3S)-3-(2-aminobenzamido)-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide (1R,3S)-N-(3-methoxy-4-methylphenyl)-3-(2-nitrobenzamido)cyclopentanecarboxamide (150 mg, 391 μmol) was dissolved in methanol (2 mL), to which was added ammonium chloride (105 mg, 1.96 mmol) and zinc powder (128 mg, 1.96 mmol), the reaction was stirred at 65 °C for 2 hours, the mixture was filtered through celite, the filtrate was concentrated to give (1R,3S)-3-(2-aminobenzamido)-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide (120 mg, crude) as a yellow solid, which was used directly in the next step. LCMS (ESI) m / z: 354.0 [M+H] + .

[0523] Step 5

[0524] (1R,3S)-N-(3-methoxy-4-methylphenyl)-3-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclopentanecarboxamide (1R,3S)-3-(2-aminobenzamido)-N-(3-methoxy-4-methylphenyl)cyclopentanecarboxamide (150 mg, 424 μmol) was dissolved in dichloromethane (2 mL), to which was added diisopropylethylamine (165 mg, 1.27 mmol, 222 μL) and triphosgene (139 mg, 467 μmol) dissolved in 2 mL dichloromethane at 0 °C. The reaction was stirred at 25 °C for 1 hour. The reaction was concentrated to give the crude product, which was separated and purified by preparative HPLC to give (1R,3S)-N-(3-methoxy-4-methylphenyl)-3-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclopentanecarboxamide (30 mg, 79 μmol, 19% yield) as a white solid. LCMS (ESI) m / z: 379.9 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.84 (s, 1H), 9.20 (s, 1H), 7.36 (s, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.08 – 6.99 (m, 2H), 6.87 (t, J = 7.4 Hz, 1H), 6.78(d, J= 7.9 Hz, 1H), 4.87 – 4.73 (m, 1H), 4.35 (s, 2H), 3.75 (s, 3H), 2.92 –2.80 (m, 1H), 2.08 (s, 3H), 1.97 – 1.66 (m, 6H).

[0525] Example 66:

[0526] (1s,4s)-4-(5-bromo-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0527] Step 1

[0528] (1s,4s)-4-(2-bromo-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide 4-Amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (600 mg, 2.29 mmol) was dissolved in toluene (20 mL), and 2-bromo-6-nitrobenzaldehyde (500 mg, 2.17 mmol) was added. The mixture was stirred at 100°C for 17 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, then diluted with methanol (10 mL). Sodium borohydride (260 mg, 6.86 mmol) was added in portions, and the reaction solution was stirred at 25°C for 2 hours. The mixture was poured into water (10 mL), extracted with ethyl acetate (20 mL), dried over reduced pressure, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 30:1 to 1:1) to obtain (1s,4s)-4-(2-bromo-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (500 mg, 1.05 mmol, yield 45.9%) as a yellow solid. LCMS ESI m / z 475.7 [M + H] + .

[0529] Step 2

[0530] (1s,4s)-4-((2-amino-6-bromobenzyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexane-1-carboxamide (1s,4s)-4-(2-bromo-6-nitrobenzamido)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (340 mg, 714 μmol) was dissolved in methanol (10 mL), and ammonium chloride (191 mg, 3.57 mmol) and zinc powder (232 mg, 3.57 mmol) were added. The mixture was stirred at 65°C for 17 hours. The mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1 to 1:1) to obtain (1s,4s)-4-(2-amino-6-bromobenzyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (300 mg, 672 μmol, yield 94.2%) as a yellow solid. LCMS ESI m / z 447.8 [M + H] + .

[0531] Step 3

[0532] (1s,4s)-4-(5-bromo-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(2-amino-6-bromobenzyl)amino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (340 mg, 762 μmol) and dicarbonylimidazolium (370 mg, 2.29 mmol) were added to acetonitrile (10 mL). The reaction mixture was stirred at 25 °C for 2 hours. The mixture was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1 to 1:1) to obtain (1s,4s)-4-(5-bromo-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (300 mg, 635 μmol, yield 83.4%) as a white solid. LCMS ESI m / z 474.8 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 9.40 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.17 – 6.92 (m, 4H), 6.76 (dd, J= 7.5, 1.4Hz, 1H), 4.30 (s, 2H), 4.22 – 4.17 (m, 1H), 3.75 (s, 3H), 2.66 – 2.64 (m,1H), 2.19 – 1.89 (m, 7H), 1.73 – 1.56 (m, 2H), 1.49 – 1.45 (m, 2H).

[0533] Example 67

[0534] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0535] Step 1

[0536] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide (1s,4s)-4-(5-bromo-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (30 mg, 64 μmol) was dissolved in methanol (5 mL), and palladium on carbon (30 mg, 64 μmol) was added. The mixture was stirred at 25 °C for 17 hours under a hydrogen atmosphere (balloon). The mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-1,2-dihydroquinazoline-3(4H)-yl)cyclohexaneformamide (5.5 mg, 14 μmol, yield 22%), as a white solid. LCMS ESI m / z 393.9 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 9.14 (s, 1H), 7.30(d, J= 1.4 Hz, 1H), 7.16 – 7.01 (m, 4H), 6.89 – 6.67 (m, 2H), 4.25 (s, 2H), 4.22 – 4.18 (m, 1H), 3.76 (s, 3H), 2.66 – 2.64 (m, 1H), 2.21 – 1.89 (m, 7H), 1.75 – 1.57 (m, 2H), 1.46 – 1.41 (m, 2H).

[0537] Example 68

[0538] (1s,4s)-4-(5-chloro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0539] Step 1

[0540] (1s,4s)-4-(2-chloro-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide 2-Chloro-6-nitrobenzaldehyde (200 mg, 1.08 mmol) and 4-amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (283 mg, 1.08 mmol) were added to toluene (10 mL), and the reaction mixture was stirred at 120 °C for 4 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was diluted with methanol:dichloromethane = 2:1 (10 mL). Sodium borohydride (122 mg, 3.23 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain (1s,4s)-4-(2-chloro-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (190 mg, 40% yield). LCMS (ESI) m / z: 431.8 [M+H] + .

[0541] Step 2

[0542] (1s,4s)-4-(2-amino-6-chlorobenzoamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(2-chloro-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (188 mg, 435 μmol), zinc powder (142 mg, 2.18 mmol), and ammonium chloride (228 mg, 4.35 mmol) were added to methanol (5 mL), and the reaction mixture was stirred at 65 °C for 2 hours. The mixture was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain (1s,4s)-4-(2-amino-6-chlorobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (150 mg, 85% yield). LCMS (ESI) m / z: 431.8 [M+H] + .

[0543] Step 3

[0544] (1s,4s)-4-(5-chloro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(2-amino-6-chlorobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (150 mg, 373 μmol) and N,N'-carbonyldiimidazole (181 mg, 1.12 mmol) were added to acetonitrile (5 mL), and the reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. The mixture was concentrated to obtain a crude product, which was purified by preparative HPLC to give (1s,4s)-4-(5-chloro-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (11 mg, yield 5.0%), a white solid. LCMS (ESI) m / z: 412.8 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 9.41 (s, 1H), 7.28 (d, J = 1.7 Hz, 1H), 7.17 – 7.08(m, 2H), 7.02 (d, J = 8.5 Hz, 1H), 6.95 (dd, J= 8.0, 0.9 Hz, 1H), 6.78 – 6.69(m, 1H), 4.33 (s, 2H), 4.22 – 4.18 (m, 1H), 3.75 (s, 3H), 2.66 – 2.64 (m,1H), 2.14 – 2.10 (m, 2H), 2.08 (s, 3H), 2.02 – 1.96 (m, 2H), 1.68 – 1.64 (m, 2H), 1.49 – 1.46 (m, 2H).

