Patent Description:
The mitogen-activated protein kinases (MAPK) pathway exists in a series of cellular processes such as cell proliferation, differentiation, apoptosis and stress response. Among them, the RAS-RAF-MEK-ERK pathway is one of the most widely known MAPK pathways. In this pathway, extracellular growth factors (PDGF or EGF) are combined with transmembrane receptors (EGFR or PDGFR, etc.) to activate the receptors, and binding and activation of RAS proteins in the membranes and GTP are made by the activated receptors through guanine nucleotide exchange factor (SOS); and the activated RAS further indirectly phosphorylates RAF; the activated RAF is phosphorylated on two serine residues of MEK1/<NUM>; the activated MEK1/<NUM> in turn activates its downstream substrate ERK1/<NUM>; and then after dimerization, phosphorylated ERK1/<NUM> moves into the cell nucleus and accumulates. ERK in the cell nucleus involves many cellular functions, including nuclear transport, signal transduction, DNA repairing, mRNA processing and translation, etc. If the genes involved in this pathway are mutated, or the growth factors, downstream signal proteins or protein kinases are over-expressed, it will lead to the continuous activation of the cell pathway, uncontrolled cell proliferation and eventually lead to tumor formation. For example, about <NUM>% of human cancer cells belong to RAS mutation, wherein KRAS mutation is the most common subtype of RAS mutation, and KRAS mutated tumors account for about <NUM>% of all human tumor cells, wherein <NUM>-<NUM>% of pancreatic cancer, <NUM>-<NUM>% of non-small cell lung cancer and <NUM>-<NUM>% of colorectal cancer belong to KRAS mutation; and about <NUM>% tumors belong to BRAF mutation, wherein <NUM>-<NUM>% melanoma and <NUM>-<NUM>% papillary thyroid cancer and the like all belong to BRAF mutation.

Extracellular signal-regulated kinase (ERK1/<NUM>) is an important member of MAPK family, and as the "final manager" downstream of RAF/RAF/MEK/ERK pathway, targeted inhibition of ERK1/<NUM> is expected to be used for the treatment of cancer caused by abnormal activation of MAPK pathway (activation variation of RAF/RAF/MEK, etc.), and may also be effective for patients who are resistant to RAF or MEK inhibitors due to reactivation of ERK1/<NUM>. According to many preclinical reports, MAPK pathway inhibitors can effectively inhibit cancer cells with BRAF and RAS mutations, and for example, BRAF inhibitors Vemurafenib, Dabrafenib and MEK inhibitor Trametinib have been approved for the treatment of melanoma with BRAF mutations. However, these medicaments still have drug resistance problems. The resistance mechanism of BRA inhibitor has been confirmed, wherein, including MEK trans-activation of CRAF and RTK, up-regulation of NRAS signal, and MEK activation mutation; and the drug resistance mechanism of MEK inhibitors includes MEK mutation to reduce its binding to medicaments or enhance the activity of MEK itself, and BRAF or KRAS amplification and the like. Both RAF inhibitor resistance and MEK inhibitor resistance will reactivate the RAS-RAF-MEK-ERK pathway and lead to the continuous amplification of cancer cells. Therefore, the development of a new type of dual-mechanism ERK inhibitor will be effective not only for patients with MAPK signaling pathway mutation, but also for patients with BRAF and MEK inhibitors resistance.

<CIT> discloses compounds that are inhibitors of ERK <NUM>/<NUM> kinases and are useful in the treatment of ERK l/<NUM>-mediated conditions. Compounds having activity as inhibitors of G12C mutant KRAS protein are disclosed in <CIT>. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and their use in modulating the activity of G12C mutant KRAS protein for the treatment of disorders, such as cancer, are also disclosed.

The present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
<CHM>
wherein,.

The present disclosure also provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
<CHM>
wherein,.

The present disclosure also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
<CHM>.

In some embodiments of the present disclosure, the compound has the structure represented by formula (I-<NUM>) or (I-<NUM>):
<CHM>
or
<CHM>
wherein, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> are as defined herein.

In some embodiments of the present disclosure, the Rb is each independently F, Cl, Br, I, D or - CH<NUM>, and the other variables are as defined herein.

In some embodiments of the present disclosure, the Rb is each independently F, Cl, Br, I or -CH<NUM>, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> is
<CHM>
wherein the
<CHM>
is optionally substituted by <NUM>, <NUM> or <NUM> Rb, and Rb and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> is
<CHM>
and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> is
<CHM>
and Rb and the other variables are as defined herein.

In some embodiments of the present disclosure, the compound has the structure represented by formula (III-<NUM>) or (III-<NUM>):
<CHM>
wherein,.

In some embodiments of the present disclosure, the compound has the structure represented by formula (I-<NUM>) or (I-<NUM>):
<CHM>
wherein, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H, D, F, Cl or -CH<NUM>, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H, F, Cl or -CH<NUM>, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> combining with the carbon atoms to which they are attached form
<CHM>
and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H or -CH<NUM>, wherein the -CH<NUM> is optionally substituted by <NUM>, <NUM> or <NUM> substituents independently selected from F, Cl, Br, I and -OH, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H or -CH<NUM>, wherein the -CH<NUM> is optionally substituted by <NUM>, <NUM> or <NUM> substituents independently selected from F, Cl, Br and I, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H or -CH<NUM>, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H or -CH<NUM>, wherein the -CH<NUM> is optionally substituted by <NUM>, <NUM>, or <NUM> substituents independently selected from F, Cl, Br, I -OH and -OCH<NUM>, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H, -CH<NUM> or
<CHM>
and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> and R<NUM> are each independently H or
<CHM>
and the other variables are as defined herein.

In some embodiments of the present disclosure, the compound has the structure represented by formula (I-<NUM>) or (I-<NUM>):
<CHM>.

In some embodiments of the present disclosure, the Ra is each independently F, Cl, Br, I, -CH<NUM>, - OCH<NUM>, -NH-CH<NUM> or
<CHM>
and the other variables are as defined herein.

In some embodiments of the present disclosure, the Ra is each independently F, Cl, Br, I, -CH<NUM> or -OCH<NUM>, and the other variables are as defined herein.

In some embodiments of the present disclosure, the Ra is each independently F, Cl, -CH<NUM>, -OCH<NUM>
<CHM>
and the other variables are as defined herein.

In some embodiments of the present disclosure, the Ra is independently F or -OCH<NUM>, and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> is
<CHM>
<CHM>
and Ra and the other variables are as defined herein.

In some embodiments of the present disclosure, the R<NUM> is
<CHM>
<CHM>
and the other variables are as defined herein.

Some embodiments of the present disclosure are formed by any combination of the above variables.

The present disclosure provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
or
<CHM>.

The present disclosure provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The compound of the present disclosure has a very good inhibitory activity on ERK1/<NUM>. It is expected to be used for canceration caused by abnormal activation of MAPK signaling pathway (activation variation such as RAS/RAF/MEK), and it may also be effective for patients with RAF or MEK inhibitor resistance due to ERK1/<NUM> reactivation; the compound of the present disclosure has good oral absorption in mice and dogs, low clearance rate, high exposure and good bioavailability; the compound of the present disclosure has a significant inhibitory effect on the growth of human lung cancer Calu-<NUM> cell subcutaneous xenograft tumor model tumor-bearing mice.

Unless otherwise specified, the following terms and phrases when used herein have the following meanings. A specific term or phrase should not be considered indefinite or unclear in the absence of a particular definition, but should be understood in the ordinary sense. When a trade name appears herein, it is intended to refer to its corresponding commodity or active ingredient thereof.

The term "pharmaceutically acceptable" is used herein in terms of those compounds, materials, compositions, and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of reliable medical judgment, with no excessive toxicity, irritation, an allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present disclosure that is prepared by reacting the compound having a specific substituent of the present disclosure with a relatively non-toxic acid or base. When the compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by bringing the compound into contact with a sufficient amount of base in a pure solution or a suitable inert solvent. The pharmaceutically acceptable base addition salt includes a salt of sodium, potassium, calcium, ammonium, organic amine or magnesium, or similar salts. When the compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by bringing the compound into contact with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salt include an inorganic acid salt, wherein the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and an organic acid salt, wherein the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and the like; and salts of amino acid (such as arginine and the like), and a salt of an organic acid such as glucuronic acid and the like. Certain specific compounds of the present disclosure contain both basic and acidic functional groups, thus can be converted to any base or acid addition salt.

