RU2799047C2 - Atr inhibitor and its use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (IА) or a pharmaceutically acceptable salt thereof. In formula (I): n is either 1, 2, 3 or 4; structural unit

selected from the group consisting of

, ring A is selected from the group consisting of 5–6 membered heteroaryl; each R₁ is independently selected from the group consisting of H, F, Cl, Br, I, C_1-6 alkyl, C_1-6 alkoxy and C_3-6 cycloalkyl, with C_1-6 alkyl, C_1-6 alkoxy and C_3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R; each R₂ is independently selected from the group consisting of H, F, Cl, Br, I, COOH, and C_1-3 alkyl, with C_1-3 alkyl optionally substituted with 1, 2, or 3 R; each R is independently selected from the group consisting of F, Cl, Br, I, OH, C_1-3 alkyl and C_1-3 alkoxy, with C_1-3 alkyl and C_1-3 alkoxy optionally substituted with 1, 2 or 3 R'; every R' independently selected from the group consisting of F, Cl, Br, I and OH; A 5–6 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms or heteroradicals independently selected from the group consisting of -NH-, -O- and N; and Z₁ is N, Z₂ and Z₃ are CH; Z₂ is N, Z₁ and Z₃ are CH; Z₃ is N, Z₁ and Z₂ are CH; Z₁ and Z₂ are N, Z₃ is CH; Z₂ and Z ₃ are N, Z₁ is CH; or Z₁ and Z₃ are N, Z₂ is CH. Also the use of the said compound for the manufacture of a medicinal product is proposed.

EFFECT: proposed compound can be used as an ATR inhibitor.

15 cl, 1 dwg, 4 tbl, 61 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority for the following applications:

China Patent Application 201810124494.2 filed February 7, 2018

China Patent Application 201811361512.5 filed November 15, 2018

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

Compounds are provided as an ATR inhibitor and their use in the preparation of an ATR inhibitor, and in particular a compound of formula (I), an isomer or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

ATR (ataxia-telangiectasia mutated and Rad3-related kinase protein) belongs to the PIKK (phosphatidylinositol-3-kinase-related kinase) family and is involved in DNA damage repair to maintain gene stability. The ATR protein kinase exerts a synergistic response to DNA damage, replicative stress, and cell cycle disorders. ATR and ATM belong to the PIKK/threonine protein kinase family, and are a common component of cell cycle and DNA damage repair; other members are Chk1, BRCA1, p53. ATR is activated primarily in response to DNA replication stress (stopping of the duplication fork) and aims to repair the single-strand break.

When double-stranded DNA breaks and replication fork arrest occur, ATR is activated by the single-stranded DNA structure. The DNA polymerase remains in the process of DNA replication and the replicative helicase continues to unwind at the leading end of the DNA replication fork, resulting in the formation of long single-stranded DNA (ssDNA), and then the association of single-stranded DNA with RPA (replicative protein A) occurs. RPA recruits an ATR/ATR active protein complex at the site of damage during replicative stress or DNA damage, the RPA-ssDNA complex activates the RAD17/rfc2-5 complex, which binds to the site of damage, DNA-ssDNA binding activates the Rad9-HUS1-RAD1 heterotrimer (9 -1-1), and 9-1-1 in turn recruits TopBP1 to activate ATR. Once activated, ATR provides DNA repair through downstream targets, stabilization and restart of stalled replication forks and a temporarily halted cell cycle. These ATR functions are mediated by the action of downstream target Chk1. ATR acts as a DNA damage checkpoint in the cell cycle during S-phase. It can mediate the degradation of CDC25A by Chk1, thereby delaying the process of DNA replication and allowing time for replication fork repair. ATR is also the main regulator of the G2/M cell cycle checkpoint, preventing premature entry of cells into mitosis before DNA replication is complete or DNA damage is complete. This ATR-dependent G2/M cell cycle arrest is mainly mediated by two mechanisms: 1. CDC25A degradation; 2. Chk1-mediated phosphorylation of Cdc25C to bind 14-3 protein. Binding of Cdc25C to the 14-3-3 protein promotes its export from the nucleus and cytoplasmic isolation, thereby inhibiting its ability to dephosphorylate and activate nuclear Cdc2, which in turn prevents entry into mitosis.

Mutations in the ATR gene are very rare, and only a few patients with Seckel syndrome have mutations in the ATR gene, which are characterized by growth retardation and microcephaly. Disruption of ATR-related pathways can lead to genome instability, and the ATR protein is upregulated by most anti-cancer chemotherapeutic agents. In addition, ATR gene duplication has been described as a risk factor for the development of rhabdomyosarcoma.

ATR is important for cellular self-replication and is activated in S-phase to regulate the origin of replication and repair damaged replication forks. Damage to replication forks can increase the sensitivity of cancer cells to platinum and hydroxyurea anticancer agents and reduce the resistance of cancer cells. Therefore, ATR suppression may become an effective cancer treatment in the future.

WO 2011154737 discloses the compound AZD6738 as an ATR inhibitor having the following structure:

SUMMARY OF THE INVENTION

In one aspect, a compound of formula (I) or an isomer or pharmaceutically acceptable salt thereof is provided.

Where

n is 1, 2, 3 or 4;

each of Z ₁ , Z ₂ and Z ₃ is independently selected from the group consisting of CH and N, and at least one of Z ₁ , Z ₂ and Z ₃ is N;

each of Τ ₁ and Τ ₂ is independently selected from the group consisting of C (R ₂ ) and N;

ring A is selected from the group consisting of 5-6 membered heteroaryl;

each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkyl, where C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R;

each R ₂ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , COOH, and C _1-3 alkyl, where C _1-3 alkyl is optionally substituted with 1, 2, or 3 R;

each R is independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl and C _1-3 alkoxy, where C _1-3 alkyl and C _1-3 alkoxy are optionally substituted with 1, 2 or 3 R';

each R' is independently selected from the group consisting of F, Cl, Br, I, OH and NH ₂ ;

A 5-6 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms or heteroradicals independently selected from the group consisting of -NH-, -O-, -S- and N.

In some embodiments, each R is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CH ₃ , Et and -O-CH ₃ and other variables are defined herein.

In some embodiments, each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, and cyclopropyl, where C _1-3 alkyl , C _1-3 alkoxy, and cyclopropyl are optionally substituted with 1, 2, or 3 R, and other variables are defined herein.

а другие переменные определены в настоящем описании.In some embodiments, each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , Et, -CH ₂ OH, -O-CH ₃ ,

and other variables are defined in the present description.

In some embodiments, each R2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , COOH, CH ₃ , Et, and -CH ₂ -OH, and other variables are defined herein.

In some embodiments, Ring A is selected from the group consisting of pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and pyridyl, with other variables defined herein.

In some embodiments, ring A is selected from the group consisting of

а другие переменные определены в настоящем описании.

and other variables are defined in the present description.

выбирают из группы, состоящей из

In some embodiments of the invention, the structural unit

selected from the group consisting of

а другие переменные определены в настоящем описании.

and other variables are defined in the present description.

выбирают из группы, состоящей из

In some embodiments of the invention, the structural unit

selected from the group consisting of

а другие переменные определены в настоящем описании.

and other variables are defined in the present description.

выбирают из группы, состоящей из

а другие переменные определены в настоящем описании. В некоторых вариантах осуществления изобретения структурную единицу

выбирают из группы, состоящей из

и

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from the group consisting of

and other variables are defined in the present description. In some embodiments of the invention, the structural unit

selected from the group consisting of

And

and other variables are defined in the present description.

Also provided is a compound of formula (I) or an isomer or pharmaceutically acceptable salt thereof.

Where

n is 1, 2, 3 or 4;

each of Z ₁ , Z ₂ , and Z ₃ is independently selected from the group consisting of CH and N, and at least one of Z ₁ , Z ₂ and Z ₃ is N;

each of T ₁ and T ₂ is independently selected from the group consisting of C(R ₂ ) and N;

ring A is selected from the group consisting of 5-6 membered heteroaryl;

each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkyl, where C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R;

each R ₂ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl, where C _1-3 alkyl is optionally substituted with 1, 2 or 3 R;

each R is independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl and C _1-3 alkoxy, where C _1-3 alkyl and C _1-3 alkoxy are optionally substituted with 1, 2 or 3 R';

each R' is independently selected from the group consisting of F, Cl, Br, I, OH and NH ₂ ;

A 5-6 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms or heteroradicals independently selected from the group consisting of -NH-, -O-, -S- and N.

In some embodiments, each R is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CH ₃ , Et and -O-CH ₃ and other variables are defined herein.

In some embodiments, each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, and cyclopropyl, where C _1-3 alkyl , C _1-3 alkoxy, and cyclopropyl are optionally substituted with 1, 2, or 3 R, and other variables are defined herein.

а другие переменные определены в настоящем описании.In some embodiments, each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , Et, -CH ₂ OH, -O-CH ₃ ,

and other variables are defined in the present description.

In some embodiments, each R ₂ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CH ₃ , Et, and —CH ₂ —OH, and other variables are defined herein.

In some embodiments, ring A is selected from the group consisting of pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and pyridyl, with other variables defined herein.

In some embodiments, ring A

selected from the group consisting of

а другие переменные определены в настоящем описании.

and other variables are defined in the present description.

выбирают из группы, состоящей из

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from the group consisting of

and other variables are defined in the present description.

выбирают из группы, состоящей из

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from the group consisting of

and other variables are defined in the present description.

выбирают из группы, состоящей из

и

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from the group consisting of

And

and other variables are defined in the present description.

выбирают из группы, состоящей из

и

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from the group consisting of

And

and other variables are defined in the present description.

Also provided is a compound of formula (I) or an isomer or pharmaceutically acceptable salt thereof.

Where

n is 1, 2, 3 or 4;

each of Z ₁ , Z ₂ and Z ₃ is independently selected from the group consisting of CH and N, and at least one of Z ₁ , Z ₂ and Z ₃ is N;

each of T ₁ and T ₂ is independently selected from the group consisting of C(R ₂ ) and N;

ring A is selected from the group consisting of 5-6 membered heteroaryl;

each R ₁ is independently selected from the group consisting of H, F, CD, Br, I, OH, NH ₂ and C _1-3 alkyl, where C _1-3 alkyl is optionally substituted with 1, 2 or 3 R;

each R ₂ is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl, where C _1-3 alkyl is optionally substituted with 1, 2 or 3 R;

each R is independently selected from the group consisting of F, Cl, Br, I, OH, ΝΗ ₂ and C _1-3 alkyl, where C _1-3 alkyl is optionally substituted with 1, 2 or 3 R';

each R' is independently selected from the group consisting of F, Cl, Br, I, OH and NH ₂ ;

A 5-6 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms or heteroradicals independently selected from the group consisting of -NH-, -O-, -S- and N.

In some embodiments of the invention, each R is independently selected from the group consisting of H, F, Cl, Br, I, OH, ΝΗ ₂ , CH ₃ and Et, and other variables are defined in the present description.

In some embodiments, each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, OH, ΝΗ ₂ , CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , Et, and —CH ₂ OH, and other variables are defined in the present description.

In some embodiments of the invention, each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, OH, ΝΗ ₂ , CH ₃ and Et, and other variables are defined in the present description.

In some embodiments, Ring A is selected from the group consisting of pyrazolyl, isoxazolyl, oxazolyl, and imidazolyl, and other variables are defined herein.

а другие переменные определены в настоящем описании.In some embodiments, ring A is selected from the group consisting of

and other variables are defined in the present description.

выбирают из группы, состоящей из

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from the group consisting of

and other variables are defined in the present description.

выбирают из группы, состоящей из

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from the group consisting of

and other variables are defined in the present description.

выбирают из группы, состоящей из

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from the group consisting of

and other variables are defined in the present description.

выбирают из группы состоящей из

и

а другие переменные определены в настоящем описании.In some embodiments of the invention, the structural unit

selected from a group consisting of

And

and other variables are defined in the present description.

Some embodiments of the present disclosure are derived from a combination of the above variables.

In some embodiments, the compound provided above, or an isomer or pharmaceutically acceptable salt thereof, is selected from:

Where

each of T ₁ and T ₂ is independently selected from the group consisting of C (R ₂ ) and N;

R ₁ , R ₂ , Z ₁ , Z ₂ and Z ₃ are as defined herein.

In some embodiments, the compound provided above, or an isomer or pharmaceutically acceptable salt thereof, is selected from:

Where

R ₁ , R ₂ , Z ₁ , Z ₂ and Z ₃ are as defined herein.

The following compound or its isomer or pharmaceutically acceptable salt is also provided:

In another aspect, the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an ATR associated disease is provided.

In some embodiments of the invention, the specified drug is used to treat a solid tumor or a hematological tumor.

TECHNICAL EFFECT

As a new ATR inhibitor, the claimed compounds show good inhibitory activity against ATR kinase. Moreover, they show good tumor suppression effects in animal models and can be used as new antitumor agents.

DEFINITION AND DESCRIPTION

Unless otherwise noted, the following terms and phrases have the following definitions. A particular term or phrase should not be considered vague or obscure unless a specific definition is given, and should be understood according to its ordinary meaning. As used herein, the trade name refers to the respective product or active ingredient. The term “pharmaceutically acceptable” means that, in terms of sound medical judgment, the compounds, materials, compositions and/or dosage form are suitable for use in contact with human and animal tissues without causing undue toxicity, irritation, allergic reaction, or other problems or complications, and have a proportionate and reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is obtained by reacting a compound of the present invention that has a particular substituent with a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be prepared by contacting the neutral form of such a compound with a sufficient amount of a base in pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts and the like. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be prepared by contacting the neutral form of such a compound with a sufficient amount of acid in pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, 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, etc. d.; and organic acid salts including, 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, methanesulfonic acid, etc.; and also include salts of amino acids (such as arginine, etc.) and salts of organic acids such as glucuronic acid. Some specific compounds of the present invention contain basic and acidic functionalities which can be converted to any base or acid addition salt.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing acid radicals or basic groups by conventional chemical processes. In general, the process for preparing such salts is carried out in water or an organic solvent, or a mixture thereof, by reacting these compounds in the free acid or base form with a stoichiometric amount of the appropriate base or acid.

The compounds of the present invention may exist in certain geometric or stereoisomeric forms. The present invention covers all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomer, (L)-isomer and their racemic mixtures and other mixtures such as enantiomerically or diastereomerically enriched mixtures. All of these mixtures are included within the scope of this disclosure. Additional asymmetric carbons may be present on the alkyl and other substituents. All of these isomers and mixtures thereof are included within the scope of the present invention.

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

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" refers to the double or single bond of the ring-forming carbon atom, which is not free to rotate.

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

Unless otherwise noted, "(D)" or "(+)" means right-handed, "(L)" or "(-)" means left-handed, and "(DL)" or "(+)" means racemic.

и связь, обозначенная пунктирной линией в форме клина

указывают на абсолютную конфигурацию стереоцентра; связь, обозначенная прямой сплошной линией

и связь, обозначенная прямой пунктирной линией

указывают на относительную конфигурацию стереоцентра; волнистая линия

указывает на связь, обозначенную сплошной линией в форме клина

или связь, обозначенную пунктирной линией в форме клина

или волнистая линия в форме клина

указывают на связь, обозначенную прямой сплошной линией

и связь, обозначенную прямой пунктирной линией

Unless otherwise indicated, a relationship indicated by a solid wedge-shaped line

and the connection, indicated by a dotted line in the form of a wedge

indicate the absolute configuration of the stereocenter; connection indicated by a straight solid line

and the link indicated by the straight dotted line

indicate the relative configuration of the stereocenter; wavy line

indicates a relationship indicated by a solid wedge-shaped line

or a connection indicated by a dotted line in the form of a wedge

or wedge-shaped wavy line

indicate a relationship indicated by a straight solid line

and the link indicated by the straight dotted line

The compounds of the present invention may be present in specific tautomeric forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature the various functional groups of the isomer are in dynamic equilibrium and can rapidly transform into each other. In the presence of a tautomer (for example, in solution), it is possible to achieve chemical equilibrium of tautomers. For example, a proton tautomer (also known as a prototropic tautomer) involves interconversion during proteolysis such as ketone-enol isomerization and imine-enamine isomerization. The valence tautomer involves some recombination of bonding electrons involved in interconversions. A specific example of keto-enol tautomerization is the interconversion of two tautomers, pentan-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise specified, the term "isomerically enriched", "isomerically enriched", "enantiomerically enriched", or "enantiomerically enriched" means that the isomer or enantiomer content is less than 100% and that isomer or enantiomer content is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99, 5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

Unless otherwise indicated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80%.

Optically active (R)- and (S)-isomers and D- and L-isomers can be obtained by the synthesis of chiral compounds or by using chiral reagents, or by other conventional methods. If an enantiomer of a compound of the present invention is desired, it can be obtained by asymmetric synthesis or derivatization with a chiral auxiliary, whereby the resulting mixture of diastereomers is separated and the auxiliary group is cleaved off to obtain the pure and desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino) or an acidic functional group (such as a carboxyl group), the diastereomeric salt is prepared using an appropriate optically active acid or base and separation of the diastereomers is performed by conventional methods known in the art, and then recover the pure enantiomer. In addition, the separation of enantiomers and diastereomers is usually carried out using chromatography, which uses a chiral stationary phase, optionally with chemical derivatization processes (eg, formation of a carbamate from an amine). The compounds of the present invention may contain unnatural proportions of atomic isotopes of one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). As another example, hydrogen can be replaced by heavy hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as fewer side effects, improved stability, improved efficacy, increased biological half-life, and the like. The scope of the invention includes the possibility of using any of the radioactive isotopes, both radioactive and non-radioactive, in the compound.

"Optional" or "optional" means that the event or condition described below may, but need not, occur, and the description includes the situation in which the event or condition occurs and the situation in which the event or condition does not occur.

The term "substituted" means that any one or more hydrogen atoms in a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, provided that the valence state of the particular atom is normal and the compound after substitution is stable. An oxygen substituent (i.e.=O) means that two hydrogen atoms have been replaced. There is no substitution of oxygen in the aromatic group. The term "optional substitution" or "optionally substituted" covers cases that may be unsubstituted or substituted. Unless otherwise indicated, the type and number of substituents may be arbitrary, provided that they can be obtained by chemical means.

When any variable (for example, R) appears more than once in the composition or structure of a compound, it is determined independently in each case. Thus, for example, if a group is substituted with 0-2 R, then the group may optionally be substituted with no more than two R's, and R in each case has independent variants. In addition, combinations of substituents and/or variants thereof are permitted, provided that such combinations give stable compounds.

When the number of linking groups is 0, -(CRR) ₀ -, this means that the linking group is a single bond.

When one of the variables is selected from a group consisting of single bonds, this means that the two groups associated with it are directly related. For example, when L is a single bond in A-L-Z, the actual structure is -A-Z.

When a substituent is absent, it means that no substituent is present. For example, when X is absent in A-X, this means that the actual structure is A. When it is not specified to which atom the listed substituents are bonded, such substituents may be bonded through any of the atoms. For example, pyridyl as a substituent may be attached to the substituted group through any carbon atom on the pyridine ring.

представляет собой -MW-, причем -MW- может соединять кольцо А с кольцом В в том же направлении, как она показана, слева направо, с образованием

или может соединять кольцо А с кольцом В в противоположном показанному слева направо направлении с образованием

Комбинация связывающей группы, заместителей и/или их вариантов допускается при условии, что такая комбинация дает стабильное соединение.If no connection direction is specified for a specified linking group, it can be attached in any direction. For example, the linking group L in

is -MW-, wherein -MW- can connect ring A to ring B in the same direction as shown, from left to right, to form

or may connect ring A to ring B in the opposite direction shown from left to right to form

A combination of linking group, substituents, and/or variants thereof is allowed, provided that such a combination results in a stable compound.

Unless otherwise indicated, the term "hetero" refers to a heteroatom or heteroradical (i.e., a radical containing a heteroatom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, , oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Αl), boron (B), -O-, -S-, -C (=O) O-, C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and -C(=O)N(H)-, -N( H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-, which are optionally substituted.

Unless otherwise indicated, "cyclo" refers to substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The ring includes a single ring and also includes bicyclic or polycyclic ring systems such as a spiro ring, a fused ring, a bridged ring, and the like. The number of atoms in a ring is generally defined as the number of ring members. For example, "5-7 membered ring" refers to 5-7 atoms forming a ring structure. Unless otherwise indicated, the ring optionally contains 1-3 heteroatoms. Accordingly, "5-7 membered ring" includes, for example, phenyl, pyridyl and piperidinyl. In another aspect, the term "5-7 membered heterocycloalkyl" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes a ring system containing at least one ring, where each "ring" independently corresponds to the above definition.

Unless otherwise indicated, the term "alkyl" refers to a linear or branched saturated hydrocarbon group. In some embodiments, the alkyl is C _1-6 alkyl; in other embodiments, alkyl is C _1-3 alkyl; in other embodiments, alkyl is C _1-3 alkyl. Alkyl may be mono-substituted (eg CH ₂ F) or polysubstituted (eg -CF ₃ ), may be monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine). Examples of alkyl include, without limitation, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and t-butyl), pentyl (including n- pentyl, isopentyl and neopentyl), hexyl or the like.

Unless otherwise indicated, the term "C _1-6 alkyl" refers to a linear or branched saturated hydrocarbon group of 1-6 carbon atoms. C _1-6 alkyl includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl or the like. The alkyl may be monovalent (eg methyl), divalent (eg methylene), or polyvalent (eg methine). Examples of C _1-6 alkyl include, without limitation, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl or the like.

Unless otherwise indicated, the term "C _1-3 alkyl" refers to a linear or branched saturated hydrocarbon group of 1-3 carbon atoms. C _1-3 alkyl includes C _1-2 and C _2-3 alkyl or the like. The alkyl may be monovalent (eg methyl), divalent (eg methylene), or polyvalent (eg methine). Examples of C _1-3 alkyl include, without limitation, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), or the like.

Unless otherwise indicated, "alkenyl" refers to a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds. The carbon-carbon double bond can be in any position of the group. In some embodiments, the alkenyl is C _2-8 alkenyl; in other embodiments, the alkenyl is C _2-6 alkenyl; in other embodiments, the alkenyl is C _2-4 alkenyl. Alkenyl may be monosubstituted or polysubstituted and may be monovalent, divalent or polyvalent. Examples of alkenyl include, without limitation, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

Unless otherwise indicated, "alkynyl" refers to a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds. The triple carbon-carbon bond can be in any position of the group. In some embodiments, the alkynyl is C _2-8 alkynyl; in other embodiments, the alkynyl is C _2-6 alkynyl; in other embodiments, the alkynyl is C _2-4 alkynyl. The alkynyl may be monosubstituted or polysubstituted and may be monovalent, divalent or polyvalent. Examples of alkynyl include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and the like.