[0545] Example 69

[0546] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0547] Step 1

[0548] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide Cesium carbonate (311 mg, 956 μmol) and 1,1-bis(diphenylphosphine)diferropalladium dichloride (10 mg, 32 μmol) were added to a solution containing trimethylcycloboroxane (3.5 M, 182 μL) and 4-(5-bromo-2-oxo-1,4-dihydroquinazolin-3-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (151 mg, 319 μmol) in 2 mL of dioxane and 1 mL of water. The mixture was stirred at 100 °C for 17 hours under nitrogen protection. The mixture was then filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide (10 mg, 25 μmol, yield 7.7%), as a white solid. LCMSESI m / z 407.9 [M + H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 9.05 (s, 1H), 7.29 (d, J= 1.7 Hz, 1H), 7.12 (dd, J = 8.0, 1.8 Hz, 1H), 7.05 – 6.95 (m, 2H), 6.68 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 4.24 – 4.20 (m, 3H), 3.75(s, 3H), 2.66 – 2.64 (m, 1H), 2.19 – 1.93 (m, 10H), 1.72 – 1.59 (m, 2H), 1.48– 1.44 (m, 2H).

[0549] Example 70

[0550] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-5-(trifluoromethyl)-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0551] Step 1

[0552] 2-(bromomethyl)-1-nitro-3-(trifluoromethyl)benzene In a solution of 2-methyl-1-nitro-3-(trifluoromethyl)benzene (1.00 g, 4.87 mmol) in carbon tetrachloride (10 mL), benzoyl peroxide (236 mg, 975 μmol) and NBS (0.95 g, 5.4 mmol) were added. The mixture was stirred at 80 °C for 17 h. A new spot was detected by TLC. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1 to 1:1) to give 2-(bromomethyl)-1-nitro-3-(trifluoromethyl)benzene (1.00 g, 3.52 mmol, yield 72.2%) as a yellow oil. The isolated product was not further characterized and was used directly in the next reaction.

[0553] Step 2

[0554] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-nitro-6-(trifluoromethyl)phenylamino)cyclohexaneformamide 4-Amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (252 mg, 960 μmol) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (291 mg, 2.88 mmol, 402 μL) and 2-(bromomethyl)-1-nitro-3-(trifluoromethyl)benzene (1.00 g, 3.52 mmol) were added. The reaction mixture was stirred at 25 °C for 17 hours, and then poured into water (20 mL). Extraction was performed with ethyl acetate (20 mL × 3). The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1 to 1:1) to obtain (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-nitro-6-(trifluoromethyl)phenylamino)cyclohexaneformamide (400 mg, 859 μmol). (Yield 89.5%), as a yellow solid. LCMS ESI m / z 465.8 [M + H] + .

[0555] Step 3

[0556] (1s,4s)-4-(2-amino-6-(trifluoromethyl)benzylamino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-nitro-6-(trifluoromethyl)benzylamino)cyclohexaneformamide (500 mg, 1.07 mmol) was dissolved in methanol (10 mL), and zinc powder (351 mg, 5.37 mmol) and ammonium chloride (287 mg, 5.37 mmol) were added. The reaction mixture was stirred at 65°C for 17 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30: 1:1) to obtain (1s,4s)-4-(2-amino-6-(trifluoromethyl)benzylamino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (400 mg, 919 μmol, yield 85.5%) as a yellow solid. LCMS ESI m / z 435.8 [M + H] + .

[0557] Step 4

[0558] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-5-(trifluoromethyl)-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide (1s,4s)-4-(2-amino-6-(trifluoromethyl)benzylamino)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (200 mg, 459 μmol) was dissolved in acetonitrile (5 mL), and N,N-carbonyldiimidazole (197 mg, 1.38 mmol) was added. The reaction mixture was stirred at 25°C for 17 hours. The mixture was concentrated to obtain a crude product, which was purified by preparative HPLC to obtain (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-5-(trifluoromethyl)-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide (20 mg, 43 μmol, yield 9.4%) as a white solid. LCMS ESI m / z 461.8 [M + H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 9.70 (s, 1H), 9.58 (s, 1H), 7.36(t, J = 7.9 Hz, 1H), 7.31 (d, J = 1.5 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.11 –7.02 (m, 3H), 4.35 (s, 2H), 4.25 – 4.13 (m, 1H), 3.76 (s, 3H), 2.65 – 2.63(m, 1H), 2.11 – 2.09 (m, 5H), 2.03 – 1.89 (m, 2H), 1.72 – 1.57 (m, 2H), 1.47 – 1.44 (m, 2H).

[0559] Example 71

[0560] (1s,4s)-4-(5-methoxy-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0561] Step 1

[0562] 2-(bromomethyl)-1-methoxy-3-nitrobenzene 1-Methoxy-2-methyl-3-nitrobenzene (1.00 g, 5.98 mmol), 1-bromopyrrolidine-2,5-dione (1.60 g, 8.97 mmol), and benzoylbenzoyl peroxide (145 mg, 598 μmol) were added to carbon tetrachloride (15 mL). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was then poured into water (30 mL), extracted three times with ethyl acetate (30 mL), and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 2-(bromomethyl)-1-methoxy-3-nitrobenzene (1.00 g, 4.06 mmol, yield 67.9%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 8.2, 1.0 Hz, 1H), 7.43 (t, J = 8.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 4.83 (s, 2H), 3.98 (s, 3H).

[0563] Step 2

[0564] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-methoxy-6-nitrobenzamide)cyclohexaneformamide 2-(bromomethyl)-1-methoxy-3-nitrobenzene (100 mg, 406 μmol), 4-amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (107 mg, 406 μmol), and N,N-diethylethylamine (123 mg, 1.22 mmol, 170 μL) were added to N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (30 mL), and the organic layer was dried and concentrated to give crude (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-methoxy-6-nitrobenzamide)cyclohexaneformamide (160 mg, yield 92.1%) as a yellow oil. LCMS (ESI) m / z: 428.2 [M+H] + .

[0565] Steps 3 and 4

[0566] (1s,4s)-4-(5-methoxy-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide Following the reaction steps described in Example 66, but using (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-methoxy-6-nitrobenzamide)cyclohexaneformamide as the starting material, the title compound was synthesized as a white solid. LCMS (ESI) m / z: 424.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.24 (s, 1H), 7.08 (t, J = 8.4 Hz, 2H), 6.81 (dd, J = 8.0, 1.9 Hz, 1H), 6.55 (s,1H), 6.44 (d, J = 8.2 Hz, 1H), 6.23 (d, J = 7.8 Hz, 1H), 4.46 – 4.38 (m, 1H), 4.32 (s, 2H), 3.87 (s, 3H), 3.79 (s, 3H), 2.66 – 2.64 (m, 1H), 2.28 – 2.24(m, 2H), 2.19 (s, 3H), 2.10 – 1.97 (m, 2H), 1.86 – 1.70 (m, 2H), 1.68 – 1.53(m, 2H).

[0567] Example 72

[0568] (1s,4s)-4-(5-ethyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0569] Step 1

[0570] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-5-vinyl-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide 4-(5-bromo-2-oxo-1,4-dihydroquinazolin-3-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (150 mg, 318 μmol) was dissolved in dioxane / water (5 / 1, 12 mL), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoborane (154 mg, 97.8 μmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (23 mg, 32 μmol), and cesium carbonate (207 mg, 635 μmol) were added to the mixture. The reaction mixture was stirred at 100 °C for 17 hours under nitrogen protection. The mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1 to 1:1) to obtain (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-5-vinyl-1,2-dihydroquinazoline-3(4H)-yl)cyclohexaneformamide (120 mg, yield 67.6%) as a yellow solid. LCMS ESI m / z 419.9 [M + H] + .