The pharmaceutically acceptable salt of the present disclosure can be prepared from the parent compound that contains an acidic or basic moiety by conventional chemical method. Generally, such salt can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture thereof.

The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomers or diastereomeric enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included within the scope of the present disclosure.

Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

Unless otherwise specified, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to rotate freely of double bonds or single bonds of ring-forming carbon atoms.

Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is not mirror images.

Unless otherwise specified, "(+)" refers to dextrorotation, "(-)" refers to levorotation, and or "(±)" refers to racemic.

Unless otherwise specified, the absolute configuration of a stereogenic center is represented by a wedged solid bond (<IMG>) and a wedged dashed bond (<IMG>), and the relative configuration of a stereogenic center is represented by a straight solid bond (<IMG>) and a straight dashed bond (<IMG>), a wave line (<IMG>) is used to represent a wedged solid bond (<IMG>) or a wedged dashed bond (<IMG>), or the wave line (<IMG>) is used to represent a straight solid bond (<IMG>) and a straight dashed bond (<IMG>).

Unless otherwise specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in enantiomers" refer to the content of one of the isomers or enantiomers is less than <NUM>%, and the content of the isomer or enantiomer is greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%.

Unless otherwise specified, the term "isomer excess" or "enantiomeric excess" refers to the differential value between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is <NUM>%, and the content of the other isomer or enantiomer is <NUM>%, the isomer or enantiomer excess (ee value) is <NUM>%.

Optically active (R)- and (S)-isomer, or D and L isomer can be prepared using chiral synthesis or chiral reagents or other conventional techniques. If one kind of enantiomer of certain compound of the present disclosure is to be obtained, the pure desired enantiomer can be obtained by asymmetric synthesis or derivative action of chiral auxiliary followed by separating the resulting diastereomeric mixture and cleaving the auxiliary group. Alternatively, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), the compound reacts with an appropriate optically active acid or base to form a salt of the diastereomeric isomer which is then subjected to diastereomeric resolution through the conventional method in the art to give the pure enantiomer. In addition, the enantiomer and the diastereoisomer are generally isolated through chromatography which uses a chiral stationary phase and optionally combines with a chemical derivative method (such as carbamate generated from amine). The compound of the present disclosure may contain an unnatural proportion of atomic isotope at one or more than one atom(s) that constitute the compound. For example, the compound can be radiolabeled with a radioactive isotope, such as tritium (<NUM>H), iodine-<NUM> (<NUM>I) or C-<NUM> (<NUM>C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen, the bond formed by deuterium and carbon is stronger than that of ordinary hydrogen and carbon, compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxic and side effects, increased drug stability, enhanced efficacy, extended biological half-life of drugs, etc. All isotopic variations of the compound of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. The term "optional" or "optionally" means that the subsequent event or condition may occur but not requisite, that the term includes the instance in which the event or condition occurs and the instance in which the event or condition does not occur.

The term "substituted" means one or more than one hydrogen atom(s) on a specific atom are substituted with the substituent, including deuterium and hydrogen variables, as long as the valence of the specific atom is normal and the substituted compound is stable. When the substituent is an oxygen (i.e., =O), it means two hydrogen atoms are substituted. Positions on an aromatic ring cannot be substituted with a ketone. The term "optionally substituted" means an atom can be substituted with a substituent or not, unless otherwise specified, the type and number of the substituent may be arbitrary as long as being chemically achievable.

When any variable (such as R) occurs in the constitution or structure of the compound more than once, the definition of the variable at each occurrence is independent. Thus, for example, if a group is substituted with <NUM>-<NUM> R, the group can be optionally substituted with up to two R, wherein the definition of R at each occurrence is independent. Moreover, a combination of the substituent and/or the variant thereof is allowed only when the combination results in a stable compound.

When the number of a linking group is <NUM>, such as -(CRR)<NUM>-, it means that the linking group is a single bond.

When one of the variables is selected from a single bond, it means that the two groups linked by the single bond are connected directly. For example, when L in A-L-Z represents a single bond, the structure of A-L-Z is actually A-Z.

When a substituent is vacant, it means that the substituent does not exist, for example, when X is vacant in A-X, the structure of A-X is actually A. When the enumerative substituent does not indicate by which atom it is linked to the group to be substituted, such substituent can be bonded by any atom thereof. For example, when pyridyl acts as a substituent, it can be linked to the group to be substituted by any carbon atom on the pyridine ring.

When the enumerative linking group does not indicate the direction for linking, the direction for linking is arbitrary, for example, the linking group L contained in
<CHM>
is -M-W-, then - M-W- can link ring A and ring B to form
<CHM>
in the direction same as left-to-right reading order, and form
<CHM>
in the direction contrary to left-to-right reading order. A combination of the linking groups, substituents and/or variables thereof is allowed only when such combination can result in a stable compound.

Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. The chemical bond between the site and other groups can be represented by a straight solid bond (<IMG>), a straight dashed bond (<IMG>) or a wavy line
<CHM>
For example, the straight solid bond in -OCH<NUM> indicates that it is connected to other groups through the oxygen atom in the group; the straight dotted bond in
<CHM>
indicates that it is connected to other groups through both ends of the nitrogen atom in the group; the wavy line in
<CHM>
indicates that the phenyl group is connected to other groups through the <NUM> and <NUM> carbon atoms in the phenyl.

Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, e.g., "<NUM>- to <NUM>-membered ring" refers to a "ring" of <NUM>-<NUM> atoms arranged around it.

Unless otherwise specified, "<NUM>-membered ring" refers to cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl consisting of five ring atoms. The ring includes single ring, and also includes double ring systems such as spiro ring, fused ring and bridged ring. Unless otherwise specified, the ring optionally contains <NUM>, <NUM> or <NUM> heteroatoms independently selected from O, S and N. The term "ring" also includes a ring system containing at least one ring, wherein each "ring" independently conforms to the above definition.

Unless otherwise specified, the term "C<NUM>-<NUM> alkyl" refers to a linear or branched saturated hydrocarbon group consisting of <NUM> to <NUM> carbon atoms. The C<NUM>-<NUM> alkyl includes C<NUM>-<NUM> and C<NUM>-<NUM> alkyl, etc; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C<NUM>-<NUM> alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc..

Unless otherwise specified, the term "C<NUM>-<NUM> haloalkyl" refers to a monohaloalkyl and polyhaloalkyl containing <NUM> to <NUM> carbon atoms. The C<NUM>-<NUM> haloalkyl includes C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>, C<NUM> and C<NUM> haloalkyl, etc. Examples of C<NUM>-<NUM> haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, <NUM>,<NUM>,<NUM>-trifluoroethyl, pentafluoroethyl, pentachloroethyl, <NUM>-bromopropyl, etc..

Unless otherwise specified, the term "C<NUM>-<NUM> alkoxy" refers to an alkyl group containing <NUM> to <NUM> carbon atoms that are connected to the rest of the molecule through an oxygen atom. The C<NUM>-<NUM> alkoxy includes C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM> and C<NUM> alkoxy, etc. Examples of C<NUM>-<NUM> alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc..

Unless otherwise specified, the term "C<NUM>-<NUM> aromatic ring" and "C<NUM>-<NUM> aryl" are used interchangeably, and the "C<NUM>-<NUM> aromatic ring" or "C<NUM>-<NUM> aryl" refers to a cyclic hydrocarbon group with conjugated π electron system consisting of <NUM> to <NUM> carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, where each ring is aromatic. It may be monovalent, divalent or polyvalent, and C<NUM>-<NUM> aryl includes C<NUM>-<NUM>, C<NUM>, C<NUM> and C<NUM> aryl, etc. Examples of C<NUM>-<NUM> aryl include, but are not limited to, phenyl, naphthyl (including <NUM>-naphthyl and <NUM>-naphthyl, etc.).

Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, for example, C<NUM>-<NUM> includes C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, and C<NUM>, and any range from n to n+m is also included, for example C<NUM>-<NUM> includes C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, and C<NUM>-<NUM>, etc.; similarly, n-membered to n+m-membered means that the number of atoms on the ring is from n to n+m, for example, <NUM>- to <NUM>-membered ring includes <NUM>-membered ring, <NUM>-membered ring, <NUM>-membered ring, <NUM>-membered ring, <NUM>-membered ring, <NUM>-membered ring, <NUM>-membered ring, <NUM>-membered ring, <NUM>-membered ring, and <NUM>-membered ring, and any range from n to n+m is also included, for example, <NUM>- to <NUM>-membered ring includes <NUM>- to <NUM>-membered ring, <NUM>- to <NUM>-membered ring, <NUM>- to <NUM>-membered ring, <NUM>- to <NUM>-membered ring, <NUM>- to <NUM>-membered ring, <NUM>- to <NUM>-membered ring, and <NUM>- to <NUM>-membered ring, etc..

The term "D" refers to deuterium, an isotope of hydrogen, and its chemical symbol can also be <NUM>H, also known as heavy hydrogen, which is composed of a proton, a neutron and an electron.

The term "leaving group" refers to a functional group or atom which can be replaced by another functional group or atom through a substitution reaction (such as affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate group, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonates, etc; acyloxy, such as acetoxy, trifluoroacetoxy, etc..

The term "protecting group" includes, but is not limited to "amino protecting group", "hydroxy protecting group" or "thio protecting group". The term "amino protecting group" refers to a protecting group suitable for blocking the side reaction on the nitrogen of an amino. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and <NUM>-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), <NUM>,<NUM>-bis-(<NUM>'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) , etc. The term "hydroxy protecting group" refers to a protecting group suitable for blocking the side reaction on hydroxy. Representative hydroxy protecting groups include, but are not limited to: alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), <NUM>-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl dimethyl silyl (TBS), etc..

The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent alternatives known to those skilled in the art, preferred implementations include but are not limited to the embodiments of the present disclosure.

The structure of the compounds of the present disclosure can be confirmed by conventional methods known to those skilled in the art, and if the disclosure involves an absolute configuration of a compound, then the absolute configuration can be confirmed by means of conventional techniques in the art. For example, in the case of single crystal X-ray diffraction (SXRD), the absolute configuration can be confirmed by collecting diffraction intensity data from the cultured single crystal using a Bruker D8 venture diffractometer with CuKα radiation as the light source and scanning mode: ϕ/ω scan, and after collecting the relevant data, the crystal structure can be further analyzed by direct method (Shelxs97) to confirm the absolute configuration.

The solvent used in the present disclosure is commercially available.

The present disclosure adopts the following abbreviations: BF<NUM>·Et<NUM>O stands for boron trifluoride diethyl etherate complex; DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; DPBS stands for Dulbecco's phosphate buffered saline; EDCI stands for <NUM>-(<NUM>-dimethylaminopropyl)-<NUM>-ethylcarbodiimide; HOBt stands for <NUM>-hydroxybenzotriazole; HPLC stands for high-pressure liquid chromatography; LCMS stands for liquid chromatography-mass spectrometry; MeOH stands for methanol; NMM stands for N-methylmorpholine; Pd(dppf)Cl<NUM>·CH<NUM>Cl<NUM> stands for [<NUM>,<NUM>'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex; Pd(PPh<NUM>)<NUM> stands for tetrakis(triphenylphosphine)palladium; PBS stands for phosphate buffer; HATU stands for O-(<NUM>-azabenzotriazol-<NUM>-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; PMB stands for p-methoxybenzyl; NMP stands for N-methyl pyrrolidone; DIEA stands for N,N-diisopropylethylamine; LiAlD<NUM> stands for deuterated lithium aluminum hydride; MsCl stands for methanesulfonyl chloride; BNS stands for N-bromosuccinimide; AIBN stands for azodiisobutyronitrile.

The present disclosure is described in detail by the embodiments below, but it does not mean that there are any adverse restrictions on the present disclosure. The present disclosure has been described in detail herein, wherein specific embodiments thereof are also disclosed, and it will be apparent to those skilled in the art that various variations and improvements can be made to specific embodiments of the present disclosure without departing from the scope of the present disclosure.

Compound SM1 (<NUM>, <NUM> mmol) and Pd/C (<NUM>, <NUM> mmol, <NUM>% purity) were dissolved in methanol (<NUM>), and the reaction solution was replaced with hydrogen for three times to discharge the air, and then stirred at <NUM> for <NUM> hours under the protection of hydrogen (<NUM> kPa (<NUM> psi)). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of 1A, and the crude product was directly used in the next reaction. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>). <CHM>
<CHM>.

A solution of compound 1A (<NUM>, <NUM> mmol) in acetonitrile (<NUM>) was added dropwise to a solution of compound copper bromide (<NUM>, <NUM> mmol, <NUM>µL) and tert-butyl nitrite (<NUM>, <NUM> mmol, <NUM>) in acetonitrile (<NUM>) at <NUM>. The reaction solution was stirred at <NUM> for <NUM> hour after the dropwise addition was completed. Then the mixture was stirred at <NUM> for <NUM> hours. The reaction solution was diluted with water (<NUM>), and the pH was adjusted to <NUM> or less with hydrochloric acid solution (<NUM> mol). Then the reaction solution was extracted with ethyl acetate (<NUM>×<NUM> times). The organic phases were combined and concentrated under reduced pressure to obtain compound 1B. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Compound 1B (<NUM>, <NUM> mmol) was dissolved in tetrahydrofuran (<NUM>), and sodium borohydride (<NUM>, <NUM> mmol) was added. The reaction solution was cooled to -<NUM>, and then BF<NUM>·Et<NUM>O (<NUM>, <NUM> mmol, <NUM>) was added dropwise at -<NUM>. And the mixture was stirred at - <NUM> for <NUM> minutes. Then the mixture was stirred at <NUM> for <NUM> hours. The reaction solution was poured into ice water (<NUM>), and the pH of the reaction solution was adjusted to <NUM> with <NUM> mol of sodium hydroxide (<NUM>) solution. The reaction solution was extracted with ethyl acetate (<NUM>). The organic phase was extracted with <NUM> mol of sodium hydroxide (<NUM>× <NUM> times) aqueous solution. The pH of the combined aqueous phase was adjusted to <NUM> with <NUM> mol of hydrochloric acid (<NUM>) solution, then the aqueous phase was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was concentrated under reduced pressure to obtain a crude product of compound 1C. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>).

Under the protection of nitrogen, compound 1C (<NUM>, <NUM> mmol), ethyl (<NUM>S)-<NUM>-bromopropanoate (<NUM>, <NUM> mmol) and potassium carbonate (<NUM>, <NUM> mmol) were dissolved in DMF (<NUM>), and the mixture was stirred for <NUM> hour at <NUM>. The reaction solution was diluted with <NUM> of water and then extracted with ethyl acetate (<NUM>×<NUM> times). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 1D. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dq, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

Under the protection of nitrogen, bis(pinacolato)diboron (<NUM>, <NUM> mmol), compound 1D (<NUM>, <NUM> mmol), Pd(dppf)Cl<NUM>·CH<NUM>Cl<NUM> (<NUM>, <NUM>µmol) and potassium acetate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>), and the mixture was stirred at <NUM> for <NUM> hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 1E.