Unless otherwise indicated, the term "heteroalkyl", by itself or in combination with another term, refers to a stable linear or branched alkyl radical or composition thereof, which consists of a certain number of carbon atoms and at least one heteroatom or heteroradical. In some embodiments, the heteroatom is selected from the group consisting of B, O, N, and S, where the N and S atoms are optionally oxidized, the N heteroatom is optionally quaternized. In some other embodiments, the heteroradical is selected from the group consisting of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -Ν(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N (H)-. In some embodiments, the heteroalkyl is C _1-6 heteroalkyl; in some other embodiments, the heteroalkyl is C _1-3 heteroalkyl. A heteroatom or heteroradical may be at any internal position of a heteroalkyl, including the position of an alkyl compound with the rest of the molecule, but the terms "alkoxy", "alkylamino", and "alkylathio" (or thioalkoxy) are common expressions and refer to alkyl groups that are bonded to the rest of the molecule. part of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Examples of heteroalkyl include, without limitation, -OCH ₃ , -OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , -OCH ₂ (CH ₃ ) ₂ , -CH ₂ -CH ₂ -O-CH ₃ , -NHCH ₃ , - N (CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N (CH ₃ ) (CH ₂ CH ₃ ), -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N (CH ₃ ) -CH ₃ , -SCH ₃ , SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ , - S(=O)-CH ₃ , -CH ₂ -CH ₂ -S(=O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , -CH ₂ -CH=N-OCH ₃ and -CH= CH-N(CH ₃ )-CH ₃ . No more than two heteroatoms can be attached directly to each other, for example -CH ₂ -NH-OCH ₃ .

Unless otherwise indicated, the term "heteroalkenyl", by itself or in combination with another term, refers to a stable linear or branched alkenyl radical or composition thereof, which consists of a specified number of carbon atoms and at least one heteroatom or heteroradical. In some embodiments, the heteroatom is selected from the group consisting of B, O, N, and S, where the N and S atoms are optionally oxidized, the N heteroatom is optionally quaternized. In some other embodiments, the heteroradical is selected from the group consisting of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -Ν(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N (H)-. In some embodiments, heteroalkenyl is C _2-6 heteroalkenyl; in some other embodiments, the heteroalkyl is C _2-4 heteroalkenyl. The heteroatom or heteroradical can be in any internal position of the hetero"alkenyloxy", "alkenylamino", and "alkenylthio" are common expressions and refer to alkenyl groups that are bonded to the rest of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Examples of heteroalkenyl include, without limitation, -O-CH=CH ₂ , -O-CH=CHCH ₃ , -O-CH=C(CH ₃ ) ₂ , -CH=CH-O-CH ₃ , -O-CH= CHCH ₂ CH ₃ , -CH ₂ -CH=CH-OCH ₃ , -NH-CH=CH ₂ , -N(CH=CH ₂ )-CH ₃ , -CH=CH-NH-CH ₃ , -CH=CH -N(CH ₃ ) ₂ , -S-CH=CH ₂ , -S-CH=CHCH ₃ , -S-CH=C(CH ₃ ) ₂ , -CH ₂ -S-CH=CH ₂ , -S( =O)-CH=CH ₂ and -CH=CH-S(=O) ₂ -CH ₃ . No more than two heteroatoms can be attached directly to each other, for example -CH=CH-NH-OCH ₃ .

Не более двух гетероатомов могут быть присоединены непосредственно друг к другу, например,

Unless otherwise indicated, the term "heteroalkynyl", by itself or in combination with another term, refers to a stable linear or branched alkynyl radical or composition thereof, which consists of a specified number of carbon atoms and at least one heteroatom or heteroradical. In some embodiments, the heteroatom is selected from the group consisting of B, O, N, and S, where the N and S atoms are optionally oxidized, the N heteroatom is optionally quaternized. In some other embodiments, the heteroradical is selected from the group consisting of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -Ν(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N (H)-. In some embodiments, the heteroalkynyl is C _2-6 heteroalkynyl; in some other embodiments, the heteroalkyl is C _2-4 heteroalkynyl. The heteroatom or heteroradical may be at any internal position of the heteroalkynyl, including the position of the alkynyl bond to the rest of the molecule, but the terms "alkynyloxy", "alkynylanino", and "alkynylthio" are common expressions and refer to alkynyl groups that are bonded to the rest of the molecule via an atom oxygen, an amino group or a sulfur atom, respectively. Examples of heteroalkynyl include, without limitation,

No more than two heteroatoms can be attached directly to each other, for example,

Unless otherwise indicated, "cycloalkyl" contains any stable cyclic alkyl, including monocyclic,

bicyclic or tricyclic systems, wherein the bicyclic and tricyclic systems include a spiro ring, a fused ring, and a bridged ring. In some embodiments, the cycloalkyl is C _3-8 cycloalkyl. In some embodiments, the cycloalkyl is C _3-6 cycloalkyl. In some embodiments, the cycloalkyl is C _5-6 cycloalkyl. Cycloalkyl may be monosubstituted or polysubstituted and may be monovalent, divalent or polyvalent. Examples of cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl alkyl, [2. 2. 2]bicyclooctane, [4. 4. 0] bicycle odecan or the like.

Unless otherwise indicated, "C _3-6 cycloalkyl" is a saturated cyclic hydrocarbon group of 3-6 carbon atoms, which is a monocyclic and bicyclic system. C _3-6 cycloalkyl includes C _3-5 , C _4-5 and C _5-6 cycloalkyl or the like. Cycloalkyl may be monovalent, divalent or polyvalent. Examples of C _3-6 cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like.

Unless otherwise noted, "cycloalkenyl" contains any stable cyclic alkenyl containing one or more unsaturated carbon-carbon double bonds at any position, which includes monocyclic, bicyclic, or tricyclic systems, with bicyclic and tricyclic systems including spiro ring, fused ring, and bridging ring , but all rings in this system are non-aromatic. In some embodiments, the cycloalkenyl is C _3-8 cycloalkenyl. In some other embodiments, the cycloalkenyl is C _3-6 cycloalkenyl. In some other embodiments, the cycloalkenyl is C _5-6 cycloalkenyl. Cycloalkenyl may be monovalent, divalent or polyvalent. Examples of cycloalkenyl include, without limitation, cyclopentenyl, cyclohexenyl, and the like.

Unless otherwise indicated, "cycloalkynyl" contains any stable cyclic alkynyl containing one or more carbon-carbon triple bonds in any position, which includes a monocyclic, bicyclic, or tricyclic system, with bicyclic and tricyclic systems including a spirocyclic, fused ring, and bridged ring. The cycloalkynyl may be monosubstituted or polysubstituted and may be monovalent, divalent or polyvalent.

Unless otherwise indicated, the term "heterocycloalkyl", by itself or in combination with another term, refers to cyclic "heteroalkyl", including monocyclic,

bicyclic and tricyclic systems, wherein the bicyclic and tricyclic systems include a spiro ring, a fused ring, and a bridged ring. In addition, with regard to "heterocycloalkyl", a heteroatom may occupy a position connecting the heterocycloalkyl to the rest of the molecule. In some embodiments, heterocycloalkyl is 4-6 membered heterocycloalkyl. In some other embodiments, heterocycloalkyl is 5-6 membered heterocycloalkyl. Examples of heterocycloalkyl include, without limitation, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl or the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl or t .p.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl or the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl or the like), morpholinyl (including 3- morpholinyl and 4-morpholinyl or the like), dioxanyl, dithianyl, isoxazolalkyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, pexapidropyridazinyl, homopiperazinyl, pomopiperidinyl, or oxepanil.

Unless otherwise indicated, the term "heterocycloalkenyl", by itself or in combination with another term, refers to cyclic "peteroalkenyl", including monocyclic, bicyclic and tricyclic systems, with bicyclic and tricyclic systems including spiro ring, fused ring and bridged ring, but all rings in this system are non-aromatic. In addition, with regard to "heterocycloalkenyl", a heteroatom may occupy a position connecting the heterocycloalkenyl to the rest of the molecule. In some embodiments, heterocycloalkenyl is a 4-6 membered heterocycloalkenyl. In some other embodiments, heterocycloalkenyl is a 5-6 membered heterocycloalkenyl. Examples of heterocycloalkenyl include, without limitation,

Unless otherwise indicated, the term "heterocycloalkynyl", by itself or in combination with another term, refers to cyclic "heteroalkynyl", including monocyclic, bicyclic and tricyclic systems, with bicyclic and tricyclic systems including spiro ring, fused ring and bridged ring. In addition, with regard to "heterocycloalkynyl", a heteroatom may occupy a position connecting the heterocycloalkynyl to the rest of the molecule. In some embodiments, heterocycloalkynyl is a 4-6 membered heterocycloalkynyl. In some other embodiments, heterocycloalkynyl is a 5-6 membered heterocycloalkynyl.

Unless otherwise indicated, the term "halogen" or "halo", by itself or as part of another substituent, refers to a F, Cl, Br, or I atom. In addition, the term "haloalkyl" includes monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" includes, without limitation, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, or the like. Unless otherwise indicated, examples of haloalkyl include, without limitation, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

"Alkoxy" refers to the aforementioned alkyl having a certain number of carbon atoms linked through an oxygen bridge. Unless otherwise indicated, C _1-6 alkoxy includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy. In some embodiments, alkoxy is C _1-3 alkoxy. Examples of alkoxy include, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, and sec-pentoxy.

Unless otherwise indicated, the term "C _1-6 alkoxy" refers to an alkyl group containing 1-6 carbon atoms linked to the rest of the molecule via an oxygen atom. C _1-6 alkoxy includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy or the like. Examples of C _1-6 alkoxy include, without limitation, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy or the like.

Unless otherwise indicated, the term "C _1-3 alkoxy" refers to an alkyl group containing 1-3 carbon atoms connected to the rest of the molecule through an oxygen atom. C _1-3 alkoxy includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy or the like. Examples of C _1-3 alkoxy include, without limitation, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), or the like.

Unless otherwise indicated, the terms "aromatic ring" and "aryl" may be used interchangeably herein. The term "aromatic ring" or "aryl" refers to a polyunsaturated carbocyclic system, which may be a monocyclic, bicyclic or polycyclic system, with at least one ring being aromatic. Every ring in a bicyclic and polycyclic system is fused together. It may be mono- or polysubstituted and may be monovalent, divalent or polyvalent. In some embodiments, the aryl is C _6-12 aryl. In some embodiments, the aryl is C _6-10 aryl. Examples of aryl include, without limitation, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, or the like). The substituent of any of the above systems containing an aryl ring may be selected from the group consisting of acceptable substituents disclosed in the present description.

Unless otherwise indicated, the terms "heteroaromatic ring" and "heteroaryl" may be used interchangeably herein. The term "heteroaryl" refers to an aryl (or aromatic ring) containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of B, N, O, and S, and may be a monocyclic, bicyclic, or tricyclic system, wherein the atom the nitrogen may be substituted or unsubstituted (eg N or NR where R is Η or other substituents as defined herein) and optionally quaternized; and heteroatoms, nitrogen and sulfur, may be optionally oxidized (ie NO and S(O) _p where ρ is 1 or 2). A heteroaryl may be linked to the rest of the molecule via a heteroatom. In some embodiments, heteroaryl is 5-10 membered heteroaryl. In some other embodiments, heteroaryl is 5-6 membered heteroaryl. Examples of heteroaryl include, without limitation, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl or the like), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl or the like), imidazolyl (including N- imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl or the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl or the like), triazolyl (1H-1,2,3 -triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl or the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl or the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl or the like), furyl (including 2-furyl and 3-furyl or the like), thienyl (including 2-thienyl and 3-thienyl or the like), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl or the like), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl or the like), benzothiazolyl (including 5-benzothiazolyl or the like), purinyl, benzimidazolyl (including 2-benzimidazolyl or the like), indolyl (including 5-indolyl or the like), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl or the like), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl or the like), quinolinyl (including 3-quinolinyl and 6-quinolinyl or the like), pyrazinyl, purinyl, benzoxazolyl. The substituent of any of the above heteroaryl ring systems may be selected from the group consisting of suitable substituents disclosed in the present description.

Unless otherwise indicated, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" may be used interchangeably herein. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5-6 ring atoms with a conjugated p-electron system, where 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from the group consisting of O, S and N, and the rest are carbon atoms, the nitrogen atom being optionally quaternized, and the nitrogen and sulfur heteroatoms optionally being oxidized (i.e., NO and S(O) _p where ρ is 1 or 2). The 5-6 membered heteroaryl may be linked to the rest of the molecule via a heteroatom or carbon atom. 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of 5-6 membered heteroaryl include, without limitation, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl or the like), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl or the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl or the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl or the like), triazolyl (1H-1 ,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl or the like), tetrazolyl, isoxazolyl (3-isoxazolyl , 4-isoxazolyl and 5-isoxazolyl or the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl or the like), furyl (including 2-furyl and 3-furyl or the like) .), thienyl (including 2-thienyl and 3-thienyl or the like), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl or the like), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl or the like).

Unless otherwise indicated, the term "aralkyl" includes groups in which an aryl is attached to an alkyl. In some embodiments, aralkyl is C _6-10 aryl-C _1-4 alkyl. In some other embodiments, aralkyl is C _6-10 aryl-C _1-2 alkyl. Examples of aralkyl include, without limitation, benzyl, phenethyl, naphthylmethyl, or the like. "Aryloxy" and "arylthio" refers to groups in which a carbon atom (such as methyl) in aralkyl is replaced by an O or S atom. In some embodiments, aryloxy is C _6-10 aryl-O-C _1-2 alkyl. In some other embodiments, the aryloxy is C _6-10 aryl-C _1-2 alkyl-O-. In some embodiments, the arylthio is C _6-10 aryl-SC _1-2 alkyl. In some other embodiments, the arylthio is C _6-10 aryl-C _1-2 alkyl-S-. Examples of aryloxy and arylthio include, without limitation, phenoxymethyl, 3-(1-naphthyloxy)propyl, phenylthiomethyl, or the like.

Unless otherwise indicated, the term "heteroaralkyl" includes groups in which a heteroaryl is attached to an alkyl group. In some embodiments, heteroaralkyl is 5-8 membered heteroaryl-C _1-4 alkyl. In some other embodiments, heteroaralkyl is 5-6 membered heteroaryl-C _1-2 alkyl. Examples of heteroaralkyl include, without limitation, pyrrolylmethyl, pyrazolylmethyl, pyridylmethyl, pyrimidinylmethyl, or the like. "Heteroaryloxy" and "heteroarylthio" refer to groups in which a carbon atom (such as methyl) in the heteroaralkyl group is replaced by an O or S atom. In some embodiments, heteroaryloxy is 5-8 membered heteroaryl-O-C _1-2 alkyl. In some embodiments, heteroaryloxy is 5-6 membered heteroaryl-C _1-2 alkyl-O-. In some embodiments, heteroarylthio is 5-8 membered heteroaryl-S-C _1-2 alkyl. In some other embodiments, heteroarylthio is 5-6 membered heteroaryl-C _1-2 alkyl-S-. Examples of heteroaryloxy and heteroarylthio include, without limitation, pyrrolyloxymethyl, pyrazolyloxymethyl, 2-pyridyloxymethyl, pyrrolylthiomethyl, pyrazolylthiomethyl, 2-pyridylthiomethyl, or the like.

Unless otherwise indicated, C _n-n+m or C _n -C _n+m includes any specific case in which the number of carbon atoms is from n to n+m. For example, C _1-12 covers C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ , as well as any value ranging from n to n+m, for example, C _1-12 covers C _1-3 , C _1-6 , C _1-9 , C _3-6 , C _3-9 , C _3-12 , C _6-9 , C _{6 -12} and C _9-12 , etc. Similarly, a value from n-membered to n+m-membered means that the number of atoms in the ring is from n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring and 12-membered ring, and also includes any number from n to n+m, e.g. 3-12 membered ring contains 3-6 membered ring, 3-9 membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring and a 6- to 10-membered ring or the like.

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom as a result of a substitution reaction (eg, an affine substitution reaction). For example, representative leaving groups include triflat; Cl, Br, I; a sulfonate such as mesylate, tosylate, p-bromobesylate, p-toluenesulfonate or the like; acyloxy, for example acetoxy, trifluoroacetoxy or the like.

The term "protecting group" includes, without limitation, "amino protecting group", "hydroxyl protecting group", or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Exemplary amino protecting groups include, without limitation, formyl; acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as t-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluoromethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Βn), triphenylmethyl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) or the like.

Compounds of the present invention can be obtained by various synthetic methods well known to the person skilled in the art, including the specific embodiments listed below. Embodiments formed by combination with other chemical synthesis processes and equivalences well known to those skilled in the art and preferred embodiments include, without limitation, the examples provided herein.

The compounds of the present invention may have a variety of uses or indications, including, without limitation, the specific compounds listed herein.

The solvents used herein are commercially available. The following abbreviations are used in the present description: aq.: water; HATU: O-(7-azabenzotriazol-1-yl)-N, N,N',N'-tetramethylurea hexafluorophosphate; EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA: 3-chloroperoxybenzoic acid; eq.: equivalent, equivalence; CDI: carbonyldiimidazole; DCM: dichloromethane; PE: petroleum ether; DIAD: diisopropyl azodicarboxylate; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; EtOH: ethanol; MeOH: methanol; CBz: benzyloxycarbonyl, amino protecting group; BOC: tert-butoxycarbonyl, amino protecting group; HOAc: acetic acid; NaCNBH ₃ : sodium cyanoborohydride; r.t.: room temperature; O/N: during the night; THF: tetrahydrofuran; Boc ₂ O: di-tert-butyl dicarbonate; TFA: trifluoroacetate; DIPEA: diisopropylethylamine; SOCl ₂ : thionyl chloride; CS ₂ : carbon disulfide; TsOH: p-toluenesulfonic acid; NFSI: N-fluoro-N-(benzenesulfonyl)benzenesulfonamide; NCS: N-chlorosuccinimide; n-Bu ₄ NF: tetrabutylammonium fluoride; iPrOH: 2-propanol; mp: melting point; LDA: lithium diisopropylamide.

Compound names are manually entered or generated using ChemDraw® software. Complex names are used from the catalog of suppliers.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1: Tumor growth curve in tumor-bearing mice in a LoVo human colorectal cancer subcutaneous xenograft model following administration of a compound of the present invention.

Examples

The present invention is described in detail in the following examples, which should not be construed as limiting. The present invention is described in detail in the present description, which also discloses its specific embodiments. For a person skilled in the art it will be obvious that various changes and modifications can be made to specific embodiments of the present invention without deviating from the essence and scope of the invention.

Intermediate 1

Synthesis scheme:

Step 1: Synthesis of Compound A1

To a solution of compound A1-1 (65 g, 331.56 mmol) in dimethyl sulfoxide (1 L) was added bispinacol borate (126.29 g, 497.34 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (12, 13 g, 16.58 mmol) and potassium acetate (113.89 g, 1.16 mol). The reaction mixture was stirred under nitrogen protection at 90° C. for 16 h. Then the reaction mixture was filtered through celite, the filtrate was extracted with 1 l of ethyl acetate (500 ml × 2), and the organic phase was washed with 3 l of water (1 l × 3) and dried over anhydrous sodium sulfate. After the desiccant (desiccant) was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 4:1) to give Compound A1.

MS-ESI m/h: 243.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 13 H) 7.09 (t, J=2.13 Hz, 1 H) 7.21-7.25 (m, 1 H ) 7.52 (d, J=8.03 Hz, 1 H) 7.67 (d, J=7.03 Hz, 1 H) 8.23 (br.s, 1 H).

Intermediate 2

Synthesis scheme:

Step 1: Synthesis of Compound B1-2

To a solution of compound B1-1 (90 g, 456.78 mmol) in dichloromethane (1 L) was added sodium hydroxide solution (2M, 685.17 ml) and tetrabutylammonium hydrogen sulfate (7.75 g, 22.84 mmol) and then p-toluenesulfonyl chloride (174.17 g, 913.56 mmol) was added slowly. The reaction mixture was stirred at 25° C. for 15 h and extracted with 500 ml of dichloromethane (250 ml×2) and the organic phase was washed with 3 l of water (1 l×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 1:0) to give compound B1-2.

MS-ESI m/h: 352.9 [M+H] ⁺ .

Step 2: Synthesis of Compound B1

To a solution of compound B1-2 (25 g, 71.18 mmol) in N,N-dimethylformamide (500 ml) was added bispinacol borate (36.15 g, 142.36 mmol), 1,1-bis(diphenylphosphino)palladium ferrocene chloride (5.21 g, 7.12 mmol) and potassium acetate (20.96 g, 213.54 mmol). The reaction mixture was stirred under nitrogen protection at 90° C. for 16 hours. Then the reaction mixture was filtered through Celite, the filtrate was extracted with 1 L of ethyl acetate (500 ml × 2), and the organic phase was washed with 3 L of water (1 L * 3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 4:1) to give compound B1.

MS-ESI m/z: 399.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CHPOROFORM-d) δ ppm 1.27 (d, J=2.76 Hz, 3 H) 1.32-1.39 (m, 1 H) 1.33-1.38 ( m, 1 N) 1.36 (s, 10 N) 6.95-7.05 (m, 1 N) 7.02 (d, J=4.02 Hz, 1 N) 7.20-7.26 (m, 1 N) 7.24 (d, J=8.03 Hz, 1 N) 7.52 (d, J=4.77 Hz, 1 N) 7.72-7.78 (m, 1 N ) 7.75 (d, J=3.76 Hz, 1 H) 8.02-8.04 (m, 2 H) 8.43 (d, J=4.77 Hz, 1 H).

Intermediate 3

Synthesis scheme:

Step 1: Synthesis of Compound C1-3

At room temperature, to a solution of compound C1-1 (3.00 g, 12.82 mmol) in N,N-dimethylformamide (30.00 ml) was added C1-2 (7.65 g, 64.23 mmol, 8.50 ml) which was stirred under nitrogen atmosphere at 160° C. for 8 hours. The reaction system was cooled, diluted with dichloromethane (50 ml), washed with water (20 ml×5) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product. The crude product was dissolved in acetic acid (5 ml) and added dropwise to a refluxing solution of iron powder (7.16 g, 128.19 mmol) in acetic acid (5 ml). The reaction mixture was heated at reflux for 40 minutes. The reaction mixture was cooled to room temperature, adjusted to basic pH with saturated sodium carbonate solution and extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/dichloromethane=3/1) to give compound C1-3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.50 (t, J=2.26 Hz, 1 H) 6.96-7.00 (m, 1 H) 7.05 (dd, J= 9.04, 2.01 Hz, 1 N) 7.16 (t, J=2.76 Hz, 1 N) 7.47 (dd, J=8.52, 5, 52 Hz, 1 N) 8, 20 (br. s, 1 N).