[0571] Step 2

[0572] (1s,4s)-4-(5-ethyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(2-oxo-5-vinyl-1,2-dihydroquinazoline-3(4H)-yl)cyclohexaneformamide (120 mg, 286 μmol) was dissolved in methanol (2 mL), and palladium on carbon (10 mg) was added. The reaction mixture was stirred at 25°C for 17 hours under hydrogen atmosphere. The mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-4-(5-ethyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (10.5 mg, yield 8.71%) as a white solid. LCMS ESI m / z 422.3 [M + H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 9.08 (s, 1H), 7.30 (d, J=1.7 Hz, 1H), 7.13 – 6.98 (m, 3H), 6.72 (d, J = 7.3 Hz, 1H), 6.62 (d, J = 7.8Hz, 1H), 4.24 (s, 2H), 4.22 – 4.20 (m, 1H), 3.76 (s, 3H), 2.66 – 2.64 (m,1H), 2.54 – 2.52 (m, 1H), 2.48 – 2.46 (m, 1H), 2.17 – 1.93 (m, 7H), 1.73 –1.59 (m, 2H), 1.48 – 1.44 (m, 2H), 1.12 (t, J = 7.5 Hz, 3H).

[0573] Example 73

[0574] (1s,4s)-4-(5-chloro-1-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0575] Step 1

[0576] (1s,4s)-4-(5-chloro-1-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide The (1s,4s)-4-(5-chloro-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (50.0 mg, 117 μmol), potassium tert-butoxide (10.5 mg, 93.5 μmol), and methyl iodoformamide (13.3 mg, 93.5 μmol, 5.82 μL) prepared in Example 68 were added to acetonitrile / N,N-dimethylformamide (1 / 1, 5 mL). After stirring the reaction mixture at room temperature for 1 hour, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-4-(5-chloro-1-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)cyclohexaneformamide. (4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (6.0 mg, 10% yield) is a white solid. LCMS (ESI) m / z: 443.8 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) δ 9.70 (s, 1H), 7.32 – 7.27 (m, 2H), 7.13 – 7.03 (m, 2H), 7.02(d, J = 8.5 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 4.31 (s, 2H), 4.19 – 4.16 (m,1H), 3.76 (s, 3H), 3.18 (s, 3H), 2.66 – 2.64 (m, 1H), 2.12 – 2.09 (m, 5H),2.04 – 1.93 (m, 2H), 1.72 – 1.61 (m, 2H), 1.51 – 1.43 (m, 2H).

[0577] Example 74

[0578] (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0579] Step 1

[0580] 2-(4-bromo-2-methyl-6-nitrophenyl)-N,N-dimethylethyleneamine 5-Bromo-1,2-dimethyl-3-nitrobenzene (8.8 g, 38 mmol) and 1,1-dimethoxy-N,N-dimethylmethylamine (9.12 g, 76.5 mmol, 10.2 mL) were added to N,N-dimethylformamide (40 mL). The reaction solution was stirred at 100 °C for 16 hours, and the reaction mixture was used directly in the next step.

[0581] Step 2

[0582] 4-Bromo-2-methyl-6-nitrobenzaldehyde Sodium periodate (32.7 g, 153 mmol) was dissolved in water (10 mL) and N,N-dimethylformamide (10 mL). 2-(4-bromo-2-methyl-6-nitrophenyl)-N,N-dimethylethyleneamine (10.9 g, 38.2 mmol) was added to the mixture at 0–10 °C, and the reaction mixture was stirred at 25 °C for 5 hours. Ethyl acetate (250 mL) was added to the reaction mixture, and the organic phase was washed with water (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether, 0–10%) to obtain 4-bromo-2-methyl-6-nitrobenzaldehyde (2.00 g, yield 21.4%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.10(d, J = 1.6 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 2.50 (s, 3H).

[0583] Step 3

[0584] (1s,4s)-4-(4-bromo-2-methyl-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide 4-Bromo-2-methyl-6-nitrobenzaldehyde (233 mg, 953 μmol) and 4-amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.10 g, 380 μmol) were dissolved in tetrahydrofuran (3 mL). After stirring the reaction solution at 25°C for 16 hours, sodium cyanoborohydride (120 mg, 1.91 mmol) was added. The resulting reaction solution was stirred at 25°C for 1 hour, then ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL × 3). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether, 0-40%) to obtain (1s,4s)-4-(4-bromo-2-methyl-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (50 mg, yield 27%), as a white solid. (TLC: petroleum ether / ethyl acetate = 2 / 1, R f =0.3), LCMS (ESI) m / z:489.7 [M+H] + .

[0585] Step 4

[0586] (1s,4s)-4-(2-amino-4-bromo-6-methylbenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(4-bromo-2-methyl-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (50 mg, 100 μmol) was dissolved in methanol (10 mL), and ammonium chloride (54 mg, 1.0 mmol) and zinc powder (66 mg, 1.0 mmol) were added. The reaction mixture was stirred at 65°C for 1 hour, then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain (1s,4s)-4-(2-amino-4-bromo-6-methylbenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.046 g, 100 μmol, 98% yield), a white solid. LCMS (ESI) m / z: 459.8 [M+H] + .

[0587] Step 5

[0588] (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(2-amino-4-bromo-6-methylbenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.060 g, 130 μmol) was dissolved in acetonitrile (10 mL), and triphosgene (116 mg, 391 μmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed three times with water (50 mL × 3), and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.0134 g, 27.6 μmol, yield 21.1%), as a white solid. LCMS(ESI) m / z: 486.1 [M+H] + . 1 H NMR (400 MHz, MeOD- d 4) δ 7.25 (d, J = 1.6 Hz, 1H),7.05 – 7.02 (m, 1H), 6.99 – 6.96 (m, 1H), 6.92 (d, J = 1.2 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 4.34 – 4.30 (m, 3H), 3.82 (s, 3H), 2.71 – 2.68 (m, 1H), 2.27 –2.09 (m, 10H), 1.85-1.70 (m, 2H), 1.65-1.55 (m, 2H).

[0589] Example 75

[0590] (1s,4s)-4-(5-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0591] Step 1

[0592] (1s,4s)-4-(2-fluoro-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide 2-Fluoro-6-nitrobenzaldehyde (516 mg, 3.05 mmol) and 4-amino-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.40 g, 1.52 mmol) were added to tetrahydrofuran (10 mL), and the reaction mixture was stirred at 25°C for 16 hours. Sodium borohydride (116 mg, 3.05 mmol) was then added, and the mixture was stirred at 25°C for another hour. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (50 mL × 3), washed with water (50 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 0-30%) to obtain (1s,4s)-4-(2-fluoro-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.14 g, 340 μmol, yield 22%) as a white solid. LCMS ESI m / z 416.2 [M + H] + .

[0593] Step 2

[0594] (1s,4s)-4-(2-amino-6-fluorobenzoamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(2-fluoro-6-nitrobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.12 g, 290 μmol) was dissolved in ethanol (5 mL), and stannous chloride (165 mg, 867 μmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give (1s,4s)-4-(2-amino-6-fluorobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.10 g, 260 μmol, 90% yield) as a white solid. LCMS ESI m / z 385.9 [M + H] + .