Under the protection of nitrogen, compound 1E (<NUM>, <NUM> mmol), <NUM>,<NUM>,<NUM>-trichloropyrimidine (<NUM>, <NUM> mmol), Pd(PPh<NUM>)<NUM> (<NUM>, <NUM>µmol) and sodium carbonate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>) and water (<NUM>), and the mixture was stirred at <NUM> for <NUM> hours. The reaction solution was filtered, and then ethyl acetate (<NUM>) was added to the filtrate, and the solution was washed with saturated sodium chloride solution (<NUM>×<NUM> times). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 1F. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dq, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

Under the protection of nitrogen, compound 1F (<NUM>, <NUM> mmol), <NUM>-aminotetrahydropyran (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were dissolved in dioxane (<NUM>), and the mixture was stirred at <NUM> for <NUM> hours. The reaction solution was diluted with ethyl acetate (<NUM>) and washed with <NUM> mol of hydrochloric acid (<NUM>×<NUM> time) aqueous solution, and then the aqueous phase was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time), dried and concentrated under reduced pressure to obtain a crude product of compound <NUM>. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dq, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Lithium hydroxide monohydrate (<NUM> mol, <NUM>) was added to a solution of compound <NUM> (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) and methanol (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to <NUM> with <NUM> mol of hydrochloric acid (<NUM>) solution, and then the solution was extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound <NUM>. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Under the protection of nitrogen, compound <NUM> (<NUM>, <NUM>µmol), (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM>µmol), HOBt (<NUM>, <NUM>µmol), NMM (<NUM>, <NUM>µmol, <NUM>µL) and EDCI (<NUM>, <NUM>µmol) were dissolved in a mixed solvent of DMF (<NUM>) and dichloromethane (<NUM>), and the mixture was stirred at <NUM> for <NUM> hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was diluted with dichloromethane (<NUM>) and then washed with hydrochloric acid aqueous solution (<NUM> mol, <NUM>× <NUM> times). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (trifluoroacetic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, MeOH-d<NUM>) δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (br dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI) m/z: <NUM> [M+<NUM>].

Compound 2A (<NUM>, <NUM>µmol, HCl) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound 1F (<NUM>, <NUM>µmol) in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (<NUM>) and washed with 1mol of hydrochloric acid (<NUM>×<NUM> time) aqueous solution. The aqueous phase was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time), dried and concentrated under reduced pressure to obtain a crude product of compound 2B. <NUM>H NMR (<NUM>, CDCl<NUM>) δ=<NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>]. <CHM>
<CHM>.

An aqueous (<NUM>) solution of lithium hydroxide monohydrate (<NUM>, <NUM>µmol) was added to a solution of compound 2B (<NUM>, <NUM>µmol) in tetrahydrofuran (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to <NUM> with <NUM> mol of hydrochloric acid (<NUM>) solution, and then the solution was extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 2C. LCMS (ESI): m/z: <NUM> [M+<NUM>].

(<NUM>)-<NUM>-Amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM>µmol, <NUM>µL) were added to a solution of compound 2C (<NUM>, <NUM>µmol) in dichloromethane (<NUM>), and the mixture was stirred at <NUM> for <NUM> minutes, and then HATU (<NUM>, <NUM>µmol) was added to the mixture, and the reaction solution was stirred at <NUM> for <NUM> hour. The pH of the reaction solution was adjusted to below <NUM> with hydrochloric acid (<NUM>) aqueous solution, then the mixture was extracted with dichloromethane (<NUM>×<NUM> times), and then washed with water (<NUM>×<NUM> time). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (CD<NUM>OD, <NUM>) δ=<NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>), <NUM> (td, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dt, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 1E (<NUM>, <NUM> mmol), 3A (<NUM>, <NUM> mmol, <NUM>µL), Pd(PPh<NUM>)<NUM> (<NUM>, <NUM>µmol) and sodium carbonate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>) and water (<NUM>), and the mixture was stirred at <NUM> for <NUM> hour. The reaction solution was filtered, and then ethyl acetate (<NUM>) was added to the filtrate, and the solution was washed with saturated sodium chloride solution (<NUM>×<NUM> time). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM>) to obtain compound 3B. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>]. LCMS (ESI): m/z: <NUM> [M+<NUM>].

DIEA (<NUM>, <NUM>µmol, <NUM>µL) and <NUM>-aminotetrahydropyran (<NUM>, <NUM>µmol) were added to a solution of compound 3B (<NUM>, <NUM>µmol) in dioxane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the mixture was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM>) to obtain compound 3C. LCMS (ESI): m/z: <NUM> [M+<NUM>].

An aqueous (<NUM>) solution of lithium hydroxide monohydrate (<NUM>, <NUM>µmol) was added to a solution of compound 3C (<NUM>, <NUM>µmol) in tetrahydrofuran (<NUM>) and ethanol (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to <NUM> with hydrochloric acid (<NUM> mol) aqueous solution, and then the solution was extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 3D. LCMS (ESI): m/z: <NUM> [M+<NUM>].

(<NUM>)-<NUM>-Amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM>µmol, <NUM>µL) were added to a solution of compound 3D (<NUM>, <NUM>µmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> minutes. Then HATU (<NUM>, <NUM>µmol) was added to the reaction solution, and continued to react for <NUM> hours. The pH of the reaction solution was adjusted to below <NUM> with hydrochloric acid (<NUM>) aqueous solution, then the mixture was extracted with dichloromethane (<NUM>×<NUM> times), and then washed with water (<NUM>×<NUM> time). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, CD<NUM>OD) δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 1E (<NUM>, <NUM>µmol), compound 4A (<NUM>, <NUM>µmol), Pd(dppf)Cl<NUM>·CH<NUM>Cl<NUM> (<NUM>, <NUM>µmol) and sodium carbonate (<NUM>, <NUM>µmol) were dissolved in dioxane (<NUM>) and water (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, <NUM> of hydrochloric acid (<NUM> mol) was added to reaction solution to quench the reaction, and the mixture was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM>) to obtain compound 4B. <NUM>H NMR (<NUM>, CDCl<NUM>) δ=<NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 4B (<NUM>, <NUM> mmol), <NUM>-aminotetrahydropyran (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were dissolved in NMP (<NUM>), and the mixture was stirred at <NUM> for <NUM> hours. The reaction solution was diluted with ethyl acetate (<NUM>) and washed with <NUM> mol of hydrochloric acid (<NUM>×<NUM> time) aqueous solution. The organic phase was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate = <NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 4C. <NUM>H NMR (<NUM>, CDCl<NUM>) δ=<NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br t, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

An aqueous (<NUM>) solution of lithium hydroxide monohydrate (<NUM>, <NUM>µmol) was added to a solution of compound 4C (<NUM>, <NUM>µmol) in tetrahydrofuran (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to <NUM> with <NUM> mol of hydrochloric acid aqueous solution, and then the solution was extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 4D. <NUM>H NMR (<NUM>, CD<NUM>OD) δ=<NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (q, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

At <NUM>, DIEA (<NUM>, <NUM>µmol, <NUM>µL) was added to a solution of compound 4D (<NUM>, <NUM>µmol) and (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM>µmol) in dichloromethane (<NUM>), and the mixture was stirred at <NUM> for <NUM> minutes, then HATU (<NUM>, <NUM>µmol) was added and the mixture was continued to stir at <NUM> for <NUM> minutes. The pH of the reaction solution was adjusted to below <NUM> with hydrochloric acid (<NUM> mol) aqueous solution, then the mixture was extracted with dichloromethane (<NUM>×<NUM> times), and then washed with water (<NUM>×<NUM> time). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, CD<NUM>OD) δ=<NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (td, <NUM>, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br dd, <NUM>, J=<NUM>, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, a solution of compound 5A (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) was slowly added to a solution of isopropyl magnesium bromide (<NUM> mol, <NUM>) in tetrahydrofuran (<NUM>) at -<NUM>. The mixture was stirred at -<NUM> for <NUM> hours, then a solution of compound 5B (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) was added thereto, and the reaction solution was continued to stir at -<NUM> for <NUM> hours. After the reaction was completed, saturated ammonium chloride (<NUM>) solution was added to quench the reaction solution, then the mixture was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times), and the organic phase was washed with brine (<NUM>×<NUM> time). The combined organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain compound 5C. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br t, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), -<NUM> (d, J = <NUM>, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Hydrochloric acid/dioxane (<NUM> mol, <NUM>) was added to a solution of compound 5C (<NUM>, <NUM>µmol) in dioxane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product of 5D, and the crude product was directly used in the next step.

