WO2018108064A1 - Spiro-aryl-phosphorus-oxygen compound as fourth generation of egfr kinase inhibitor - Google Patents

Abstract

Disclosed are a fourth generation (T790M/C797S mutation) of an EGFR kinase inhibitor, i.e. a spiro-aryl-phosphorous-oxygen compound, in particular a compound as represented by formula (I) and a pharmaceutically acceptable salt thereof, used for treating cancers.

Description

Spiroarylphosphonates as fourth-generation EGFR kinase inhibitors

Cross-reference to related applications

The present application claims priority to Chinese Patent Application No. CN201611142656.2, filed on Dec.

Technical field

The present invention relates to a novel spiroarylphosphonate as a fourth generation (T790M/C797S mutant) EGFR kinase inhibitor, and specifically discloses a compound of the formula (I) and a pharmaceutically acceptable salt thereof.

Background technique

In the past decade, molecular targeted therapy has achieved remarkable results in patients with advanced non-small-cell lung cancer (NSCLC) with a driver gene, the most representative of which is directed against the epidermal growth factor receptor. Targeted therapy for (epidermal growth factor receptor, EGFR). EGFR is an important member of the HER/ErbB family. It is widely distributed on the cell membrane of various tissues of human body. Its structure is divided into the satiety zone, the transmembrane zone, and the intracellular zone. When the EGFR receptor receives the corresponding ligand Thereafter, the gram-inducing receptor forms a homodimer or a heterodimer, causing a conformational change in the satiety structure, thereby activating the tyrosine kinase in the intracellular region, phosphorylating the residue, and further activating the downstream signaling pathway. Such as MARK pathway and PI3K pathway, etc., eventually lead to a series of biological behaviors, such as tumor development, proliferation, invasion and metastasis.

EGFR tyrosine kinase inhibitor (TKI) acts as a small molecule EGFR inhibitor that competes with EGFR by endogenous ligands and inhibits tyrosine kinase activation, thereby blocking the EGFR signaling pathway. Finally, a series of biological effects such as inhibiting the proliferation of tumor cells, metastasizing and promoting apoptosis of tumor cells are produced. The EGFR kinase domain activating mutation is the most important predictor of EGFR-TKI. The EGFR mutation mainly occurs in exon 18-21. The mutation of exon 19 and the L858R point of exon 21 are the most common EGFR. The mutant subtype, which accounts for 90% of all mutation types, is a sensitive mutation in the EGFR gene mutation. In patients with lung adenocarcinoma, the proportion of EGFR mutations in the Caucasian population is about 10%, while in Asian patients with lung cancer, the gram is as high as 50%. The majority of patients with Asian, non-smoking women have lung adenocarcinoma.

Although the previous generations of EGFR-TKIs have developed rapidly, the problem of drug resistance has also followed with the development of drugs. Most of the drug resistance is the T790M secondary mutation in the ATP receptor. The recently developed third-generation series of irreversible inhibitors have very good inhibitory activity against T790M, but inevitable mutations in C797S have occurred. AZD9291 is a third-generation EGFR-TKI targeting drug with excellent response rates for resistance to T790M mutations. Approved by the FDA in November 2015, it is still in clinical stage in China. In May 2015, Thress KS published an online article on Nature for the first time, indicating that the acquired EGFR C797S mutation is one of the mechanisms leading to the drug resistance of the star drug AZD9291. . The study suggested that three molecular subtypes appeared in AZD9291 resistance: 1) acquired C797S mutation and EGFR-sensitive mutation and T790M mutation; 2) continued T790M mutation and EGFR-sensitive mutation, no acquired C797S mutation; 3) There are still EGFR-sensitive mutations, but the T790M mutation disappears and there is no acquired C797S mutation. The most important cause of drug resistance is the third mutation in EGFR, C797S, which accounts for about 40%. For the C797S mutation, we urgently need to develop a new, safer and more effective EGFR-TKI.

The compound of the present invention is mainly aimed at solving the problem of drug resistance caused by the third-generation inhibitor, that is, the third mutation C797S problem occurred in EGFR.

Summary of the invention

The present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

among them,

R _{1 is} selected from the group consisting of H and methyl;

R _{2 is} selected from the group consisting of halogen, CN, C _1-5 alkyl, C _1-5 heteroalkyl, C _1-5 alkenyl, C _1-5 heteroalkenyl, C _1-5 alkynyl, C _1-5 hetero Alkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl, said C _1-5 alkyl, C _1-5 heteroalkyl, C _{1 -5} alkenyl, C _1-5 heteroalkenyl, C _1-5 alkynyl, C _1-5 heteroalkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl and 5- The 6-membered heteroaryl is optionally substituted by 1, 2 or 3 R;

Or R ₁ and R _{2 are} bonded to form a 5- to 6-membered ring, and the 5- to 6-membered ring is optionally substituted by 1, 2 or 3 R;

R ₃ and R ₄ are each independently selected from H and halogen;

R _{5 is} selected from the group consisting of H, halogen, CN, C _1-3 alkyl, C _1-3 heteroalkyl, C _1-3 alkenyl, C _1-3 heteroalkenyl, C _3-6 cycloalkyl, 3~ a 6-membered heterocycloalkyl group, a phenyl group and a 5- to 6-membered heteroaryl group, said C _1-3 alkyl group, a C _1-3 heteroalkyl group, a C _1-3 alkenyl group, a C _1-3 heteroalkenyl group, C _3-6 cycloalkyl, 3-6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 R;

R _{6 is} selected from H, C _1-3 alkyl and C _1-3 heteroalkyl, and the C _1-3 alkyl and C _1-3 heteroalkyl are optionally substituted by 1, 2 or 3 R;

m, n, m', n' are each independently selected from 1 and 2;

R ₇ and R ₈ are each independently selected from the group consisting of H, CN, halogen, C _1-3 alkyl, C _1-3 heteroalkyl, cyclopropyl, phenyl and 5- to 6-membered heteroaryl, said C _{1 -3} alkyl, C _1-3 heteroalkyl, cyclopropyl, phenyl and 5- to 6-membered heteroaryl optionally substituted by 1, 2 or 3 R;

M is selected from C _1-3 alkyl;

Or, M and M are joined to form a 4-8 membered ring, and the 4-8 membered ring is optionally substituted by 1, 2 or 3 R;

R is selected from the group consisting of halogen, OH, CN, NH ₂ , C _1-3 alkyl and C _1-3 heteroalkyl, the C _1-3 alkyl and C _1-3 heteroalkyl optionally being 1, 2 or 3 R'substitutions;

R' is selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , CH ₃ , CH ₃ CH ₂ , CF ₃ , CHF ₂ and CH ₂ F;

"C _1-5 heteroalkyl", "C _1-5 heteroalkenyl", "C _1-5 heteroalkynyl", "3- to 6-membered heterocycloalkyl", "5 to 6-membered heteroaryl" , "C _1-3 heteroalkyl", "C _1-3 alkenyl heteroaryl group" of the "heteroaryl" represents a hetero atom or hetero atom groups, each independently selected from -O -, - S -, = O, = S, -ON=, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) ₂ -, -C (=O) NH-, -NH-, -C(=NH)-, -S(=O) ₂ NH-, -S(=O)NH-, and -NHC(=O)NH-; any of the above In this case, the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.

In some aspects of the invention, R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH ₂ , CH ₃ , CH ₃ CH ₂ , CF ₃ , CHF ₂ , CH ₂ F, NH ₂ CH ₂ , (NH ₂ ) ₂ CH, CH ₃ O, CH ₃ CH ₂ O, CH ₃ OCH ₂ , CH ₃ NH and (CH ₃ ) ₂ N.

In some embodiments of the invention, R ₁ above is selected from the group consisting of H and methyl.

In some embodiments of the invention, the above R _{2 is} selected from the group consisting of halogen, CN, C _1-3 alkyl, C _1-3 heteroalkyl, C _1-3 alkenyl, C _1-3 alkynyl, C _3-6 Cycloalkyl and phenyl, said C _1-3 alkyl, C _1-3 heteroalkyl, C _1-3 alkenyl, C _1-3 alkynyl, C _3-6 cycloalkyl and phenyl optionally Replaced by 1, 2 or 3 R.

所述CH₃、CH₃CH₂、CH₃CH₂CH₂、(CH₃)₂CH₂、CH₃O、CH₃CH₂O、CH₃OCH₂、CH₃NH、NH₂CH₂、(NH₂)₂CH、(CH₃)₂N、CH₂＝CH、CH₂＝CHCH₂、CH₃CH₂＝CH、CH₂＝C(CH₃)、

任选被1、2或3个R取代的。In some embodiments of the invention, the above R _{2 is} selected from the group consisting of F, Cl, Br, CN, CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH ₂ , CH ₃ O, CH ₃ CH ₂ O, CH ₃ OCH ₂ , CH ₃ NH, NH ₂ CH ₂ , (NH ₂ ) ₂ CH, (CH ₃ ) ₂ N, CH ₂ =CH, CH ₂ =CHCH ₂ , CH ₃ CH ₂ =CH, CH ₂ =C(CH ₃ ),

The _{CH 3, CH 3 CH 2,} CH 3 CH 2 CH 2, (CH 3) 2 CH 2, CH 3 O, CH 3 CH 2 O, CH 3 OCH 2, CH 3 NH, NH 2 CH 2, ( NH ₂ ) ₂ CH, (CH ₃ ) ₂ N, CH ₂ =CH, CH ₂ =CHCH ₂ , CH ₃ CH ₂ =CH, CH ₂ =C(CH ₃ ),

Optionally substituted by 1, 2 or 3 R.

In some embodiments of the invention, the above R _{2 is} selected from the group consisting of Cl, Br, CN, CH ₃ , CF ₃ , CH ₃ CH ₂ , CH ₃ O,

选

In some aspects of the invention, the structural unit

selected

In some aspects of the invention, R ₃ and R ₄ above are each independently selected from the group consisting of H and Cl.

In some embodiments of the invention, R ₅ above is selected from the group consisting of H, halogen, CN, C _1-3 alkyl, C _1-3 alkenyl, and 5- to 6-membered heteroaryl, said C _1-3 alkyl, The C _1-3 alkenyl group and the 5- to 6-membered heteroaryl group are optionally substituted by 1, 2 or 3 R groups.

和吡啶基，所述CH₃、

和吡啶基任选被1、2或3个R取代。In some aspects of the invention, the above R _{5 is} selected from the group consisting of H, F, Cl, Br, CN, CH ₃ ,

And a pyridyl group, the CH ₃ ,

And pyridyl is optionally substituted by 1, 2 or 3 R.

In some aspects of the invention, the above R _{5 is} selected from the group consisting of H, F, Cl, Br, CN, CH ₃ ,

In some embodiments of the invention, the above R _{6 is} selected from the group consisting of H and C _1-3 alkyl, and the C _1-3 alkyl group is optionally substituted by 1, 2 or 3 R.

In some embodiments of the invention, the above R _{6 is} selected from the group consisting of H, CH ₃ , CH ₃ CH ₂ and

In some aspects of the present invention, the above-described R ₇ and R ₈ are each independently selected from H, CN, _{halogen, CH 3, CH 3 CH 2} , CH 3 O, isopropyl, cyclopropyl, phenyl and pyrrolyl , the CH ₃ , CH ₃ CH ₂ , CH ₃ O, isopropyl, cyclopropyl, phenyl and pyrrolyl are optionally substituted by 1, 2 or 3 R;

In some aspects of the invention, R ₇ and R ₈ are each independently selected from the group consisting of H, CN, F, Cl, Br, CH ₃ , CF ₃ , CH ₃ CH ₂ , CH ₃ O,

In some aspects of the invention, the above M are both CH ₃ or both CH ₃ CH ₂ .