Step 2: Synthesis of Compound C1

At room temperature, to a solution of compound C1-3 (1.00 g, 4.67 mmol) in 1,4-dioxane (15.00 ml) was added bispinacol borate (1.78 g, 7.00 mmol), 1.1 -bis(diphenylphosphino)ferrocene palladium chloride (341.71 mg, 467.00 µmol), potassium acetate (1.37 g, 14.01 mmol), which was stirred under nitrogen for 12 h. After cooling, the reaction system was diluted with ethyl acetate (40 ml) and filtered. The organic phase was washed with water (20 ml×2) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/dichloromethane=3/1) to give compound C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.34 (s, 12 H) 6.74 (br. s, 1 H) 7.12 (dd, 47=10.04, 2.51 Hz , 1 N) 7.30 (dd, J=10.04, 2.01 Hz, 1 N) 7.38 (t, J=2.76 Hz, 1 N) 11.18 (br.s, 1 N ).

Intermediate 4

Synthesis scheme:

Step 1: Synthesis of Compound D1-2

To a solution of compound D1-1 (2.00 g, 10.90 mmol, 1.25 ml) in dichloromethane (20 ml) was added triethylamine (3.15 g, 31.14 mmol, 4.32 ml) and slowly [R)-3-methylmorpholine was added dropwise at -5°C. The reaction mixture was slowly warmed to 15° C. and stirred for 15 hours. The compound was concentrated to dryness and the crude product was purified on a silica gel column (petroleum ether/ethyl acetate=10:1, 5:1) to give compound D1-2.

MS-ESI m/h: 247.9 [M+H] ⁺ .

Step 2: Synthesis of Compound D1

To a solution of compound D1-2 (1.5 g, 6.05 mmol) in 1,4-dioxane (40 ml) was added A1 (1.62 g, 6.65 mmol), bistriphenylphosphine palladium dichloride (424.35 mg, 604.57 µmol) and sodium carbonate (2 M, 9.07 ml). The reaction mixture was stirred under nitrogen protection at 110° C. for 15 hours. Then the reaction mixture was filtered through celite, the filtrate was extracted with 50 ml of ethyl acetate (25 ml ×2). The organic phase was washed with 60 ml of water (20 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 1:1) to give compound D1.

MS-ESI m/z: 32 8.9 [M+H] ⁺ .

Intermediate 5

Synthesis scheme:

Step 1: Synthesis of compound E1

To a solution of compound D1-2 (9.03 g, 36.41 mmol) in 1,4-dioxane (100 ml) was added B1 (14.5 g, 36.41 mmol), bistriphenylphosphine palladium dichloride (2.555 g, 3.641 mmol ) and sodium carbonate (2 M, 54.61 ml). The reaction mixture was stirred under nitrogen protection at 110° C. for 15 hours. Then the reaction mixture was filtered through celite, the filtrate was extracted with 600 ml of ethyl acetate (200 ml ×3). The organic phase was washed with 600 ml of water (200 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=4:1, 4:3) to give compound E1.

MS-ESI m/h: 484.2 [M+H] ⁺ .

Intermediate 6

Synthesis scheme:

Step 1: Synthesis of Compound F1

To a solution of compound D1-2 (0.5 g, 2.02 mmol) in 1,4-dioxane (10 ml) was added C1 (578, 80 mg, 2.22 mmol), bistriphenylphosphine palladium dichloride (70.73 mg, 100.76 µmol) and sodium carbonate (2 M, 3.02 ml). The reaction mixture was stirred under nitrogen protection at 110°C for 15 h. Then the reaction mixture was filtered through celite, the filtrate was extracted with 60 ml of ethyl acetate (20 ml ×3). The organic phase was washed with 60 ml of water (20 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=4:1, 1:1) to give compound F1.

MS-ESI m/h: 347.1 [M+H] ⁺ .

Intermediate 7

Synthesis scheme:

Step 1: Synthesis of Compound G1-2

To a solution of compound G1-1 (1 g, 5.13 mmol) in 1,4-dioxane (25 ml) was added A1 (1.37 g, 5.64 mmol), bistriphenylphosphine palladium dichloride (359.82 mg, 512. 64 µmol) and sodium carbonate (2 M, 7.69 ml). The reaction mixture was stirred under nitrogen protection at 90° C. for 15 hours. Then the reaction mixture was filtered through celite, the filtrate was extracted with 90 ml of ethyl acetate (30 ml ×3). The organic phase was washed with 90 ml of water (30 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 4:1) to give compound G1-2.

MS-ESI m/z: 275.9 [M+H]+

Step 2: Compound G1 Synthesis

To a solution of compound G1-2 (1.09 g, 3.95 mmol) in dichloromethane (20 ml) was added sodium hydroxide solution (2 M, 5.93 ml) and tetrabutylammonium hydrogen sulfate (671.36 mg, 1.98 mmol) and then p-toluenesulfonyl chloride (1.13 g, 5.93 mmol) was added slowly. The reaction mixture was stirred at 25° C. for 15 hours. The reaction mixture was extracted with 90 ml dichloromethane (30 ml×3). The organic phase was washed with 90 ml of water (30 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 4:1) to give compound G1.

MS-ESI m/h: 429.8 [M+H] ⁺ .

Intermediate 8

Synthesis scheme:

Step 1: Synthesis of Compound H1

To a solution of compound G1-1 (48 7.08 mg, 2.50 mmol) in 1,4-dioxane (20 ml) was added B1 (1 g, 2.50 mmol), bistriphenylphosphine palladium dichloride (87.63 mg, 124 .85 µmol) and sodium carbonate (2 M, 3.75 ml). The reaction mixture was stirred under nitrogen protection at 90° C. for 15 hours. Then the reaction mixture was filtered through celite, the filtrate was extracted with 90 ml of ethyl acetate (30 ml ×3). The organic phase was washed with 90 ml of water (30 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 5:1) to give compound H1.

MS-ESI m/h: 431.0 [M+H] ⁺ .

Intermediate 9

Synthesis scheme:

Step 1: Synthesis of Compound I1

To a solution of compound G1-1 (493.09 mg, 2.53 mmol) in 1,4-dioxane (20 ml) was added C1 (0.66 g, 2.53 mmol), bistriphenylphosphine palladium dichloride (88.71 mg, 126.39 µmol) and sodium carbonate (2 M, 3.79 ml). The reaction mixture was stirred under nitrogen protection at 90° C. for 15 hours. Then the reaction mixture was filtered through celite, the filtrate was extracted with 90 ml of ethyl acetate (30 ml ×3). The organic phase was washed with 90 ml of water (30 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 5:1) to give compound I1.

MS-ESI m/h: 2 9 3.9 [M+H] ⁺ .

Intermediate 10

Synthesis scheme:

Step 1: Synthesis of compound XX1-2

(R)-3-methylmorpholine (304.87 mg, 3.01 mmol), potassium carbonate (946.74 mg, 6.85 mmol) which was stirred under nitrogen at 100° C. for 12 hours. The reaction system was diluted with ethyl acetate (30 ml). The organic phase was washed with water (20 ml×3) and brine (20 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=10/1, 5/1) to give compound XX1-2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.14 (d, J=6.53 Hz, 3 H) 3.09 (td, J=12.80, 3.51 Hz, 1 H) 3.44 (td, J=11.80, 3.01 Hz, 1 N) 3.56-3.62 (m, 1 N) 3.67-3.73 (m, 1 N) 3.82- 3.96 (m, 2 N) 4.28 (br.dd, J=6.52, 2.51 Hz, 1 N) 6.83 (d, J=1.00 Hz, 1 N) 6.87 (d, J=1.5 0 Hz, 1 N).

Step 2: Synthesis of Compound XX1

At room temperature, to a solution of XX1-2 (1.05 g, 4.25 mmol) in 1,4-dioxane (10.00 mL) was added compound B1 (1.69 g, 4.25 mmol), dichlorobis triphenylphosphine) palladium (298.23 mg, 424.89 µmol), sodium carbonate solution (2 M, 6.37 ml) which was stirred under nitrogen at 100°C for 9 hours. The reaction system was diluted with 20 ml of water and extracted ethyl acetate (30 ml). The organic phase was washed with water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=3/1, 1/1) to give compound XX1.

MS m/z: 483.1 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.19 (d, J=6.78 Hz, 3 H) 2.34 (s, 3 H) 3.17 (td, J=12.74 , 3, 89 Hz, 1 N) 3, 45-3.54 (m, 1 N) 3.62-3.67 (m, 1 N) 3.71-3.78 (m, 1 N) 3, 92-3.99 (m, 2 N) 4.42 (br.l, J=6.27 Hz, 1 N) 6.99 (d, J=1.00 Hz, 1 N) 7.23 (d , J=4.02 Hz, 1 H) 7.33 (d, J=1.25 Hz, 1 H) 7.43 (d, J=8.03 Hz, 2 H) 7.74 (d, J=5.27 Hz, 1 N) 7.99 (d, J=4.02 Hz, 1 N) 8.02 (d, J=8.53 Hz, 2 N) 8.44 (d, J= 5.02 Hz, 1 N).

Intermediate 11

Synthesis scheme:

Step 1: Synthesis of Compound XX2-1

At 0°C, to a solution of 4-methoxybenzyl alcohol (1.11 g, 8.06 mmol) in tetrahydrofuran (30 ml) was added sodium hydride (386.89 mg, 9.67 mmol, 60%) with stirring for 0. 5 h. D1-2 (2 g, 8.09 mmol) was added to the reaction mixture and purged with nitrogen three times. The reaction mixture was stirred at 20°C with heating for 12 h, the reaction was stopped by adding water (30 ml) and was extracted with ethyl acetate (50 ml). The organic phase was washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound XX2-1.

MS-ESI m/h: 350.2 [M+H] ⁺ .

Step 2: Synthesis of compound XX2-2

To a solution of compound XX2-1 (4.5 g, 12.86 mmol) in N,N-dimethylformamide (50 ml) was added 1,4-dimethyltriazole (1.87 g, 19.30 mmol) bis(triphenylphosphine)palladium dichloride (451.46 mg, 643.2 µmol) and tetramethylammonium acetate (2.06 g, 15.44 mmol). The reaction mixture was stirred in a sealed tube at 130°C with heating for 12 h and then diluted with ethyl acetate (200 ml), washed with water (VO ml × 2) and brine (80 ml × 2), dried over anhydrous sodium sulfate and filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound XX2-2.

MS-ESI m/h: 411.3 [M+H] ⁺ .

Step 3: Synthesis of compound XX2-3

To a solution of compound XX2-2 (0.85 g, 2.07 mmol) in ethanol (20 ml) was added wet Pd/C (0.2 g, 2.07 mmol, 10%) and purged with hydrogen three times. The reaction mixture was stirred at 30° C. with heating for 12 hours and then filtered. The filtrate was concentrated to give the crude compound XX2-3.

MS-ESI m/h: 291.2 [M+H] ⁺ .

Step 4: Synthesis of compound XX2

Compound XX2-3 (0.6 g, 2.07 mmol) was added to phosphorus oxychloride (20.35 g, 132.72 mmol) and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was quenched by adding a saturated solution sodium bicarbonate at 0° C., adjusted to pH 9, extracted with dichloromethane (100 ml), washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude compound XX2.

MS-ESI m/z: 309.1 [M+H] ⁺ .

Intermediate 12

Synthesis scheme:

Step 1: Synthesis of compound XX3

To a solution of compound XX3-1 (2 g, 7.87 mmol), bispinacol borate (4.00 g, 15.74 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (0.3 g, 410.00 µmol) in 1,4-dioxane (25 ml) was added potassium acetate (2.32 g, 23.61 mmol) and purged with nitrogen three times. The reaction mixture was stirred at 100° C. with heating for 8 hours and then filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound XX3.

MS-ESI m/z: 302.1 [M+H] ⁺ .

Intermediate 13

Synthesis scheme:

Step 1: Synthesis of Compound 1

To a solution of compound D1-2 (3.70 g, 14.91 mmol), 1,4-dimethylpyrazole-5-pinacol borate (3.31 g, 14.91 mmol) and bis(triphenylphosphine)palladium dichloride (523.3 6 mg, 745.64 µmol) in 1,4-dioxane (90 ml) was added 2M aqueous sodium carbonate solution (22.37 ml) and the solution was purged with nitrogen three times. The reaction mixture was stirred at 110° C. with heating for 15 hours and then filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound XX4.

MS-ESI m/z: 308.2 [M+H] ⁺ .

Intermediate 14

Synthesis scheme:

Step 1: Synthesis of compound XX5

Except for using the appropriate starting materials, the procedure for preparing compound XX5 is identical to that used for compound D1 in the Synthesis Example of Intermediate D1.

MS-ESI m/h: 386.2 [M+H] ⁺ .

Intermediate 15

Synthesis scheme:

Step 1: Synthesis of compound XX6-2

At 0° C., to a solution of compound XX6-1 (2 g, 17.84 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (856.07 mg, 21.40 mmol, purity: 60%). The reaction mixture was stirred at 25° C. for 1 h and then cooled to 0° C. and methyl iodide (11.4 g, 80.32 mmol, 5.00 ml) was added. The reaction mixture was stirred at 25° C. for 10 hours. Saturated brine (30 ml) was added to the reaction mixture and extracted with ethyl acetate (50 ml×3). The organic phases were combined and washed successively (70 ml) and brine (70 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound XX6-2.

MS-ESI m/h: 253.1 [M+H] ⁺ .

Step 2: Synthesis of compound XX6

At 0°C, to a solution of compound XX6-2 (0.5 g, 3.96 mmol) in tetrahydrofuran (15 ml) was added n-butyllithium (2.5 M, 4.76 ml). The reaction mixture was stirred at 25° C. for 1 h and then cooled to -78° C. and isopropanol pinacol borate (818.52 mg, 4.40 mmol) was added. The reaction mixture was stirred at -78°C for 0.5 h and heated to 0°C with stirring for 1 h. hydrochloric acid and was extracted with ethyl acetate (40 ml ×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was separated by column chromatography to give compound XX6.

MS-ESI m/h: 127.0 [M+H] ⁺ .

Intermediate 16

Synthesis scheme:

Step 1: Synthesis of compound XX7-2

At 0°C, to a solution of compound XX7-1 (1 g, 5.12 mmol) in dichloromethane (10 ml), benzyltriethylammonium chloride (233.33 mg, 1.02 mmol), methyl iodide (2.06 g, 14, 51 mmol, 903.51 µl) and an aqueous solution of sodium hydroxide (10 ml) with a concentration of 30%. The reaction mixture was stirred at 0° C. for 3 hours and at 25° C. for 2 hours. The reaction mixture was diluted with water (130 ml) and extracted with dichloromethane (75 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was separated by column chromatography to give compound XX7-2.

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=7.90 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 4.61 ( k, J=6.9 Hz, 1H), 2.52 (s, 3H), 1.77 ppm (d, J=6.8 Hz, 3H)

Step 2: Synthesis of compound XX7-4

To a solution of compound XX7-3 (1 g, 4, 10 mmol) in dichloromethane (20 ml) was added Dess-Martin periodinan (2.61 g, 6.16 mmol). The reaction mixture was stirred at 30° C. for 8 h, diluted with water (20 ml), extracted with dichloromethane (20 ml ×3). The organic phases were combined, washed with brine (20 ml), filtered and concentrated to give the crude product, which was separated by column chromatography to give compound XX7-4.

MS-ESI m/h: 242.0 [M+H]+.

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=9.86 (s, 1H), 6.95 (s, 1H), 4.38 (br. s, 1H), 4.06 (dd, J =11.8, 3.8 Hz, 1H), 4.14 (br. d, J=7.5 Hz, 1H), 3.80-3.87 (m, 1H), 3.69-3, 76 (m, 1H), 3.58 (td, J=12.0, 2.9 Hz, 1H), 3.37 (br. t, J=11.8 Hz, 1H), 1.38 ppm ( e, J=6.8 Hz, 3H).

Step 3: Synthesis of compound XX7-5

Triethylamine (2.14 g, 21.10 mmol ) and anhydrous sodium sulfate (4.50 g, 31.65 mmol). The reaction mixture was stirred at 50° C. for 13 hours and the organic solvent was filtered off and concentrated to give the crude compound XX7-5.

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=8.13 (d, J=1.8 Hz, 1H), 6.97 (s, 1H), 4.37 (br. s, 1H), 4.08 (br.s, 1H), 4.00 (dd, J=11.4, 3.6 Hz, 1H), 3.75-3.81 (m, 1H), 3.64-3, 71 (m, 1H), 3.49-3.57 (m, 4H), 3.25-3.35 (m, 1H), 1.33 ppm (d, J=6.8 Hz, 3H)

Step 4: Synthesis of compound XX7

Potassium carbonate (725.71 mg, 5.25 mmol) was added to a solution of compounds XX7-5 (0.535 g, 2.10 mmol) and XX7-2 (439.54 mg, 2.10 mmol) in ethanol (25 ml) . The reaction mixture was stirred at 25° C. for 48 h and heated to 70° C. with stirring for 12 h. The reaction mixture was filtered and concentrated to give the crude product, which was separated by column chromatography to give compound XX7.

MS-ESI m/z: 308.1 [M+H] ⁺ .

Intermediate 17

Synthesis scheme:

Step 1: Synthesis of Compound XX8-2

At 0°C, to a solution of compound XX8-1 (10 g, 60.98 mmol) and 4-dimethylaminopyridine (744.96 mg, 6.10 mmol) in dichloromethane (100 ml) was slowly added di-tert-butyl decarbonate (29 .28 g, 134.15 mmol). The reaction mixture was stirred at 30° C. for 36 h and ice water (120 ml) was added and extracted with dichloromethane (150 ml×2). The organic phases were combined, washed with brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was separated by column chromatography to give compound XX8-2.

MS-ESI m/z: 364.1 [M+H] ⁺ .

Step 2: Synthesis of compound XX8

To a solution of compound XX8-2 (6 g, 16.47 mmol) and (R)-3-methylmorpholine (1.83 g, 18.12 mmol) in 1,4-dioxane (50 ml) was added N,N-diisopropylethylamine (2.13 g, 16.47 mmol). The reaction mixture was stirred at 50° C. for 10 h and then concentrated under reduced pressure to give a crude product, which was separated by column chromatography to give compound XX8.

MS-ESI m/h: 429.3 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=6.76 (s, 1H), 4.30 (br.s, 1H), 3.99 (br.dd, J=11.5, 3, 5 Hz, 2H), 3.74-3.81 (m, 1H), 3.64-3.72 (m, 1H), 3.54 (td, J=11.9, 3.0 Hz, 1H ), 3.28 (td, J=12.9, 3.9 Hz, 1H), 1.54 (s, 18H), 1.31 ppm (d, J=6, 8 Hz, 3H).

Intermediate 18

Synthesis scheme:

Step 1: Synthesis of compound XX9-2

To a solution of compound XX9-1 (6.2 g, 33.29 mmol) in propionic acid (10 mL) was added 1,1-dichloroacetone (4.57 g, 35.96 mmol). The reaction mixture was stirred at 30°C for 14 h and filtered. The precipitate was washed with cyclohexane (100 ml) and the solid was centrifuged to remove the solvent to give the crude compound XX9-2.

¹ H NMR (DMSO-d6, 400 MHz): δ=11.88 (br. s, 1H), 9.19 (s, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 2.39 (s, 3H), 1.84 ppm (s, 3H)

Step 2: Synthesis of compound XX9

At 0° C., triethylamine (11.08 g, 109.45 mmol) was added to a solution of cyclopropylamine (1.25 g, 21.89 mmol, 1.52 ml) in ethanol (50 ml). The reaction mixture was stirred at 0° C. for 10 h, then a solution of XX9-2 (7.11 g, 24.08 mmol) in acetonitrile (50 mL) was added and heated to 30° C. with stirring for 16 h. concentrated to give the crude product, which was separated by column chromatography to give compound XX9.

MS-ESI m/h: 124.0 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=7.32 (s, 1H), 3.73 (m, 1H), 2.34 (s, 3H), 1.20-1.27 (m , 2H), 1.10-1.17 ppm (m, 2H).

Intermediate 19

Synthesis scheme:

Step 1: Synthesis of compound XX10-2

N,N -diisopropylethylamine (1.74 g, 13.50 mmol). The reaction mixture was heated under microwave radiation at 180° C. for 1 hour, and the reaction mixture was concentrated to give a crude product, which was separated by column chromatography to give compound XX10-2.

MS-ESI m/z: 228.0 M+H] ⁺ .

Step 2: Synthesis of compound XX10

At 0-5°C, di-tert-butyl decarbonate was slowly added to a solution of XX10-2 (1.4 g, 6.15 mmol) and 4-dimethylaminopyridine (1 g, 8.19 mmol) in dichloromethane (30 ml). (4.03 g, 18.45 mmol). The reaction mixture was stirred at 30°C for 5 h, then added water (30 ml) and was extracted with dichloromethane (50 ml ×3). The organic phases were combined, washed with brine (70 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was separated by column chromatography to give compound XX10.

MS-ESI m/z: 428.6 M+H] ⁺ .

Example 1: Connection WX01

Synthesis scheme:

Step 1: Synthesis of compound WX01-2

At room temperature, to a solution of compound A1 (300.00 mg, 1.64 mmol) in 1,4-dioxane (10.00 ml) was added compound XX1-1 (398.70 mg, 1.64 mmol), dichlorobis(triphenylphosphine ) palladium (115.11 mg, 164.00 µmol), sodium carbonate solution (2 M, 2.46 ml) and stirred at 90°C for 12 hours. The reaction system was diluted with 20 ml of water and extracted with ethyl acetate (40 ml) . The organic phase was washed with brine (20 ml×2) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=10/1, 6/1) to give compound WX01-2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.03 (br. s, 1 H) 7.23 (t, J=7.78 Hz, 1 H) 7.51 (t, J=2 .76 Hz, 1 H) 7.57 (d, J=8.03 Hz, 1 H) 7.63 (d, J=7.53 Hz, 1 H) 7.71 (d, J=1.51 Hz, 1 N) 8.07 (d, J=1.51 Hz, 1 N) 11.41 (br. s, 1 N).