At <NUM>, compound 5D (<NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM>µmol, <NUM>µL) were added to a solution of compound <NUM> (<NUM>, <NUM>µmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> minutes, and then HATU (<NUM>, <NUM>µmol) was added thereto and the mixture was continued to react for <NUM> hours. After the reaction was completed, the reaction solution was diluted with water (<NUM>) and extracted with dichloromethane (<NUM>×<NUM> times), washed with water (<NUM>×<NUM> time). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, CD<NUM>OD) δ = <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Copper sulfate (<NUM>, <NUM> mmol, <NUM>) and (S)-<NUM>-methylpropyl-<NUM>-sulfenamide (<NUM>, <NUM> mmol) were added to a solution of compound 6A (<NUM>, <NUM> mmol) in dichloromethane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, 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 (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 6B. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

At -<NUM>, under the protection of nitrogen, methyl magnesium bromide (<NUM> mol, <NUM>) was added to a solution of compound 6B (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, saturated ammonium chloride (<NUM>) solution was added to the reaction solution, and the organic phase was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate = <NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 6C. LCMS (ESI): m/z: <NUM> [M+<NUM>]. <CHM>
<CHM>.

Hydrochloric acid/dioxane (<NUM> mol, <NUM>) was added to a solution of compound 6C (<NUM>, <NUM> mmol) in dioxane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of the hydrochloride of 6D, which was directly used in the next step.

Compound 6D hydrochloride (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>) were added to a solution of compound 6E (<NUM>, <NUM> mmol) in dichloromethane (<NUM>) at <NUM>. Then HATU (<NUM>, <NUM> mmol) was added thereto, and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was diluted with water (<NUM>), and the organic phase was extracted with dichloromethane (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with dichloromethane:methanol = <NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 6F. LCMS (ESI): m/z: <NUM> [M+<NUM>].

At <NUM>, trifluoroacetic acid (<NUM>, <NUM> mmol, <NUM>) was added to a solution of compound 6F (<NUM>, <NUM>µmol) in dichloromethane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product of <NUM>, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

DIEA (<NUM>, <NUM> mmol, <NUM>µL) and compound <NUM> (<NUM>, <NUM> mmol) were added to a solution of compound <NUM> (<NUM>, <NUM>µmol) in acetonitrile (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was diluted with water (<NUM>), and then the organic phase was extracted with dichloromethane (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with dichloromethane:methanol = <NUM>:<NUM>) to obtain compound 6I. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>]. <CHM>
<CHM>.

Under the protection of nitrogen, compound 6I (<NUM>, <NUM>µmol), bis(pinacolato)diboron, Pd(dppf)Cl<NUM>·CH<NUM>Cl<NUM> (<NUM>, <NUM>µmol), potassium tert-butoxide (<NUM>, <NUM>µmol) were dissolved in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 6J, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 6J (<NUM>, <NUM>µmol), <NUM>,<NUM>,<NUM>-trichloropyrimidine (<NUM>, <NUM>µmol, <NUM>µL), Pd(PPh<NUM>)<NUM> (<NUM>, <NUM>µmol) and sodium carbonate (<NUM>, <NUM>µmol) were dissolved in dioxane (<NUM>) and water (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the filtrate was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM>) to obtain compound <NUM>. LCMS (ESI): m/z: <NUM> [M+<NUM>]. <CHM>
<CHM>.

DIEA (<NUM>, <NUM>µmol, <NUM>µL) and <NUM>-aminotetrahydropyran (<NUM>, <NUM>µmol) were added to a solution of compound <NUM> (<NUM>, <NUM>µmol) in dioxane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. The reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), and the organic phases were combined, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, CD<NUM>OD) δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (br dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

At <NUM>, compound 7A (<NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM>µmol, <NUM>µL) were added to a solution of compound <NUM> (<NUM>, <NUM>µmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> minutes, and then HATU (<NUM>, <NUM>µmol) was added thereto and the mixture was continued to stir for <NUM> hours. The reaction solution was diluted with water (<NUM>) and extracted with dichloromethane (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), and the combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, CD<NUM>OD) δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Copper sulfate (<NUM>, <NUM> mmol, <NUM>) and (S)-<NUM>-methylpropyl-<NUM>-sulfenamide (<NUM>, <NUM> mmol) were added to a solution of compound 8A (<NUM>, <NUM> mmol) in dichloromethane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 8B.

At -<NUM>, under the protection of nitrogen, a solution of compound 8B (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) was added to a solution of allyl magnesium bromide (<NUM> mol, <NUM>) in tetrahydrofuran (<NUM>), and the reaction solution was stirred at -<NUM> for <NUM> hour. After the reaction was completed, saturated ammonium chloride (<NUM>) solution was added thereto to quench the mixture, then the mixture was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times), and the organic phase was washed with brine (<NUM>×<NUM> time). The combined organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain compound 8C. LCMS (ESI): m/z: <NUM> [M+<NUM>].

At -<NUM>, compound 8C (<NUM>, <NUM> mmol) was dissolved in dichloromethane (<NUM>) and methanol (<NUM>) under the condition of ozone (<NUM> mmol, <NUM> kPa (<NUM> psi)), and sodium borohydride (<NUM>, <NUM> mmol) was added to the reaction solution, and then the mixture was stirred at -<NUM> for <NUM> hours. After the reaction was completed, saturated ammonium chloride (<NUM>) solution was added to quench the reaction solution, and the mixture was diluted with water (<NUM>), extracted with ethyl acetate (<NUM>×<NUM> times), and the organic phase was washed with brine (<NUM>×<NUM> time). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate = <NUM>:<NUM>) to obtain compound 8D. LCMS (ESI): m/z: <NUM> [M+<NUM>].

Compound 8D (<NUM>, <NUM>µmol) was dissolved in dimethylamine (<NUM> mol, <NUM>) and reacted at <NUM> for <NUM> hours under microwave. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with dichloromethane:methanol= <NUM>:<NUM>) to obtain compound 8E. LCMS (ESI): m/z: <NUM> [M+<NUM>].

Hydrochloric acid/dioxane (<NUM> mol, <NUM>) was added to a solution of compound 8E (<NUM>, <NUM>µmol) in dioxane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of the hydrochloride of compound 8F, which was directly used in the next step. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br s, <NUM>), <NUM> (br t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Compound 8F (<NUM>, <NUM>µmol, HCl) and DIEA (<NUM>, <NUM>µmol, <NUM>µL) were added to a solution of compound <NUM> (<NUM>, <NUM>µmol) in dichloromethane (<NUM>) at <NUM>. After the reaction solution was stirred for <NUM> minutes, HATU (<NUM>, <NUM>µmol) was added thereto, and the reaction solution was continued to stir for <NUM> hours. The reaction solution was diluted with water (<NUM>) and extracted with dichloromethane (<NUM>× <NUM> times). The organic phase was washed with brine (<NUM>× <NUM>), and then the organic phases were combined and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated by preparative high performance liquid chromatography (formic acid system), and then a freebase of compound <NUM> was obtained by chiral separation method (<NUM> % ammonia water-methanol system, retention time of <NUM> minutes, ee value: <NUM>%). <NUM>H NMR (<NUM>, MeOH-d<NUM>) δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dq, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Compound 9A (<NUM>, <NUM> mmol, <NUM>) was dissolved in methanol (<NUM>), and compound 9B (<NUM>, <NUM> mmol, <NUM>) was added, and the mixture was stirred at <NUM> for <NUM> hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 9C. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (quin, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

(Boc)<NUM>O (<NUM>, <NUM> mmol, <NUM>) and DIEA (<NUM>, <NUM> mmol, <NUM>) were added to a solution of compound 9C (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>). The mixture was stirred at <NUM> for <NUM> hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 9D. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (br s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (brd, J=<NUM>, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>]. <CHM>
<CHM>.

Under the protection of nitrogen, LiAlD<NUM> (<NUM>, <NUM> mmol, <NUM>) was added to a solution of compound 9D (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>). The reaction solution was stirred at <NUM> for <NUM> minutes. After the reaction was completed, <NUM>% sodium hydroxide (<NUM>) aqueous solution was added to the mixture to quench, and then the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of 9E, and the crude product was directly used in the next step. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

Potassium tert-butoxide (<NUM>, <NUM> mmol) was added to a solution of compound 9E (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>), and the mixture was stirred for <NUM> minutes, then MsCl (<NUM>, <NUM> mmol, <NUM>µL) and potassium tert-butoxide (<NUM>, <NUM> mmol) were added thereto. The mixture was stirred at <NUM> for <NUM> hours, and after the reaction was completed, saturated ammonium chloride (<NUM>) solution was added to the reaction solution, then the mixture was extracted with ethyl acetate (<NUM>×<NUM> times). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 9F. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br t, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>)
<CHM>.