选自

In some aspects of the invention, the structural unit

Selected from

选自

In some aspects of the invention, the structural unit

Selected from

选自

In some aspects of the invention, the structural unit

Selected from

选自

In some aspects of the invention, the structural unit

Selected from

In some aspects of the invention, R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH ₂ , CH ₃ , CH ₃ CH ₂ , CF ₃ , CHF ₂ , CH ₂ F, NH ₂ CH ₂ , (NH ₂ ) ₂ CH, CH ₃ O, CH ₃ CH ₂ O, CH ₃ OCH ₂ , CH ₃ NH and (CH ₃ ) ₂ N, other variables are as defined above.

In some aspects of the invention, R ₁ above is selected from the group consisting of H and methyl, and other variables are as defined above.

In some embodiments of the invention, the above R _{2 is} selected from the group consisting of halogen, CN, C _1-3 alkyl, C _1-3 heteroalkyl, C _1-3 alkenyl, C _1-3 alkynyl, C _3-6 Cycloalkyl and phenyl, said C _1-3 alkyl, C _1-3 heteroalkyl, C _1-3 alkenyl, C _1-3 alkynyl, C _3-6 cycloalkyl and phenyl optionally Substituted by 1, 2 or 3 R, other variables are as defined above.

所述CH₃、CH₃CH₂、CH₃CH₂CH₂、(CH₃)₂CH₂、CH₃O、CH₃CH₂O、CH₃OCH₂、CH₃NH、NH₂CH₂、(NH₂)₂CH、(CH₃)₂N、CH₂＝CH、CH₂＝CHCH₂、CH₃CH₂＝CH、CH₂＝C(CH₃)、

任选被1、2或3个R取代的，其他变量如上述所定义。In some embodiments of the invention, the above R _{2 is} selected from the group consisting of F, Cl, Br, CN, CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH ₂ , CH ₃ O, CH ₃ CH ₂ O, CH ₃ OCH ₂ , CH ₃ NH, NH ₂ CH ₂ , (NH ₂ ) ₂ CH, (CH ₃ ) ₂ N, CH ₂ =CH, CH ₂ =CHCH ₂ , CH ₃ CH ₂ =CH, CH ₂ =C(CH ₃ ),

The CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH ₂ , CH ₃ O, CH ₃ CH ₂ O, CH ₃ OCH ₂ , CH ₃ NH, NH ₂ CH ₂ , ( NH ₂ ) ₂ CH, (CH ₃ ) ₂ N, CH ₂ =CH, CH ₂ =CHCH ₂ , CH ₃ CH ₂ =CH, CH ₂ =C(CH ₃ ),

Optionally substituted by 1, 2 or 3 R, the other variables are as defined above.

其他变量如上述所定义。In some embodiments of the invention, the above R _{2 is} selected from the group consisting of Cl, Br, CN, CH ₃ , CF ₃ , CH ₃ CH ₂ , CH ₃ O,

Other variables are as defined above.

选

其他变量如上述所定义。In some aspects of the invention, the structural unit

selected

Other variables are as defined above.

In some aspects of the invention, R ₃ and R ₄ above are each independently selected from H and Cl, and other variables are as defined above.

In some embodiments of the invention, R ₅ above is selected from the group consisting of H, halogen, CN, C _1-3 alkyl, C _1-3 alkenyl, and 5- to 6-membered heteroaryl, said C _1-3 alkyl, The C _1-3 alkenyl group and the 5- to 6-membered heteroaryl group are optionally substituted by 1, 2 or 3 R, and other variables are as defined above.

和吡啶基，所述CH₃、

和吡啶基任选被1、2或3个R取代，其他变量如上述所定义。In some aspects of the invention, the above R _{5 is} selected from the group consisting of H, F, Cl, Br, CN, CH ₃ ,

And a pyridyl group, the CH ₃ ,

And the pyridyl group is optionally substituted by 1, 2 or 3 R, and the other variables are as defined above.

其他变量如上述所定义。In some aspects of the invention, the above R _{5 is} selected from the group consisting of H, F, Cl, Br, CN, CH ₃ ,

Other variables are as defined above.

In some embodiments of the invention, the above R _{6 is} selected from the group consisting of H and C _1-3 alkyl, the C _1-3 alkyl group is optionally substituted by 1, 2 or 3 R, and the other variables are as defined above.

其他变量如上述所定义。In some embodiments of the invention, the above R _{6 is} selected from the group consisting of H, CH ₃ , CH ₃ CH ₂ and

Other variables are as defined above.

In some embodiments of the invention, R ₇ and R ₈ above are each independently selected from the group consisting of H, CN, halogen, CH ₃ , CH ₃ CH ₂ , CH ₃ O, isopropyl, cyclopropyl, phenyl, and pyrrolyl. The CH ₃ , CH ₃ CH ₂ , CH ₃ O, isopropyl, cyclopropyl, phenyl and pyrrolyl are optionally substituted by 1, 2 or 3 R, the other variables being as defined above.

其他变量如上述所定义。In some aspects of the invention, R ₇ and R ₈ are each independently selected from the group consisting of H, CN, F, Cl, Br, CH ₃ , CF ₃ , CH ₃ CH ₂ , CH ₃ O,

Other variables are as defined above.

In some aspects of the invention, the above M are both CH ₃ or both CH ₃ CH ₂ , and other variables are as defined above.

选自

其他变量如上述所定义。In some aspects of the invention, the structural unit

Selected from

Other variables are as defined above.

选自

其他变量如上述所定义。In some aspects of the invention, the structural unit

Selected from

Other variables are as defined above.

选自

其他变量如上述所定义。In some aspects of the invention, the structural unit

Selected from

Other variables are as defined above.

选自

其他变量如上述所定义。In some aspects of the invention, the structural unit

Selected from

Other variables are as defined above.

In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and M are as defined above.

The invention also provides a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for preparing a medicament for treating cancer use.

Still other aspects of the invention are arbitrarily combined from the above variables.

Technical effect

The invention relates to a series of novel spirocyclic arylphosphine oxides, which focus on the modification of different positions of the left benzene ring and the pyrimidine 5-position, and different modifications to various spiro ring structures to make the target compound The EGFR Ba/F3 (Δ19del/T790M/C797S) triple mutant cell activity and the phosphorylation activity of the EGFR Ba/F3 (Δ19del/T790M/C797S) triple mutant cell model were significantly improved, and Ba/F3 in mice. (Δ19del/T 790M/C797S) The three-mutant in vivo pharmacodynamic model has a good effect on tumor suppression.

Modification of different substituents on the left side of the compound, mainly by different halogens, greatly improved the activity of the compound EGFR Ba/F3 (Δ19del/T790M/C797S) triple mutant cells and EGFR Ba/F3 (Δ19del/T790M/ C797S) Trimutation phosphorylation activity. When the 2-position of the benzene ring on the left side is substituted, both the cell activity and the phosphorylation activity are largely lost, and when the substituent is removed, the activity is better; the 3-position of the left benzene ring is substituted. The activity remains good. When the substituent is methyl, the activity remains good but it has greater toxicity from the in vivo effect. When the methyl group is replaced by halogen (chlorine or bromine), the activity remains good and from The in vivo pharmacodynamic model also showed a significant reduction in toxicity. The 6-spiro-6 and 6-spiro-4 rings have better activity and lower toxicity from the in vivo results.

From the results of in vitro in vivo pharmacological effects, the compounds of the present invention have a good therapeutic effect on diseases caused by abnormal mutation of EGFR T790M/C797S.

Definition and description

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat 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, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the invention wherein the salt is formed by salting with an acid or with a base. The parent compound is modified. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acrylic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, Tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.

Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.

Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.

表示一个立体中心的绝对构型，用

表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。Wedge and dashed keys unless otherwise stated

Represents the absolute configuration of a stereocenter,

Represents the relative configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art. The diastereomers are resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). All isotopic compositional transformations of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.

The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of. When the substituent is a keto group (ie, =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When the number of one linking group is 0, such as -(CRR) ₀ -, it indicates that the linking group is a single bond.

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

表示其可在环己基或者环己二烯上的任意一个位置发生取代。When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit

It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.

Unless otherwise specified, the term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), 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 (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and optionally substituted -C(=O)N (H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, indanyl, mesoindolyl, fluorenyl, 3H-indole Mercapto, isobenzofuranyl, isodecyl, isoindoline, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl , octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxymethyl, pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine , benzoxanthyl, phenoloxazinyl, pyridazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridinyl, fluorenyl, pyranyl, Pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridylthiazole, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl , pyrrolyl, quinazolinyl, quinolyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 -thiadiazolyl, thiazolidine, thiazolyl, isothiazolylthiophenyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazole Base, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic. The hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C ₁ -C ₁₂ represents 1 to 12 carbons) , C _{1-12 is} selected from 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 ; C _{3-12 is} selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ .). "Hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "hydrocarbyl" means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Examples include, but are not limited to, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -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 . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise specified, the term "alkyl" is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH ₂ F) or polysubstituted (eg, -CF ₃ ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of the alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.

Unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent. Examples of the alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.

Unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.

Unless otherwise specified, a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.

Unless otherwise specified, a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

Unless otherwise specified, a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The above-described alkyl groups having the specified number of carbon atoms, "alkoxy" represents attached through an oxygen bridge, unless otherwise specified, C _1-6 alkoxy groups include _{C 1, C 2, C 3} , C 4, C 5 , and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

Unless otherwise specified, aryl groups, when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen. Those alkyl groups substituted by an atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.

The term "leaving group" refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" means suitable A protecting group that is used to prevent side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing hydroxy side reactions. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.

The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butylcarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH ₃ for sodium cyanoborohydride ; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ stands for chloride Sulfone; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF stands for fluorine Tetrabutylammonium; iPrOH represents 2-propanol; mp mp Representative; Representative LDA lithium diisopropylamide.

软件命名，市售化合物采用供应商目录名称。Compound by hand or

Software naming, commercially available compounds using the supplier catalog name.

detailed description

The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.

The compound of the present invention can be prepared by referring to the following reaction scheme:

Example 1

Compound 1A:

3-Benzyl-3,9-diazaspiro[5.5]undecane (10.0 g, 40.9 mmol, 1.00 eq.) was dissolved in tetrahydrofuran (100 mL) and water (50 mL). Marlin (3.21 g, 409 mmol, 30.5 ml, 37% purity), formic acid (18.84 g, 409.20 mmol, 15.44 ml). After the addition, the reaction mixture was warmed to 100 ° C and stirred for 3 hours. After the completion of the reaction was monitored by LC-MS, the reaction mixture was cooled to room temperature, and aqueous sodium hydroxide (5 mol) was added to adjust the pH of the reaction mixture to 10, and then extracted three times with dichloromethane (50 ml). The combined organic layers were washed with EtOAc EtOAc EtOAc. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 7.34-7.30 (m, 4H), 7.28-7.23 (m, 1H), 3.51 (s, 2H), 2.43-2.33 (m, 7H), 2.43-2.32 ( m, 1H), 2.28 (s, 3H), 1.58-1.47 (m, 8H).