Step 2: Synthesis of compound WX01-3

At room temperature, to a solution of compound WX01-2 (100.00 mg, 380.05 µmol) in 1,4-dioxane (3.00 mL) was added 1-methyl-1H-pyrazole-5-boric acid (47.86 mg , 380.05 µmol), palladium dichlorobis(triphenylphosphine) (26.68 mg, 38.00 µmol) and sodium carbonate solution (2 M, 570.08 µl) and stirred at 90°C for 12 h. The reaction system was diluted 20 ml water and extracted with ethyl acetate (30 ml). The organic phase was washed with brine (20 ml×2) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was separated and purified on a silica gel plate (petroleum ether/ethyl acetate=2/1) to give compound WX01-3.

MS m/z: 308.9 [M+H] ⁺

Step 3: Synthesis of compound WX01

At room temperature, (R)-3-methylmorpholine (45.86 mg, 453.43 µmol ), palladium acetate (26.68 mg, 38.00 µmol), 2-dicyclohexylphosphono-2,4,6-triisopropylbiphenyl (21.62 mg, 45.34 µmol), cesium carbonate (221.60 mg, 680.14 µmol) and stirred at 100° C. under nitrogen for 12 hours. The reaction system was diluted with 20 ml of water and extracted with ethyl acetate (25 ml). The organic phase was washed with brine (15 ml×2) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was separated by preparative HPLC (neutral conditions) to give compound WX01.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J=6.52 Hz, 3 H) 3.31-3.38 (m, 1 H) 3.49 (br. s, 1 N) 3.70-3.77 (m, 1 N) 3.88 (s, 2 N) 4.04-4.13 (m, 2 N) 4.32 (s, 3 N) 6.60 (d, J=2.00 Hz, 1 H) 6.93 (d, J=2.52 Hz, 1 H) 7.00 (br.s, 1 H) 7.19 (d, J=2, 00 Hz, 1 N) 7.31-7.36 (m, 2 N) 7.50 (d, J=8.52 Hz, 1 N) 7.53 (d, J=2.00 Hz, 1 N ) 7.61 (d, J=7.52 Hz, 1 H) 8.33 (br. s, 1 H). MS m/s: 374.0 [M+H] ⁺ .

Example 2: Connection WX02

Synthesis scheme:

Step 1: Synthesis of compound WX02

To a solution of compound D1 (0.08 g, 243.31 µmol) in 1,4-dioxane (5 ml) was added 1-methylpyrazole-5-pinacol borate (75.94 mg, 364.97 µmol), bistriphenylphosphine palladium dichloride (17.08 mg, 24.33 µmol) and sodium carbonate (2 M, 364.97 µl). The reaction mixture was stirred at 90° C. under nitrogen protection for 15 hours. The reaction mixture was filtered through celite and the filtrate was extracted with 30 ml of ethyl acetate (10 ml x3). The organic phase was washed with 30 ml of water (10 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was separated by preparative HPLC (neutral conditions) to give compound WX02.

MS-ESI m/h: 375.0 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.78 Hz, 3 H) 3.28-3.32 (m, 1 H) 3.31 (s, 1 H ) 3.55 (td, J=11.80, 2, 76 Hz, 1 N) 3.70 (dd, J=11.29, 2.76 Hz, 1 N) 3.79-3.86 (m , 1 H) 4.03 (dd, J=11.17, 3.14 Hz, 1 H) 4.29 (s, 4 H) 4.68 (br. s, 1 H) 6.98-7, 04 (m, 1 N) 7.01 (s, 1 N) 7.00 (d, J=2.01 Hz, 1 N) 7.22 (t, J=7.78 Hz, 1 N) 7, 30 (br.s, 1 N) 7.47 (t, J=2.64 Hz, 1 N) 7.52-7.57 (m, 2 N) 8.13 (d, J=7.28 Hz , 1 N) 11.22-11.34 (m, 1 N) 11.29 (br. s, 1 N).

Example 3: Connection WX03

Synthesis scheme:

Step 1: Synthesis of compound WX03

To a solution of compound D1 (0.08 g, 243.31 µmol) in 1,4-dioxane (5 ml) was added 1,3-dimethylpyrazole-5-pinacol borate (54.04 mg, 243.31 µmol), palladium bistriphenylphosphine dichloride (17.08 mg, 24.33 µmol) and sodium carbonate (2 M, 364.97 µl). The reaction mixture was stirred at 90° C. under nitrogen protection for 15 hours. The reaction mixture was filtered through celite and the filtrate was extracted with 30 ml of ethyl acetate (10 ml x3). The organic phase was washed with 30 ml of water (10 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was separated by preparative HPLC (neutral conditions) to give compound WX03.

MS-ESI m/z: 389.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.53 Hz, 3 H) 2.18-2.26 (m, 1 H) 2.21 (s, 1 H ) 2.26-2.27 (m, 1 N) 3.23-3.30 (m, 1 N) 3.24-3.31 (m, 1 N) 3.48-3.59 (m, 1 N) 3.69 (dd, J=11.42, 2.64 Hz, 1 N) 3.77-3.88 (m, 1 N) 3.77-3.84 (m, 1 N) 4 .02 (br.dd, J=11.29, 3.01 Hz, 1 N) 4.20 (s, 2 N) 4.17-4.22 (m, 1 N) 4.26 (br. d , J=13.55 Hz, 1 N) 4.54-4.80 (m, 1 N) 4.65 (br.s, 1 N) 6.64-6.85 (m, 1 N) 6, 69-6.83 (m, 1 N) 6.71-6.82 (m, 1 N) 6.78 (s, 1 N) 6.96 (s, 1 N) 6.92-7.03 ( m, 1 N) 7.21 (t, J=7.78 Hz, 1 N) 7.27-7.33 (m, 1 N) 7.29 (br.s, 1 N) 7.46 (t , J=2.64 Hz, 1 H) 7.55 (d, J=8.03 Hz, 1 H) 8.11 (d, J=7.28 Hz, 1 H) 11.27 (br.s , 1 H).

Example 4: Connection WX04

Synthesis scheme:

Step 1: Synthesis of compound WX04-1

To a solution of compound G1 (0.3 g, 69 7.77 µmol) in 1,4-dioxane (5 ml) was added 1-methylpyrazole-5-pinacol borate (188.74 mg, 907.10 µmol), bistriphenylphosphine palladium dichloride (48.98 mg, 69.78 µmol) and sodium carbonate (2 M, 1.05 ml). The reaction mixture was stirred at 90° C. under nitrogen protection for 15 hours. The reaction mixture was filtered through celite and the filtrate was extracted with 60 ml of ethyl acetate (20 ml×3). The organic phase was washed with 45 ml of water (15 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 3:1) to give compound WX04-1.

MS-ESI m/h: 476.1 [M+H] ⁺ .

Step 2: Synthesis of compound WX04-2

To a solution of compound WX04-1 (0.205 g, 431.05 µmol) in dichloromethane (5 ml) was added m-chloroperoxybenzoic acid (87.51 mg, 431.05 µmol). The reaction mixture was stirred at 20° C. for 15 hours. The reaction mixture was quenched at 20° C. with 20 ml of saturated sodium sulfite solution and then extracted with 40 ml of dichloromethane (20 ml ×2). The organic phase was washed with 45 ml of water (15 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give crude WX04-2.

MS-ESI m/h: 492.0 [M+H] ⁺ .

Step 3: Synthesis of compound WX04-3

Diisopropylethylamine (562 .36 mg, 4.35 mmol). The reaction mixture was stirred at 100° C. for 65 hours. The reaction mixture was extracted with 60 ml of ethyl acetate (20 ml×3) and the organic phase was washed with 60 ml of water (20 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give crude WX04-3.

MS-ESI m/z: 529.1 [M+H] ⁺ .

Step 4: Synthesis of compound WX04

To a solution of compound WX04-3 (0.35 g, 662.10 µmol) in methanol (5 ml) was added sodium hydroxide (2 M, 993, 14 µl). The reaction mixture was stirred at 60° C. for 17 hours. The reaction mixture was extracted with 40 ml of ethyl acetate (20 ml×2) and the organic phase was washed with 60 ml of water (20 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by preparative HPLC (neutral) to give compound WX04.

MS-ESI m/z: 375.0 [M+H]+

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (d, J=6.78 Hz, 3 H) 3.44 (td, J=12.99, 3.89 Hz, 1 H) 3 .65 (td, J=11.86, 2.89 Hz, 1 N) 3.77-3.83 (m, 1 N) 3.84-3.89 (m, 1 N) 4.07 (dd , J=11.29, 3.51 Hz, 1 N) 4.35 (s, 3 N) 4.54 (br.d, J=13.80 Hz, 1 N) 4.90 (br.d, J=4.02 Hz, 1 N) 6.78 (d, J=2.01 Hz, 1 N) 7.16 (br.s, 1 N) 7.30-7.35 (m, 1 N) 7.35-7.38 (m, 2 N) 7.52-7.57 (m, 2 N) 7.69 (d, J=7.53 Hz, 1 N) 8.35 (br. s, 1 N)

Example 5: Connection WX05

Synthesis scheme:

Step 1: Synthesis of compound WX05-1

Other than using the appropriate starting materials, the procedure for preparing WX05-1 is identical to that used for compound WX04-1 in Synthesis Example 4.

MS-ESI m/h: 490.1 [M+H]+.

Step 2: Synthesis of compound WX05-2

To a solution of compound WX05-1 (0.193 g, 394.19 µmol) in dichloromethane (5 ml) was added m-chloroperoxybenzoic acid (80.03 mg, 394.19 µmol). The reaction mixture was stirred at 20° C. for 15 hours. The reaction mixture was quenched by adding saturated sodium sulfite solution at 20° C. and extracted with 40 ml dichloromethane (20 ml×2). The organic phase was washed with 45 ml of water (15 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give crude WX05-2.

MS-ESI m/h: 522.1 [M+H]+.

Step 3: Synthesis of compound WX05-3

Other than using the appropriate starting materials, the procedure for obtaining crude WX05-3 is identical to that used for compound WX04-3 in Synthesis Example 4.

MS-ESI m/h: 543.1 [M+H]+.

Step 4: Synthesis of compound WX05

Other than using the appropriate starting materials, the procedure for preparing Compound WX05 is identical to that used for Compound WX04 in Synthesis Example 4.

MS-ESI m/h: 389.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (d, J=6.78 Hz, 3H) 2.29 (s, 3H) 3.43 (td, J=12.86, 3.39 Hz, 1 N) 3.59-3.69 (m, 1 N) 3.75-3.81 (m, 1 N) 3.83-3.88 (m, 1 N) 4.06 (br.dd, J=11.04, 3.26 Hz, 1 N) 4.17 (br.s, 1 N) 4.15 (s, 2 N) 4.56 (br.d, J=12 .05 Hz, 1 N) 4.92 (br.d, J=5.02 Hz, 1 N) 7.17 (br. s, 1 N) 7.20 (s, 1 N) 7.29-7 .35 (m, 1 N) 7.37 (br.s, 1 N) 7.40 (s, 1 N) 7.55 (d, J=8.03 Hz, 1 N) 7.68 (d, J=7.28 Hz, 1 N) 8.42 (br.s, 1 N).

Example 6: Connection WX06

Synthesis scheme:

Step 1: Synthesis of compound WX06-1

To a solution of compound H1 (200.46 mg, 465.18 µmol) in 1,4-dioxane (5 ml) was added 1-methylpyrazole-5-pinacol borate (125.82 mg, 604.73 µmol), bistriphenylphosphine palladium dichloride ( 16.3 3 mg, 23.26 µmol) and sodium carbonate (2M, 697.77 µl). The reaction mixture was stirred under nitrogen protection at 90° C. for 15 h. Then the reaction mixture was filtered through celite, the filtrate was extracted with 60 ml of ethyl acetate (20 ml × 3) and the organic phase was washed with 45 ml of water (15 ml × 3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 3:1) to give compound WX06-1.

MS-ESI m/h: 477.0 [M+H] ⁺ .

Step 2: Synthesis of compound WX06-2

To a solution of compound WX06-1 (0.21 g, 440.65 µmol) in dichloromethane (5 ml) was added m-chloroperoxybenzoic acid (89.46 mg, 440.65 µmol). The reaction mixture was stirred at 20° C. for 15 hours. The reaction mixture was quenched with 20 ml of saturated sodium sulfite solution at 20° C. and then extracted with 40 ml of dichloromethane (20 ml ×2). The organic phase was washed with 45 ml of water (15 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give crude WX06-2.

MS-ESI m/h: 493.0 [M+H]+.

Step 3: Synthesis of compound WX06-3

Diisopropylethylamine (594 .17 mg, 4.60 mmol). The reaction mixture was stirred at 100° C. for 65 hours. The reaction mixture was extracted with 60 ml of ethyl acetate (20 ml×3) and the organic phase was washed with 30 ml of water (10 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give crude WX06-3.

MS-ESI m/h: 530.1 [M+H] ⁺ .

Step 4: Synthesis of Compound WX06

To a solution of compound WX06-3 (0.330 g, 623.10 µmol) in methanol (5 ml) was added sodium hydroxide (2 M, 934.65 µl). The reaction mixture was stirred at 60° C. for 17 hours. The reaction mixture was extracted with 60 ml of ethyl acetate (20 ml×3) and the organic phase was washed with 45 ml of water (15 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by preparative HPLC (neutral) to give compound WX06.

MS-ESI m/h: 376.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (br.d, J=6.78 Hz, 3 H) 3.37-3.53 (m, 1 H) 3.60-3, 71 (m, 1 N) 3.78-3.84 (m, 1 N) 3.84-3.91 (m, 1 N) 4.09 (br. d, J=9.04 Hz, 1 N ) 4.35 (s, 3 N) 4.54 (br.d, J=13.30 Hz, 1 N) 5.04 (s, 1 N) 4.88 (br.d, J=4.52 Hz, 1 N) 6.75-6.88 (m, 1 N) 6.81 (s, 1 N) 6.98-7.13 (m, 1 N) 7.06 (br.s, 1 N ) 7.40 (s, 1 N) 7.50 (br. s, 1 N) 7.56 (s, 1 N) 7.62 (br. d, J=5.02 Hz, 1 N) 8, 47 (br. d, J=4.77 Hz, 1 N) 9.84 (br. s, 1 N).

Example 7: Connection WX07

Synthesis scheme:

Step 1: Synthesis of compound WX07-1

Other than using the appropriate starting materials, the procedure for preparing WX07-1 is identical to that used for compound WX06-1 in Synthesis Example 6.

MS-ESI m/h: 491.1 [M+H] ⁺ .

Step 2: Synthesis of compound WX07-2

Other than using the appropriate starting materials, the procedure for preparing crude WX07-2 is identical to that used for compound WX06-2 in Synthesis Example 6.

MS-ESI m/z: 507.1 [M+H] ⁺ .

Step 3: Synthesis of compound WX07-3

Other than using the appropriate starting materials, the procedure for preparing crude WX07-3 is identical to that used for compound WX06-3 in Synthesis Example 6.

MS-ESI m/h: 544.2 [M+H] ⁺ .

Step 4: Synthesis of compound WX07

Other than using the appropriate starting materials, the procedure for preparing Compound WX07 is identical to that used for Compound WX06 in Synthesis Example 6.

MS-ESI m/h: 390.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (d, J=6.78 Hz, 3 H) 2.31 (s, 3 H) 3.44 (td, J=12.86, 3.64 Hz, 1 N) 3.64 (td, J=11.92, 3.01 Hz, 1 H) 3.77-3.82 (m, 1 N) 3.84-3.89 (m , 1 N) 4.07 (dd, J=11.54, 3.51 Hz, 1 N) 4.16 (s, 3 N) 4.55 (br.d, J=13.30 Hz, 1 N ) 4.90 (br.d, J=4.77 Hz, 1 H) 7.06 (br. s, 1 H) 7.24 (s, 1 H) 7.41 (s, 1 H) 7, 48 (br. s, 1 N) 7.59-7.66 (m, 1 N) 8.46 (br. s, 1 N) 9.09 (br. s, 1 N).

Example 8: Connection WX08

Synthesis scheme:

Step 1: Synthesis of compound WX08-1

Other than using the appropriate starting materials, the procedure for preparing WX08-1 is identical to that used for compound WX06-1 in Synthesis Example 6.

MS-ESI m/h: 491.3 [M+H] ⁺ .

Step 2: Synthesis of compound WX08-2

Other than using the appropriate starting materials, the procedure for preparing crude WX08-2 is identical to that used for compound WX06-2 in Synthesis Example 6.

MS-ESI m/z: 507.1 [M+H] ⁺ .

Step 3: Synthesis of compound WX08-3

Other than using the appropriate starting materials, the procedure for preparing crude WX08-3 is identical to that used for compound WX06-3 in Synthesis Example 6.

MS-ESI m/h: 544.2 [M+H] ⁺ .

Step 4: Synthesis of compound WX08

Other than using the appropriate starting materials, the procedure for preparing Compound WX08 is identical to that used for Compound WX06 in Synthesis Example 6.

MS-ESI m/h: 390.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (br. s, 3 H) 1.39 (br. s, 3 H) 3.32 (br. s, 1 H) 3.51 ( br.d, J=11.04 Hz, 1 N) 3.59-3.81 (m, 1 N) 3.71 (br. d, J=16.56 Hz, 1 N) 3.95 (br. .d, J=9.79 Hz, 1 N) 4.39 (br.d, J=11.80 Hz, 1 N) 4.72 (br.s, 3 N) 6.66 (br.s, 1 N) 6.93 (br. s, 1 N) 7.13 (br. s, 1 N) 7.32-7.74 (m, 3 N) 8.35 (br. s, 1 N) 9 .83 (br. s, 1 N).

Example 9: Connection WX09

Synthesis scheme:

Step 1: Synthesis of compound WX09-1

To a solution of compound II (0.1 g, 340.43 µmol) in 1,4-dioxane (5 ml) was added 1-methylpyrazole-5-pinacol borate (92.08 mg, 442.56 µmol), bistriphenylphosphine palladium dichloride ( 11.95 mg, 17.02 µmol) and sodium carbonate (2M, 510.64 µl). The reaction mixture was stirred under nitrogen protection at 90° C. for 15 hours. Then the reaction mixture was filtered through celite, the filtrate was extracted with 60 ml of ethyl acetate (20 ml ×3). The organic phase was washed with 45 ml of water (15 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified on a silica gel column (petroleum ether/ethyl acetate=1:0, 3:1) to give compound WX09-1.

MS-ESI m/h: 340.0 [M+H] ⁺ .

Step 2: Synthesis of compound WX09-2

To a solution of compound WX09-1 (102 mg, 300.54 µmol) in dichloromethane (5 ml) was added m-chloroperoxybenzoic acid (61.02 mg, 300.54 µmol). The reaction mixture was stirred at 20° C. for 15 hours. The reaction mixture was quenched with 20 ml of saturated sodium sulfite solution at 20° C. and then extracted with 40 ml of dichloromethane (20 ml ×2). The organic phase was washed with 45 ml of water (15 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to obtain crude WX09-2.

MS-ESI m/z: 356.0 [M+H] ⁺ .

Step 3: Synthesis of compound WX09

Diisopropylethylamine (749.14 mg, 5.80 mmol). The reaction mixture was stirred at 100° C. for 65 hours. The reaction mixture was extracted with 60 ml of dichloromethane (20 ml×3). The organic phase was washed with 30 ml of water (10 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by preparative HPLC (neutral) to give compound WX09.

MS-ESI m/h: 393.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (d, J=6.78 Hz, 3 H) 3.44 (td, J=12.86, 3.64 Hz, 1 H) 3 .65 (td, J=11.80, 2.76 Hz, 1 N) 3.77-3.83 (m, 1 N) 3.84-3.89 (m, 1 N) 4.07 (dd , J=11.29, 3.51 Hz, 1 N) 4.35 (s, 3 N) 4.53 (br.d, J=11.80 Hz, 1 N) 4.88 (br.d, J=6.53 Hz, 1 H) 6.79 (d, J=1.76 Hz, 1 H) 7.08 (br.s, 1 H) 7.23 (br. d, J=8.78 Hz, 1 N) 7.32-7.36 (m, 2 N) 7. 45-7.50 (m, 1 N) 7.48 (dd, J=10.67, 2.13 Hz, 1 N ) 7.55 (d, J=2.01 Hz, 1 H) 8.36 (br. s, 1 H).

Example 10: WX10 connection

Synthesis scheme:

Step 1: Synthesis of Compound WX10-1

Other than using the appropriate starting materials, the procedure for preparing WX10-1 is identical to that used for compound WK09-1 in Synthesis Example 9.

MS-ESI m/z: 353.9 [M+N] ⁺

Step 2: Synthesis of compound IH10-2

Other than using the appropriate starting materials, the procedure for preparing crude WX10-2 is identical to that used for compound HX09-2 in Synthesis Example 9.

MS-ESI m/s: 3 7 0.0 [M+H] ⁺ .

Step 3: Synthesis of compound IH10

Other than using the appropriate starting materials, the procedure for preparing Compound WX10 is identical to that used for Compound WX09 in Synthesis Example 9.

MS-ESI m/h: 407.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (d, J=6.78 Hz, 3 H) 2.30 (s, 3 H) 3.43 (td, J=12.86, 3.64 Hz, 1 N) 3.61-3.69 (m, 1 N) 3.76-3.81 (m, 1 N) 3.83-3.88 (m, 1 N) 4.06 (dd, J=11.17, 3.39 Hz, 1 H) 4.15 (s, 3 H) 4.55 (br.d, J=12.30 Hz, 1 H) 4.91 (br. d, J=4.52 Hz, 1 N) 7.08 (br.s, 1 N) 7.16 (s, 1 N) 7.23 (dd, J=8.78, 1.51 Hz, 1 H) 7.34 (t, J=2.76 Hz, 1 H) 7.40 (s, 1 H) 7.48 (dd, J=10.54, 2.26 Hz, 1 H) 8.50 (br.s, 1 N).

Example 11: WX11 Connection

Synthesis scheme:

Step 1: Synthesis of Compound WX11-1

Other than using the appropriate starting materials, the procedure for preparing WX11-1 is identical to that used for compound WX09-1 in Synthesis Example 9.

MS-ESI m/h: 354.0 [M+H] ⁺ .

Step 2: Synthesis of Compound WX11-2

Other than using the appropriate starting materials, the procedure for obtaining crude WX11-2 is identical to the procedure used for compound WX09-2 in Synthesis Example 9.

MS-ESI m/h: 370.0 [M+H] ⁺ .

Step 3: Synthesis of Compound WX11

Other than using the appropriate starting materials, the procedure for preparing Compound WX11 is identical to that used for Compound WX09 in Synthesis Example 9.