[0595] Step 3

[0596] (1s,4s)-4-(5-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(2-amino-6-fluorobenzamide)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (25 mg, 65 μmol) and triphosgene (38 mg, 130 μmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was stirred at 25°C for 2 hours, then quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-4-(5-fluoro-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (10 mg, 23 μmol, yield 35%), a white solid. LCMS ESI m / z 411.9 [M + H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 9.41 (s, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.19 – 7.08 (m, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.70 (t, J = 8.8 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.35 – 4.16 (m, 3H), 3.76 (s, 3H), 2.66 – 2.64 (m, 1H), 2.13 – 2.09 (m, 5H), 2.04 – 1.91 (m, 2H), 1.74– 1.59 (m, 2H), 1.47 – 1.43 (m, 2H).

[0597] Example 76

[0598] (1s,4s)-4-(7-amino-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0599] Step 1

[0600] (1s,4s)-4-(7-(diphenylmethylamino)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide To a solution of dioxane (2 mL) containing 4-(7-bromo-5-methyl-2-oxo-1,4-dihydroquinazolin-3-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (100 mg, 206 μmol) and benzophenone imine (75 mg, 410 μmol), tris(dibenzylacetone)palladium (19 mg, 21 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (26 mg, 41 μmol), and sodium tert-butoxide (59 mg, 620 μmol) were added. The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was filtered and concentrated to give a crude oily product. Purified by silica gel column chromatography, (1s,4s)-4-(7-(diphenylmethylamino)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (60 mg, 72 μmol, yield 35%, purity 70%) was obtained as a yellow solid. LCMS ESI m / z: 587.3 [M+H] + . Step 2

[0601] (1s,4s)-4-(7-amino-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide Add 0.1 mL of 2 M hydrochloric acid aqueous solution to a 2 mL solution of tetrahydrofuran containing (1s,4s)-4-(7-(diphenylmethylamino)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (45 mg, 77 μmol). The resulting solution was stirred at room temperature for 10 minutes, then separated by water and ethyl acetate. The pH of the aqueous phase was adjusted to 9 with concentrated ammonia, and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, filtered, and concentrated under reduced pressure to obtain a yellow crude solid. The crude solid was purified by preparative HPLC to obtain (1s,4s)-4-(7-amino-5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (6.7 mg, 16 μmol, yield 20%), a white solid. LCMS ESI m / z: 422.9 [M+H] +. 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 8.79 (s, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.11 (dd, J =8.0, 1.8 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 5.95 (d, J = 1.5 Hz, 1H), 5.85 (d, J = 1.9 Hz, 1H), 4.85 (s, 2H), 4.21 – 4.19 (m, 1H), 4.07 (s, 2H), 3.76 (s, 3H), 2.66 – 2.64 (m, 1H), 2.13 – 2.09 (m, 5H), 2.04 – 1.92 (m, 5H), 1.68 – 2.63 (m, 2H), 1.46 – 1.42 (m, 2H).

[0602] Example 77

[0603] (1s,4s)-4-(7-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0604] Step 1

[0605] (1s,4s)-4-(7-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(7-bromo-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (100 mg, 205.59 μmol), potassium hydroxide (23 mg, 410 μmol), tris(dibenzylideneacetone)dipalladium (19 mg, 21 μmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (8.7 mg, 21 μmol) were added to dioxane / water (4:1, 5 mL). The reaction mixture was purged with nitrogen and stirred at 90 °C for 3 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-4-(7-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (13 mg, 14% yield), as a white solid. LCMS (ESI) m / z: 424.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68(s, 1H), 9.14 (s, 1H), 8.91 (s, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.11 (dd, J =8.0, 1.7 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.12 (d, J = 1.8 Hz, 1H), 6.07 (d, J = 2.1 Hz, 1H), 4.22 – 4.16 (m, 1H), 4.11 (s, 2H), 3.75 (s, 3H), 2.65 – 2.63(m, 1H), 2.13 – 2.10 (m, 2H), 2.08 (s, 3H), 2.05 (s, 3H), 2.01 – 1.91 (m,2H), 1.68 – 1.60 (m, 2H), 1.45 – 1.43 (m, 2H).

[0606] Example 78

[0607] (1s,4s)-4-(7-formyl-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0608] Step 1

[0609] (1s,4s)-4-(7-formyl-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide 4-(7-bromo-5-methyl-2-oxo-1,4-dihydroquinazolin-3-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.17 g, 350 μmol), triethylamine (71 mg, 700 μmol), triethylsilane (406 mg, 3.50 mmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (26 mg, 35 μmol) were added to N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 80 °C in a carbon dioxide atmosphere (balloon) for 5 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (methanol / dichloromethane, 0-10%) and then purified by preparative HPLC to obtain (1s,4s)-4-(7-formyl-5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.058 g, 130 μmol, yield 38%), a white solid. LCMS ESI m / z: 436.3 [M+H] + . 1 H NMR (400 MHz, MeOD- d 4) δ 9.84 (s, 1H), 7.32 (s, 1H), 7.26 (d, J = 1.6 Hz,1H), 7.12 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.97(dd, J= 8.0, 2.0 Hz, 1H),4.46 (s, 2H), 4.40 - 4.30 (m, 1H), 3.83 (s, 3H), 2.73 - 2.71 (m, 1H), 2.34(s, 3H), 2.29 - 2.16 (m, 4H), 2.14 (s, 3H), 1.85-1.73 (m, 2H), 1.63-1.55 (m, 2H).

[0610] Example 79

[0611] 3-((1s,4s)-4-(3-methoxy-4-methylphenylcarbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

[0612] Step 1

[0613] 3-((1s,4s)-4-(3-methoxy-4-methylphenylurea)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid methyl ester 4-(7-bromo-5-methyl-2-oxo-1,4-dihydroquinazolin-3-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.15 g, 310 μmol) was added to methanol (15 mL) along with triethylamine (62 mg, 620 μmol, 86 μL) and 1,1-bis(diphenylphosphine)diferropalladium dichloride (23 mg, 31 μmol). The reaction mixture was stirred at 80 °C in a carbon monoxide atmosphere (balloon) for 16 hours. The reaction mixture was concentrated to obtain a crude residue, which was purified by silica gel column chromatography (mobile phase: ethyl acetate / dichloromethane, 0-50%) to obtain a white solid methyl 3-((1s,4s)-4-(3-methoxy-4-methylphenylurea)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid ester (0.14 g, 300 μmol, yield 98%). TLC: petroleum ether / ethyl acetate = 1 / 1, R f =0.5. LCMS ESI m / z: 465.9 [M+H] + .

[0614] Step 2

[0615] 3-((1s,4s)-4-(3-methoxy-4-methylphenylurea)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid Methyl 3-((1s,4s)-4-(3-methoxy-4-methylphenylurea)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (0.12 g, 260 μmol) and lithium hydroxide (19 mg, 770 μmol) were dissolved in water (0.5 mL) and ethanol (2 mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure and extracted twice with ethyl acetate (50 mL × 2). The pH of the aqueous solution was adjusted to <4 with 6M hydrochloric acid, and extraction with ethyl acetate was continued (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to give 3-((1s,4s)-4-(3-methoxy-4-methylphenylurea)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (0.0108 g, 23.9 μmol, yield 9.28%), as a white solid. LCMS ESI m / z: 452.2 [M+H] + . 1 H NMR (400 MHz, MeOD- d 4) δ7.43 (s, 1H), 7.26 (s, 2H), 7.04(d, J = 8.0 Hz, 1H), 6.97(dd, J = 8.0, 2.0 Hz, 1H), 4.43 (s, 2H), 4.40 – 4.26 (m, 1H), 3.83 (s, 3H), 2.72 – 2.70 (m, 1H), 2.35 – 2.07 (m, 10H), 1.88 – 1.73 (m, 2H), 1.65-1.58 (m,2H).