Compound 1B:

To a solution of Compound 1A (8.00 g, 30.9 mmol) in EtOAc (EtOAc) (EtOAcield. The reaction solution was replaced with hydrogen three times, and then the reaction was stirred at 50 ° C under hydrogen (50 Psi) for 22 hours. The disappearance of the starting material was monitored by LC-MS, the reaction mixture was cooled and filtered, and the filter cake was washed three times with methanol (10 ml), and the filtrate was dried to give a residue. The residue was redissolved in dichloromethane (30 mL) and aqueous sodium hydroxide (5 mol) was added dropwise to adjust to pH 11. The mixture was separated and EtOAc (3 mL)EtOAc. , 63.6% yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 2.81-2.73 (m, 2H), 2.41-2.22 (m, 9H), 1.58-1.36 (m, 8H).

Compound 1C:

To a solution of 1-fluoro-2methyl-4-nitrobenzene (500 mg, 3.22 mmol) and compound 1B (542 mg, 3.22 mmol) in nitromethylpyrrolidone (5 mL) at rt. Diisopropylethylenediamine (1.25 g, 9.67 mmol, 1.69 ml) was then warmed to 100 ° C and stirred for 4 hours. After the reaction was completed by LC-MS, the reaction mixture was evaporated, EtOAcjjjjjjjjjjjjjjjj Residue. The residue was purified by EtOAc EtOAc EtOAcjjjjjjj ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.02 (d, J = 9.3 Hz, 2H), 6.98 (d, J = 8.7 Hz, 1H), 3.04 - 2.90 (m, 4H), 2.48-2.39 (m) , 4H), 2.36-2.33 (m, 3H), 2.32 (s, 3H), 1.73-1.58 (m, 8H).

Compound 1D:

To a solution of Compound 1C (370 mg, 1.22 mmol) in MeOH (5 mL) EtOAc (EtOAc) The reaction flask was replaced with hydrogen three times, and then the reaction was stirred at room temperature under hydrogen (15 Psi) for 4 hours. After the reaction was completed by TLC, the reaction mixture was filtered, and the filtrate was concentrated to afford compound 1D (310 mg, 1.13 mmol, 92.9% yield). ^{1 H NMR (400MHz, METHANOL-} d4) δ = 6.88 (d, J = 8.3Hz, 1H), 6.60 (d, J = 2.6Hz, 1H), 6.54 (dd, J = 2.6,8.3Hz, 1H), 2.78-2.71 (m, 4H), 2.47 (brs, 4H), 2.29 (s, 3H), 2.19 (s, 3H), 1.62 (brs, 8H).

Compound 1:

2,5-Dichloro-N-(2-dimethylphosphorylphenyl)pyrimidin-4-amine (116 mg, 366 μmol) and Compound 1D (100 mg, 365 μmol) of N-methyl at room temperature Methanesulfonic acid (105 mg, 1.10 mmol, 78.1 μl) was added dropwise to the solution of the pyrrolidone (2 ml). After the dropwise addition, the reaction mixture was warmed to 95 ° C and stirred for 10 hours. After completion of the reaction by LC-MS, the reaction mixture was cooled and diluted with ethyl acetate, and then, the mixture was adjusted to pH 9 with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered and evaporated The residue was isolated by high performance liquid chromatography column (formic acid) to afford compound 1 (96.6 mg, 175 micromoles). ^{1 H NMR (400MHz, DMSO-} d6) δ = 11.12 (s, 1H), 9.22 (s, 1H), 8.60 (brs, 1H), 8.33 (brs, 2H), 8.15 (s, 1H), 7.59 (dd , J = 7.7, 13.9 Hz, 1H), 7.49 (brt, J = 7.8 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.39-7.32 (m, 1H), 7.18 (brt, J = 7.1 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 2.80-2.63 (m, 8H), 2.42 (s, 3H), 2.18 (s, 3H), 1.80 (s, 3H), 1.79- 1.75 (m, 3H), 1.59 (brs, 8H).

Example 2

Compound 2A:

2-Chloro-1-fluoro-4-nitrobenzene (500 mg, 2.85 mmol, 1.00 equiv) and compound 1B (479 mg, 2.85 mmol, 1.00 equiv) were added to DMSO (6 mL) Potassium carbonate (787 mg, 5.70 mmol, 2 equivalents) was added. The reaction solution was reacted at 100 ° C for 2 hours. LC-MS and TLC showed the reaction was completed. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Concentration gave the crude product, which was purified eluting mjjjjjjj ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.24 (d, J = 2.5 Hz, 1H), 8.08 (dd, J = 2.8, 9.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 3.21-3.11 (m, 4H), 2.42 (brs, 4H), 2.31 (s, 3H), 1.71-1.66 (m, 4H), 1.63 (t, J = 5.6 Hz, 4H). LC-MS (ESI) (0-60AB): m/z: 323.7 [M+1].

Compound 2B:

Compound 2A (100 mg, 309 μmol, 1 eq.) was dissolved in MeOH (2 mL). The two were mixed, and reduced iron powder (172 mg, 3.09 mmol, 10 equivalents) was added to the mixture at 20-30 °C. The reaction solution was reacted at 80 ° C for 1 hour. LC-MS and TLC showed the reaction was completed. The mixture was filtered to remove the Fe powder, and the residue was evaporated. The organic phases were combined and concentrated to give a crude material. Compound 2B (62 mg, 211 μmol) was used in the next step without purification. LC-MS (ESI) (5-95.

Compound 2:

Compound 2B (62 mg, 211 μmol, 1.00 equivalent) and 2,5-dichloro-N-(2-dimethylphosphorylphenyl)pyrimidine-4-amine (66.7 mg, 211 μmol, 1.00 eq. Dissolved in NMP (2 ml), and then added methanesulfonic acid (60.8 mg, 633 micromoles, 45.1 microliters, 3 equivalents). The reaction mixture was heated to 100 ° C and stirred for 1 hour. LC-MS and TLC showed product formation. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Concentration gave the crude product. After concentration, the crude product was partitioned under basic conditions to give compound 2 (64.3 mg, yield 52.6%). ^{1 H NMR (400MHz, DMSO-} d6) δ = 11.15 (s, 1H), 9.43 (s, 1H), 8.57 (brs, 1H), 8.20 (s, 1H), 7.80 (d, J = 2.0Hz, 1H ), 7.65-7.52 (m, 2H), 7.45 (dd, J = 2.3, 8.7 Hz, 1H), 7.20 (brt, J = 7.5 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 2.91 - 2.80 (m, 4H), 2.28 (brs, 4H), 2.15 (s, 3H), 1.79 (d, J = 13.4 Hz, 6H), 1.61-1.43 (m, 8H). LCMS (ESI) (5- 95CD): m/z: 573.2 [M+1].

Example 3

To a mixture of compound 5 (80 mg, 129 μmol, 1 equivalent), 2-isopropenylboronic acid pinacol ester (26.1 mg, 155 μmol, 1.2 eq.) and DME (2 mL) Palladium (29.9 mg, 25.9 micromoles, 0.2 equivalents), sodium carbonate (27.4 mg, 258.9 micromoles, 2 equivalents) and water (500 microliters) were heated and stirred at 100 ° C for 3 hours under nitrogen atmosphere. TLC showed the reaction was completed. EtOAc (20 mL) was evaporated. The organic phase was dried and concentrated. ^{1 H NMR (400MHz, METHANOL-} d4) δ = 8.44 (dd, J = 3.9,7.8Hz, 1H), 8.07 (s, 1H), 7.62 (dd, J = 6.6,13.9Hz, 1H), 7.54 (t , J = 8.1 Hz, 1H), 7.42 (dd, J = 2.7, 8.8 Hz, 1H), 7.29-7.25 (m, 1H), 7.24 (d, J = 2.7 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.06 (s, 1H), 4.97 (s, 1H), 3.13 (brs, 4H), 3.00-2.92 (m, 4H), 2.79 (s, 3H), 2.19 (s, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.81 (brs, 4H), 1.71 (brs, 4H). LCMS (ESI) (0-60AB): m/z: 579.1 [M+1].

Example 4

Compound 4A:

To a solution of compound 1B (1.00 g, 5.94 mmol, 1.00 eq.) and 3-bromo-4-fluoronitrobenzene (1.31 g, 5.94 mmol, 1.00 eq.) in DMSO (15.0 mL) , 11.9 mmol, 2 equivalents), heated and stirred at 90 ° C for 4 hours. TLC showed the reaction was completed. EtOAc mjjjjjjjjjjjjj rate). ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.45 (d, J = 2.7 Hz, 1H), 8.15 (dd, J = 2.7, 8.8 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 3.19-3.12 (m, 4H), 2.44 (brt, J = 5.3 Hz, 4H), 2.33 (s, 3H), 1.70 (brd, J = 5.6 Hz, 4H), 1.67-1.63 (m, 4H). LCMS (ESI) (0-60AB): m/z: 368.0 [M+1].

Compound 4B:

To a mixture of compound 4A (200 mg, 543 μmol, 1.00 eq.), 2-isopropenylboronic acid pinacol ester (109 mg, 652 μmol, 1.2 eq.) and DME (4 mL). Palladium (126 mg, 109 μmol, 0.20 eq.), sodium carbonate (115 mg, 1.09 mmol, 2 eq.) and water (1.00 rn.). TLC showed the reaction was completed. EtOAc (20 mL) was evaporated. The organic phase was dried and concentrated, and crude material was purified eluting elute ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 8.07 (dd, J = 2.8,8.9Hz, 1H), 8.00 (d, J = 2.7Hz, 1H), 6.93 (d, J = 9.0Hz, 1H), 5.22-5.17 (m, 2H), 3.20-3.13 (m, 4H), 2.42 (brs, 4H), 2.31 (s, 3H), 2.13 (s, 3H), 1.66-1.57 (m, 8H). LCMS ( ESI) (0-60AB): m/z: 330.1 [M+1].

Compound 4C:

Palladium/carbon (20.00 mg) was added to a solution of compound 4B (150 mg, 455 micromoles, 1.00 equivalents) in methanol (3.00 ml). The reaction flask was passed through a hydrogen balloon and replaced with hydrogen three times at a pressure of 20-30 Stir at °C for 1 hour. TLC showed the reaction was completed, the reaction mixture was filtered, and then evaporated. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 6.99 (d, J = 8.6Hz, 1H), 6.60 (d, J = 2.7Hz, 1H), 6.50 (dd, J = 2.9,8.3Hz, 1H), 3.57-3.41 (m, 3H), 2.72 (brd, J = 4.6 Hz, 4H), 2.40 (brs, 4H), 2.30 (s, 3H), 1.60 (brs, 8H), 1.18 (s, 3H), 1.16 (s, 3H). LC-MS (ESI) (0-60.