MS-ESI m/h: 407.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (d, J=6.78 Hz, 3 H) 1.52 (t, J=7.15 Hz, 3 H) 3, 40-3 , 48 (m, 1 N) 3.64-3.69 (m, 1 N) 3.77-3.82 (m, 1 N) 3.83-3.89 (m, 1 N) 4.04 -4.10 (m, 1 N) 4.53 (br.l, J=13.05 Hz, 1 N) 4.73-4.90 (m, 3 N) 6.77 (d, J=1 .76 Hz, 1 N) 7.08 (br. s, 1 N) 7.23 (br. d, J=8.78 Hz, 1 N) 7.33 (s, 2 N) 7.48 (dd , J=10.67, 1.88 Hz, 1 H) 7.57 (d, J=1.51 Hz, 1 H) 8.42 (br.s, 1 H).

Example 12: WX12 connection

Synthesis scheme:

Step 1: Synthesis of compound WX12-1

Other than using the appropriate starting materials, the procedure for preparing WX12-1 is identical to that used for compound WX04-1 in Synthesis Example 4.

MS-ESI m/h: 490.1 [M+H] ⁺ .

Step 2: Synthesis of the WX12-2 Compound

Other than using the appropriate starting materials, the procedure for obtaining crude yellow WX12-2 is identical to that used for the WX04-2 compound in Synthesis Example 4.

MS-ESI m/h: 522.1 [M+H] ⁺ .

Step 3: Synthesis of compound WX12-3

Other than using the appropriate starting materials, the procedure for preparing crude WX12-3 is identical to that used for compound WX04-3 in Synthesis Example 4.

MS-ESI m/h: 543.1 [M+H] ⁺ .

Step 4: Synthesis of the WX12 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX12 is identical to that used for Compound WX04 in Synthesis Example 4.

MS-ESI m/h: 389.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.45 (m, 1 H) 1.43 (d, J=6.78 Hz, 2 H) 1.53 (t, J= 7.15 Hz, 3 N) 3.45 (td, J=12.92, 3.51 Hz, 1 N) 3.66 (td, J=11.73, 2.64 Hz, 1 N) 3, 77-3.83 (m, 1 N) 3.84-3.89 (m, 1 N) 4.07 (br.dd, J=11.29, 3.01 Hz, 1 N) 4.55 ( br.d, J=13.55 Hz, 1 N) 4.74-4.86 (m, 2 N) 4.88 (br. d, J=7.03 Hz, 1 N) 6.76 (d , J=1.51 Hz, 1 N) 7.16 (br. s, 1 N) 7.30-7.35 (m, 1 N) 7.37 (s, 2 N) 7.52-7, 58 (m, 2 H) 7.69 (d, J=7.28 Hz, 1 H) 8.41 (br. s, 1 H).

Example 13: Connection WX13

Synthesis scheme:

Step 1: Synthesis of compound WX13

To a solution of compound D1 (0.075 g, 228.11 µmol) in 1,4-dioxane (5 mL) was added 1,4-dimethylpyrazole-5-pinacol borate (75.99 mg, 342.17 µmol), bistriphenylphosphine palladium dichloride ( 8.01 mg, 11.41 µmol) and sodium carbonate (2 M, 342.17 µl). The reaction mixture was stirred under nitrogen protection at 90° C. for 15 h. Then the reaction mixture was filtered through celite, the filtrate was extracted with 30 ml of ethyl acetate (10 ml × 3) and the organic phase was washed with 30 ml of water (10 ml × 3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by preparative HPLC (neutral) to give compound WX13.

MS-ESI m/h: 389.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (d, J=6.78 Hz, 3 H) 2.25 (s, 3 H) 3f43 (td, J=12.74, 3, 89 Hz, 1 N) 3.69 (td, J=11.92, 3.01 Hz, 1 N) 3.80-3.85 (m, 1 N) 3.87-3.92 (m, 1 N) 4.12 (dd, J=11.29, 3.51 Hz, 1 N) 4.15-4.20 (m, 1 N) 4.16 (s, 2 N) 4.34 (s, 1 N) 4.27 (br. d, J=13.30 Hz, 1 N) 4.51 (br. d, J=4.02 Hz, 1 N) 6.41-6.56 (m, 1 N) 6.47 (s, 1 N) 7.29-7.36 (m, 1 N) 7.33-7.35 (m, 1 N) 7.41 (s, 1 N) 7.50- 7.58 (m, 1 H) 7.52-7.56 (m, 1 H) 8.25-8.37 (m, 2 H).

Example 14: Connection WX14

Synthesis scheme:

Step 1: Synthesis of compound WX14

To a solution of compound D1 (0.075 g, 228.11 µmol) in 1,4-dioxane (5 ml) was added 1-ethylpyrazole-5-pinacol borate (75.99 mg, 342.17 µmol), bistriphenylphosphine palladium dichloride (8, 01 mg, 11.41 µmol) and sodium carbonate (2 M, 342, 17 µl). The reaction mixture was stirred under nitrogen protection at 90° C. for 15 h. Then the reaction mixture was filtered through celite, the filtrate was extracted with 30 ml of ethyl acetate (10 ml × 3) and the organic phase was washed with 30 ml of water (10 ml × 3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by preparative HPLC (neutral) to give compound WX14.

MS-ESI m/z: 389.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (d, J=6.78 Hz, 3 H) 1.51 (t, J=7.15 Hz, 3 H) 3.44 (td , J=12, 74, 3, 89 Hz, 1 N) 3.68 (td, J=11.92, 3.01 Hz, 1 N) 3, 79-3, 86 (m, 1 N) 3, 87-3, 92 (m, 1 N) 4.11 (dd, J=11.42, 3.64 Hz, 1 N) 4.23 (br. d, J=13.05 Hz, 1 N) 4 .58 (br.d, J=4.77 Hz, 1 H) 4.86 (c, J=7.03 Hz, 2 H) 6.63 (s, 1 H) 6.65 (d, J= 2.01 Hz, 1 N) 7.30-7.36 (m, 2 N) 7.50 (br.s, 1 N) 7.54 (d, J=8.03 Hz, 1 N) 7, 57 (d, J=1.76 Hz, 1 H) 8.26 (d, J=7.53 Hz, 1 H) 8.35 (br. s, 1 H).

Example 15: Connection WX15

Synthesis scheme:

Step 1: Synthesis of Compound WX15-1

To a solution of compound E1 (0.05 g, 103.31 µmol) in 1,4-dioxane (5 ml) was added 1-methylpyrazole-5-pinacol borate (25.79 mg, 123.97 µmol), bistriphenylphosphine palladium dichloride ( 7.25 mg, 10.33 µmol) and sodium carbonate (2 M, 154, 97 µl). The reaction mixture was stirred under nitrogen protection at 90° C. for 15 h. Then the reaction mixture was filtered through celite, the filtrate was extracted with 30 ml of ethyl acetate (10 ml × 3) and the organic phase was washed with 45 ml of water (15 ml × 3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give crude WX15-1.

MS-ESI m/h: 530.2 [M+H] ⁺ .

Step 2: Synthesis of Compound WX15

To a solution of compound WX15-1 (103 mg, 194.48 µmol) in methanol (2 ml) was added sodium hydroxide (2 M, 291.72 µl). The reaction mixture was stirred at 60° C. for 15 hours. The reaction mixture was extracted with 60 ml of ethyl acetate (20 ml×3) and the organic phase was washed with 60 ml of water (20 ml×3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by preparative HPLC (neutral) to give compound WX15.

MS-ESI m/h: 376.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (d, J=6.78 Hz, 3 H) 3.45 (td, J=12.74, 3.89 Hz, 1 H) 3 .68 (td, J=11.92, 3.01 Hz, 1 N) 3.80-3.85 (m, 1 N) 3.88-3.94 (m, 1 N) 4.13 (dd , J=11.29, 3.51 Hz, 1 N) 4.22 (br.d, J=13.05 Hz, 1 N) 4.38 (s, 3 H) 4.58 (br.d, J=4.77 Hz, 1 N) 6.66-6.71 (m, 2 N) 7.37 (d, J=1.51 Hz, 1 N) 7.45-7.50 (m, 1 N) 7.56 (d, J=2.01 Hz, 1 N) 8.13 (d, J=5.02 Hz, 1 N) 8.47 (d, J=5.02 Hz, 1 N) 9.74 (br. s, 1 H).

Example 16: Connection 17X16

Synthesis scheme:

Step 1: Synthesis of Compound WX16-1

Other than using the appropriate starting materials, the procedure for preparing crude WX16-1 is identical to that used for compound WX15-1 in Synthesis Example 15.

MS-ESI m/h: 544.1 [M+H] ⁺ .

Step 2: Synthesis of compound WX16

Except for using the appropriate starting materials, the procedure for preparing Compound WX16 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/z: 390.0 [M+N] ⁺

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (d, J=6.78 Hz, 3 H) 2.34 (s, 3 H) 3.44 (td, J=12.61, 3.89 Hz, 1 N) 3.67 (td, J=11.80, 3.01 Hz, 1 N) 3.78-3.85 (m, 1 N) 3.87-3.93 (m , 1 N) 4.12 (dd, J=11, 29, 3, 76 Hz, 1 N) 4.21 (br.d, J=12.80 Hz, 1 N) 4.30 (s, 3 N ) 4.56 (br.d, J=4.52 Hz, 1 N) 6.47 (s, 1 N) 6.66 (s, 1 N) 7.3

Example 17: Connection WX17

Step 1: Synthesis of Compound WX17-1

Other than using the appropriate starting materials, the procedure for obtaining crude WX17-1 is identical to that used for compound WX15-1 in Synthesis Example 15.

MS-ESI m/h: 544.1 [M+H] ⁺ .

Step 2: Synthesis of Compound WX17

Other than using the appropriate starting materials, the procedure for preparing Compound WX17 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/h: 390.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (d, J=6.78 Hz, 3 H) 2.25 (s, 3 H) 3.45 (td, J=12, 80, 3, 76 Hz, 1 N) 3.69 (td, J=11.92, 2.76 Hz, 1 N) 3.80-3.86 (m, 1 N) 3.88-3.93 (m , 1 N) 4.11-4.17 (m, 4 N) 4.26 (br.d, J=12.80 Hz, 1 N) 4.50 (br. s, 1 N) 6.54 ( s, 1 N) 7, 38-7, 44 (m, 2 N) 7.46 (br. s, 1 N) 8.15 (br. d, J=3.51 Hz, 1 N) 8.46 (br.s, 1 N) 9.67 (br.s, 1 N).

Example 18: Connection WX18

Synthesis scheme:

Step 1: Synthesis of Compound WX18-1

Other than using the appropriate starting materials, the procedure for obtaining crude WX18-1 as a white solid is identical to that used for the WX15-1 compound in Synthesis Example 15.

MS-ESI m/h: 544.2 [M+H] ⁺ .

Step 2: Synthesis of Compound WX18

Except for using the appropriate starting materials, the procedure for preparing Compound WX18 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/h: 390.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (br.d, J=6.53 Hz, 3 H) 1.51 (br. d, J=6.90 Hz, 3 H) 3 .42-3.55 (m, 1 N) 3.68 (br. t, J=11.67 Hz, 1 N) 3.75-3.86 (m, 1 N) 3.89-3.97 (m, 1 N) 4.11-4.22 (m, 2 N) 4.54 (br.s, 1 N) 4.69-4.82 (m, 2 N) 6.70 (s, 1 N) 6.78 (br.s, 1 N) 7.51-7.60 (m, 1 N) 7.60-7.70 (m, 2 N) 8.38 (br. d, J=18 .32 Hz, 2 N) 12.42 (br.s, 1 N).

Example 19: Connection WX19

Synthesis scheme:

Step 1: Synthesis of Compound WX19

To a solution of compound F1 (50 mg, 144.18 µmol) in 1,4-dioxane (5 ml) was added 1-methylpyrazole-5-pinacol borate (36.00 mg, 173.02 µmol), bistriphenylphosphine palladium dichloride (10, 12 mg, 14.42 µmol) and sodium carbonate (2M, 216.27 µl). The reaction mixture was stirred under nitrogen protection at 9° C. for 15 h. Then the reaction mixture was filtered through celite, the filtrate was extracted with 30 ml of ethyl acetate (10 ml × 3) and the organic phase was washed with 45 ml of water (15 ml × 3) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by preparative EELC (neutral) to give compound WX19.

MS-ESI m/h: 393.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (d, J=6.78 Hz, 3 H) 3.43 (td, J=12.61, 3.89 Hz, 1 H) 3 .67 (td, J=11.80, 2.76 Hz, 1 N) 3.79-3.84 (m, 1 N) 3.87-3.92 (m, 1 N) 4.11 (dd , J=11.54, 3.51 Hz, 1 N) 4.22 (br.d, J=13.05 Hz, 1 N) 4.36 (s, 3 N) 4.56 (br. s, 1 N) 6.64 (s, 1 N) 6.62-6.65 (m, 1 N) 6.67 (d, J=l.76 Hz, 1 N) 7.23 (br. d, J =7.78 Hz, 1 N) 7.32 (br. s, 1 N) 7.48 (br. s, 1 N) 7.55 (d, J=l.76 Hz, 1 N) 8.03 (dd, J=11.17, 1.88 Hz, 1 H) 8.34 (br.s, 1 H).

Example 20: WX20 connection

Synthesis scheme:

Step 1: Synthesis of the WX20 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX20 is identical to that used for Compound WX19 in Synthesis Example 19.

MS-ESI m/h: 407.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (d, J=6.78 Hz, 3 H) 2.34 (s, 3 H) 3.42 (td, J=12.74, 3.64 Hz, 1 N) 3.66 (td, J=11.80, 2.76 Hz, 1 N) 3.78-3.83 (m, 1 N) 3.86-3.92 (m , 1 N) 4.11 (br. dd, J=11.42, 3.39 Hz, 1 N) 4.21 (br. d, J=13.30 Hz, 1 N) 4.28 (s, 3 N) 4.55 (br.d, J=5.02 Hz, 1 N) 6.46 (s, 1 N) 6.61 (s, 1 N) 7.21 (br. d, J=7 .53 Hz, 1 N) 7.31 (br. s, 1 N) 7.48 (br. s, 1 N) 8.02 (dd, J=11.17, 1.63 Hz, 1 N) 8 .41 (br. s, 1 N).

Example 21: Connection WX21

Synthesis scheme:

Stage 1: Synthesis of compound WX21

Except for using the appropriate starting materials, the procedure for preparing Compound WX21 is identical to that used for Compound WX19 in Synthesis Example 19.

MS-ESI m/h: 407.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.78 Hz, 3 H) 2.10 (s, 3 H) 3.28 (td, J=12.74, 3.64 Hz, 1 N) 3.54 (td, J=11.86, 2.64 Hz, 1 N) 3.66-3.71 (m, 1 N) 3.73-3.77 (m , 1 N) 3.95-4.01 (m, 4 N) 4.11 (br.d, J=12.30 Hz, 1 N) 4.34 (br. s, 1 N) 6.34 ( s, 1 N) 7.05-7.16 (m, 2 N) 7.36 (br. s, 1 N) 7.90 (br. d, J=10.54 Hz, 1 N) 8.35 (br.s, 1 N).

Example 22: WX22 connection

Synthesis scheme:

Step 1: Synthesis of the WX22 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX22 is identical to that used for Compound WX19 in Synthesis Example 19.

MS-ESI m/z: 407.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (d, J=6.78 Hz, 3 H) 1.52 (t, J=7.15 Hz, 3 H) 3.43 (td , J=12.80, 3.76 Hz, 1 N) 3.67 (td, J=11.92, 2.76 Hz, 1 N) 3.78-3.84 (m, 1 N) 3, 87-3.92 (m, 1 N) 4.11 (dd, J=11.54, 3.51 Hz, 1 N) 4.21 (br.l, J=13.05 Hz, 1 N) 4 .56 (br.d, J=5.02 Hz, 1 N) 4.83 (c, J=7.03 Hz, 2 N) 6.62-6.66 (m, 2 N) 7.22 ( dd, J=8, 66, 1, 88 Hz, 1 H) 7.31 (t, J=2.64 Hz, 1 H) 7.46 (br.s, 1 H) 7.57 (d, J =l.76 Hz, 1 N) 8.01 (dd, J=11.42, 2.13 Hz, 1 N) 8.49 (br.s, 1 N).

Example 23: Connection WX23

Synthesis scheme:

Step 1: Synthesis of compound WX23-1

At room temperature, to a solution of compound E1 (0.16 g, 330.60 µmol) in 1,4-dioxane (2.00 ml) was added 3,5-dimethylpyrazole-4-boric acid pinacol ester (110.13 mg, 495 .90 µmol), dipalladium tris(dibenzylacetone) (30.27 mg, 33.06 µmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38.26 mg, 66.12 µmol), potassium phosphate (210.53 mg, 991.80 µmol) and water (0.2 ml) and stirred at 120° C. in the microwave for 20 minutes. The reaction system was cooled and then diluted with ethyl acetate (50 ml). The organic phase was washed with water (30 ml) and brine (30 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=4/1.2/1) to give compound WX23-1.

MS m/s: 544.1 [M+H] ⁺ .

Step 2: Synthesis of the WX23 Compound

At room temperature, to a solution of compound WX23-1 (0.045 g, 82.78 µmol) in methanol (10.00 ml) was added sodium hydroxide solution (2 M, 206.94 µl) and stirred at 30°C for 16 h. The reaction system was concentrated under reduced pressure at 45° C. to give a mixture which was dissolved with ethyl acetate (30 ml), washed with water (20 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (dichloromethane/methanol=100/1.10/1) to give compound WX23.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 ppm 1.30 (br.d, J=7.03 Hz, 3 H) 2.43-2.45 (m, 6 H) 3.37-3 .42 (m, 1 N) 3.51-3.62 (m, 1 N) 3.71 (br.d, J=11.54 Hz, 1 N) 3.82 (br.d, J=11 .54 Hz, 1 N) 4.03 (br.d, J=10.04 Hz, 1 N) 4.21 (br.d, J=12.55 Hz, 1 N) 4.60 (br. s , 1 N) 6.67 (s, 1 N) 7.24 (br. s, 1 N) 7.58 (br. s, 1 N) 8.02 (d, J=4.77 Hz, 1 N ) 8.34 (d, J=5.02 Hz, 1 N) 11.77 (br. s, 1 N) 12.54 (br. s, 1 N).

MS m/s: 390.0 [M+H] ⁺ .

Example 24: WX24 connection

Synthesis scheme:

Step 1: Synthesis of the WX24-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for WX23-1 in Example 23 to give a crude product which was purified by column chromatography (petroleum ether:ethyl acetate=2/1.1/2) to give WX24-1.

MS m/s: 558.1 [M+H] ⁺ .

Step 2: Synthesis of the WX24 Compound

At room temperature, to a solution of compound WX24-1 (0.105 g, 188.28 µmol) in methanol (10.00 ml) was added sodium hydroxide solution (2 M, 941.42 µl), which was stirred at 30°C for 15 h The reaction system was concentrated under reduced pressure at 45° C. to give a mixture which was dissolved in dichloromethane (30 ml), washed with water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (dichloromethane/methanol=100/1.12/1) to give compound WX24.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (d, J=6.53 Hz, 3 H) 2.36 (s, 3 H) 2.51 (br. s, 3 H) 3.30 (br.s, 1 N) 3.50-3.57 (m, 1 N) 3.68 (br. d, J=8.53 Hz, 1 N) 3.73 (s, 3 N ) 3.77-3.84 (m, 1 N) 4.01 (br.d, J=8.53 Hz, 1 N) 4.20 (br. d, J=11.29 Hz, 1 N) 4.55 (br.s, 1 H) 6.63 (s, 1 H) 7.22 (dd, J=3.26, 2.01 Hz, 1 H) 7.56 (t, J=2, 89 Hz, 1 N) 7.99 (d, J=5.02 Hz, 1 N) 8.32 (d, J=5.02 Hz, 1 N) 11.75 (br.s, 1 N).

MS m/s: 404.0 [M+H] ⁺ .

Example 25: Connection WK25

Synthesis scheme:

Step 1: Synthesis of the WX25-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX23-1 in Example 23, whereby a crude product was obtained, which was purified by column chromatography (petroleum ether:ethyl acetate=2/1.1/2) to give compound WX25-1.

MS m/z: 544.1[M+H] ⁺

Step 2: Synthesis of the WX25 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX23 in Example 23, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=100/1.10/1) to give compound WX25.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (d, J=6.78 Hz, 3 H) 2.55 (s, 3 H) 3.20-3.27 (m, 1 N) 3.49-3.58 (m, 1 N) 3.68 (dd, (J=11.29, 2.76 Hz, 1 N) 3.78-3.85 (m, 4 N) 4 .01 (br.d, J=8.28 Hz, 1 N) 4.18 (br.d, J=13.80 Hz, 1 N) 4.60 (br. s, 1 N) 6.85 ( s, 1 H) 7.23 (dd, J=3.26, 2.01 Hz, 1 H) 7.57 (t, J=2.89 Hz, 1 H) 8.02 (d, J=5 .02 Hz, 1 N) 8.32 (d, J=5.02 Hz, 1 N) 8.40 (s, 1 N) 11.75 (br. s, 1 N).

MS m/s: 390.0 [M+H] ⁺ .

Example 26: Connection WX26

Synthesis scheme:

Step 1: Synthesis of the WX26-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX23-1 in Example 23, whereby a crude product was obtained, which was purified by column chromatography (petroleum ether:ethyl acetate=2/1.1/2) to give compound WX26-1.

MS m/z: 544.2 [M+H] ⁺ .

Stage 2: Synthesis of compound WX26

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX23 in Example 23, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=100/1.12/1) to give compound WX26.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (d, J=6.78 Hz, 3 H) 2.74 (s, 3 H) 3.22-3.28 (m, 1 N) 3.48-3.57 (m, 1 N) 3.68 (dd, J=11.54, 2.76 Hz, 1 N) 3.78-3.84 (m, 4 N) 3, 96-4.04 (m, 1 N) 4.21 (br.l, J=12.55 Hz, 1 N) 4.65 (br. s, 1 N) 6.92 (s, 1 N) 7 .21 (dd, J=3.26, 2.01 Hz, 1 H) 7.55-7.59 (m, 1 H) 7.98 (d, J=5.02 Hz, 1 H) 8, 11 (s, 1 H) 8.33 (d, J=5.02 Hz, 1 H) 11.76 (br. s, 1 H).

MS m/s: 390.1 [M+H] ⁺ .