Hydrochloric acid/dioxane (<NUM> mol, <NUM>) was added to a solution of compound 9F (<NUM>, <NUM> mmol) in methanol (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was poured into methyl tert-butyl ether (<NUM>), filtered to obtain a filter cake. The filter cake was dissolved in water (<NUM>), and the pH was adjusted to <NUM> with sodium hydroxide (<NUM> mol) aqueous solution, and then the mixture was extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phase was concentrated under reduced pressure to obtain a crude product of <NUM>, and the crude product was directly used in the next step. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (tt, J=<NUM>, <NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>).

Palladium/carbon (<NUM>, <NUM>% purity) was added to a solution of compound <NUM> (<NUM>, <NUM>µmol) in methanol (<NUM>). Under the condition of hydrogen (<NUM> Mpa), the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure and then dissolved in methanol (<NUM>). The pH of the mixture was adjusted to <NUM> with hydrochloric acid/dioxane (<NUM> mol), and then methyl tert-butyl ether (<NUM>) was added to the mixture and filtered to obtain a crude product of <NUM>, and the crude product was directly used in the next step. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (br t, J=<NUM>, <NUM>).

Lithium hydroxide monohydrate (<NUM>, <NUM> mmol) was added to a solution of compound 1F (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) and water (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hour. After the reaction was completed, water (<NUM>) was added to the reaction solution, then the mixture was extracted with ethyl acetate (<NUM>×<NUM> time). The pH of the aqueous phase was adjusted to <NUM> with hydrochloric acid (<NUM> mol), and the mixture was extracted with dichloromethane (<NUM>×<NUM> times). The organic phases were combined, filtered, and concentrated under reduced pressure to obtain a crude product of 9I, and the crude product was directly used in the next step. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

At <NUM>, HATU (<NUM>, <NUM> mmol), (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound 9I (<NUM>, <NUM> mmol, <NUM>% purity) in dichloromethane (<NUM>). The reaction solution was stirred at <NUM> for <NUM> minutes. The reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phases were combined and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM>) to obtain compound 9F. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

DIEA (<NUM>, <NUM>µmol, <NUM>µL) was added to a solution of compound 9J (<NUM>, <NUM>µmol) and <NUM> (<NUM>, <NUM>µmol) in dioxane (<NUM>). The reaction solution was stirred at <NUM> under sealed tank conditions for <NUM> hours. The reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times), and the organic phases were combined, dried, and then filtered and concentrated under reduced pressure to obtain a crude product, and the crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, MeOH-d<NUM>) δ = <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (td, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 1C (<NUM>, <NUM> mmol), ethyl ethyl-<NUM>-bromoacetate (<NUM>, <NUM> mmol, <NUM>µL) and potassium carbonate (<NUM>, <NUM> mmol) were dissolved in DMF (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the mixture was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 10A. <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 10A (<NUM>, <NUM> mmol), bis(pinacolato)diboron (<NUM>, <NUM> mmol), Pd(dppf)Cl<NUM>·CH<NUM>Cl<NUM> (<NUM>, <NUM>µmol) and potassium acetate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hour. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 10B, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 10B (<NUM>, <NUM> mmol), <NUM>,<NUM>,<NUM>-trichloropyrimidine (<NUM>, <NUM> mmol), Pd(PPh<NUM>)<NUM> (<NUM>, <NUM>µmol) and sodium carbonate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>) and water (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM>) to obtain compound 10C. LCMS (ESI): m/z: <NUM> [M+<NUM>].

<NUM>-Aminotetrahydropyran (<NUM>, <NUM> mmol, <NUM>µL) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound 10C (<NUM>, <NUM>µmol) in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. Water (<NUM>) and ammonium chloride (<NUM>) were added to the reaction solution, and the reaction solution was extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product of 10D, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

An aqueous (<NUM>) solution of lithium hydroxide monohydrate (<NUM>, <NUM>µmol) was added to a solution of compound 10D (<NUM>, <NUM>µmol) in tetrahydrofuran (<NUM>) and ethanol (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. The reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> time), and the pH of the aqueous phase was adjusted to <NUM> with hydrochloric acid (<NUM> mol) aqueous solution, and the mixture was extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phases were combined, dried, filtered and concentrated under reduced pressure to obtain a crude product of 10E, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

At <NUM>, (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound 10E (<NUM>, <NUM>µmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> minutes. Then HATU (<NUM>, <NUM>µmol) was added to the reaction solution, and the mixture was continued to react for <NUM> hours. The reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (formic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, CD<NUM>OD) δ = <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (br dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

At <NUM>, chlorosulfonic acid (<NUM>, <NUM> mmol, <NUM>) was added to a solution of compound 11A (<NUM>, <NUM> mmol, <NUM>) in dichloromethane (<NUM>), and the mixture was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was slowly added into ice water, then extracted with dichloromethane (<NUM>×<NUM> times). The combined organic phase was washed with water (<NUM>×<NUM> times), dried, filtered and concentrated under reduced pressure to obtain a crude product of 11B, and the crude product was directly used in the next step. <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>).

NBS (<NUM> mmol, <NUM> mmol) and AIBN (<NUM>, <NUM>µmol) were added to a solution of compound 11B (<NUM>, <NUM> mmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether) to obtain compound 11C. <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>).

An aqueous (<NUM>) solution of sodium carbonate (<NUM>, <NUM> mmol) was added to a solution of compound 11C (<NUM>, <NUM> mmol) and compound (R)-tert-butyl-<NUM>-aminopropionate (<NUM>, <NUM> mmol) in acetonitrile (<NUM>), and the mixture was stirred at <NUM> for <NUM> hour, and then stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product of compound 11D, and the crude product was directly used in the next step. <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 11D (<NUM>, <NUM> mmol), bis(pinacolato)diboron (<NUM>, <NUM> mmol), Pd(dppf)Cl<NUM>·CH<NUM>Cl<NUM> (<NUM>, <NUM> mmol) and potassium acetate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hour. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 11E, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 11E (<NUM>, <NUM> mmol), <NUM>,<NUM>,<NUM>-trichloropyrimidine (<NUM>, <NUM> mmol), Pd(PPh<NUM>)<NUM> (<NUM>, <NUM>µmol) and sodium carbonate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>) and water (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 11F. <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>).

Compound <NUM> (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>) were added to a solution of compound 11F (<NUM>, <NUM> mmol) in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours, and then the reaction solution was diluted with ethyl acetate (<NUM>) and washed with <NUM> mol of hydrochloric acid (<NUM>×<NUM> time) aqueous solution. The aqueous phase was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time), dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound <NUM>. <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (q, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br dd, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>), LCMS (ESI): m/z: <NUM> [M+<NUM>].

Trifluoroacetic acid (<NUM>, <NUM> mmol, <NUM>) was added to a solution of compound <NUM> (<NUM>, <NUM> mmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product of compound 11I, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

At -<NUM>, (<NUM>S)-<NUM>-amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound 11I (<NUM>, <NUM> mmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> minutes. Then HATU (<NUM>, <NUM> mmol) was added to the reaction solution, and continued to react for <NUM> hour. The reaction solution was diluted with water (<NUM>) and extracted with dichloromethane (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (trifluoroacetic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (CD<NUM>OD, <NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (td, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 11E (<NUM>, <NUM> mmol), <NUM>,<NUM>-dichloropyrimidin-<NUM>-amine (<NUM>, <NUM> mmol), Pd(PPh<NUM>)<NUM> (<NUM>, <NUM> mmol) and sodium carbonate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>) and water (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 12A. LCMS (ESI): m/z: <NUM> [M+<NUM>]. <CHM>
<CHM>.