Compound 4:

To 2,5-dichloro-N-(2-dimethylphosphorylphenyl)-4-aminopyrimidine (100 mg, 316 μmol, 1.00 equivalent) and compound 4C (95.4 mg, 316 μmol, 1.00 equivalents) Methanesulfonic acid (91.2 mg, 949 μmol, 67.6 μl, 3.00 equivalent) was added to a solution of isopropyl alcohol (3 ml), and stirred at 100 ° C for 1 hour. TLC showed the reaction was completed. EtOAc (EtOAc) (EtOAc) The organic phase was dried and concentrated, and the crude material was purified by preparative HPLC to afford compound 4 (43.2 mg, 68.6 micromoles, 21.7% yield, 99.6% purity, trifluoroacetate). ^{1 H NMR (400MHz, DMSO-} d6) δ = 11.16 (s, 1H), 9.21 (s, 1H), 8.64 (brs, 1H), 8.31 (s, 2H), 8.16 (s, 1H), 7.64-7.55 (m, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.21-7.14 (m, 1H), 7.09 (d, J = 8.5 Hz, 1H) , 3.40 (td, J = 6.8, 13.7 Hz, 1H), 2.72 (brs, 4H), 2.54-2.52 (m, 4H), 2.31 (s, 3H), 1.81 (s, 3H), 1.77 (s, 3H) ), 1.57 (brs, 8H), 1.12 (d, J = 6.8 Hz, 6H). LCMS (ESI) (0-60AB): m/z: 581.2 [M+1].

Example 5

Compound 5A:

The compound was prepared according to the procedure of Compound 1A, and 1-fluoro-2-methyl-4-nitro was replaced by 2-bromo-1-fluoro-4-nitrobenzene to give compound 5A (530 mg, 1.44 mmol, 63.4%). Yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.43 (d, J = 2.6 Hz, 1H), 8.13 (dd, J = 2.6, 8.9 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 3.18-3.10 (m, 4H), 2.49-2.39 (m, 4H), 2.32 (s, 3H), 1.73-1.60 (m, 8H).

Compound 5B:

This compound was prepared according to the method of Compound 2B, and Compound 2A was replaced with Compound 5A to give Compound 5B (390 mg, crude). ^{1 H NMR (300MHz, METHANOL-} d4) δ = 6.98 (brs, 1H), 6.83-6.58 (m, 1H), 3.31 (brs, 5H), 2.87 (brs, 8H), 2.15-1.42 (m, 8H) .

Compound 5:

This compound was prepared according to the procedure of Compound 2, and Compound 2B was replaced by Compound 5B to give Compound 5 (430 mg, 694 μmol, 55.9% yield, 99.7% purity). ^{1 H NMR (400MHz, DMSO-} d6) δ = 11.18 (s, 1H), 9.43 (s, 1H), 8.58 (brs, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.97-7.92 (m, 1H), 7.64 - 7.51 (m, 3H), 7.19 (brt, J = 7.0 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 2.88-2.82 (m, 4H), 2.50- 2.46 (m, 4H), 2.29 (s, 3H), 1.82-1.79 (m, 3H), 1.77 (s, 3H), 1.56 (brs, 8H).

Example 6

Compound 6A:

To a mixture of compound 5B (70 mg, 207 micromoles, 1.00 equivalents), 4-pyridineboronic acid (28 mg, 228 micromoles, 1.1 eq.) and dioxane (2 ml) was added tetrakis(triphenylphosphine) Palladium (23.9 mg, 20.7 micromolar, 0.1 equivalent), potassium carbonate (57.2 mg, 414 Micromolar, 2 equivalents) and water (1 ml) were stirred and heated at 100 ° C for 3 hours under nitrogen. TLC showed the reaction was completed. EtOAc (EtOAc) (EtOAc) The organic phase was dried and concentrated. LC-MS (ESI) (0-60.).

Compound 6:

Prepared according to the procedure of Compound 1, substituting compound 1D to compound 6A afforded compound 6 (9.40 mg, 14.2 micromoles, 19.1% yield, formate). ^{1 H NMR (400MHz, METHANOL-} d4) δ = 8.52 (d, J = 6.1Hz, 2H), 8.48 (brs, 1H), 8.35 (brs, 1H), 8.10 (s, 1H), 7.66 (d, J = 6.1 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.59 - 7.54 (m, 1H), 7.49 (dd, J = 2.6, 8.7 Hz, 1H), 7.29 - 7.22 (m, 1H) , 7.16-7.08 (m, 2H), 3.26-3.10 (m, 4H), 2.86-2.77 (m, 7H), 1.87 (d, J = 13.4 Hz, 6H), 1.81-1.63 (m, 4H), 1.54 (brs, 4H). LCMS (ESI) (0-60.

Example 7

Compound 7A:

a mixed solution of 5-trifluoromethyl-2,4-dichloropyrimidine (1476 mg, 2.2 mmol, 1.2 eq.) of 1,2-dichloroethane (10 ml) and tert-butanol (10 ml) Zinc bromide (1.24 g, 5.49 mmol, 3 equivalents) was added thereto, and the reaction was carried out at 25 ° C for 0.5 hour. The reaction solution was cooled to 0 ° C, and then 3-methyl-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)aniline (500) was added dropwise to the reaction mixture. Methanol 1.83 mmol, 1 eq.), reacted at 25 ° C for 3 hours. LC-MS showed the starting material remained and the reaction was continued for 16 hours until the reaction was completed. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 ml), and extracted twice with methylene chloride (20 ml). The organic phase was washed once with saturated brine (20 ml) and then concentrated. Methyl chloride / methanol = 10/1) gave compound 7A (250 mg, 30.1% yield). ^{1 H NMR (400MHz, CHLOROFORM-} d) δ8.54 (s, 1H), 7.38 (brd, J = 7.7Hz, 1H), 7.34-7.28 (m, 2H), 7.04 (d, J = 8.5Hz, 1H ), 2.90-2.78 (m, 4H), 2.60 (brs, 4H), 2.43 (s, 3H), 2.31 (s, 3H), 1.73 (brd, J = 5.3 Hz, 4H), 1.68-1.64 (m, 1H), 1.66 (brd, J = 5.4 Hz, 1H), 1.68-1.63 (m, 1H), 1.44 (s, 1H), 1.27 (brd, J = 4.6 Hz, 1H), 0.93-0.80 (m, 2H) ).

Compound 7:

To a solution of compound 7A (100 mg, 220 μmol, 1.00 eq.) and 2-dimethylphosphine oxide aniline (44.7 mg, 264 μmol, 1.2 eq.) in N,N-dimethylacetamide (3 mL) Methanesulfonic acid (63.5 mg, 661 micromoles, 47.1 microliters, 3 equivalents) was added, and the reaction solution was stirred at 130 ° C for 16 hours. The product was obtained by EtOAc (EtOAc) (EtOAc) Compound 7 (10.9 mg, 7.73% yield) was obtained after dichloromethane/methanol = 15/1. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ10.39 (s, 1H), 8.40-8.33 (m, 2H), 7.44 (brt, J = 7.6Hz, 1H), 7.36-7.28 (m, 3H), 7.20 -7.13(m,1H),7.06(brs,1H),6.99-6.91(m,1H),2.88-2.76(m,4H),2.44(brs,4H),2.32(s,3H),2.24(s , 3H), 1.84 (s, 3H), 1.80 (s, 3H), 1.71 (brs, 11H), 1.67-1.62 (m, 8H), 1.43 (s, 1H), 1.26 (s, 4H), 1.08- </ RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;

Example 8

Compound 8A:

Compound 12 (200 mg, 335 micromoles), cuprous iodide (12.8 mg, 66.9 micromoles), tetrakis(triphenylphosphine)palladium (77.4 mg, 66.9 micromoles), triphenyl at 60 °C Phosphine (35.1 mg, 134 μmol) was dissolved in DNF (3.00 mL). To this mixture was added trimethylsilylacetylene (165 mg, 1.67 mmol), triethylamine (169 mg, 1.68 mmol). Stir for 16 hours. LC-MS showed that the reaction was completed, and the reaction mixture was concentrated by filtration. The crude product was purified by preparative high-performance liquid chromatography (trifluoroacetic acid) to give compound 8A (62 mg, Yield 30.1%, yellow oil). LC-MS (ESI) (0-60.).

Compound 8:

Compound 8A (60 mg, 97.6 μmol) was dissolved in methanol (2.00 mL), and anhydrous potassium carbonate (26.9 mg, 195 micromoles) was added to the mixture and stirred for 15 minutes. TLC showed the completion of the reaction. Water (5 ml) was added to the mixture, and the mixture was extracted with dichloromethane (15 ml). The organic phase was combined and concentrated, and the crude product was purified by preparative high-performance liquid chromatography (trifluoroacetic acid) to give compound 8 (5.27 mg, yield 8.26%). ^{1 H NMR (400MHz, CD3OD)} δ8.25 (s, 1H), 8.11 (brs, 1H), 7.78 (brdd, J = 12.80,7.20Hz, 1H), 7.70 (brt, J = 7.20Hz, 1H), 7.62-7.93 (m, 1H), 7.35-7.60 (m, 3H), 5.99 (d, J = 6.00 Hz, 1H), 4.19 (s, 1H), 3.63 (brs, 4H), 3.48 (brd, J = 12.80 Hz, 2H), 3.18-3.30 (m, 2H), 2.94 (s, 3H), 2.48 (s, 3H), 1.99-2.32 (m, 5H), 1.90 (s, 3H), 1.75-1.88 (m , 6H). LCMS (ESI) (0-60AB): m/z: 543.2 [M+1].

Example 9

Compound 12 (100 mg, 167 micromoles, 1 equivalent), zinc powder (5.47 mg, 83.7 micromoles, 0.5 equivalents), bisbenzylideneacetone palladium (30.7 mg, 33.5 micromoles, 0.2 equivalents) at 25 °C 1,1'-bis(diphenylphosphino)ferrocene (18.6 mg, 33.5 micromoles, 0.2 equivalents) and Zn(CN)2 (39.3 mg, 334 micromoles, 21.2 microliters, 2 equivalents) were dissolved in The mixture was heated and stirred at 120 ° C for 12 hours under nitrogen atmosphere in DMF (5 mL). TLC showed the completion of the reaction. Water (5 ml) was added to the mixture, and the mixture was extracted with dichloromethane (15 ml). The organic phase was combined and concentrated, and the crude product was purified by preparative high-performance liquid chromatography (trifluoroacetic acid) to give compound 9 (4.90 mg, 9.01 micromolar, 5.39% yield). ¹ H NMR (400 MHz, CD 3 OD) δ 8.27 (s, 1H), 8.06 (brs, 1H), 7.57 (brdd, J = 12.80, 7.20 Hz, 1H), 7.62 - 7.93 (m, 5H), 7.84 (s) , 1H), 2.71 (t, J = 6 Hz, 4H), 2.5 (m, 4H), 2.29 (s, 3H), 2.74 (s, 3H), 2.71 (s, 3H), 1.57 (m, 8H). LC-MS (ESI) (0-60.).

Example 10

Compound 10A:

The compound 2,4-dichloro-5,6-dimethyl (200 mg, 1.13 mmol, 1 eq.) and 2-dimethylphosphoranilide (191 mg, 1.13 mmol, 1 eq.) were dissolved in N -Methylpyrrolidone (2 ml), followed by DIEA (584 mg, 4.52 mmol, 789 microliters, 4 eq.) under a nitrogen atmosphere. The mixture was stirred at 135 ° C for 8 hours, and TLC showed that the material was consumed. The reaction mixture was diluted with ethyl acetate and then washed three times with brine (40 ml). The organic phase was dried over anhydrous sodium sulfate and then dried. The residue obtained was isolated using a preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to afford compound 10A (120 mg, 387 micromoles, 34.3% yield). ^{1 H NMR (400MHz, CD3OD)} δ8.65 (m, 1H), 7.55 (m, 1H), 7.32 (m, 1H), 7.11 (m, 1H), 7.84 (s, 1H), 2.71 (t, J =6 Hz, 4H), 2.5 (m, 4H), 2.29 (s, 3H), 2.74 (s, 3H), 1.80 (s, 3H), 1.83 (s, 3H). LC-MS (ESI) (0- 60AB): m/z: 544.2 [M+1].