Example 27: Connection WX27

Synthesis scheme:

Step 1: Synthesis of compound IH.27-1

Other than using the appropriate starting materials, the procedure is identical to that used for WK23-1 in Example 23, whereby a crude product was obtained, which was purified by column chromatography (petroleum ether:ethyl acetate=4/1.2/1) to give WX27-1.

MS m/z: 598.1 [M+H] ⁺ .

Step 2: Synthesis of the WX27 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX23 in Example 23, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=100/1, 20/1) to give compound WX27.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29 (d, J=6.76 Hz, 3 H) 3.25-3.30 (m, 1 H) 3.54 (td, J =11.84, 3.14 Hz, 1 N) 3.69 (dd, J=11.52, 2.76 Hz, 1 N) 3.82 (d, J=11.28 Hz, 1 N) 3 .98-4.06 (m, 4 N) 4.19 (br.l, J=11.52 Hz, 1 N) 4.56 (br. s, 1 N) 6.95 (s, 1 N) 7.22 (dd, J=3.40, 1.88 Hz, 1 H) 7.55-7.59 (m, 1 H) 8.07 (d, J=5.28 Hz, 1 H) 8 .32 (d, J=5.04 Hz, 1 H) 8.67 (s, 1 H) 11.77 (br. s, 1 H).

MS m/s: 444.0 [M+H] ⁺ .

Example 28: WX28 connection

Synthesis scheme:

Step 1: Synthesis of the WX28-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX23-1 in Example 23, whereby a crude product was obtained, which was purified by column chromatography (petroleum ether:ethyl acetate=2/1.2/1) to give compound WX28-1.

MS m/z: 545.1 [M+H] ⁺

Step 2: Synthesis of the WX28 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX23 in Example 23, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=100/1.9/1) to give compound WX28.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.32 (br. d, J=6.28 Hz, 3 H) 2.31-2.47 (m, 3 H) 2.70 (br .s, 3 N) 3.56 (br. t, J=11.16 Hz, 1 N) 3.71 (br. d, J=11.28 Hz, 1 N) 3.79-3.89 ( m, 1 N) 4.04 (br. d, J=8.76 Hz, 1 N) 4.27 (br. d, J=10.56 Hz, 1 N) 4.64 (br. s, 1 N) 6.84 (br.s, 1 N) 7.22 (br.s, 1 N) 7.60 (br.s, 1 N) 8.02 (br.s, 1 N) 8.36 ( br.s, 1 N) 11.82 (br.s, 1 N).

MS m/s: 391.0 [M+H] ⁺ .

Example 29: Connection WX29

Synthesis scheme:

Step 1: Synthesis of compound WX29-2

Bispinacol borate (90.16 mg, 464.91 µmol), complex [1.1 '-bis(diphenylphosphino)ferrocene]palladium dichloride-dichloromethane (64.81 mg, 79.36 mmol) and potassium acetate (467.32 mg, 4.76 mmol), which was stirred at 100°C in a microwave oven for 1 h. The reaction system was cooled and then diluted with ethyl acetate (30 ml). After filtration, the solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=10/1.5/1) to obtain compound WK29-2.

MS m/s: 237.0 [M+H] ⁺ .

Step 2: Synthesis of compound WX29-3

At room temperature, to a solution of compound E1 (0.15, 309.94 µmol) in 1,4-dioxane (2.00 ml) was added WX29-2 (87.80 mg, 371.93 µmol), dipalladium tris(dibenzylacetone) (28.38 mg, 30.99 µmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35.87 mg, 61.99 µmol), potassium phosphate (197.37 mg, 929.82 µmol ) and water (0.2 ml), which was stirred at 120° C. in a microwave oven for 20 minutes. The reaction system was cooled and then diluted with ethyl acetate (30 ml). The organic phase was washed with water (30 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=2/1.1/2) to give compound WX29-3.

MS m/s: 558.1 [M+H] ⁺ .

Step 3: Synthesis of compound WX29-4

Sodium borohydride (16.28 mg, 430.40 µmol) was added at room temperature to a solution of compound WX29-3 (0.12 g, 215.20 µmol) in methanol (8.00 ml) and stirred at 30°C for 4 hours The reaction system was concentrated under reduced pressure at 45°C to obtain a mixture, which was dissolved with ethyl acetate (30 ml), washed with water (20 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give crude compound WX29-4.

MS m/s: 560.1 [M+H] ⁺ .

Step 4: Synthesis of Compound WX29

At room temperature, to a solution of compound WX29-4 (0.09 g, 150.60 µmol) in methanol (10.00 ml) was added sodium hydroxide solution (2 M, 753.00 µl) and stirred at 30°C for 15 hours The reaction system was concentrated under reduced pressure at 45°C to obtain a mixture, which was dissolved with dichloromethane (30 ml), washed with saturated saline (20 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (dichloromethane/methanol=100/1.15/1) to give compound WX29.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.30 (d, J=6.52 Hz, 3 H) 3.26-3.30 (m, 1 H) 3.51-3.60 (m, 1 N) 3.71 (br.d, J=9.04 Hz, 1 N) 3.79-3.87 (m, 1 N) 3.93 (s, 3 N) 4.04 ( br.d, J=8.04 Hz, 1 N) 4.24 (br.d, J=12.56 Hz, 1 N) 4.65 (br.s, 1 N) 5.05 (br.d , J=4.52 Hz, 2 N) 5.61 (br. s, 1 N) 7.04 (s, 1 N) 7.23 (br. s, 1 N) 7.60 (t, J= 2.76 Hz, 1 N) 7.98 (d, J=4.76 Hz, 1 N) 8.15 (s, 1 N) 8.36 (d, J=5.04 Hz, 1 N) 11 .79 (br. s, 1 N).

MS m/s: 406.0 [M+H] ⁺ .

Example 30: WX30 Connection

Synthesis scheme:

Step 1: Synthesis of the WX30-1 Compound

At room temperature, to a solution of compound XX1 (0.1 g, 207.05 µmol) in 1,4-dioxane (10.00 ml) was added 3,5-dimethylisoxazole-4-boric acid pinacol ester (55.42 mg, 248 .46 µmol), tris(dibenzylacetone)dipalladium (18.96 mg, 20.70 µmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.96 mg, 41.41 µmol), potassium phosphate (131.85 mg, 621.14 µmol) and water (0.2 ml) and stirred at 120° C. in the microwave for 20 minutes. The reaction system was cooled and then diluted with ethyl acetate (30 ml). The organic phase was washed with water (30 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=2/1.1/1) to give compound WX30-1.

MS m/z: 566.1 [M+Na] ⁺ .

Step 2: Synthesis of the WX30 Compound

At room temperature, to a solution of compound WX30-1 (0.06 g, 110.37 µmol) in methanol (10.00 ml) was added sodium hydroxide solution (2 M, 551.84 µl), which was stirred at 40°C for 15 hours The reaction system was concentrated under reduced pressure at 45°C to obtain a mixture, which was dissolved with ethyl acetate (30 ml), washed with water (20 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (dichloromethane/methanol=40/1.20/1) to give compound WX30.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.23 (d, J=6.53 Hz, 3 H) 2.34 (s, 3 H) 2.52 (br. s, 3 H) 3.20 (td, J=12.67, 3.76 Hz, 1 N) 3.50-3.60 (m, 1 N) 3.66-3.73 (m, 1 N) 3.76- 3.82 (m, 1 N) 4.00 (dd, J=11.04, 3.01 Hz, 1 N) 4.10 (br.l, J=11.29 Hz, 1 N) 4.50 (br.d, J=6.78 Hz, 1 H) 6.80 (s, 1 H) 6.93 (dd, J=3.39, 1.88 Hz, 1 H) 7.27 (s, 1 N) 7.55-7.60 (m, 2 N) 8.30 (d, J=5.02 Hz, 1 N) 11.79 (br. s, 1 N).

MS m/s: 390.2 [M+H] ⁺ .

Example 31: Connection WX31

Synthesis scheme:

Step 1: Synthesis of the WX31-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that described for compound WX30-1 in Example 30, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=30/1.10/1) to give compound WX31-1.

MS m/s: 543.1 [M+H] ⁺ .

Step 2: Synthesis of the WX31 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX30 in Example 30, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=30/1.10/1) to give compound WX31.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.24 (d, J=6.53 Hz, 3 H) 2.08 (s, 3 H) 3.21 (td, J=12.61 , 3.64 Hz, 1 N) 3.55 (td, J=11.73, 2.89 Hz, 1 N) 3.67-3.73 (m, 1 N) 3.76-3.81 ( m, 1 N) 3.84 (s, 3 N) 3.97-4.02 (m, 1 N) 4.14 (br.d, J=12.05 Hz, 1 N) 4.50 (br. .d, J=6, 27 Hz, 1 N) 6.84 (s, 1 N) 6.93 (dd, J=3, 39, 1.88 Hz, 1 N) 7.28 (s, 1 N ) 7.39 (s, 1 H) 7.56-7.60 (m, 2 H) 8.30 (d, J=5.02 Hz, 1 H) 11.80 (br.s, 1 H) .

MS m/s: 389.2 [M+H] ⁺ .

Pripper 32: Compound WX32

Synthesis scheme:

Step 1: Synthesis of the WX32-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that used to prepare compound WX30-1 in Example 30, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=30/1.10/1) to obtain compound WX32-1.

MS m/s: 543.1 [M+H] ⁺ .

Step 2: Synthesis of the WX32 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX30 in Example 30, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=30/1.10/1) to give compound WX32.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (d, J=6.53 Hz, 3 H) 2.27-2.39 (m, 6 H) 3.18 (td, J =12.61, 3.64 Hz, 1 N) 3.50-3.59 (m, 1 N) 3.65-3.73 (m, 1 N) 3.75-3.81 (m, 1 N) 3.95-4.03 (m, 1 N) 4.07 (br.d, J=11.54 Hz, 1 N) 4.47 (br. d, J=5.27 Hz, 1 N ) 6.68 (s, 1 H) 6.91 (dd, J=3.39, 1.88 Hz, 1 H) 7.21 (s, 1 H) 7.52-7.59 (m, 2 H) 8.29 (d, J=5.02 Hz, 1 N) 11.76 (br. s, 1 N) 12.48 (br. s, 1 N).

MS m/s: 389.2 [M+H] ⁺ .

Example 33: WX33 Connection

Synthesis scheme:

Step 1: Synthesis of the WX33-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX3Q0-1 in Example 30, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=30/1.10/1) to give compound WX33-1.

MS m/z: 529.1 [M+H] ⁺ .

Step 2: Synthesis of the WX33 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX30 in Example 30, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=30/1.10/1) to give compound WX33.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.24 (d, J=6.53 Hz, 3 H) 3.22 (td, J=12.61, 3.64 Hz, 1 H) 3.55 (td, J=11.73, 2, 64 Hz, 1 N) 3.67-3.74 (m, 1 N) 3.76-3.81 (m, 1 N) 3.99 ( s, 4 N) 4.11 (br. d, J=11.54 Hz, 1 N) 4.55 (br. d, J=7.03 Hz, 1 N) 6.67 (d, J=1 .76 Hz, 1 N) 6.89-7.01 (m, 2 N) 7.40 (s, 1 N) 7.54 (d, J=1.76 Hz, 1 N) 7, 56-7 .58 (m, 1 N) 7.60 (d, J=5.02 Hz, 1 N) 8.31 (d, J=5.02 Hz, 1 N) 11.79 (br.s, 1 N )

MS m/s: 375.2 [M+H] ⁺ .

Example 34

Synthesis scheme:

Step 1: Synthesis of the WX34-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX15-1 in Synthesis Example 15, and a crude product was obtained, which was separated by column chromatography to give compound WX34-1.

MS-ESI m/h: 545.4 [M+H] ⁺ .

Step 2: Synthesis of Compound 34

Except for using the appropriate starting materials, the procedure for preparing Compound WX34 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/h: 391.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.32 (d, J=6.53 Hz, 3 H) 2.47 (s, 3 H) 3.37 (br. d, J=3 .51 Hz, 1 N) 3.56 (td, J=11.80, 2.76 Hz, 1 N) 3.71 (dd, J=11, 42, 2, 89 Hz, 1 N) 3.79 -3.89 (m, 1 N) 4.04 (dd, J=11.17, 3.39 Hz, 1 N) 4.22-4.37 (m, 4 N) 4.65 (br.s , 1 H) 6.99 (s, 1 H) 7.20 (dd, J=3.39.1, 88 Hz, 1 H) 7.61 (t, J=3.01 Hz, 1 H) 8 .02 (d, J=5.02 Hz, 1 N) 8.36 (d, J=5.02 Hz, 1 N) 11.85 (br.s, 1 N).

Example 35

Synthesis scheme:

Step 1: Synthesis of the WX35 Compound

Except for using the appropriate starting materials, the procedure for preparing Compound WX35 is identical to that used for Compound WX13 in Synthesis Example 13.

MS-ESI m/h: 390.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.28 (s, 3 H) 2.58 (br. s, 3 H) 3.49 (s, 1 H) 3.73 (s, 1 H) 3.91 (br. s, 2 N) 4.14 (br. s, 1 N) 4.29 (s, 1 N) 4.39 (br. s, 3 N) 4.53 (s, 1 N ) 6.52 (s, 1 N) 7.34 (br. s, 1 N) 7.38 (br. s, 1 N) 7.48 (br. s, 1 N) 7.57 (s, 1 N) 8.27 (br.d, J=7.53 Hz, 1 N) 8.37 (s, 1 N)

Example 36

Synthesis scheme:

Step 1: Synthesis of the WX36 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX36 is identical to that used for Compound WX13 in Synthesis Example 13.

MS-ESI m/z: 408.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.32 (d, J=6, 70 Hz, 3 H) 2.46 (s, 3 H) 3.36 (br. d, J=4 .27 Hz, 1 N) 3.50-3.62 (m, 1 N) 3.67-3.74 (m, 1 N) 3.79-3.86 (m, 1 N) 4.04 ( dd, J=10.92, 3.14 Hz, 1 H) 4.25 (s, 3 H) 4.29 (br.d, J=11, 29 Hz, 1 H) 4.63 (br. s, 1 N) 6.93 (s, 1 N) 7.29 (br.s, 1 N) 7.36 (dc, J=9.29, 2.01 Hz, 1 N) 7.48 (t , J=2.64 Hz, 1 H) 7.90 (dd, J=11.29, 2.51 Hz, 1 H) 11.36 (br. s, 1 H).

Example 37

Synthesis scheme:

Step 1: Synthesis of the WX37-1 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX37-1 is identical to that used for Compound WX13 in Synthesis Example 13.

MS-ESI m/h: 411.3 [M+H] ⁺ .

Step 2: Synthesis of the WX37 Compound

At 0°C, to a solution of compound WX37-1 (0.15 g, 335.20 µmol) in tetrahydrofuran (10 ml) was added lithium aluminum hydride (25.44 mg, 670.41 µmol) and the reaction mixture was stirred at 0°C for 0.5 h. At 0° C., anhydrous sodium sulfate was added to the reaction mixture, quenched by adding water (1 ml) and filtered. The filtrate was concentrated to give the crude product, which was separated by column chromatography to give compound WX37.

MS-ESI m/h: 420.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.32 (d, J=6, 78 Hz, 3 H) 1.34-1.34 (m, 1 H) 2.46 (s, 3 N) 3.39 (br.s, 1 N) 3.56 (td, J=11.92, 3.01 Hz, 1 N) 3.71 (dd, J=11.54, 2.76 Hz, 1 N) 3.83 (d, J=11.54 Hz, 1 N) 4.04 (br.dd, J=11, 42, 3.14 Hz, 1 N) 4.25 (s, 3 N) 4.30 (br.d, J=12.80 Hz, 1 N) 4.65 (s, 3 N) 6.88 (s, 1 N) 7.24 (br. s, 1 N) 7.43 (t, J=2, 64 Hz, 1 N) 7.52 (s, 1 N) 8.10 (s, 1 N) 11.23 (br. s, 1 N).

Example 38

Synthesis scheme:

Step 1: Synthesis of the WX38-1 Compound

To a solution of compound XX5 (0.28 g, 725.68 µmol) in N,N-dimethylformamide (5 ml) was added 1,4-dimethyl-1H-1,2,3-triazole (140.95 mg, 1.45 mmol), bis(triphenylphosphine)palladium dichloride (50.94 mg, 72.57 µmol) and tetramethylammonium acetate (115.98 mg, 870.82 µmol). The reaction mixture was stirred in a sealed tube at 140°C with heating for 4 h and then diluted with ethyl acetate (50 ml), washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate and filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound W38-1.

MS-ESI m/h: 447.3 [M+H] ⁺ .

Step 2: Synthesis of the WX38 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX38 is identical to that used for Compound WX37 in Synthesis Example WX37.

MS-ESI m/h: 419.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.23 (br. d, J=6.53 Hz, 3 H) 2.32 (s, 3 H) 3.16-3.23 (m , 1 N) 3.50-3.60 (m, 1 N) 3.67-3.73 (m, 1 N) 3.75-3.81 (m, 1 N) 4.00 (br.l , J=8.28 Hz, 1 N) 4.05 (s, 3 N) 4.13 (br.d, J=11.80 Hz, 1 N) 4.50 (br.d, J=4, 77 Hz, 1 N) 4.63 (d, J=5.52 Hz, 2 N) 5.13 (t, J=5, 65 Hz, 1 N) 6.79 (s, 1 N) 6.88 (br.s, 1 N) 7.16 (s, 1 N) 7.40 (br.s, 1 N) 7.46 (d, J=11.80 Hz, 2 N) 11, 21 (br. s, 1 N)

Example 39

Synthesis scheme:

Step 1: Synthesis of compound WX39-1

Other than using the appropriate starting materials, the procedure for preparing compound WX39-1 is identical to that used for compound WX38-1 in the Synthesis Example of Intermediate LC38-1.

MS-ESI m/h: 544.4 [M+H] ⁺ .

Step 2: Synthesis of the WX39 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX39 is identical to that used for Compound WX15 described in Synthesis Example 15.

MS-ESI m/h: 390.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.24 (d, J=6.78 Hz, 3 H) 2.33 (s, 3 H) 3.18-3.26 (m, 1 N) 3.55 (td,, J = 11.86, 2.64 Hz, 1 N) 3.66-3.74 (m, 1 N) 3.76-3.82 (m, 1 N) 4 .01 (dd, J=11.42, 3.14 Hz, 1 H) 4.06 (s, 3 H) 4.14 (br.d, J=10, 79 Hz, 1 H) 4.51 ( br.d, J=7.03 Hz, 1 N) 6.92 (s, 1 N) 6.95 (dd, J=3.51, 2.01 Hz, 1 N) 7.36 (s, 1 N) 7.57-7.61 (m, 2 N) 8.31 (d, J=5.02 Hz, 1 N) 11.80 (br.s, 1 N)

Example 40

Synthesis scheme:

Step 1: Synthesis of the WX40-1 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX40-1 is identical to that used for Compound WX15-1 described in Synthesis Example of Intermediate WX15-1.

MS-ESI m/h: 559.1 [M+H] ⁺ .

Step 2: Synthesis of the WX40 Compound

To a solution of compound WX40-1 (0.095 g, 170.06 µmol) in methanol (15 ml) was added 2M sodium hydroxide (2M, 1 ml). The reaction mixture was stirred at 15-20°C for 72 h, and then diluted with water (30 ml). The aqueous phase was extracted with dichloromethane (50 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was centrifuged to dryness to give a crude product, which was separated by column chromatography to give compound WX40.

MS-ESI m/h: 417.0 [M+H] ⁺ .

¹ H NMR (CDCl ₃ , 400 MHz): δ=9.53 (br. s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.27-8.34 (m, 1H), 8.14 (d, J=5, 1 Hz, 1H), 7.37-7.47 (m, 2H), 6.72 (s, 1H), 6.55 (s, 1H), 4.62 (s, 1H), 4.53 (br.s, 1H), 4.26 (br.l, J=13.3 Hz, 1H), 3.97-4.02 (m, ZN) , 3.87-3.94 (m, 1H), 3.79-3.86 (m, 1H), 3.69 (td, J=11.9, 3.1 Hz, 1H), 3.44 (td, J=12.8, 3.9 Hz, 1H), 2.54 (s, 3H), 1.44 ppm (d, J=6.9 Hz, 3H)

Example 41

Synthesis scheme:

Step 1: Synthesis of Compound WX41-1

To a solution of compound E1 (2 g, 4.13 mmol) in ethanol (25 ml) was added 2 M sodium hydroxide (10.33 ml) and the reaction mixture was stirred at 15-20°C for 14 h and then heated to 60 °C with stirring for 5 hours. The pH of the reaction mixture was adjusted to 6-7 with 2 M hydrochloric acid, diluted with water (40 ml) and extracted with ethyl acetate (60 ml ×3). The organic phases were combined, washed with brine (80 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was centrifuged to dryness to give crude compound WX41-1.

MS-ESI m/h: 330.0 [M+H] ⁺ .

Step 2: Synthesis of the WX41 Compound

To a solution of compound WX41-1 (0.06 g, 181.94 µmol), 2-fluoro-6-methylpyridine-5-boric acid (42.28 mg, 272.91 µmol) and tetrakis(triphenylphosphine)palladium (14, 72 mg, 12.74 μmol) in 1,4-dioxane (8 ml) was added 2 M aqueous sodium carbonate solution (2 M, 272.91 μl), the solution was purged with nitrogen three times. The reaction mixture was stirred with heating at 95°C for 5 h and then filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give WX41.

MS-ESI m/h: 405.2 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=10.24 (br.s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.15 (d, J=5 .3 Hz, 1H), 7.98 (t, J=8.0 Hz, 1H), 7.45-7.57 (m, 1H), 7.36-7.41 (m, 1H), 6 .91 (dd, J=8.3, 3.0 Hz, 1H), 6.55 (s, 1H), 4.54 (br.s, 1H), 4.27 (br.d, J=12 .3 Hz, 1H), 4.13 (dd, J=115, 3.5 Hz, 1H), 3.88-3.96 (m, 1H), 3.78-3.86 (m, 1H) , 3.69 (td, J=11.9, 3.0 Hz, 1H), 3.45 (td, J=12.8, 3.8 Hz, 1H), 2.71 (s, 33H), 1.45 ppm (d, J=6.8 Hz, 3H)

WX42 example

Synthesis scheme:

Step 1: Synthesis of the WX42-1 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX42-1 is identical to that used for Compound WX37-1 in Synthesis Example WX37:

To a solution of compounds XX4 (0.11 g, 357, 40 µmol), XX3 (161.44 mg, 536.10 µmol) and tetrakis (triphenylphosphine) palladium (0.03 g, 25.96 µmol) in 1, 4- dioxane (8 ml) was added 2 M aqueous sodium carbonate solution (534, 1 μl) and purged with nitrogen three times. The reaction mixture was stirred with heating at 100° C. for 5 hours and then filtered. The solution was concentrated to give a crude product, which was separated by column chromatography (ethyl acetate/petroleum ether: 20-55%) to give compound WX42-1.