A solution of compound 12A (<NUM>, <NUM>µmol) in acetonitrile (<NUM>) was added to a solution of cuprous bromide (<NUM>, <NUM>µmol, <NUM>µL) and tert-butyl nitrite (<NUM>, <NUM>µmol, <NUM>µL) in acetonitrile (<NUM>), and the reactant was stirred at <NUM> for <NUM> hours. The reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate= <NUM>:<NUM>) to obtain compound 12B. <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Compound <NUM> (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>) were added to a solution of compound 12B (<NUM>, <NUM> mmol) in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours, and then the reaction solution was diluted with ethyl acetate (<NUM>) and washed with <NUM> mol of hydrochloric acid (<NUM>×<NUM> time) aqueous solution. The aqueous phase was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time), dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 12C. <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (q, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>). LCMS (ESI): m/z:<NUM>[M+<NUM>].

Trifluoroacetic acid (<NUM>, <NUM> mmol, <NUM>) was added to a solution of compound 12C (<NUM>, <NUM> mmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product of compound 12D, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

At -<NUM>, (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound 12D (<NUM>, <NUM>µmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> minutes. Then HATU (<NUM>, <NUM> mmol) was added to the reaction solution, and continued to react for <NUM> hour. The reaction solution was diluted with water (<NUM>) and extracted with dichloromethane (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (trifluoroacetic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (CD<NUM>OD, <NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Compound <NUM> (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>) were added to a solution of compound 12B (<NUM>, <NUM> mmol) in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours, and then the reaction solution was diluted with ethyl acetate (<NUM>) and washed with <NUM> mol of hydrochloric acid (<NUM>×<NUM> time) aqueous solution. The aqueous phase was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time), dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 13A. LCMS (ESI): m/z: <NUM> [M+<NUM>]. Compound 13B:
<CHM>.

Trifluoroacetic acid (<NUM>, <NUM> mmol, <NUM>) was added to a solution of compound 13A (<NUM>, <NUM> mmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product of compound 13B, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

At -<NUM>, (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound 13B (<NUM>, <NUM> mmol) in dichloromethane (<NUM>), and the reaction solution was stirred at -<NUM> for <NUM> minutes. Then HATU (<NUM>, <NUM> mmol) was added to the reaction solution, and continued to react for <NUM> hour. The reaction solution was diluted with water (<NUM>) and extracted with dichloromethane (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (trifluoroacetic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (CD<NUM>OD, <NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>), <NUM> (br d, <NUM>, J=<NUM>), <NUM> (td, <NUM>, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br t, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dq, <NUM>, J=<NUM>, <NUM>), <NUM> (br dd, <NUM>, J=<NUM>, <NUM>), <NUM> (d, <NUM>, J=<NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Sodium borodeuteride (<NUM>, <NUM> mmol) was added to a solution of compound 1B (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>), then the temperature of the reaction solution was reduced to -<NUM>, and boron trifluoride etherate (<NUM>, <NUM> mmol, <NUM>) was slowly added to the reaction solution, and the mixture was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was quenched with ammonium chloride aqueous solution (<NUM>) at <NUM>, and ethyl acetate (<NUM>) was added, then the reaction solution was filtered, and the filtrate was extracted with ethyl acetate (<NUM>×<NUM> times), and the combined organic phase was washed with brine (<NUM>×<NUM> time), dried and concentrated under reduced pressure to obtain a crude product. The crude product was stirred with petroleum ether:ethyl acetate=<NUM>:<NUM> at <NUM> for <NUM> hours, and the filter cake obtained by filtration was compound 14A. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>). LCMS (ESI): m/z: <NUM>.

Under the protection of nitrogen, compound 14A (<NUM>, <NUM> mmol), ethyl (<NUM>)-<NUM>-bromopropanoate (<NUM>, <NUM> mmol) and potassium carbonate (<NUM>, <NUM> mmol) were dissolved in DMF (<NUM>), and the mixture was stirred for <NUM> hours at <NUM>. The reaction mixture was diluted with <NUM> of water and then extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phase was washed with water (<NUM>×<NUM> times) and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 14B. <NUM>H NMR (<NUM>, CDCl<NUM>, <NUM>) δ = <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 14B (<NUM>, <NUM> mmol), bis(pinacolato)diboron (<NUM>, <NUM> mmol), Pd(dppf)Cl<NUM>·CH<NUM>Cl<NUM> (<NUM>, <NUM>µmol) and potassium acetate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product of compound 14C, and the crude product was directly used in the next step. LCMS (ESI): m/z: <NUM> [M+<NUM>].

Under the protection of nitrogen, compound 14C (<NUM>, <NUM> mmol), <NUM>,<NUM>-dichloropyrimidin-<NUM>-amine (<NUM>, <NUM> mmol), Pd(PPh<NUM>)<NUM> (<NUM>, <NUM>µmol) and sodium carbonate (<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>) and water (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was filtered, dried, filtered and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 14D. <NUM>H NMR (CDCl<NUM>,<NUM>) δ = <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>]. <CHM>
<CHM>.

At <NUM>, a solution of compound 14D (<NUM>, <NUM> mmol) in acetonitrile (<NUM>) was added to a solution of cuprous bromide (<NUM>, <NUM> mmol, <NUM>µL) and tert-butyl nitrite (<NUM>, <NUM> mmol, <NUM>µL) in acetonitrile (<NUM>), and the reactant was stirred at <NUM> for <NUM> hours. The reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=<NUM>:<NUM> to <NUM>:<NUM>) to obtain compound 14E. <NUM>H NMR (CDCl<NUM>,<NUM>) δ = <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Compound aminotetrahydropyran (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound 14E (<NUM>, <NUM>µmol) in dioxane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours, and then the reaction solution was diluted with water (<NUM>) and extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phase was dried and concentrated under reduced pressure to obtain a crude product of 14F, and the crude product was directly used in the next step. <NUM>H NMR (CDCl<NUM>,<NUM>) δ = <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

An aqueous (<NUM>) solution of lithium hydroxide monohydrate (<NUM>, <NUM> mmol) was added to a solution of compound 14F (<NUM>, <NUM>µmol) in tetrahydrofuran (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to <NUM> with <NUM> mol of hydrochloric acid aqueous solution, and then the solution was extracted with ethyl acetate (<NUM>×<NUM> times). The combined organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

HATU (<NUM>, <NUM>µmol) and DIEA (<NUM>, <NUM> mmol, <NUM>µL) were added to a solution of compound <NUM> (<NUM>, <NUM>µmol) and (<NUM>)-<NUM>-amino-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-phenyl)ethanol (<NUM>, <NUM>µmol) in dichloromethane (<NUM>), and the reaction solution was stirred at <NUM> for <NUM> hour. The reaction solution was diluted with water (<NUM>) and extracted with dichloromethane (<NUM>×<NUM>). The organic phase was washed with brine (<NUM>×<NUM> time), dried, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (trifluoroacetic acid system) to obtain a freebase of compound <NUM>. <NUM>H NMR (<NUM>, CD<NUM>OD) δ = <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J=<NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). LCMS (ESI): m/z: <NUM> [M+<NUM>].

Experimental conclusion: The compound of the present disclosure has a certain antiproliferative activity of Calu-<NUM> cells.

<NUM>) Experimental reagents and consumables:.

The equation (Sample-Min)/(Max-Min)*<NUM>% was used to convert the original data into inhibition rate, and the IC<NUM> value could be obtained by curve fitting with four parameters (obtained by "log (inhibitor) vs. response -- variable slope" mode in GraphPad Prism).

Experimental conclusion: The compound of the present disclosure has good antiproliferative activity of HCT116 cells.

Cell line A375 (purchased from Procell), DMEM culture medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. CellTiterglo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.

A375 cells were seeded in a white <NUM> well plate with <NUM>µmol of cell suspension per well containing <NUM> of A375 cells. The cell plate was placed in a carbon dioxide incubator and cultured overnight. The compound to be tested was diluted <NUM>-fold to the 9th concentration with a pipette, that is, diluted from <NUM> mmol to <NUM>µmol, and a double-duplicate experiment was set-up. <NUM>µmol of culture medium was added to the middle plate, then <NUM>µmol of gradient dilution compound per well was transferred to the middle plate according to the corresponding position, and <NUM>µmol per well was mixed and transferred to the cell plate. The concentration of the compound transferred to the cell plate ranged from <NUM>µmol to <NUM> nmol. The cell plate was placed in a carbon dioxide incubator and cultured for <NUM> days. Another cell plate was prepared, and the signal value was read as the maximum value (max value in the following equation) on the day of administration to participate in data analysis. <NUM>µmol of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for <NUM> minutes to stabilize the luminescence signal. A multi-marker analyzer reading was used. After the incubation of the cell plate added with the compound was finished, <NUM>µmol of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for <NUM> minutes to stabilize the luminescence signal. A multi-marker analyzer reading was used.