Compound 10:

Prepared according to the method of compound 2, replacing 2,5-dichloro-N-(2-dimethylphosphorylphenyl)pyrimidine-4-amine with 2-chloro-N-(2-(dimethylphosphoryl) Phenyl)-5,6-dimethylpyrimidin-4-amine gave compound 10 (430 mg, 694 micromoles, 55.9% yield, 99.7% purity). ^{1 H NMR (400MHz, DMSO-} d6) δ = 8.39 (m, 1H), 7.59 (m, 1H), 7.47 (m, 1H), 7.33 (s, 1H), 7.24 (m, 2H), 6.97 (s , 1H), 3.38 (m, 8H), 2.88 (s, 3H), 2.85 (m, 4H), 2.37 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H), 1.82 (m, 8H). LC-MS (ESI) (5-95.

Example 11

Compound 11A:

Prepared according to the method of compound 10A, 2,4-dichloro-5,6-dimethylpyrimidine was replaced with 2,4-dichloro-5-methoxypyrimidine to give compound 11A (430 mg, 694 μmol, 55.9) % yield, 99.7% purity). ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 11.22 (brs, 1H), 8.92-8.61 (m, 1H), 7.68 (s, 1H), 7.50 (brd, J = 1.1 Hz, 1H), 7.20-7.15 (m, 1H), 7.08-7.01 (m, 1H), 3.91 (s, 3H), 1.78 (s, 3H), 1.75 (s, 3H). LC-MS (ESI) (??

Compound 11:

According to the method of Compound 2, 2,5-dichloro-N-(2-dimethylphosphorylphenyl)pyrimidine-4-amine was replaced with Compound 11A to give Compound 11. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 10.79 (s, 1H), 8.75 (dd, J = 4.5,8.6Hz, 1H), 7.68-7.61 (m, 1H), 7.39 (brt, J = 8.1Hz , 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.27-7.22 (m, 1H), 7.16 (brd, J = 7.6 Hz, 1H), 6.98 (brt, J = 7.2 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.63-6.54 (m, 1H), 3.86-3.82 (m, 3H), 2.78-2.71 (m, 4H), 2.31 (brs, 4H), 2.22 (s, 3H) ), 1.79-1.76 (m, 4H), 1.75-1.72 (m, 4H), 1.65-1.56 (m, 11H). LC-MS (ESI) (0-60.

Example 12

Prepared according to the method of compound 2, replacing 2,5-dichloro-N-(2-dimethylphosphorylphenyl)pyrimidine-4-amine with 5-bromo-2-chloro-N-(2-(2) Methylphosphoryl)phenyl)pyrimidine-4-amine gave compound 12 (5.00 g, 13.9 mmol, 63.2% yield).

Example 13

Compound 13A:

Prepared according to the method of Compound 10A, 2,4-dichloro-5,6-dimethylpyrimidine was replaced with 2,4-dichloro-5-methylpyrimidine to give compound 13A (260 mg, yield: 13.0%). ^{1 H NMR (400MHz, CDCl3)} δ = 10.96 (brs, 1H), 8.76 (dd, J = 8.80,4.80Hz, 1H), 8.01 (d, J = 1.2,1H), 7.58 (m, 1H), 7.23 -7.27 (m, 1H), 7.11-7.15 (m, 1H), 2.25 (s, 3H), 1.85 (s, 3H), 1.81 (s, 3H). LC-MS (ESI) (0-60AB): m/z: 296.0 [M + 1].

Compound 13:

Preparation according to the procedure of Compound 2, 2,5-dichloro-N-(2-dimethylphosphorylphenyl)pyrimidine-4-amine was replaced with Compound 13A to give Compound 13 (116 mg, yield: 25.6%). ^{1 H NMR (400MHz, CD3Cl)} δ10.40 (s, 1H), 8.75 (dd, J = 8.80,4.80Hz, 1H), 7.90 (S, 1H), 7.43 (td, J = 8.00Hz, 1H), 7.31-7.36 (m, 2H), 7.23 (dd, J = 14.00, 7.60 Hz, 1H), 7.02-7.07 (m, 1H), 6.98 (d, J = 7.20, 1H), 6.86 (s, 1H), 2.82 (m, 4H), 2.40 (brs, 4H), 2.29 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H), 1.83 (s, 3H), 1.80 (s, 3H), 1.62 (m, 8H). LC-MS (ESI) (.

Example 14

Compound 14A:

Prepared according to the method of Compound 10A, 2,4-dichloro-5,6-dimethylpyrimidine was replaced with 2,4-dichloro-5-ethylpyrimidine to give Compound 14A (120 mg, yield 25.0%). ^{1 H NMR (400MHz, CDCl3)} δ10.95 (brs, 1H), 8.76 (dd, J = 8.40,4.80Hz, 1H), 8.04 (s, 1H), 7.58 (t, J = 8.00Hz, 1H), 7.22-7.30 (m, 1H), 7.22-7.31 (m, 1H), 7.10-7.15 (m, 1H), 2.63-2.71 (m, 2H), 2.01 (s, 1H), 1.85 (s, 3H), 1.82 (s, 3H), 1.60-1.75 (m, 2H), 1.24-1.39 (m, 4H). LC-MS (ESI) (0-60AB): m/z: 310.0

Compound 14:

Prepared according to the method of Compound 10A, and 2,4-dichloro-5,6-dimethylpyrimidine was replaced with Compound 14A to give Compound 14 (35.2 mg, yield 15.5%). ^{1 H NMR (400MHz, CD3OD)} δ8.26 (dd, J = 8.00,4.00Hz, 1H), 7.66-7.82 (m, 3H), 7.59 (d, J = 2.00Hz, 1H), 7.49 (brdd, J =8.80, 2.40 Hz, 2H), 3.77 (brd, J = 16.00 Hz, 4H), 3.49 (brd, J = 12.00 Hz, 2H), 3.27 (brs, 2H), 2.95 (s, 3H), 2.64 - 2.77 (m, 5H), 2.55 (s, 3H), 2.03-2.44 (m, 5H), 1.91 (s, 3H), 1.87 (s, 3H), 1.29-1.38 (m, 3H). LC-MS (ESI) (0-60AB): m/z: 547.1 [M+1].

Example 15

Compound 15A:

Prepared according to the method of compound 4A, replacing 3-methyl-3,9-diazaspiro[5.5]undecane with tert-butyl-2,8-diazaspiro[4.5]decane-8-carboxylate Ethyl acetate gave compound 15A (80 mg, 9.42% yield). ^{1 H NMR (400MHz, CHLOROFORM-} d) δ: 8.01 (d, J = 2.4Hz, 1H), 7.98 (s, 1H), 6.66 (d, J = 2.4Hz, 1H), 3.60 (m, 2H), 3.48 (m, 4H), 2.45 (s, 3H), 1.62 (m, 8H), 1.48 (s, 9H).

Compound 15B:

Compound 15A (120 mg, 332 micromoles, 1 equivalent), trifluoroacetic acid (500 mg, 4.39 mmol, 325 μL, 13 eq) was dissolved in dichloromethane (2 mL). Stir for 1 hour. The TLC monitoring reaction was completed. The reaction mixture was dried and concentrated to give Compound 15B (l. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ: 7.92 (d, J = 2.4Hz, 1H), 7.91 (s, 1H), 6.62 (d, J = 2.4Hz, 1H), 3.53 (m, 2H), 3.28 (m, 6H), 2.35 (s, 3H), 1.92 (m, 8H).

Compound 15C:

Compound 15B (120 mg, 319 μmol), paraformaldehyde (43.2 mg, 479 μmol, 1.5 equivalents) and potassium carbonate (88.4 mg, 639 μmol, 2 equivalents) were dissolved in methanol under nitrogen at 30 °C. (2 ml), sodium cyanoborohydride was added in portions and stirred for 16 hours. The reaction was completed by TLC and the reaction was concentrated in vacuo. Water was added to the concentrate and extracted three times with dichloromethane, the organic phases were combined and dried in vacuo then concentrated. The crude product was purified by column chromatography to afford compound 15C (60.0 mg, 218 ^{1 H NMR (400MHz, CHLOROFORM-} d) δ: 7.92 (d, J = 2.4Hz, 1H), 7.89 (s, 1H), 6.56 (d, J = 2.4Hz, 1H), 3.50 (m, 2H), 3.39 (m, 4H), 2.37 (s, 3H), 2.23 (s, 3H), 1.60 (m, 8H).

Compound 15D:

Prepared according to the procedure of Compound 1D, Compound 1C was replaced by 15C to give compound 15D (70.0 mg, 269 mmol, 60.1% yield). ^{1 H NMR (400MHz, CHLOROFORM-} d) δ: 6.74 (d, J = 2.4Hz, 1H), 6.67 (s, 1H), 6.42 (d, J = 2.4Hz, 1H), 3.01 (m, 2H), 2.31 (m, 4H), 2.20 (s, 3H), 2.16 (s, 3H), 1.63 (m, 8H).

Compound 15:

This compound was prepared according to the procedure of Compound 1E, and Compound 1E was replaced by 15D to give Compound 15 (25.8 mg, 47.8 mmol, 23.1% yield). ^{1 H NMR (400MHz, CHLOROFORM-} d) δ: 10.91 (s, 1H), 8.65 (d, J = 2.4Hz, 1H), 8.51 (s, 1H), 8.06 (s, 1H), 7.45 (m, 1H ), 3.01 (m, 2H), 2.31 (m, 4H), 2.20 (s, 3H), 2.16 (s, 3H), 1.63 (m, 8H).

Example 16

Compound 16A:

Prepared according to the method of compound 4A, replacing 3-methyl-3,9-diazaspiro[5.5]undecane with tert-butyl 2,7-diazaspiro[3.5]decane-2-carboxylic acid Ethyl ester gave compound 16A (120 mg, 332 micromoles, 75.1% yield). ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 8.09-8.01 (m, 2H), 6.99 (d, J = 8.4Hz, 1H), 3.73 (s, 4H), 2.98-2.91 (m, 4H), 2.37 (s, 3H), 1.98-1.91 (m, 4H), 1.48 (s, 9H).

Compound 16B:

Prepared according to the method of Compound 15B, Compound 15A was replaced with 16A to give Compound 16B (120 mg, crude). ^{1 H NMR (400MHz, METHANOL-} d4) δ = 8.10-8.01 (m, 2H), 7.14 (d, J = 8.8Hz, 1H), 3.94 (s, 4H), 3.02-2.94 (m, 4H), 2.39 (s, 3H), 2.10-2.04 (m, 4H).

Compound 16C:

Prepared according to the procedure of Compound 15C, Compound 15B was replaced with Compound 16B to afford compound 16C (60.0 mg, 218 micromoles, 68.2% yield). 1H NMR (400MHz, CHLOROFORM-d) δ=7.99-7.92 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H), 3.09 (s, 4H), 2.89-2.79 (m, 4H), 2.35 ( s, 3H), 2.27 (s, 3H), 1.93-1.83 (m, 4H).