MS-ESI m/h: 447.1 [M+H] ⁺ .

Step 2: Synthesis of the WX42 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX42 is identical to that used for Compound WX37-1 in Synthesis Example WX37:

At 0-5°C, to a solution of compound WX42-1 (0.13 g, 291.15 µmol) in tetrahydrofuran (10 ml) was added lithium aluminum hydride (0.05 g, 1.32 mmol). The reaction mixture was stirred at 0-5°C for 1 hour and then heated to 25°C with stirring for 2 hours. At 0-5°C, one drop of water, two drops of 10% sodium hydroxide, and three drops of water, then filtered. The filtrate was concentrated to give a crude product, which was separated by column chromatography (ethyl acetate/petroleum ether: 50-100%) to give compound WX42.

MS-ESI m/h: 419.2 [M+H] ⁺ .

¹ H NMR (CDCl ₃ , 400 MHz): δ=8.44 (br. s, 1H), 8.25 (s, 1H), 7.54 (s, 1H), 7.49 (br. s, 1H), 7.41 (s, 1H), 7.32 (t, J=2.8 Hz, 1H), 6.47 (s, 1H), 4.87 (s, 2H), 4.48 ( br.d, J=4.5 Hz, 1H), 4.29 (br.d, J=13.8 Hz, 1H), 4.14 (s, 3H), 4.11 ((m, 1H) , 3.86-3.94 (m, 1H), 3.79-3.86 (m, 1H), 3.69 (td, J=11.9, 3.1 Hz, 1H), 3.43 (td, J=12.7, 3.9 Hz, 1H), 2.24 (s, 3H), 1.70 (t, J=6.0 Hz, 1H), 1.43 ppm (d, J =6.8Hz, 3H)

Example 43

Synthesis scheme:

Step 1: Synthesis of Compound WX43-1

Other than using the appropriate starting materials, the procedure for obtaining crude WX43-1 is identical to the procedure used for compound WX15-1 in Synthesis Example 15.

MS-ESI m/h: 574.4 [M+H] ⁺ .

Step 2: Synthesis of the WX43 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX43 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/h: 420.1 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=9.74 (br.s, 1H), 8.46 (br.s, 1H), 8.16 (br.s, 1H), 7.60 (s, 1H), 7.48 (d, J=3.3 Hz, 1H), 7.40 (d, J=3.0 Hz, 1H), 7.09 (s, 1H), 4.53 (br.s, 1H), 4.38 (s, 2H), 4.26 (s, 4H), 4.13 (dd, J=11.4, 3.6 Hz, 1H), 3.88- 3.95 (m, 1H), 3.79-3.85 (m, 1H), 3.65-3.74 (m, 1H), 3.39-3.49 (m, 4H), 1, 45 ppm (d, J=6.8 Hz, 3H).

Example 44

Synthesis scheme:

Step 1: Synthesis of the WX44-1 Compound

To a solution of compound XX7 (0.05 g, 162.45 µmol), B1 (77.64 mg, 194.95 µmol) and tetrakis (triphenylphosphine) palladium (18.77 mg, 16.25 µmol) in 1,4- dioxane (5 ml) was added 2 M aqueous sodium carbonate solution (2 M, 243.68 μl) and purged with nitrogen three times. The reaction mixture was stirred with heating at 100°C for 14 h and then filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound WX44-1.

MS-ESI m/h: 544.4 [M+H] ⁺ .

Step 2: Synthesis of the WX44 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX44 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/h: 390.3 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=9.09 (br.s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.09 (d, J=5 .0 Hz, 1H), 7.53 (br.s, 1H), 7.44 (br.s, 1H), 7.35 (d, J=2.3 Hz, 1H), 6.53 (s , 1H), 4.51 (br.d, J=5, 4 Hz, 1H), 4.23 (br.d, J=12.6 Hz, 1H), 4.13 (dd, J=11, 5, 3.5 Hz, 1H), 3.97 (s, 3H), 3.89-3.93 (m, 1H), 3.80-3.86 (m, 1H), 3.64-3 .70 (m, 1H), 3.44 (td, J=12.7, 3.9 Hz, 1H), 2.48 (s, 3H), 1.44 ppm (d, J=6.8 Hz , 3H).

Example 45

Synthesis scheme:

Stage 1: Synthesis of the shx45-1 compound

To a solution of compound XX8 (1.6 g, 3.73 mmol), pinacolopo ester of indole-4-6oric acid (1.18 g, 4.85 mmol) and bis(triphenylphosphine)palladium dichloride (183.28 mg, 261, 13 μmol) in 1,4-dioxane (20 ml) was added 2 M aqueous sodium carbonate solution (2 M, 5.6 ml) and purged with nitrogen three times. The reaction mixture was stirred with heating at 95°C for 16 h and then filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound WX45-1.

MS-ESI m/h: 510.8 [M+H] ⁺ .

Step 2: Synthesis of the WX45-2 Compound

Sodium hydride (127.54 mg, 3.19 mmol, purity: 60 %). The reaction mixture was stirred at 0-5° C. for 10 min, then p-toluenesulfonyl chloride (561.17 mg, 2.94 mmol) was added. The reaction mixture was stirred at 0-5°C for 50 min, quenched by adding water (30 ml) and extracted with ethyl acetate (40 ml x3). The organic phases were combined and washed successively with water (30 ml×-2) and brine (50 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound WX45-2.

MS-ESI m/h: 664.5 [M+H] ⁺ .

Step 3: Synthesis of the WX45-3 Compound

To a solution of compound WX45-2 (1.7 g, 2.56 mmol) in 1,4-dioxane (10 ml) was added a mixture of 4 M hydrochloric acid in 1,4-dioxane (4 M, 5 ml). The reaction mixture was stirred at 30° C. for 2 h, adjusted to pH 7-8 with saturated sodium bicarbonate solution, diluted with water (30 ml) and extracted with ethyl acetate (40 ml x3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was separated by column chromatography

(ethyl acetate/petroleum ether: 25-75%) to give compound WX45-3.

MS-ESI m/h: 464.7 [M+H] ⁺ .

Step 4: Synthesis of the WX45-4 Compound

To a solution of compound WX45-3 (0.3 g, 647.18 µmol), 2,5-dimethyl-1,3,4-oxadiazole (190.47 mg, 1.94 mmol) in 1-methyl-2-pyrrolidone (3 ml) anhydrous p-toluenesulfonic acid (111.45 mg, 647.18 µmol) was added and the reaction mixture was stirred at 200° C. under microwave radiation for 1.5 h. The reaction mixture was diluted with water (20 ml) and was extracted with dichloromethane (30 ml x 4). The organic phases were combined, washed with brine (50 ml) and dried over anhydrous sodium sulfate. The filtered organic phase was concentrated to give a crude product, which was separated by column chromatography (methanol/dichloromethane: 0-10%) to give compound WX45-4.

MS-ESI m/h: 544.4 [M+H] ⁺ .

Step 5: Synthesis of the WX45 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX45 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/h: 390.3 [M+H] ⁺ .

¹ H NMR (CDCl ₃ , 400 MHz): δ=8.60 (br. s, 1H), 8.26 (dc, J=7.5, 0.8 Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 7.45(t, J=2.3Hz, 1H), 7.36(t, J=2.8Hz, 1H), 7.31(t, J= 7.8 Hz, 1H), 6.20-6.25 (m, 1H), 4.49 (br. s, 1H), 4.25 (br. d, J=12.3 Hz, 1H), 4.13 (ds, J=11.5, 3.8 Hz, 1H), 3.88-3.96 (m, 1H), 3.80-3.87 (m, 1H), 3.68 ( td, J=11.9, 3.1 Hz, 1H), 3.47 (td, J=12.8, 3.9 Hz, 1H), 2.54 (s, 6H), 1.45 ppm ( e, J=6.8 Hz, 3H).

Example 46

Synthesis scheme:

Step 1: Synthesis of the WX46-1 Compound

To a solution of compound C1 (1.3 g, 3.03 mmol), XX8 (830.95 mg, 3.18 mmol) and bis(triphenylphosphine)palladium dichloride (148.92 mg, 212.17 µmol) in 1.4 -dioxane (20 ml) was added 2M aqueous sodium carbonate solution (2 M, 4.55 ml) and purged with nitrogen three times. The reaction mixture was stirred with heating at 85°C for 16 h and then filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound WX46-1.

MS-ESI m/h: 528.4 [M+H] ⁺ .

Step 2: Synthesis of the WX46-2 Compound

Sodium hydride (133.06 mg, 3.33 mmol, 60% pure ). The reaction mixture was stirred at 0-5° C. for 10 min and p-toluenesulfonyl chloride (585.40 mg, 3.07 mmol) was added. The reaction mixture was stirred at 0-5°C for 30 min, quenched by adding water (30 ml) and was extracted with ethyl acetate (40 ml ×3). The organic phases were combined and washed successively with water (30 ml x2) and brine (50 ml x2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound WX46-2.

MS-ESI m/h: 682.5 [M+H] ⁺ .

Step 3: Synthesis of the WX46-3 Compound

To a solution of compound WX46-2 (1.75 g, 2.56 mmol) in 1,4-dioxane (10 ml) was added a mixture of 4M hydrochloric acid in 1,4-dioxane (4 M, 10 ml). The reaction mixture was stirred at 30°C for 12 h, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, the mixture was diluted with water (40 ml) and was extracted with ethyl acetate (50 ml ×3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was separated by column chromatography to give compound WX46-3.

MS-ESI m/h: 482.3 [M+H] ⁺ .

Step 4: Synthesis of the WX46-4 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX46-4 is identical to that used for compound WX15-1 in Synthesis Example 15.

MS-ESI m/h: 562.4 [M+H] ⁺ .

Step 5: Synthesis of the WX46 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX46 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/z: 408.2 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=8.27-8.59 (m, 1H), 7.93-7.96 (m, 1H), 7.34 (t, J=2.3 Hz, 1H), 7.26 (t, J=2.8 Hz, 1H), 7.20 (br. d, J=2.4 Hz, 1H), 6.16-6.22 (m, 1H ), 4.40 (br. s, 1H), 4.17 (br. d, J=10.6 Hz, 1H), 4.06 (dd, J=11.6, 3.7 Hz, 1H) , 3.79-3.87 (m, 1H), 3.72-3.78 (m, 1H), 3.61 (td, J=11.9, 3.0 Hz, 1H), 3.39 (td, J=12.8, 3.9 Hz, 1H), 2.46 (s, 6H), 1.37 ppm (d, J=6.8 Hz, 3H).

Example 47

Synthesis scheme:

Step 1: Synthesis of compound WX47-1

To a solution of compound XX9 (0.3 g, 857.61 µmol), XX2-1 (126.74 mg, 1.03 mmol), potassium carbonate (237.05 mg, 1.72 mmol), tricyclohexylphosphine (126.74 mg, 1.03 mmol) and trimethylacetic acid (17.52 mg, 171.52 µmol) in N,N-dimethylacetamide (2 ml) were added palladium acetate (19.25 mg, 85.76 µmol). The reaction mixture was purged with nitrogen three times and stirred at 130-150° C. for 18 hours. The reaction mixture was concentrated to give a crude product, which was separated by column chromatography to give compound WX47-1.

MS-ESI m/h: 437.4 [M+H]+.

Step 2: Synthesis of compound WX47-2

To a solution of compound WX47-1 (, 45 g, 1.03 mmol) in ethanol (25 ml) was added Pd/C (0.1 g, 1.03 mmol, purity: 10%). The mixture was purged with nitrogen several times and stirred for 16 hours under a hydrogen atmosphere (15 psi (103 kPa)) at 30°C. The reaction mixture was filtered through celite and the filtrate was concentrated to give crude compound WX47-2.

MS-ESI m/z: 317.2 M+H]+.

Step 3: Synthesis of the WX47-3 Compound

WX47-2 (0.33 g, 1.04 mmol) was added to a solution of phosphorus oxychloride (11.75 g, 76.63 mmol) and the reaction solution was heated to 30° C. and stirred under nitrogen for 5 h. the mixture was concentrated and then diluted with dichloromethane (50 ml). The pH of the organic phase was adjusted to 8 with saturated sodium bicarbonate solution, the mixture was extracted with dichloromethane (30 ml ×8). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give compound WX47-3.

MS-ESI m/z: 335.2 M+H] ⁺ .

Step 4: Synthesis of Compound WX47-4

Other than using the appropriate starting materials, the procedure for preparing compound WX47-4 is identical to that used for compound WX15-1 in Synthesis Example 15.

MS-ESI m/z: 571.4 M+H] ⁺ .

Step 5: Synthesis of Compound WX47

Except for using the appropriate starting materials, the procedure for preparing compound WX47 is identical to that used for compound WX15 in Synthesis Example 15.

MS-ESI m/h: 417.3 [M+H] ⁺ .

H NMR (CDCl ₃ , 400 MHz): δ=9.41 (br. s, 1H), 8.45 (d, J=5.0 Hz, 1H), 8.13 (d, J=5.0 Hz , 1H), 7.45-7.51 (m, 1H), 7.39 (dd, J=3.5, 2.0 Hz, 1H), 6.62 (s, 1H), 4.52 ( br. s, 1H), 4.28-4.31 (m, 1H), 4.25 (tT, J=7.5, 3.8 Hz, 1H), 4.12-4.17 (m, 1H), 3.89-3.95 (m, 1H), 3.79-3.88 (m, 1H), 3.70 (td, J=11.9, 3.0 Hz, 1H), 3 .47 (td, J=12.7, 3.8 Hz, 1H), 2.54 (s, 3H), 1.46 (d, J=6, 8 Hz, 3H), 1.35-1, 42 (m, 2H), 1.04-1.14 ppm (m, 2H).

Example48

Synthesis scheme:

Step 1: Synthesis of the WX48-1 Compound

To a solution of compound XX10 (1.6 g, 3.74 mmol), B1 (2.23 g, 5.61 mmol) and tetrakis(triphenylphosphine)palladium (18.77 mg, 16.25 µmol) in 1,4- dioxane (5 ml) was added 2M aqueous sodium carbonate solution (2 M, 4.67 ml) and purged with nitrogen three times. The reaction mixture was stirred with heating at 100°C for 20 h and then filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound WX48-1.

MS-ESI m/h: 664.5 [M+H] ⁺ .

Step 2: Synthesis of the WX48-2 Compound

To a solution of compound WX48-1 (2 g, 3.01 mmol) in 1,4-dioxane (10 ml) was added a 4M solution of hydrochloric acid in 1,4-dioxane (4 M, 5 ml). The reaction mixture was stirred at 30°C for 35 min, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, diluted with water (30 ml) and was extracted with dichloromethane (40 ml ×3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was separated by column chromatography to give compound WX48-2.

MS-ESI m/z: 464.7 M+H] ⁺ .

Step 3: Synthesis of the WX48-3 Compound

To a solution of compound WX48-2 (0.3 g, 647.18 µmol), 2,5-dimethyl-1,3,4-oxadiazole (1240.00 mg, 2.45 mmol) in 1-methyl-2-pyrrolidone (2 ml) was added anhydrous p-toluenesulfonic acid (111.44 mg, 647.18 μmol) and the reaction mixture was stirred at 200°C under microwave radiation for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated using column chromatography to obtain compound WX48-3.

MS-ESI m/z: 544, 1 M+H] ⁺ .

Step 4: Synthesis of the WX48 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX48 is identical to that used for Compound WX15 in Synthesis Example 15.

MS-ESI m/h: 390.3 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=9.75 (br. s, 1H), 6.44 (d, J=5.0 Hz, 1H), 7.56 (d, J=5, 0 Hz, 1H), 7.42-7.51 (m, 1H), 7.06 (d, J=1.3 Hz, 1H), 6.94 (dd, J=3.4, 1.9 Hz, 1H), 6.38 (d, J=1.3 Hz, 1H), 4.39 (br. d, J=6.5 Hz, 1H), 4.04-4.21 (m, 2H ), 3.87-3.95 (m, 1H), 3.78-3.86 (m, 1H), 3.69 (td, J=12.0, 3.1 Hz, 1H), 3, 39 (td, J=12.6, 3.9 Hz, 1H), 2.41 (s, 6H), 1.39 ppm (d, J=6, 8 Hz, 3H)

Example 49

Synthesis scheme:

Step 1: Synthesis of Compound WX49-1

To a solution of compound WX47-3 (0.1 g, 298, 68 µmol), XX3 (125.93 mg, 418.16 µmol) and tetrakis(triphenylphosphine)palladium (24.16 mg, 20.91 µmol) in 1, 4-dioxane (8 ml) was added with 2M aqueous sodium carbonate solution (2M, 448.02 μl) and purged with nitrogen three times. The reaction mixture was stirred with heating at 90°C for 16 h and then filtered. The solution was concentrated to give the crude product, which was separated by column chromatography to give compound WX49-1.

MS-ESI m/h: 474.4 [M+H] ⁺ .

Step 2: Synthesis of compound WX49

Lithium aluminum hydride (0.05 g, 1.32 mmol) was added to a solution of compound WX49-1 (0.06 g, 126.71 µmol) in tetrahydrofuran (10 ml) at a temperature of 0-5°C. The reaction mixture was heated to 30° C. with stirring for 3 hours. At 0-5° C., one drop of water, two drops of 10% sodium hydroxide, and three drops of water were added slowly to the reaction mixture, then filtered. The filtrate was concentrated to give the crude product, which was separated by column chromatography to give compound WX49.

MS-ESI m/h: 446.1 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=8.43 (br. s, 1H), 8.27 (d, J=1.0 Hz, 1H), 7.57 (s, 1H), 7 .50 (t, J=2.3 Hz, 1H), 7.34 (t, J=2.8 Hz, 1H), 6.54 (s, 1H), 4.88 (s, 2H), 4 .50 (br. d, J=4.5 Hz, 1H), 4.21-4.35 (m, 2H), 4.13 (dd, J=11.4, 3.6 Hz, 1H), 3.88-3.93 (m, 1H), 3.79-3.88 (m, 1H), 3.64-3.73 (m, 2H), 3.45 (td, J=12.8 , 4.0 Hz, 1H), 2.52 (s, 3H), 1.44 (d, J=6.8 Hz, 3H), 1.33-1.40 (m, 2H), 1.02 -1.11 ppm (m, 2H).

Example 50

Synthesis scheme:

Step 1: Synthesis of the WX50-1 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for WX30-1 in Example 30, whereby a crude product was obtained, which was separated by column chromatography (ethyl acetate/petroleum ether: 0-60%) to give WX50-1.

MS-ESI: 544.4 [M+H] ⁺

Step 2: Synthesis of the WX50 Compound

Other than using the appropriate starting materials, the procedure is identical to that used for compound WX30 in Example 30, whereby a crude product was obtained, which was purified by column chromatography (dichloromethane:methanol=30/1, 10/1) to give compound WX50.

MS-ESI: 390.1 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.24 (d, J=6, 78 Hz, 3 H) 2.33 (s, 3 H) 3.22 (td, J=12.67 , 4.02 Hz, 1 N) 3.37-3.42 (m, 1 N) 3.55 (td, J=11.86, 2.64 Hz, 1 N) 3.66-3.73 ( m, 1 N) 3.76-3.83 (m, 1 N) 4.01 (dc, J=11.42, 3.14 Hz, 1 N) 4.06 (s, 3 N) 4.14 (br. d, J=10.79 Hz, 1 H) 4.51 (br. d, J=7.03 Hz, 1 H) 6.92 (s, 1 H) 6.95 (dd, J= 3.51, 2.01 Hz, 1 N) 7.36 (s, 1 N) 7.57-7.61 (m, 2 N) 8.31 (d, J=5.02 Hz, 1 N) 11.80 (br. s, 1 N)

Example 51

Synthesis scheme:

Step 1: Synthesis of Compound WX51-1

To a solution of compound D1-2 (4.51 g, 18.18 mmol), XXZ (4.96 g, 16.47 mmol) and bis (triphenylphosphine) palladium dichloride (893.11 mg, 1.27 mmol) in 1 , 4-dioxane (60 ml) was added with 2M aqueous sodium carbonate solution (27.27 ml) and purged with nitrogen three times. The reaction mixture was stirred at 110° C. with heating for 15 hours and then filtered. The solution was concentrated to give a crude product, which was separated by column chromatography (ethyl acetate/petroleum ether: 15-35%) to give WX51-1.

MS-ESI: 386.9[M+H] ⁺

Step 2: Synthesis of compound WX51-2

At room temperature, to a solution of compound WX51-1 (0.21 g, 542.87 µmol) in 1,4-dioxane (10 ml) was added 3,5-dimethylisoxazole-4-boric acid pinacol ester (181.65 mg, 814 .31 µmol), tetrakis(triphenylphosphine)palladium (62.73 mg, 54.29 µmol), sodium carbonate (2 M, 814.31 µl) and stirred at 100° C. under nitrogen for 12 hours. The reaction system was cooled to room temperature, diluted with ethyl acetate (50 ml), washed with water (20 ml) and brine (20 ml), respectively, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate: 33%-50%) to obtain compound WX51-2.

MS-ESI: 448.3[M+H] ⁺

Step 3: Synthesis of the WX51 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX50 is identical to that used for Compound WX37 in Synthesis Example WX37.

MS-ESI m/h: 420.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.30 (d, J=6.78 Hz, 3 H) 2.48 (s, 3 H) 2.68 (s, 3 H) 3, 24-3.30 (m, 1 N) 3.51-3.61 (m, 1 N) 3.67-3.74 (m, 1 N) 3.79-3.86 (m, 1 N) 4.03 (br. d, J=7.78 Hz, 1 N) 4.26 (br. d, J=13.05 Hz, 1 N) 4.58-4.63 (m, 1 H) 4 .65 (d, J=5.77 Hz, 2 N) 5.16 (t, J=5.77 Hz, 1 N) 5.76 (s, 1 N) 6.73 (s, 1 N) 7 .25 (br. s, 1 N) 7.41 (t, J=2.64 Hz, 1 N) 7.50 (s, 1 N) 8.09 (d, J=l.25 Hz, 1 N ) 11.20 (br. s, 1 N)

Example 52

Synthesis scheme:

Step 1: Synthesis of the WX52 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX52 is identical to that used for Compound WX13 in Synthesis Example 13.