[0616] Example 80

[0617] 3-((1s,4s)-4-(3-methoxy-4-methylphenylurea)cyclohexyl)-N,5-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxamide

[0618] Step 1

[0619] 3-((1s,4s)-4-(3-methoxy-4-methylphenylcarbamate)cyclohexyl)-N,5-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide Methylamine (21 mg, 310 μmol, hydrochloride), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (71 mg, 190 μmol), and triethylamine (47 mg, 470 μmol, 65 μL) were added to N,N-dimethylformamide (5 mL) and stirred for 10 minutes. Then, 3-[4-[(3-methoxy-4-methylphenyl)carboxyl]cyclohexyl]-5-methyl-2-oxo-1,4-dihydroquinazoline-7-carboxylic acid (0.070 g, 150 μmol) was added. The reaction mixture was stirred at 25 °C for 1 hour and then poured into ethyl acetate (50 mL). The mixture was washed with water (50 mL). (mL×3), combine the organic phases and dry with sodium sulfate, concentrate under reduced pressure to obtain crude product. The crude product is purified by preparative HPLC to obtain 3-((1s,4s)-4-(3-methoxy-4-methylphenylurea)cyclohexyl)-N,5-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (14 mg, 31 μmol, yield 20%), a white solid. LCMS ESI m / z: 465.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 9.21 (s, 1H), 8.30 - 8.20 (m, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.18 – 7.08 (m,2H), 7.05 – 7.00 (m, 2H), 4.26 (s, 2H), 4.25 – 4.05 (m, 1H), 3.76 (s, 3H), 2.73 (d, J = 4.5 Hz, 3H), 2.66 – 2.64 (m, 1H), 2.20 (s, 3H), 2.15 – 2.12 (m,2H), 2.09 (s, 3H), 2.05 – 1.95 (m, 2H), 1.70-1.60 (m, 2H), 1.50 - 1.40 (m,2H).

[0620] Example 81

[0621] (1s,4s)-4-(7-(hydroxymethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0622] Step 1

[0623] (1s,4s)-4-(7-(hydroxymethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide Sodium borohydride (3.5 mg, 92 μmol) was added to a solution of tetrahydrofuran (5 mL) containing (1s,4s)-4-(7-formyl-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.040 g, 92 μmol), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into ethyl acetate (50 mL), washed with water (50 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-4-(7-(hydroxymethyl)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.0146 g, 33.3 μmol, yield 36.3%), a white solid. LCMS ESI m / z: 438.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68(s, 1H), 9.05 (s, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.11 (dd, J = 8.0, 2.0 Hz, 1H), 7.02 (d, J =8.0 Hz, 1H), 6.62 (s, 1H), 6.57 (s, 1H), 5.06 (t, J = 5.6 Hz, 1H), 4.34 (d, J= 5.6 Hz, 2H), 4.25-4.15 (m, 3H), 3.75 (s, 3H), 2.66 – 2.64(m, 1H), 2.27 – 1.82 (m, 10H), 1.76 – 1.59 (m, 2H), 1.50-1.40 (m,2H).

[0624] Example 82

[0625] (1s,4s)-4-(7-(2-(dimethylamino)ethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0626] Step 1

[0627] (1s,4s)-4-(7-(2-(dimethylamino)ethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1s,4s)-4-(7-hydroxy-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (prepared in Example 77) (30 mg, 71 μmol), 2-chloroethyldimethylamine hydrochloride (10 mg, 71 μmol), and cesium carbonate (69 mg, 210 μmol) were added to acetonitrile (1 mL), and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-4-(7-(2-(dimethylamino)ethoxy)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (14 mg, 71 μmol, yield 40%), as a pale yellow solid. LCMS (ESI) m / z: 494.9 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.68 (s, 1H),8.98 (s, 1H), 7.29 (d, J = 1.7 Hz, 1H), 7.11 (dd, J= 8.0, 1.8 Hz, 1H), 7.02(d, J = 8.1 Hz, 1H), 6.32 (d, J = 2.2 Hz, 1H), 6.18 (d, J = 2.2 Hz, 1H), 4.23 –4.12 (m, 3H), 3.93 (t, J = 5.8 Hz, 2H), 3.75 (s, 3H), 2.66 – 2.64 (m, 1H), 2.59 (t, J = 5.8 Hz, 2H), 2.22 (s, 6H), 2.15 – 2.08 (m, 8H), 2.04 – 1.98 (m,2H), 1.68 – 1.65 (m, 2H), 1.46 – 1.43 (m, 2H).

[0628] Example 83

[0629] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-7-vinyl-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0630] Step 1

[0631] (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-7-vinyl-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide 4-(7-bromo-5-methyl-2-oxo-1,4-dihydroquinazolin-3-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.050 g, 100 μmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoborane (32 mg, 210 μmol), potassium carbonate (43 mg, 310 μmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (7.5 mg, 10 μmol) were added to dioxane (3 mL), and the reaction was stirred at 90°C under nitrogen protection for 16 hours. The reaction solution was extracted with ethyl acetate (50 mL), washed with water (50 mL × 3), and the combined organic phases were dried over sodium sulfate. The solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain (1s,4s)-N-(3-methoxy-4-methylphenyl)-4-(5-methyl-2-oxo-7-vinyl-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide (0.0108 g, 24.0 μmol, yield 23.4%), as a white solid. LCMS (ESI) m / z: 434.3 [M+H] + . 1 H NMR (400 MHz, MeOD- d 4) δ 7.25 (d, J =1.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0, 2.0 Hz, 1H), 6.83 (s,1H), 6.68 (s, 1H), 6.65 - 6.55 (m, 1H), 5.69 (d, J = 17.6Hz, 1H), 5.17 (d, J =11.2 Hz, 1H), 4.40 - 4.25 (m, 3H), 3.83 (s, 3H), 2.72 - 2.70 (m, 1H), 2.32 -2.05 (m, 10H), 1.85 - 1.75 (m, 2H), 1.65 - 1.55 (m, 2H).

[0632] Example 84

[0633] N-(2-(dimethylamino)ethyl)-3-((1s,4s)-4-(3-methoxy-4-methylphenylcarbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxamide

[0634] Step 1

[0635] N-(2-(dimethylamino)ethyl)-3-((1s,4s)-4-(3-methoxy-4-methylphenylcarbamoyl)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxamide N',N'-dimethylethane-1,2-diamine (9.8 mg, 110 μmol, 12 μL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (51 mg, 130 μmol), triethylamine (34 mg, 330 μmol, 46 μL) and 3-[4-[(3-methoxy-4-methylphenyl)carboxylyl]cyclohexyl]-5-methyl-2-oxo-1,4-dihydroquinazoline-7-carboxylic acid (prepared in Example 79) (0.050 g, 110 μmol) were added to N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was extracted with ethyl acetate (50 mL), washed with water (50 mL × 3), and the combined organic phases were dried over sodium sulfate. The solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain N-(2-(dimethylamino)ethyl)-3-((1s,4s)-4-(3-methoxy-4-methylphenylurea)cyclohexyl)-5-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxamide (0.014 g, 27 μmol, yield 24%), a white solid. LCMS (ESI) m / z: 521.9 [M+H] + . 1 H NMR (400 MHz, MeOD- d 4) δ 8.48 (s, 1H), 7.8 - 7.23 (m, 2H), 7.08 (s,1H), 7.04 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 8.0, 2.0 Hz, 1H), 4.43 (s, 2H), 4.40 - 4.30 (m, 1H), 3.84 (s, 3H), 3.64 (t, J= 6.0 Hz, 2H), 3.10 - 3.06 (m,2H), 2.73 - 2.71 (m, 7H), 2.31 (s, 3H), 2.26 - 2.08 (m, 7H), 1.85 - 1.75 (m,2H), 1.65 - 1.55 (m, 2H).