Experimental conclusion: The compound of the present disclosure has good antiproliferative activity of A375 cells.

Cell line COLO205 (purchased from Procell), RPMI1640 culture medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. CellTiterglo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.

Antiproliferative experiment of COLO205 cells:
COLO205 cells were seeded in a white <NUM>-well plate with <NUM>µmol of cell suspension per well containing <NUM> of COLO205 cells. The cell plate was placed in a carbon dioxide incubator and cultured overnight. The compound to be tested was diluted <NUM>-fold to the 9th concentration with a pipette, that is, diluted from <NUM>µmol to <NUM>µmol, and a double-duplicate experiment was set-up. <NUM>µmol of culture medium was added to the middle plate, then <NUM>µmol of gradient dilution compound per well was transferred to the middle plate according to the corresponding position, and <NUM>µmol of per well was mixed and transferred to the cell plate. The concentration of the compound transferred to the cell plate ranged from <NUM>µmol to <NUM> nmol. The cell plate was placed in a carbon dioxide incubator and cultured for <NUM> days. Another cell plate was prepared, and the signal value was read as the maximum value (max value in the following equation) on the day of administration to participate in data analysis. <NUM>µmol of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for <NUM> minutes to stabilize the luminescence signal. A multi-marker analyzer reading was used. After the incubation of the cell plate added with the compound was finished, <NUM>µmol of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for <NUM> minutes to stabilize the luminescence signal. A multi-marker analyzer reading was used.

Experimental conclusion: The compound of the present disclosure has good antiproliferative activity of Colo205 cells.

Compound information (other compounds were derived from the mother liquid of the compound configured with L1000).

Experimental conclusion: The compound of the present disclosure has good Calu-<NUM> ERK phosphorylation inhibition activity.

This experiment was aimed to study the pharmacokinetics of the test compound in mice and dogs in vivo after a single oral administration of the compound.

After intravenous or oral administration, blood samples were collected and the actual blood collection time was recorded. After the blood sample was collected, the sample was immediately transferred to a labeled centrifuge tube containing K2-EDTA, and then the plasma was taken after centrifugation. The plasma was transferred to a precooled centrifuge tube, quickly frozen in dry ice, and stored in an ultra-low temperature refrigerator at -<NUM>±<NUM> until LC-MS/MS analysis.

Pharmacokinetic software was used to process the plasma drug concentration data of the compound with non-atrioventricular model. The peak concentration (Cmax) and peak time (Tmax), as well as the end time of quantification, were obtained directly from the plasma drug concentration-time graph. The following pharmacokinetic parameters were calculated by logarithmic linear trapezoidal method: half-life (T<NUM>/<NUM>), apparent distribution volume (Vdss) and clearance rate (Cl), and the area under the time-plasma concentration curve from <NUM> to the end time point (AUC<NUM>-last).

Experimental conclusion: The compound of the present disclosure has good oral absorption and high exposure in mice.

Experimental conclusion: The compound of the present disclosure has good oral absorption, low clearance rate, high exposure and has good bioavailability in dogs.

Cells: Calu-<NUM> cells of human lung cancer were cultured in vitro, and <NUM> Units/mL bovine insulin, <NUM>% fetal bovine serum were added to EMEM culture medium in a <NUM> and <NUM>% CO<NUM> incubator for culture. Conventional digestion with trypsin-EDTA was performed twice a week for passage. When the cell saturation was <NUM>%-<NUM>% and the number of the cells reached the requirement, and the cells were collected, counted, and seeded.

Cell inoculation: <NUM> of Calu-<NUM> cell (mixed in a ratio of <NUM>:<NUM> with matrix gel) was subcutaneously inoculated on the right back of each mouse, and group administration was started when the average tumor volume reached <NUM><NUM>.

Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume was: V = <NUM>a × b<NUM>, and a and b represent the long and short diameters of the tumor, respectively.

The tumor inhibition efficacy of the compounds was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C (%) = TRTV / CRTV × <NUM>% (TRTV: RTV in the treatment group; CRTV: RTV in the negative control group). The relative tumor volume (RTV) was calculated according to the results of tumor measurement, and the formula was RTV = Vt / V<NUM>, wherein V<NUM> was the tumor volume measured at the time of group administration (i.e., D<NUM>), and Vt was the tumor volume measured at a certain measurement, and TRTV and CRTV were taken on the same day.

TGI (%), reflecting the tumor growth inhibition rate. TGI (%)=[<NUM>-(average tumor volume at the end of administration in a treatment group - average tumor volume at the beginning of administration in this treatment group)/(average tumor volume at the end of treatment in a solvent control group - average tumor volume at the beginning of treatment in this solvent control group)] × <NUM>%.

Statistical analysis was based on the data of RTV at the end of the experiment, and SPSS software was used for analysis. One-way ANOVA was used for comparison between two groups, and the variance was uneven (there was significant difference in F value), and Games-Howell method was used to test. p < <NUM> was considered a significant difference.

This experiment evaluated the efficacy of the subject in human lung cancer xenograft tumor model, using solvent control group as a reference. The tumor volumes of each group at different time points are shown in reference source, which was wrong and not found. The TGI of the administration group compound <NUM> was <NUM>%, the TGI of the compound <NUM> was <NUM>%, the TGI of the compound <NUM> was <NUM>% and the TGI of the compound <NUM> was <NUM>%, which showed a significant tumor suppressor effect (P<<NUM>).

There was no obvious abnormality in the weight and state of the mice. The effect of the subject on the body weight of the mice is as shown in <FIG>.

Claim 1:
A compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
<CHM>
wherein,
T<NUM> is CH or N;
n is <NUM> or <NUM>;
R<NUM> and R<NUM> are each independently H, D, F, Cl or C<NUM>-<NUM> alkyl, wherein the C<NUM>-<NUM> alkyl is optionally substituted by <NUM>, <NUM> or <NUM> substituents independently selected from F, Cl, Br and I;
or R<NUM> and R<NUM> combining with the carbon atoms to which they are attached form
<CHM>
R<NUM> and R<NUM> are each independently H or C<NUM>-<NUM> alkyl, wherein the C<NUM>-<NUM> alkyl is optionally substituted by <NUM>, <NUM> or <NUM> substituents independently selected from F, Cl, Br, I and -OH;
R<NUM> and R<NUM> are each independently H or C<NUM>-<NUM> alkyl, wherein the C<NUM>-<NUM> alkyl is optionally substituted by <NUM>, <NUM> or <NUM> substituents independently selected from F, Cl, Br, I, -OH and -OCH<NUM>;
R<NUM> is phenyl or pyridyl, wherein the phenyl and pyridyl are optionally substituted by <NUM>, <NUM>, <NUM> or <NUM> Ra;
R<NUM> is H, F, Cl or Br;
R<NUM> is tetrahydro-<NUM>H-pyranyl, wherein the tetrahydro-<NUM>H-pyranyl is optionally substituted by <NUM>, <NUM>, <NUM> or <NUM> Rb;
Ra is each independently F, Cl, Br, I, C<NUM>-<NUM> alkyl, C<NUM>-<NUM> alkoxy, NH-C<NUM>-<NUM> alkyl or N-(C<NUM>-<NUM> alkyl)<NUM>, wherein the C<NUM>-<NUM> alkyl, C<NUM>-<NUM> alkoxy, -NH-C<NUM>-<NUM> alkyl and -N-(C<NUM>-<NUM> alkyl)<NUM> are each independently and optionally substituted by <NUM>, <NUM> or <NUM> substituents independently selected from F, Cl, Br, I and -OH;
Rb is each independently F, Cl, Br, I, D or C<NUM>-<NUM> alkyl, wherein the C<NUM>-<NUM> alkyl is optionally substituted by <NUM>, <NUM> or <NUM> substituents independently selected from F, Cl, Br, I and -OH.