Compound 16D:

Prepared according to the method of Compound 1D, Compound 1C was replaced with Compound 16C to give Compound 16D (50 mg, crude). ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 6.82 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 6.49 (dd, J = 8.4 Hz, 1H), 3.11 (s) , 4H), 2.72-2.65 (m, 4H), 2.38 (s, 3H), 2.22 (s, 3H), 1.88-1.85 (m, 4H).

Compound 16:

Prepared according to the procedure of Compound 1, Compound 1D was replaced with Compound 16D to give Compound 16 (11.0 mg, 19.3 micromoles, 9.45% yield). ^{1 H NMR (400MHz, METHANOL-} d4) δ = 8.49-8.38 (m, 3H), 8.06 (s, 1H), 7.63 (ddd, J = 1.2,7.8,14.1Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.31 - 7.23 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 4.03 (brs, 4H), 2.97 (s, 3H), 2.85-2.75 (m, 4H), 2.23 (s, 3H), 2.04 (brt, J = 5.2 Hz, 4H), 1.88 (s, 3H), 1.85 (s, 3H). LC-MS (ESI) (5-95.

Example 17

Compound 12 (150 mg, 251 μmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (63.3 mg, at 100 ° C, 377 μmol, sodium carbonate (53.2 mg, 502 μmol) was dissolved in DME (3 ml) and water (0.5 ml). To this mixture was added tetrakis(triphenylphosphine)palladium (29 mg, 25.1 μmol) ), stirring for 12 hours. LC-MS showed the reaction was completed, water (10 ml) was added to the mixture, and the mixture was extracted with dichloromethane (40 ml). The organic phase was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 17 (70 mg, yield 45.9%). ^{1 H NMR (400MHz, DMSO)} δ10.36 (s, 1H), 9.02 (s, 1H), 8.55 (brd, J = 4.40Hz, 1H), 8.32 (s, 2H), 7.91 (s, 1H), 7.38-7.55 (m, 4H), 7.11 (t, J = 7.40 Hz, 1H), 6.94 (d, J = 8.80 Hz, 1H), 5.23 (s, 1H), 5.08 (s, 1H), 2.72-2.75 (m, 4H), 2.34 - 2.38 (m, 4H), 2.22 (s, 3H), 2.16 (s, 3H), 2.04 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H), 1.49-1.59 (m, 8H). LCMS (ESI) (.

Example 18

Prepared according to the procedure of compound 1, substituting compound 1D for 3-chloro-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)aniline to give compound 18 (29.0 mg) , 46.4 micromolar, 16.7% yield, 98.8% purity). ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.72 (brs, 4H) 1.83 (d, J = 13.18 Hz, 9H), 1.83 (brs, 1H), 2.65 (s, 3H), 2.84 - 3.12 (m, 8H) 6.96 (d, J = 8.66 Hz, 1H) 7.14 (td, J = 7.47, 1.38 Hz, 1H) 7.23 (dd, J = 8.66, 2.38 Hz, 1H) 7.30 (td, J = 6.96, 1.25 Hz, 1H) 7.36 (brs, 1H) 7.54 (t, J = 7.91 Hz, 1H) 7.75 (d, J = 2.51 Hz, 1H) 8.17 (s, 1H) 8.46 (dd, J = 8.34, 4.33 Hz, 1H) 8.52 - 8.57 ( m, 1H) 10.62-10.72 (m, 1H) 10.67 (s, 1H).

Example 19

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 5B to give Compound 19 (64.5 mg, 97.1 micromoles, 29.9% yield, 99.8% purity). 1H NMR (400MHz, CHLOROFORM-d) δppm 1.73-1.77 (m, 4H) 1.82-1.85 (m, 7H) 1.88 (s, 3H) 2.62 (s, 3H) 2.89-2.99 (m, 8H) 6.97-7.02 ( m,2H)7.13-7.19(m,1H)7.30-7.36(m,2H)7.54-7.60(m,1H)7.90(d,J=2.51Hz,1H)8.21(s,1H)8.48(dd,J = 8.09, 4.20 Hz, 1H) 8.57 (s, 1H) 10.70 (s, 1H).

Example 20

Compound 20A:

Prepared according to the procedure of Compound 4A, 1-fluoro-2-methyl-4 nitro. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 7.85 (s, 1H), 7.02 (s, 1H), 2.99-2.94 (m, 4H), 2.42 (brs, 4H), 2.32 (d, J = 4.1Hz , 6H), 1.65 (brs, 8H). LC-MS (ESI) (5-95CD): m/z: 338.1 [M+1].

Compound 20B:

Prepared according to the method of Compound 2B, Compound 2A was replaced with Compound 20A to give Compound 20B (110 mg, crude). ¹ H NMR (400 MHz, CHLOROFORM-d) δ=6.95 (s, 1H), 6.64 (s, 1H), 2.78-2.74 (m, 4H), 2.65 (brd, J = 4.9 Hz, 4H), 2.20 (s , 3H), 1.92 (brs, 3H), 1.71-1.66 (m, 8H). LC-MS (ESI) (5-95CD): m/z: 308.1 [M+1].

Compound 20:

This compound was prepared according to the procedure of Compound 2, and 2B was replaced with Compound 20B to give Compound 20 (430 mg, 694 μmol, 55.9% yield, 99.7% purity). ^{1 H NMR (400MHz, DMSO-} d6) δ = 8.72 (s, 1H), 8.43 (brdd, J = 4.2,8.1Hz, 1H), 8.29 (s, 2H), 8.10 (s, 1H), 7.53 (ddd , J=1.4, 7.7, 14.1 Hz, 1H), 7.35 (s, 1H), 7.22 (brt, J = 7.6 Hz, 1H), 7.14 (s, 1H), 7.11-7.04 (m, 1H), 2.85- 2.76 (m, 4H), 2.44 (brs, 4H), 2.26 (s, 3H), 2.20 (s, 3H), 1.79 (s, 3H), 1.75 (s, 3H), 1.62-1.51 (m, 8H) . LC-MS (ESI) (5-95.

Example 21

Compound 12 (30.0 mg, 53.7 micromoles) was dissolved in methanol (3 mL). To this mixture was added wet palladium carbon (30 mg, 10%), and replaced with hydrogen three times to continue hydrogen protection at 50 °C. Stir under (15 psi) for 1 hour. LC-MS showed the reaction was completed, filtered, and organic layer was concentrated to afford compound 21 (21.5 mg, yield 66.3%). ^{1 H NMR (400MHz, CD3OD)} δ8.40 (dd, J = 8.00,4.65Hz, 1H), 7.83 (s, 1H), 7.46 (dd, J = 14.40,8.00Hz, 1H), 7.37 (brt, J = 8.00 Hz, 1H), 7.19 (d, J = 2.40 Hz, 1H), 7.04-7.15 (m, 2H), 6.85 (d, J = 8.40 Hz, 1H), 2.93 - 3.00 (m, 1H), 2.67 -2.77 (m, 4H), 2.37 (brs, 4H), 2.19 (s, 3H), 2.11 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H), 1.54 (m, 8H), 1.21 (brs, 3H), 1.19 (s, 3H). LCMS (ESI) (0-60AB): m/z:

Example 22

Compound 22A:

5-Bromo-2-chloro-N-(2-dimethylphosphorylphenyl)pyrimidin-4-amine (200 mg, 527 μmol, 1 equivalent), cyclopropylboronic acid (under normal nitrogen) 54.3 mg, 632 μmol, 1.20 equivalents), tricyclohexylphosphine (29.6 mg, 105 μmol, 340 μL, 0.20 equivalent), palladium acetate (11.8 mg, 52.7 μmol, 0.1 equivalent) and potassium phosphate (279) Milligrams, 1.32 mmol, 2.5 eq.) were dissolved in toluene and water, warmed to 110 ° C and stirred for 16 hours. The reaction was monitored by LC-MS. The reaction solution was filtered, and the filtrate was dried under vacuum. The concentrate was dissolved in water (5 ml), EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography to afford compound 22A (150 mg, 466. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 10.99 (brs, 1H), 8.72 (dd, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.60 (dt, J = 8.0 Hz, 1H), 7.34-7.28(m,1H), 7.18-7.12(m,1H),1.85(s,3H),1.82(s,3H),1.45-1.38(m,1H),1.16-1.09(m,2H), 0.68-0.63 (m, 2H).

Compound 22:

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 22A to afford Compound 22 (20.9 mg, 35.7 micromoles, 7.66% yield, 95.5% purity). ^{1 H NMR (400MHz, DMSO-} d6) δ = 10.74 (s, 1H), 8.74 (dd, J = 8.4Hz, 1H), 8.51 (s, 1H), 7.84 (s, 1H), 7.56-7.42 (m , 3H), 7.39 (dd, J = 8.0 Hz, 1H), 7.12 (brt, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 2.80-2.75 (m, 4H), 2.36 -2.33 (m, 4H), 2.22-2.18 (m, 6H), 1.82-1.79 (m, 3H), 1.78-1.75 (m, 3H), 1.72-1.66 (m, 1H), 1.60-1.56 (m, 4H), 1.56-1.52 (m, 4H), 0.97-0.91 (m, 2H), 0.61-0.55 (m, 2H).

Example 23

To a mixture of compound 12 (60.0 mg, 100 μmol, 1 equivalent) and pinacol benzoate (30.7 mg, 151 μmol, 1.5 eq.) in ethylene glycol dimethyl ether (3 ml) and water (600 μl) Tetrakis(triphenylphosphine)palladium (17.4 mg, 15.1 μmol, 0.15 equivalent) and sodium carbonate (21.3 mg, 201 μmol, 2 equivalents) were added to the solution, and the reaction mixture was stirred at 100 ° C for 3 hours under nitrogen atmosphere. LC-MS showed a portion of the starting material and product and continued to react for three hours. After completion of the reaction, the mixture was filtered. EtOAc mjjjjjjjj ^{1 H NMR (400MHz, CHLOROFORM-} d) δ9.65 (s, 1H), 8.40 (dd, J = 4.5,8.8Hz, 1H), 8.04 (s, 1H), 7.53 (s, 1H), 7.53-7.44 (m, 4H), 7.44 - 7.39 (m, 1H), 7.38-7.33 (m, 2H), 7.24 (brd, J = 7.4 Hz, 1H), 7.14 - 7.06 (m, 1H), 6.97 (d, J = 8.9 Hz, 1H), 6.85 (s, 1H), 2.84 - 2.79 (m, 4H), 2.44 (brd, J = 0.8 Hz, 4H), 2.32 (s, 3H), 2.27-2.23 (m, 3H) , 1.69 (s, 3H), 1.66 (s, 3H), 1.63 (brd, J = 5.6 Hz, 8H), 0.97 (d, J = 6.7 Hz, 1H), 0.93 - 0.78 (m, 5H). LC-MS (ESI) (5-95.

Example 24

Compound 24A:

This compound was prepared according to the procedure of Compound 4A, and 1-fluoro-2-methyl-4 nitro was replaced by 2-fluoro-5-nitrobenzonitrile to give compound 24A (400 mg, 1.27 mmol, 42.3% yield) . ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.42 (d, J = 2.8 Hz, 1H), 8.24 (dd, J = 2.8, 9.3 Hz, 1H), 6.95 (d, J = 9.3 Hz, 1H), 3.56-3.47 (m, 4H), 2.46 (brs, 4H), 2.33 (s, 3H), 1.75-1.69 (m, 4H), 1.66 (t, J = 5.6 Hz, 4H). LC-MS (ESI) (5-95AB): m/z: 315.1 [M+1].