[0636] Example 85

[0637] (1r,4r)-4-(7-(2-(dimethylamino)ethylamino)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide

[0638] Step 1

[0639] (1r,4r)-4-(7-(diphenylmethylamino)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide Benzophenone imine (559 mg, 3.08 mmol), benzyl-[1-[2-[benzyl(phenyl)phosphino]-1-naphthyl]-2-naphthyl]-phenyl-phosphine (40 mg, 62 μmol), 4-(7-bromo-5-methyl-2-oxo-1,4-dihydroquinazolin-3-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.30 g, 620 μmol) (prepared in Example 74), sodium tert-butoxide (119 mg, 1.23 mmol), and tris(dibenzylideneacetone)dipalladium (56 mg, 62 μmol) were added to toluene (10 mL), and the reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was extracted with ethyl acetate (50 mL), washed with water (50 mL × 3), and the combined organic phases were dried over sodium sulfate. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane, 0-5%) to obtain (1r,4r)-4-(7-(diphenylmethylamino)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.30 g, 510 μmol, yield 83%), as a white solid. LCMS (ESI) m / z: 586.8 [M+H] + .

[0640] Step 2

[0641] (1r,4r)-4-(7-amino-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1r,4r)-4-(7-(diphenylmethylamino)-5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.30 g, 510 μmol) was dissolved in tetrahydrofuran (10 mL), and 2M hydrochloric acid (3 mL) was added. The reaction mixture was concentrated under reduced pressure and recrystallized from ethyl acetate (10 mL) to give (1r,4r)-4-(7-amino-5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.20 g, 510 μmol, 93% yield) as a yellow solid. LCMS (ESI) m / z: 422.9 [M+H] + .

[0642] Step 3

[0643] (1r,4r)-4-(7-(2-(dimethylamino)ethylamino)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (1r,4r)-4-(7-amino-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.20 g, 470 μmol) and 2-(dimethylamino)acetaldehyde (82 mg, 950 μmol) were added to methanol (10 mL), followed by sodium borohydride cyanide (89 mg, 1.4 mmol). The reaction mixture was reacted at 25 °C for 16 hours. The reaction mixture was extracted with ethyl acetate (50 mL), washed with water (50 mL × 3), and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain (1r,4r)-4-(7-(2-(dimethylamino)ethylamino)-5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-methoxy-4-methylphenyl)cyclohexaneformamide (0.0148 g, 29.9 μmol, yield 6.31%), a white solid. LCMS ESI m / z: 493.9 [M+H] +1H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.80 (s, 1H), 7.36 (s,1H), 7.05 – 6.98 (m, 2H), 5.99 (s, 1H), 5.85 (s, 1H), 5.18 – 5.14 (m, 1H),4.20 – 4.05 (m, 3H), 3.74 (s, 3H), 3.05 - 2.95 (m, 2H), 2.45 - 2.35 (m, 2H), 2.34 - 2.28 (m, 1H), 2.16 (s, 6H), 2.10 - 1.05 (m, 5H), 2.00 - 1.87 (m, 2H),1.70-1.65 (m, 2H), 1.64 – 1.50 (m, 2H).

[0644] Example 86

[0645] (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0646] Step 1

[0647] 1-Bromo-2-(bromomethyl)-3-nitrobenzene 1-Bromo-2-methyl-3-nitrobenzene (15 g, 69 mmol) was dissolved in carbon tetrachloride (150 mL), and benzoyl peroxide (1.68 g, 6.94 mmol) and N-succinimide bromide (13.6 g, 76.4 mmol) were added. The reaction mixture was stirred overnight at 80 °C. The solution was poured into water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1-bromo-2-(bromomethyl)-3-nitrobenzene (18 g, 61 mmol, yield 88%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ7.90 – 7.85 (m, 2H), 7.35 (t, J = 8.1 Hz, 1H), 4.89 (s, 2H).

[0648] Step 2

[0649] (1s,4s)-4-(2-bromo-6-nitrobenzamide)cyclohexanecarboxylic acid methyl ester To a solution of acetonitrile (49 mL) containing 1-bromo-2-(bromomethyl)-3-nitrobenzene (5.00 g, 17.0 mmol) and methyl 4-aminocyclohexanecarboxylate (4.00 g, 25.4 mmol), diisopropylethylamine (8.76 g, 67.8 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to (1s,4s)-4-(2-bromo-6-nitrobenzamide)cyclohexanecarboxylate (5.00 g, 13.5 mmol, yield 79.5%), as a yellow oil. LCMS (ESI) m / z: 370.7 [M+H] + .

[0650] Step 3

[0651] (1s,4s)-4-(2-amino-6-bromobenzamide)cyclohexanecarboxylic acid methyl ester Methyl (1s,4s)-4-(2-bromo-6-nitrobenzamide)cyclohexanecarboxylate (3.4 g, 9.2 mmol) was dissolved in methanol (20 mL), and stannous chloride dihydrate (5.63 g, 45.8 mmol) was added. The reaction mixture was stirred overnight at 65°C. After cooling the reaction mixture to room temperature, the pH was adjusted to 8 with sodium bicarbonate. The solution was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl (1s,4s)-4-(2-amino-6-bromobenzamide)cyclohexanecarboxylate (2.40 g, 7.03 mmol, yield 76.8%), as a yellow oil. LCMS (ESI) m / z: 343.1 [M+H] + .

[0652] Step 4

[0653] (1s,4s)-4-(5-bromo-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxylic acid methyl ester Methyl (1s,4s)-4-(2-amino-6-bromobenzamide)cyclohexanecarboxylate (1.50 g, 4.40 mmol) was dissolved in dichloromethane (10 mL), to which triphosgene (2.6 g, 8.8 mmol) and triethylamine (1.33 g, 13.2 mmol, 1.84 mL) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl (1s,4s)-4-(5-bromo-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxylate (1.2 g, 3.3 mmol, 74% yield) as a white solid. LCMS (ESI) m / z: 369.1 [M+H] + .

[0654] Step 5

[0655] (1s,4s)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxylic acid methyl ester Methyl (1s,4s)-4-(5-bromo-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxylate (1.46 g, 3.98 mmol) and trimethylcycloboroxane (998 mg, 7.95 mmol) were added to dioxane (15 mL) and water (5 mL), followed by 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (291 mg, 398 μmol) and cesium carbonate (3.89 g, 11.9 mmol). The reaction mixture was stirred overnight at 100°C under nitrogen protection. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography to (1S,4S)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxylate methyl ester (900 mg, 2.98 mmol, yield 74.9%), as a white solid. LCMS (ESI) m / z: 303.2 [M+H] + .