MS-ESI m/z: 404.21 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) δ=8.15 (br. s, 1H), 7.99 (s, 1H), 7.30 (t, J=2.3 Hz, 1H), 7, 28 (s, 1H), 7.20 (br. s, 1H), 6.41 (s, 1H), 4.44 (br. s, 1H), 4.28 (s, 3H), 4.19 (br. d, J=12.5 Hz, 1H), 4.05 (dd, J=3.6, 11.4 Hz, 1H), 3.85-3.80 (m, 1H), 3, 77-3.72 (m, 1H), 3.61 (dt, J=3.0, 11.9 Hz, 1H), 3.36 (dt, J=4, 0, 12.7 Hz, 1H) , 2.48 (s, 3H), 2.47 (s, 3H), 1.36 (d, J=6.8 Hz, 3H)

Example 53

Synthesis scheme:

Step 1: Synthesis of the WX53 Compound

To a solution of compound WX42-1 (100 mg, 166.48 µmol) in 1,4-dioxane (2 ml) was added 2M aqueous sodium hydroxide solution (0.25 ml). The reaction mixture was stirred with heating at 80°C for 1.5 h, then the pH was adjusted to 5 with hydrochloric acid, and then the mixture was extracted with dichloromethane and water. The organic phase was washed once with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was separated by preparative HPLC (neutral) to give compound 2.

MS-ESI m/h: 433.31 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=11.65 (br. s, 1H), 8.78 (d, J=l, 5 Hz, 1H), 8.17 (s, 1H), 7 .69 (t, J=2.8 Hz, 1H), 7.41 (s, 1H), 7.38 (br. s, 1H), 6.82 (s, 1H), 4.60 (br. s, 1H), 4.29 (br. d, J=11.3 Hz, 1H), 4.05 (br. s, 1H), 4.03 (s, 3H), 3.86-3.80 (m, 1H), 3.71 (br. d, J=9, 4 Hz, 1H), 3.61-3.53 (m, 1H), 3.28 (s, 1H), 2.20 ( s, 3H), 1.32 (d, J=6.6 Hz, 3H).

Example 54

Synthesis scheme:

Step 1: Synthesis of the WX54-1 Compound

To a solution of compound XX10 (0.35 g, 817.91 µmol), C1 (256.27 mg, 981.49 µmol) and tetrakis (triphenylphosphine) palladium ((66.16 mg, 57.25 µmol) in 1.4 -dioxane (8 ml)) was added 2M aqueous sodium carbonate solution (2M, 1.02 ml) and purged with nitrogen three times. The reaction mixture was stirred with heating at 90°C for 36 h and then filtered. The solution was concentrated to give a crude product, which was separated by column chromatography (ethyl acetate/petroleum ether: 15-45%) to give compound WX54-1.

MS-ESI m/h: 527.4 [M+H] ⁺ .

Step 2: Synthesis of the WX54-2 Compound

Sodium hydride (37.56 mg, 939.05 mmol, purity: 60 %). The reaction mixture was stirred at 0-5°C for 15 min and p-toluenesulfonyl chloride (186.81 mg, 979.87 µmol) was added. The reaction mixture was stirred at 0-5°C for 2 h, quenched by adding water (40 ml) at 0-5°C and extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine (80 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give WX54-2.

MS-ESI m/h: 681.5 [M+H] ⁺ .

Step 3: Synthesis of the WX54-3 Compound

To a solution of compound WX54-2 (0.56 g, 822.58 mmol) in 1,4-dioxane (10 ml) was added a 4M solution of hydrochloric acid in 1,4-dioxane (4M, 4.67 ml). The reaction mixture was stirred at 30°C for 36 h, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, diluted with water (30 ml) and the mixture was extracted with dichloromethane (40 ml ×3). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was separated by column chromatography (ethyl acetate/petroleum ether: 25-50%) to give compound WX54-3 .

MS-ESI m/z: 481.3[M+N] ⁺

Step 4: Synthesis of compound WX54-4

To a solution of compound WX54-3 (0.12 g, 249.71 µmol), 2,5-dimethyl-1,3,4-oxadiazole (97.99 mg, 998.85 µmol) in 1-methyl-2-pyrrolidone (2 ml) was added anhydrous p-toluenesulfonic acid (43.00 mg, 249.71 µmol) and stirred at 220° C. under microwave radiation for 1.5 h. The reaction mixture was concentrated to obtain a crude product, which was separated using column chromatography (methanol/dichloromethane: 2-8%) to give compound WX54-4.

MS-ESI m/z: 561.4[M+N] ⁺

Step 5: Synthesis of the WX54 Compound

To a solution of compound WX54-4 (0.05 g, 89.18 µmol) in 1,4-dioxane (10 ml) was added 2M sodium hydroxide (2 M, 3 ml). The reaction mixture was stirred at 80°C for 12 h, the pH was adjusted to 7 with 1M hydrochloric acid, the mixture was diluted with water (15 ml) and was extracted with dichloromethane (25 ml ×3). The organic phases were combined, washed with brine (30 ml) and dried over anhydrous sodium sulfate. The filtered organic phase was concentrated to give a crude product, which was separated by column chromatography (methanol/dichloromethane: 10:1) to give compound WX54.

MS-ESI m/z: 407.2 [M+N] ⁺

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=8.50 (br. s, 1H), 7.32 (dd, J=10.5, 2.3 Hz, 1H), 7.25 (t, J=2.8 Hz, 1H), 7.12 (dd, J=8.9, 1.6 Hz, 1H), 6.88 (s, 1H), 6.85 (br. s, 1H), 6.26 (s, 1H), 4.30 (br. d, J=6.0 Hz, 1H), 3.97-4.08 (m, 2H), 3.72-3.83 (m, 2H), 3.60 (td, J=11.9, 3.1 Hz, 1H), 3.29 (td, J=12.7, 3.9 Hz, 1H), 2.34 (s, 6H ), 1.30 ppm (d, J=6.8 Hz, 3H).

Example 55

Synthesis scheme:

Step 1: Synthesis of the WX55-1 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX55-1 is identical to that used for compound WX54-1 in Synthesis Example 54.

MS-ESI m/z: 510.4 [M+N] ⁺

Step 2: Synthesis of the WX55-2 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX55-2 is identical to that used for compound WX54-2 in Synthesis Example 54.

MS-ESI m/z: 664.5 [M+N] ⁺

Step 3: Synthesis of the WX55-3 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX55-3 is identical to that used for compound WX54-3 in Synthesis Example 54.

MS-ESI m/z: 464.3 [M+N] ⁺

Step 4: Synthesis of the WX55-4 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX55-4 is identical to that used for compound WX54-3 in Synthesis Example 54.

MS-ESI m/z: 544.4 [M+N] ⁺

Step 5: Synthesis of the WX55 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX55 is identical to that used for Compound WX54 in Synthesis Example 54.

MS-ESI m/z: 390.2 [M+N] ⁺

¹ H NMR (CHLOROFORM-d, 400 MHz): δ=8.80 (br. s, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.62 (d, J=8, 1 Hz, 1H), 7.41-7.45 (m, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.13 (br. s, 1H), 6.95 ( s, 1H), 4.85 (br. s, 1H), 4.54 (br. d, J=12.8 Hz, 1H), 4.08 (dd, J=11.4, 3.1 Hz , 1H), 3.83-3.92 (m, 1H), 3.74-3.83 (m, 1H), 3.64 (td, J=11.9, 2.6 Hz, 1H), 3.45 (td, J=12.9, 3.4 Hz, 1H), 2.58 (s, 6H), 1.44 ppm (d, J=6.8 Hz, 3H)

Example 56

Synthesis scheme:

Step 1: Synthesis of the WX56-1 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX56-1 is identical to that used for compound WX54-1 in Synthesis Example 54.

MS-ESI m/z: 528.4 [M+N] ⁺

Step 2: Synthesis of the WX56-2 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX56-2 is identical to that used for compound WX54-2 in Synthesis Example 54.

MS-ESI m/z: 682.5 [M+N] ⁺

Step 3: Synthesis of the WX56-3 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX56-3 is identical to that used for compound WX54-3 in Synthesis Example 54.

MS-ESI m/z: 482.6 [M+N] ⁺

Step 4: Synthesis of the WX56-4 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX56-4 is identical to that used for compound IH54-3 in Synthesis Example 54.

MS-ESI m/z: 562.3 [M+N] ⁺

Step 5: Synthesis of the WX56 Compound

Other than using the appropriate starting materials, the procedure for preparing Compound WX56 is identical to that used for Compound WX54 in Synthesis Example 54.

MS-ESI m/z: 407.9 [M+N] ⁺

¹ H NMR (400 MHz, CHLOROFORM-d) δ=8.47 (br. s, 1H), 7.48 (br. d, J=10.6 Hz, 1H), 7.39 (br. s, 1H ), 7.31 (s, 1H), 7.03 (br. s, 1H), 6.92 (s, 1H), 4.84 (br. s, 1H), 4.51 (br. s, 1H), 4.08 (br. d, J=10.4 Hz, 1H), 3.90-3.83 (m, 1H), 3.81-3.75 (m, 1H), 3.64 (br. t, J=11.6 Hz, 1H), 3.50-3.39 (m, 1H), 2.58 (s, bN), 1.44 (br. d, J=6.5 Hz, 3H).

Example 57

Synthesis scheme:

Step 1: Synthesis of the WX57-1 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX57-1 is identical to that used for compound WX54-1 in Synthesis Example 54.

MS-ESI m/z: 509.4 [M+H] ⁺ .

Step 2: Synthesis of compound WX57-2

Other than using the appropriate starting materials, the procedure for preparing compound WX57-2 is identical to that used for compound WX54-2 in Synthesis Example 54.

MS-ESI m/h: 663.5 [M+H] ⁺ .

Step 3: Synthesis of the WX57-3 Compound

Other than using the appropriate starting materials, the procedure for preparing compound WX57-3 is identical to that used for compound WX54-3 in Synthesis Example 54.

MS-ESI m/z: 463.3 [M+N] ⁺

Step 4: Synthesis of Compound WX57-4

Other than using the appropriate starting materials, the procedure for preparing compound WX57-4 is identical to that used for compound WX54-4 in Synthesis Example 54.

MS-ESI m/z: 542.9 [M+N] ⁺

Step 5: Synthesis of compound WX57

Other than using the appropriate starting materials, the procedure for preparing compound WX57 is identical to that used for compound WX54 in Synthesis Example 54.

MS-ESI m/z: 389.0 [M+N] ⁺

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (d, J=6.78 Hz, 3 H) 2.41 (s, 6 H) 3.37 (td, J=12.67, 4.02 Hz, 1 N) 3.68 (td, J=11.86, 3.14 Hz, 1 H) 3.80-3.89 (m, 2 N) 4.05-4.15 (m , 2 N) 4.39 (br. d, J=6.78 Hz, 1 N) 6.28 (d, J=l.25 Hz, 1 N) 6.98 (d, J=1.00 Hz , 1 N) 7.01 (br. s, 1 N) 7.28-7.33 (m, 1 N) 7.36 (t, J=2.89 Hz, 1 N) 7.52 (d, J=8.28 Hz, 1 N) 7.58 (d, J=7.28 Hz, 1 N) 8.69 (br. s, 1 N)

Experimental Example 1: In Vitro Evaluation

IC ₅₀ values were determined to evaluate the inhibitory activity of test compounds against human ATR kinase.

ATR/ATRIP (h) was incubated in assay buffer containing 50 nM GST-cMyc-p53 and Mg/ATP (at the required concentration). The reaction was initiated by adding a mixture of Mg/ATP. After incubation for 30 minutes at room temperature, a stop solution containing EDTA was added to stop the reaction. Finally, a detection buffer was added containing a d ² labeled monoclonal anti-GST antibody and an antiphospho-Ser15-phosphorylated p53 antibody labeled with europium. Then the plate was read in the homogeneous fluorescence mode with time resolution.

The fluorescence signal (HTRF) was determined by the formula: HTRF=10000×(Em665 nm/Em620 nm).

IC ₅₀ data were analyzed using XLFit software version 5.3 (ID Business Solutions). Non-linear regression analysis was used to fit a sigmoid dose-response curve (variable slope). The results of the experiments are presented in table 1.

Conclusion: The compounds of the present invention have good ATR inhibitory activity.

Experimental Example 2: In Vitro Cell Viability Test

In this experiment, the inhibitory effect of compounds on cell proliferation was investigated by testing the effect on cell viability in vitro in the LoVo tumor cell line.

Cell Viability Test by Luminescence Intensity CellTiter-Glo

The protocols described below were performed according to the instructions provided with the Promega kit (Promega-G7573) to test cell viability by CellTiter-Glo luminescence intensity.

(1) Thaw the CellTiter-Glo buffer and allow it to warm to room temperature.

(2) Allow the CellTiter-Glo substrate to warm to room temperature.

(3) Add CellTiter-Glo Buffer to CellTiter-Glo Substrate Vial to dissolve substrate to obtain CellTiter-Glo working solution.

(4) Stir slowly until completely dissolved.

(5) Remove the cell culture dishes and leave them for 30 min to bring to room temperature.

(6) Add 50 µl (equivalent to half the volume of cell culture medium in each well) of CellTiter-Glo working solution to each well, wrap the cell plate with aluminum foil to protect from light.

(7) Shake the culture plate on an orbital shaker for 2 minutes to induce cell lysis.

(8) Leave culture dishes at room temperature for 10 min to stabilize the luminescence signal.

(9) Perform luminescence signal detection on a SpectraMax i3x plate reader from Molecular Devices.

Data analysis

To calculate the level of inhibition provided by the test compound, the following formula was used (inhibition level, IR): IR(%)=(1-(RLU compound - RLU blank control)/(RLU vehicle control - RLU blank control)) * 100% .

The level of inhibition provided by different concentrations of compounds was calculated in Excel, and GraphPad Prism software was used to plot the inhibition curve and calculate the relevant parameters, including the minimum degree of inhibition, the maximum degree of inhibition and IC ₅₀ .

The results of the experiments are shown in Table 2.

Conclusion: The compounds of the present invention have a good inhibitory effect on LoVo tumor cells with mutations in the ATM signaling pathway.

Experimental Example 3: In vivo pharmacokinetic study.

Samples for testing: Based on the results obtained in the experiments described above, some of the highly active compounds with representative structures were selected for further research.

Experimental Method: The aim of this study was to determine the pharmacokinetic parameters of the compounds and to measure oral bioavailability in female Balb/c Nude mice.

6 female Balb/c Nude mice were used in the experiment. 3 mice were intravenously administered at a dose of 1 mg/kg and plasma samples were collected at 0 h (prior to administration) and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration, the remaining 3 mice were administered by gavage at a dose of 10 mg/kg or 25 mg/kg, and plasma samples were collected at 0 h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 8, 24 hours after administration. The collected samples were then tested by LC/MS/MS analysis and data collected. The data collected was used to calculate the relevant pharmacokinetic parameters using Phoenix WinNonlin 6.2.1 software.

The experimental results are presented in Table 3.1 and Table 3.2.

3.1 Results of intravenous administration

3.2 Results of oral administration

Conclusion: The compounds of the present invention show good oral absorption and exposure and are suitable for oral administration.

Experimental Example 4: In Vivo Efficacy Study in LoVo CDX Colorectal Cancer Model

Target:

LoVo is a colorectal adenocarcinoma tumor cell line with the MRE11A mutation (MRE11A is a key component of the ATM signaling pathway that repairs the DNA double-strand break) that is sensitive to an ATR inhibitor. In this experiment, the LoVo CDX model of colorectal cancer was used to test the inhibitory effect of an ATR inhibitor in monotherapy of a tumor with a defect in the ATM signaling pathway.

Procedures:

1. Laboratory animal

Style: mouse

Strain: BALB/c nude mice

Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd.

Weeks and weight: 6-8 weeks, weight 18-22g

Gender: female

2. Cell culture

Human Colorectal Cancer LoVo Cells (ECACC, CatLog: 87060101), in vitro monolayer culture, culture conditions: Ham's F-12 medium with 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin, and 2 mM glutamine, 37 °C, 5% CO ₂ culture. Total passage with trypsin-EDTA digestion was performed twice a week. When the saturation of the cells was 80%-90%, the cells were harvested, counted and inoculated. 0.1 ml (10×10 ⁶ ) LoVo cells were inoculated subcutaneously into the right flank of each Nude mouse. When the average tumor volume reached 173 mm ³ , the animals were divided into groups and administration was started.

3. Preparation and dose of test substances.

1) WX15 connection

25.51 mg of WX15 was taken and dissolved in 0.500 ml of DMSO, 2.000 ml of propylene glycol and 2.500 ml of deionized water were added to this solution, shaken until homogeneous, the pH was adjusted to 6.0, obtaining a clear solution. Methods for preparing compound WX42, compound WX45, compound WX46 are similar to the method for preparing compound WX15.

Dosage: All test compounds were administered orally at a dose of 25 mg/kg twice a day with an interval of 8 hours a day.

4. Measurement of tumors and experimental indicators

A caliper was used to measure the tumor diameter, which was performed twice a week. Tumor volume was calculated using the following formula: V=0.5a×b2, a and b are long and short tumor diameters, respectively.

The antitumor efficacy of a compound was assessed by TGI(%) or relative tumor proliferation rate T/C(%).

Relative tumor proliferation rate T/C(%)=TRTV/CRTV×100% (TRTV: mean RTV of treatment group; CRTV: mean RTV of negative control group). Relative tumor volume (Relative Tumor Volume, RTV) was calculated based on tumor measurement results using the following formula: RTV=Vt/V0 where V0 is the tumor volume measured at the time of splitting into administration groups (i.e. DO), Vt is the volume tumors at the measurement points, and for TRTV and CRTV used data obtained on the same day.

TGI(%) reflects the degree of suppression of tumor growth. TGI(%)=[1-(mean tumor volume at end of treatment in treatment group - average tumor volume at start of administration in this treatment group)/(mean tumor volume at end of treatment in vehicle control group - average tumor volume at start of treatment in the control group with solvent)]×100%.

At the end of the experiment, the weight of the tumors was weighed and the percentage of T/C was calculated. T _weight and C _weight are tumor weights in the administration group and the vehicle control group, respectively.

5. Results of the experiment.

In this experiment, the efficacy of the compounds was evaluated in a human colorectal cancer xenograft model relative to a control group with a solvent as a reference. Tumor volumes in each group at different time points are shown in FIG. 1. On day 17, T/C and TGI administration in the WX42 (25 mg/kg) group were 27.8% and 90.7%, respectively, compared to the vehicle control group; T/C and TGI in the WX45 (25 mg/kg) group were 32.3% and 79.9%, respectively, compared to the vehicle control group; T/C and TGI in the WX46 (25 mg/kg) group were 43.8% and 79.9%, respectively, compared to the vehicle control group; T/C and TGI in the WX15 (25 mg/kg) group were 46.7% and 66.8%, respectively, compared to the vehicle control group.

6. Conclusion

In this experiment, the compounds of the present invention showed an inhibitory effect on tumor growth in mice in a tumor model with a subcutaneous xenograft of human colorectal LoVo cells.

Claims (43)

1. The compound of formula (I) or its tautomer or pharmaceutically acceptable salt

where n is 1, 2, 3 or 4; structural unit

selected from the group consisting of

ring A is selected from the group consisting of 5-6 membered heteroaryl; each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkyl, with C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R; each R ₂ is independently selected from the group consisting of H, F, Cl, Br, I, COOH, and C _1-3 alkyl, with C _1-3 alkyl optionally substituted with 1, 2, or 3 R; each R is independently selected from the group consisting of F, Cl, Br, I, OH, C _1-3 alkyl and C _1-3 alkoxy, with C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1, 2 or 3 R'; each R' is independently selected from the group consisting of F, Cl, Br, I, and OH; A 5-6 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms or heteroradicals independently selected from the group consisting of -NH-, -O- and N; And Z ₁ is N, Z ₂ and Z ₃ are CH; Z ₂ is N, Z ₁ and Z ₃ are CH; Z ₃ is N, Z ₁ and Z ₂ are CH; Z ₁ and Z ₂ are N, Z ₃ is CH; Z ₂ and Z ₃ are N, Z ₁ is CH; or Z ₁ and Z ₃ are N, Z ₂ is CH. 2. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, wherein each R is independently selected from the group consisting of H, F, Cl, Br, I, OH, CH ₃ , Et, and -O-CH ₃ . 3. A compound according to claim 1 or 2, or a tautomer or pharmaceutically acceptable salt thereof, wherein each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, C _1-3 alkyl, C _1-3 alkoxy, and cyclopropyl, wherein C _1-3 alkyl, C _1-3 alkoxy and cyclopropyl are optionally substituted with 1, 2 or 3 R. 4. The compound of claim 3, or a tautomer or pharmaceutically acceptable salt thereof, wherein each R ₁ is independently selected from the group consisting of H, F, Cl, Br, I, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , Et , -CH ₂ OH, -O-CH ₃ ,

And

. 5. A compound according to claim 1 or 2, or a tautomer or pharmaceutically acceptable salt thereof, where each R ₂ is independently selected from the group consisting of H, F, Cl, Br, I, COOH, CH ₃ , Et and -CH ₂ -OH . 6. A compound according to claim 1 or 2, or a tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and pyridyl. 7. The compound of claim 6, or a tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of

8. The compound according to claim 1 or 2 or its tautomer or pharmaceutically acceptable salt, where the structural unit

selected from the group consisting of

9. The compound according to claim 8 or its tautomer or pharmaceutically acceptable salt, where the structural unit

selected from the group consisting of

10. The compound according to claim 1 or 2 or its tautomer or pharmaceutically acceptable salt, where the structural unit

selected from the group consisting of

11. Connection according to any one of paragraphs. 1-8 or a tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

where is the structural unit

selected from the group consisting of

Z ₁ , Z ₂ and Z ₃ are as defined in paragraph 1; R ₁ is as defined in any one of paragraphs. 1, 2, 3 or 4; R ₂ is as defined in claim 1 or 5. 12. A compound according to claim 11, or a tautomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

where Z ₁ , Z ₂ and Z ₃ are as defined in paragraph 1; R ₁ is as defined in any one of paragraphs. 1, 2, 3 or 4; R ₂ is as defined in claim 1 or 5. 13. The compound or its tautomer or pharmaceutically acceptable salt selected from:

14. The use of a compound according to any one of paragraphs. 1-13 or a tautomer or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an ATR-associated disease. 15. Use according to claim 14, wherein the ATR-associated disease is a solid tumor or a hematological tumor.

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