Compound 24B:

Prepared according to the method of Compound 2B, Compound 2A was replaced with Compound 24A to give Compound 24B (270 mg, crude). ^{1 H NMR (400MHz, DMSO-} d6) δ = 7.04-6.94 (m, 1H), 6.86-6.77 (m, 2H), 5.32-5.13 (m, 2H), 3.28-2.99 (m, 4H), 2.88 ( Brs, 4H), 2.71 (s, 3H), 1.90-1.42 (m, 8H). LC-MS (ESI) (0-60AB): m/z: 285.0 [M+1].

Compound 24:

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 24B to give Compound 24 (65.4 mg, 107 micromoles, 33.9% yield). ^{1 H NMR (400MHz, DMSO-} d6) δ = 11.20-11.13 (m, 1H), 9.55 (s, 1H), 8.57-8.47 (m, 1H), 8.25 (s, 1H), 8.22 (s, 1H) , 8.05-8.00 (m, 1H), 7.74-7.68 (m, 1H), 7.65-7.55 (m, 2H), 7.23-7.16 (m, 1H), 7.16-7.11 (m, 1H), 3.06-2.99 ( m, 4H), 2.55-2.52 (m, 4H), 2.32 (s, 3H), 1.82-1.79 (m, 3H), 1.77 (s, 3H), 1.64-1.58 (m, 4H), 1.58-1.52 ( m, 4H). LC-MS (ESI) (??

Example 25

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 24B to give Compound 25 (45.4 mg, 65.2 micromoles, 37.1% yield, 94.0% purity). ^{1 H NMR (400MHz, DMSO-} d6) δ = 10.86 (brs, 1H), 9.54 (brs, 1H), 8.38 (brs, 1H), 8.30 (brs, 2H), 8.00 (brs, 1H), 7.75-7.67 (m, 1H), 7.65-7.53 (m, 2H), 7.26-7.16 (m, 1H), 7.16-7.06 (m, 1H), 3.02 (brs, 4H), 2.60-2.54 (m, 4H), 2.31 (brs, 3H), 1.78 (brd, J = 13.4 Hz, 6H), 1.68-1.48 (m, 8H). LC-MS (ESI) (0-60AB): m/z: 609.9 [M+1].

Example 26

Compound 26A:

Prepared according to the procedure of compound 4A, substituting 1-fluoro-2methyl-4 nitro to 1,3-dichloro-2-fluoro-5-nitrobenzene to give compound 26A (120 mg, 335 micromoles, 23.4) % yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57-1.61 (m, 4H) 1.68 (brt, J = 5.62 Hz, 4H) 2.41 (s, 3H) 2.58 (brs, 4H) 3.17-3.21 (m, 4H) 8.07 (s, 2H).

Compound 26B:

Prepared according to the method of Compound 2B, Compound 2A was replaced with Compound 26A to give Compound 26B (103 mg, crude). ^{1 H NMR (400MHz, DMSO-} d6) δppm 1.48 (brs, 8H) 2.19 (s, 3H) 2.20-2.21 (m, 1H) 2.32-2.35 (m, 4H) 2.94-2.99 (m, 4H) 6.54 (s , 2H).

Compound 26:

Prepared according to the procedure of Compound 2, Compound 2A was replaced with Compound 27B to give Compound 26 (15.7 mg, 24.7 micromoles, 16.3% yield, 96.1% purity). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.54 (brd, J = 5.01 Hz, 8H) 1.77 (s, 3H) 1.81 (s, 3H) 2.28 (s, 3H) 2.44-2.49 (m, 4H) 3.02 -3.07(m,4H)7.21(t,J=7.03Hz,1H)7.54-7.66(m,2H)7.74(s,2H)8.24-8.32(m,3H)8.49(brs,1H)9.67(s, 1H) 11.17 (brs, 1H).

Example 27

Prepared according to the method of Compound 2, Compound 2A was replaced with 3-fluoro-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenylamine to give Compound 27 (53.9 mg , 89.1 micromolar, 24.7% yield, 99.7% purity). ^{1 H NMR (400MHz, DMSO-} d6) δ = 11.13 (s, 1H), 11.17-11.09 (m, 1H), 9.45 (s, 1H), 8.55 (brs, 1H), 8.28 (s, 2H), 8.20 (s, 1H), 7.66-7.57 (m, 2H), 7.56-7.50 (m, 1H), 7.28-7.17 (m, 2H), 7.00-6.92 (m, 1H), 2.94-2.87 (m, 4H) , 2.63-2.56 (m, 4H), 2.36 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H), 1.62-1.52 (m, 8H). LC-MS (ESI) (0-60AB ): m/z: 557.1 [M+1].

Example 28

Compound 28A:

The material 1,4-dichloro-2-fluorobenzene (1.00 g, 6.06 mmol, 1.00 equiv) was dissolved in concentrated sulfuric acid (2.97 g, 30.3 mmol, 1.62 mL, 5 eq.) and the temperature was cooled to 0 ° C. Then, concentrated nitric acid (587 mg, 6.06 mmol, 419 μL, 65% purity, 1.00 equivalent) was added dropwise, and then the solution was stirred at 25 ° C for 3 h. The TLC shows that the raw material is consumed and a new point is generated. The mixture was poured into an ice-water mixture (70 ml) and ethyl acetate (40 ml). The obtained organic phase was washed twice with aq. The residue obtained was purified using column chromatography (EtOAc) eluting to afford Compound 28A (450 mg, 2.14 mmol, 35.4% yield). ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 8.10 (d, J = 6.9Hz, 1H), 7.42 (d, J = 8.2Hz, 1H).

Compound 28B:

Prepared according to the procedure of compound 4A, substituting 1-fluoro-2methyl-4 nitro to 1,4-dichloro-2-fluoro-5-nitrobenzene to give compound 28B (320 mg, 893 micromoles, 62.5 % yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ=8.08 (s, 1H), 7.08-7.02 (m, 1H), 3.20-3.12 (m, 4H), 2.41 (brs, 4H), 2.31 (s, 3H) , 1.72-1.66 (m, 4H), 1.62 (t, J = 5.6 Hz, 4H).

Compound 28C:

Prepared according to the method of Compound 2B, Compound 2A was replaced with Compound 28B to give Compound 28C (100 mg, crude). ¹ H NMR (400 MHz, CHLOROFORM-d) δ=7.01 (s, 1H), 6.84 (s, 1H), 2.92-2.82 (m, 5H), 2.41 (brs, 4H), 2.31 (s, 4H), 1.68- 1.64 (m, 4H), 1.62 (brt, J = 5.5 Hz, 4H).

Compound 28:

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 28C to give Compound 28 (15.3 mg, 22.7 micromoles, 7.44% yield, 97.1% purity). ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.47 (brs, 1H), 8.27 (dd, J = 4.4, 8.2 Hz, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7. 7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.23-7.17 (m, 2H), 3.29 (td, J = 1.7, 3.3 Hz, 3H), 3.25-3.12 (m, 3H) , 3.01-2.93 (m, 4H), 2.84 (s, 3H), 1.84 (s, 3H), 1.81 (s, 3H), 1.74 (brs, 4H).

Example 29

Prepared according to the method of Compound 2, Compound 2A was replaced with 3-fluoro-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)aniline to give Compound 29 (44.7 mg , 68.8 micromolar, 24.8% yield, 99.6% purity). ^{1 H NMR (400MHz, DMSO-} d6) δ = 10.83 (s, 1H), 9.44 (s, 1H), 8.44-8.36 (m, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.61 (s, 2H), 7.56-7.50 (m, 1H), 7.27-7.18 (m, 2H), 6.98-6.90 (m, 1H), 2.93-2.86 (m, 4H), 2.53 (d, J = 2.0 Hz) , 4H), 2.30 (s, 3H), 1.80 (s, 3H), 1.76 (s, 3H), 1.62-1.48 (m, 8H). LCMS (ESI) (0-60AB): m/z: 603.0 [ M+1].

Example 30

Compound 30A:

To a solution of compound 24A (60.0 mg, 191 μmol, 1.00 eq.) in acetonitrile (2.00 mL), N-chlorosuccinimide (28.0 mg, 210 μmol, 1.1 eq.). Stir for 1 hour. TLC showed the reaction was completed, and the reaction mixture was concentrated and purified by preparative chromatography to afford compound 30A (45 mg, 129 micromoles, 67.6% yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ=8.38-8.35 (m, 1H), 8.34-8.32 (m, 1H), 3.54-3.46 (m, 4H), 2.53-2.42 (m, 4H), 2.34 ( s, 3H), 1.75-1.64 (m, 8H). LC-MS (ESI) (0-60.

Compound 30B:

Prepared according to the procedure of Compound 2B, Compound 2A was replaced with Compound 30A to afford Compound 30B (20.0 mg, 62.7 micromoles, 48.6% yield). LC-MS (ESI) (5-95CD): m.

Compound 30:

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 30B to give Compound 30 (5.70 mg, 8.85 micromoles, 14.1% yield, 98.6% purity). ¹ H NMR (400 MHz, METHANOL-d4) δ=8.27 (s, 1H), 8.12-8.05 (m, 1H), 7.77 (s, 2H), 7.73 (s, 1H), 7.71-7.65 (m, 1H) , 7.50-7.43 (m, 1H), 3.47-3.38 (m, 2H), 3.32-3.28 (m, 4H), 3.28-3.18 (m, 2H), 2.92 (s, 3H), 2.13 - 2.05 (m, 2H), 1.91 (s, 5H), 1.88 (s, 3H), 1.79-1.65 (m, 4H). LC-MS (ESI) (0-60AB): m/z: 598.0 [M+1].

Example 31

Prepared according to the method of compound 26, replacing (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide with (2-((5-bromo-2-chloropyrimidine) 4-yl)amino)phenyl)dimethylphosphine oxide gave compound 31 (1 mg, 1.52 micromoles, 2.49% yield, 99% purity) as a white solid. ^{1 H NMR (400MHz, METHANOL-} d4) δ = 8.54 (s, 1H), 8.28 (m, 2H), 7.66 (m, 2H), 7.65 (s, 1H), 7.35 (m, 1H), 3.16 (m , 8H), 1.76 (s, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.71 (m, 8H). LC-MS (ESI) (0-60AB): m/z: 651.0 [ M+1].

Example 32

Compound 32A:

Prepared according to the method of compound 4A, replacing compound 1B with 3-benzyl-9-(4-nitro-2-(trifluoromethyl)phenyl)-3,9-diazaspiro[5.5] The alkane gave compound 32A (2.40 g, 5.54 mmol, 57.92% yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.50 (d, J = 2.7 Hz, 1H), 8.28 (dd, J = 2.7, 9.0 Hz, 1H), 7.36-7.30 (m, 4H), 7.29-7.25 (m, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.24 - 7.19 (m, 1H), 7.24 - 7.19 (m, 1H), 3.53 (s, 2H), 3.17 - 3.08 (m, 4H) ), 2.44 (brt, J = 5.4 Hz, 4H), 1.69 - 1.51 (m, 8H).