[0656] Step 6

[0657] (1s,4s)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexanecarboxylic acid Methyl (1.2 g, 4.0 mmol) of (1s,4s)-4-(5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)cyclohexanecarboxylate was dissolved in water (5 mL) and tetrahydrofuran (5 mL). Lithium hydroxide (285 mg, 11.9 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The pH was adjusted to 5–6 by slow dropwise addition of 1M hydrochloric acid. The solid was filtered off and dried to give (1s,4s)-4-(5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)cyclohexanecarboxylic acid (700 mg, 2.4 mmol, yield 61%) as a white solid. LCMS (ESI) m / z: 289.2 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 12.26 (b, 1H), 9.05 (s, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 7.9 Hz, 1H), 4.19 (s, 2H), 4.17 – 4.11(m, 1H), 2.60 – 2.58 (m, 1H), 2.16 – 2.14 (m, 5H), 1.78 – 1.6 (m, 2H), 1.46 –1.45 (m, 4H).

[0658] Step 7

[0659] (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide (1s,4s)-4-(5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)cyclohexanecarboxylic acid (50 mg, 170 μmol), HATU (79 mg, 210 μmol), and diisopropylethylamine (27 mg, 210 μmol) were added to N,N-dimethylformamide (3 mL). Then, 5-amino-2-methoxybenzonitrile (28 mg, 190 μmol) was added. After the reaction was complete, the solution was filtered and purified by preparative HPLC to obtain (1s,4s)-N-(3-cyano-4-methoxyphenyl)-4-(5-methyl-2-oxo-1,2-dihydroquinazoline-3(4H)-yl)cyclohexanecarboxamide (32 mg, 76 μmol, yield 44%), a white solid. LCMS (ESI) m / z: 418.9 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.91 (s, 1H), 9.04 (s, 1H), 7.98 (d, J = 2.6 Hz, 1H), 7.77 (dd, J = 9.2, 2.6Hz, 1H), 7.21 (d, J = 9.2Hz, 1H), 6.97 (t, J = 7.7 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 6.57 (d, J =7.8 Hz,1H),4.23 – 4.14 (m, 3H), 3.87 (s, 3H), 2.65 – 2.63 (m, 1H), 2.15 – 2.10 (m, 5H),2.04 – 1.92 (m, 2H), 1.69 – 1.63 (m, 2H), 1.46 – 1.43 (m, 2H).

[0660] Example 87

[0661] (1s,4s)-N-(4-methoxy-3-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide

[0662] Step 1

[0663] (1s,4s)-N-(4-methoxy-3-methylphenyl)-4-(5-methyl-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)cyclohexaneformamide Following the synthetic steps of Example 86, the title compound was synthesized from 4-methoxy-3-methylaniline as the starting material, and was a white solid. LCMS (ESI) m / z: 407.9 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.52(s, 1H), 9.03 (s, 1H), 7.36 (d, J = 2.3 Hz, 2H), 6.97 (t, J = 7.7 Hz,1H), 6.87 –6.81 (m, 1H), 6.68 (d, J = 7.5...

Claims

1. A compound as shown in Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X1, X2, and X3are each independently CH, C, or N; R1is R, halogen, t-butyl, cyclopropyl, cyclobutyl, CF3, CHF2, CH2F, OH, CN, CHO, C(O)Me, C(O)OMe, C(O)NH2, CHCH2, NR’R”, R’NR”R”’; Y is CR’R”, C(O), O, S, or NR; W is CH2, O, S, NR, or a single bond; Z is CH2, S, O, NR, or a single bond; R is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CN, OH, OR’, SR’, SOR’, SO2R’, NHR’, NRR’, NRC(O)R’, NRS(O)2R’, NRC(O)OR’, NRC(O)NHR’, NRC(O)NR’R”, NRC(O)OR’, NRS(O)2NHR’, NRS(O)2NR’R”, NRS(O)2OR’, NRS(O)2R’, NRC(O)R’, NRC(O)OR’, NRC(O)NHR’, NRC(O)NR’R”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, NRC(O)NRR”, ​ ​ ​ R2is unsubstituted, C1-C3alkyl, C1-C3alkenyl, NR'R", NHR'NR"R'", R'NR"R'", NHC(O)R'NR"R'", OR, CN, NO2, C(O)R, R'OR", R'NR"C(O)R"', C(O)OR, C(O)NR'R", C(O)NHR'NR"R'", P(O)R'R", R'NR"S(O)2R'", -O-R'NR"R'", halogen, CF3, A 1 , B 1 , -ORA 1 , -ORB 1 , -OA 1 , -OB 1 , ROA 1 , ROB 1 , NR'R"A 1 , NR'R"B 1 , N(R)B 1 , N(R)A 1 , NR'C(O)R"A 1 , NR'C(O)R"B 1 , N(R)C(O)A 1 , N(R)C(O)B 1 , RA 1 , RB 1； ​ ​ Q is A 2 optionally comprising one or more O, N or NR; ​ R3is A 3 , B 2 or a fused bicyclic aromatic ring system, wherein the fused bicyclic aromatic ring system optionally comprises one or more N, NR, O, or S; A 1 , A 2 and A 3 each independently is a 3- to 7-membered carbocyclic or heterocyclic ring; B 1 and B 2 each independently a 5- or 6-membered aromatic or heteroaromatic ring; wherein R, R', R", and R'" are each independently H, C 1-6 alkyl or C 1-6 alkene; Among them, R, R', R”, R”', A 1 A 2 A 3 B 1 B 2 The fused bicyclic aromatic ring system is either unsubstituted or substituted by one or more substituents selected from the following groups: CN, CF3, OR, =O, ROH, NR'R", C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Alkenes, halogens, and 3- to 7-membered carbon rings or heterocycles. ​ ， ​ ​ ​ R2is unsubstituted, C1-C3alkyl, C1-C3alkene, NR'R", NHR'NR"R'", R'NR"R'", NHC(O)R'NR"R'", OR, CN, NO2, C(O)R, R'OR", R'NR"C(O)R"', C(O)OR, C(O)NR'R", C(O)NHR'NR"R'", P(O)R'R", R'NR"S(O)2R'", -O-R'NR"R'", halogen, CF3, A 1 , B 1 , -ORA 1 , -ORB 1 , -OA 1 , -OB 1 , ROA 1 , ROB 1 , NR'R"A 1 , NR'R"B 1 , N(R)B 1 , N(R)A 1 , NR'C(O)R"A 1 , NR'C(O)R"B 1 , N(R)C(O)A 1 , N(R)C(O)B 1 , RA 1 , RB 1 ; ​ ​ R5is H, C 1-6 alkyl, C 1-6 alkene, OR, NR'R", halogen or CN; R4is H, C 1-6 alkyl, OR, NR’R”, halogen, or CN; R3is A 3 , B 2 or a fused bicyclic aromatic ring system, wherein the fused bicyclic aromatic ring system optionally comprises one or more N, NR, O, or S; A 1 and A 3 each independently is a 3- to 7-membered carbocyclic or heterocyclic ring; and B 1 and B 2 each independently a 5- or 6-membered aromatic or heteroaromatic ring; ​ wherein R, R', R", and R'" are each independently H, C 1-6 alkyl or C 1-6 alkenyl; and wherein R, R', R", R'", A 1 , A 3 , B 1 , B 2 and the fused aromatic ring system is unsubstituted or substituted by one or more substituents selected from the group consisting of: CN, CF3, OR, =0, ROH, NR'R", C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, halogen, and a 3- to 7-membered carbocyclic or heterocyclic ring. ​ or , ​ ​ R2is unsubstituted, or is C1-C3alkyl, C1-C3alkenyl, NR'R", NHR'NR"R'", R'NR"R'", NHC(O)R'NR"R'", OR, CN, NO2, C(O)R, R'OR", R'NR"C(O)R"', C(O)OR, C(O)NR'R", C(O)NHR'NR"R'", P(O)R'R", R'NR"S(O)2R'", -O-R'NR"R'", halogen, CF3, A 1 , B 1 , -ORA 1 , -ORB 1 , -OA 1 , -OB 1 , ROA 1 , ROB 1 , NR'R"A 1 , NR'R"B 1 , N(R)B 1 , N(R)A 1 , NR'C(O)R"A 1 , NR'C(O)R"B 1 , N(R)C(O)A 1 , N(R)C(O)B 1 , RA 1 , RB 1 ; ​ R3is A 3 , B 2 or a fused bicyclic aromatic ring system, wherein the fused bicyclic aromatic ring system optionally comprises one or more N, NR, O, or S; A 1 and A 3 each independently is a 3- to 7-membered carbocyclic or heterocyclic ring; and B 1 and B 2 each independently is a 5- or 6-membered aromatic or heteroaromatic ring; wherein R, R', R", and R'" are each independently H, C 1-6 alkyl or C 1-6 alkenyl; and wherein R, R', R", R'", A 1 , A 3 , B 1 , B 2 and the fused bicyclic aromatic ring system is unsubstituted or substituted by one or more substituents selected from the group consisting of CN, CF3, OR, =0, ROH, NR'R", C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, halogen, and a 3- to 7-membered carbocyclic or heterocyclic ring. ​ or , ​ ​ R2is unsubstituted, or is C1-C3alkyl, C1-C3alkenyl, NR'R", NHR'NR"R'", R'NR"R'", NHC(O)R'NR"R'", OR, CN, NO2, C(O)R, R'OR", R'NR"C(O)R"', C(O)OR, C(O)NR'R", C(O)NHR'NR"R'", P(O)R'R", R'NR"S(O)2R'", -O-R'NR"R'", halogen, CF3, A 1 , B 1 , -ORA 1 , -ORB 1 , -OA 1 , -OB 1 , ROA 1 , ROB 1 , NR'R"A 1 , NR'R"B 1 , N(R)B 1 , N(R)A 1 , NR'C(O)R"A 1 , NR'C(O)R"B 1 , N(R)C(O)A 1 , N(R)C(O)B 1 , RA 1 , RB 1 ; R3is A 3 , B 2 or a fused bicyclic aromatic ring system, wherein the fused bicyclic aromatic ring system optionally comprises one or more N, NR, O, or S; A 1 and A 3 each independently is a 3- to 7-membered carbocyclic or heterocyclic ring; and B 1 and B 2 each independently is a 5- or 6-membered aromatic or heteroaromatic ring; wherein R, R', R", and R'" are each independently H, C 1-6 alkyl or C 1-6 alkenyl; and wherein R, R', R", R'", A 1 , A 3 , B 1 , B 2 and the fused bicyclic aromatic ring system is unsubstituted or substituted with substituents selected from the group consisting of CN, CF3, OR, =0, ROH, NR'R", C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, halogen, and a 3- to 7-membered carbocyclic or heterocyclic ring. ​ or . ​ or . ​ 8. The compound of any one of claims 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is H, C 1-6 alkyl, or halogen. ​ ​ 11. The compound according to any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A in R2 1 or B 1 is , , , , , , , , , or , optionally substituted with one or two substituents selected from C 1-6 alkyl, -O-C 1-6 alkyl, CN, OH, halogen and NH2.

12. The compound according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is CR’R” or CH2.

13. The compound of claim 3 or 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, In compounds of Formula (IIIa) Y is NR, or in compounds of Formula (IIIb) Y is NR, O or S.

14. A stereoisomer of the compound according to any one of claims 1 or 7 to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q is , , , , , or .

15. The compound of any one of claims 2 or 6-14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4is C 1-3 alkyl.

16. The compound according to any one of claims 1 or 7 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is a single bond.

17. The compound according to any one of claims 1 to 16, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the 3- to 7-membered carbocyclic or heterocyclic ring comprises one spiro ring.

18. The compound according to any one of claims 1 to 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A in R3 3 Or B 2 Substituted by one or more substituents selected from the group consisting of: CN, CF3, OR, =O, ROH, NR'R", C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Alkenes, halogens, and 3 to 7-membered carbon rings or heterocycles.

19. The compound according to claim 18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is a 5- or 6-membered aromatic or heteroaromatic ring, or a fused bicyclic aromatic ring system, substituted with one or two substituents selected from the group consisting of CN, CF3, OR, =0, ROH, NR'R", C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, halogen, and 3- to 7-membered carbocyclic or heterocyclic ring.

20. The compound of claim 18 or 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is , , , , , , , , , , , , , , , , and is unsubstituted, or substituted with one, two, or three substituents selected from the group consisting of CN, CF3, OR, =0, C1-6alkyl, -O-C1-6alkyl, C1-6alkene, ROH, halogen, and a 3- to 7-membered carbocyclic or heterocyclic ring.

21. The compound of any one of claims 1 or 7-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A 2 substituted with one or two substituents selected from the group consisting of CN, CF3, OR, =0, ROH, NR’R”, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkene, F, Cl, Br, I, and a 3- to 7-membered carbocyclic or heterocyclic ring.

22. The compound of any one of claims 1 to 21, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

23. The compound of any one of claims 1 to 22, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: , , , , , , and .

24. The compound of any one of claims 1 to 22, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is .

25. The compound of any one of claims 1 to 22, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is .

26. A compound according to any one of claims 1 to 25, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in medicine.

27. A compound according to any one of claims 1 to 26, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment of a disease responsive to OGG1 inhibition.

28. A compound according to any one of claims 1 to 25, or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease responsive to OGG1 inhibition.

29. The compound according to claim 27 or 28, wherein the disease is selected from the group consisting of cancer, cardiovascular disease, nervous system disease, inflammatory disease, autoimmune disease and infectious disease.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition according to claim 30, wherein the composition is for use in the treatment of a disease mediated by OGG1.

32. The pharmaceutical composition according to claim 30 or 31, wherein the disease is selected from the group consisting of cancer, cardiovascular disease, nervous system disease, inflammatory disease, autoimmune disease and infectious disease.

33. A method of treating a disease in a subject, comprising: administering to the subject a compound according to any one of claims 1 to 29, or a stereoisomer or pharmaceutically acceptable salt thereof; wherein the disease is mediated by OGG1.

34. The method according to claim 33, wherein the disease is selected from the group consisting of cancer, cardiovascular disease, nervous system disease, inflammatory disease, autoimmune disease and infectious disease.

35. The method according to claim 33 or 34, wherein the disease is cancer, and the cancer is derived from a solid organ or from the hematopoietic system.

36. The method according to any one of claims 33 to 35, wherein the disease is cancer, the cancer is derived from a solid organ, and the solid organ is selected from the group consisting of brain, breast, colon, endometrium, esophagus, head and neck, upper digestive tract, respiratory tract, lung, kidney, liver, lower digestive tract, small intestine, large intestine, ovary, pancreas, prostate, stomach, testis, and urinary tract.

37. The method according to any one of claims 33 to 35, wherein the disease is cancer, and the cancer is leukemia or lymphoma.

38. The method of claim 37, wherein the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML).

39. The method of claim 37, wherein the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, or Burkitt's lymphoma.

40. The method of any one of claims 33-35, wherein the disease is cancer, and the cancer is selected from bladder cancer, bone cancer, cervical cancer, epithelial cancer, gallbladder cancer, rectal cancer, skin cancer, thyroid cancer, and uterine cancer.

41. The method of claim 33 or 34, wherein the disease is an inflammatory disease, the inflammatory disease is selected from inflammatory bowel disease (IBD), atherosclerosis, rheumatoid arthritis, fibrosis, Alzheimer's disease, and Parkinson's disease.

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