Compound 32B:

Compound 32A (2.40 g, 5.54 mmol, 1.00 eq.) was added to dichloromethane (20 mL), EtOAc (1·········· After completion of the reaction, it was diluted with petroleum ether (40 ml) and filtered, and then filtered and dried to afford compound 32B (3.00 g, 5.21 mmol, 94.1% yield). ^{1 H NMR (400MHz, DMSO-} d6) δ = 8.43-8.36 (m, 2H), 7.61-7.50 (m, 6H), 4.64 (s, 2H), 3.54-3.37 (m, 2H), 3.31-3.29 ( m,1H), 3.24 (brd, J = 12.7 Hz, 2H), 3.14 (td, J = 5.5, 10.7 Hz, 4H), 2.94 (s, 3H), 2.58-2.52 (m, 2H), 2.02-1.89 (m, 2H), 1.88-1.74 (m, 4H), 1.68 (brs, 2H).

Compound 32C

Compound 32B (3.00 g, 6.69 mmol, 1.00 eq.) was dissolved in NMP (30 mL). Grams, 20% by weight) and acetic acid (1.21 g, 20.07 mmol, 1.15 ml, 3.00 equiv). The mixture was heated to 80 ° C psi under hydrogen pressure for 18 hours. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was adjusted to pH 11 with sodium hydroxide.

Compound 32

Prepared according to the procedure of Compound 2, Compound 2A was replaced with Compound 32B to give Compound 32 (89.9 mg, 144 micromoles, 45.4% yield, 96.9% purity). ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ=8.23 (s, 1H), 8.12 (brs, 1H), 7.77-7.57 (m, 4H), 7.54-7.39 (m, 2H), 4.96 (s, 20H) ), 3.40 (brd, J = 12.5 Hz, 2H), 3.21 (brt, J = 12.3 Hz, 2H), 3.03 - 2.93 (m, 4H), 2.90 (s, 3H), 2.10 (brd, J = 14.7 Hz) , 2H), 1.89 (s, 3H), 1.86 (s, 3H), 1.78-1.68 (m, 2H), 1.68-1.61 (m, 2H). LC-MS (ESI) (5-95AB): m/ z: 607.1 [M+1].

Example 33

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 32C to Compound 33 (85.9 mg, 122 micromoles, 44.8% yield, 97.6% purity). ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.29 (s, 1H), 8.02 (brs, 1H), 7.74-7.66 (m, 2H), 7.63-7.48 (m, 3H), 7.46-7.39 (m, 1H), 4.91 (s, 21H), 3.52-3.44 (m, 1H), 3.44-3.37 (m, 2H), 3.20 (brt, J = 12.3 Hz, 2H), 2.97-2.91 (m, 4H), 2.90 (s, 3H), 2.09 (brd, J = 14.4 Hz, 2H), 1.88 (s, 3H), 1.85 (s, 3H), 1.78-1.62 (m, 4H). LC-MS (ESI) (5- 95AB): m/z: 651.0 [M+1].

Example 34

Compound 34A:

Prepared according to the method of compound 1C, replacing compound 1B with tert-butyl-6-(2-methyl-4-nitro-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate The acid ester gave Compound 34A (1.1 g). ¹ H NMR (400 MHz, CDCl ₃ ): 7.97 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 6.30 (d, J = 8.8 Hz, 1H) , 4.25 (s, 4H), 4.12 (s, 4H), 2.30 (s, 3H), 1.45 (s, 9H). LCMS (ESI) (5-95AB): m/z: 334.1 [M+1].

Compound 34B:

Prepared according to the method of Compound 2B, Compound 2A was replaced with Compound 34A to give Compound 34B (1.15 g, crude). LC-MS (ESI) (5-95.

Compound 34C:

Compound 34B (1.2 g, 1 eq.) and 2,5-dichloro-N-(2-dimethylphosphinophenyl)pyrimidin-4-amine (1.25 g, 1 eq.) in THF (5 mL) Sodium tert-butoxide (570 mg, 1.5 eq.) and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) were added under a nitrogen atmosphere. 2-(2'-Amino-1,1'-biphenyl)]palladium(II) methanesulfonate (31.4 mg, 0.01 eq.), and the reaction mixture was stirred at 95 ° C for 12 hours. The reaction mixture was concentrated and purified by silica gel column chromatography eluting eluting ^{1 H NMR (400MHz, CDCl3)} : 10.87 (s, 1H), 8.63 (dd, J = 8.4Hz, J = 4.0Hz, 1H), 8.05 (s, 1H), 7.46-7.40 (m, 1H), 7.28 –7.21(m,2H), 7.12–7.08(m,1H), 6.86(s,1H), 6.45(d,J=8.4Hz,1H), 4.10(s,4H),3.97(s,4H), 2.19 (s, 3H), 1.85 (s, 3H), 1.81 (s, 3H), 1.45 (s, 9H). LC-MS (ESI) (5-95AB): m/z: 583.1 [M+1] .

Compound 34:

A solution of the compound 34C (440 mg, 1 eq.) in dichloromethane (20 ml) was added to the trifluoromethanesulfonic acid trimethylsilyl ester (503 mg, 3 eq.), and the mixture was stirred at 0 ° C for 1 hour. After the TLC reaction was completed, water (0.1 ml) was added, and the mixture was concentrated under reduced pressure, and then water (5 ml) and saturated sodium carbonate (2 ml), solid precipitated, filtered, dried, Neutral) Compound 34 was prepared (16 mg, purity 100%). ^{1 H NMR (400MHz, CD3OD)} : 8.44 (dd, J = 8.8Hz, J = 4.0Hz, 1H), 8.01 (s, 1H), 7.62-7.57 (m, 1H), 7.52-7.48 (m, 1H) , 7.26–7.24(m,1H), 7.20–7.16(m,2H), 6.48(d,J=8.8Hz,1H),3.95(s,4H),3.92(s,4H),2.14(s,3H) ), 1.86 (s, 3H), 1.83 (s, 3H). LCMS (ESI) (0-60AB): m/z: 483.2 [M+1].

Example 35

A solution of compound 34C (60 mg, 1 eq.) in dichloromethane (3 mL). 5 equivalents), stirred at 25 ° C for 11 hours. The reaction mixture was concentrated under reduced pressure, and then purified, m. ^{1 H NMR (400MHz, CD3OD)} : 8.44 (dd, J = 8.0Hz, J = 4.0Hz, 1H), 8.01 (s, 1H), 7.60-7.57 (m, 1H), 7.52-7.48 (m, 1H) , 7.25–7.23 (m, 1H), 7.20–7.16 (m, 2H), 6.48–6.46 (m, 1H), 3.90 (s, 4H), 3.47 (s, 4H), 2.36 (s, 3H), 2.13 (s, 3H), 1.86 (s, 3H), 1.83 (s, 3H). LC-MS (ESI) (0-60AB): m/z: 497.2 [M+1].

Example 36

Prepared according to the procedure of Compound 35, a 37% aqueous solution of formaldehyde was replaced with 40% aqueous acetaldehyde to give compound 36 (15.2 mg, purity 100%). ^{1 H NMR (400MHz, CD3OD)} : 8.44 (dd, J = 8.0Hz, J = 4.0Hz, 1H), 8.01 (s, 1H), 7.62-7.58 (m, 1H), 7.52-7.48 (m, 1H) , 7.26–7.23 (m, 1H), 7.20–7.16 (m, 2H), 6.47 (d, J=9.6 Hz, 1H), 3.91 (s, 4H), 3.42 (s, 4H), 2.54 (q, J) = 7.2 Hz, 2H), 2.13 (s, 3H), 1.86 (s, 3H), 1.83 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H). LC-MS (ESI) (0-60AB ): m/z: 511.2 [M+1].

Example 37

Prepared according to the procedure of Compound 36, substituting 37% aqueous formaldehyde to acetone to give compound 37 (15.0 mg, purity 100%). ^{1 H NMR (400MHz, CD3OD)} : 8.44 (dd, J = 8.4Hz, J = 4.0Hz, 1H), 8.01 (s, 1H), 7.62-7.58 (m, 1H), 7.52-7.47 (m, 1H) , 7.26–7.23 (m, 1H), 7.20–7.16 (m, 2H), 6.47 (d, J=8.4 Hz, 1H), 3.90 (s, 4H), 3.49 (s, 4H), 2.51–2.48 (m) , 1H), 2.13 (s, 3H), 1.86 (s, 3H), 1.83 (s, 3H), 1.00 (d, J = 6.4 Hz, 6H). LC-MS (ESI) (0-60AB): m /z:525.1[M+1].

Example 38

Compound 38A:

Prepared according to the procedure of Compound 4A, Compound 1B was replaced with ethyl tert-butyl-2,8-diazaspiro[4.5]decane-8-carboxylate to afford compound 38A (370 mg, 44.9% yield). ^{1 H NMR 400MHz, CHLOROFORM-d} ) δ = 8.21-8.18 (m, 1H), 8.02-7.97 (m, 1H), 6.69-6.65 (m, 1H), 3.78-3.72 (m, 2H), 3.50 (s , 2H), 3.49-3.37 (m, 4H), 1.92-1.87 (m, 2H), 1.63-1.58 (m, 4H), 1.47 (s, 9H). LCMS (ESI) (5-95AB): m/ z:396.1[M+1].

Compound 38B:

Prepared according to the procedure of Compound 16B, Compound 16A was replaced with 38A to afford compound 38B (200 mg, crude). ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 8.23-8.21 (m, 1H), 8.05-8.01 (m, 1H), 6.74-6.68 (m, 1H), 3.82-3.76 (m, 2H), 3.60- 3.48 (m, 2H), 3.28-3.07 (m, 4H), 2.03-1.93 (m, 4H), 1.90-1.87 (m, 2H). LC-MS (ESI) (0-60AB): m/z: 296.1 [M+1].

Compound 38C:

Prepared according to the procedure of Compound 16C, Compound 16B was taken to Compound 38B to afford compound 38C (220 mg, 710 rn. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 8.11 (d, J = 2.8Hz, 1H), 7.95-7.88 (m, 1H), 6.63-6.55 (m, 1H), 3.66 (t, J = 7.0Hz , 2H), 3.40 (s, 2H), 2.53-2.28 (m, 4H), 2.26 (s, 3H), 1.83-1.74 (m, 2H), 1.63 (brt, J = 5.5 Hz, 4H). LC- MS (ESI) (0-60): m/z: 310.1 [M+1].

Compound 38D:

Prepared according to the method of Compound 1D, Compound 1C was replaced with 38C to give Compound 38D (50 mg, crude). ^{1 H NMR (400MHz, DMSO-} d6) δ = 6.86 (brd, J = 8.8Hz, 1H), 6.62 (d, J = 2.3Hz, 1H), 6.47 (brd, J = 7.8Hz, 1H), 5.00 ( Brs, 2H), 3.20-3.06 (m, 2H), 3.06-2.83 (m, 4H), 2.74 (brd, J = 10.5 Hz, 3H), 2.53 (d, J = 2.0 Hz, 2H), 1.91-1.62 (m, 6H). LC-MS (ESI) (5-95CD): m/z: 280.3 [M+1].

Compound 38:

Prepared according to the procedure of Compound 1, Compound 1D was replaced with Compound 38D to give Compound 38 (45.2 mg, 75.7 micromoles, 42.4% yield). ^{1 H NMR (400MHz, DMSO-} d6) δ = 11.77 (brd, J = 9.5Hz, 1H), 10.61 (brs, 1H), 10.21 (brs, 1H), 8.43 (brs, 1H), 8.34 (s, 1H ), 7.71-7.61 (m, 2H), 7.53 (brt, J = 7.7 Hz, 1H), 7.37-7.23 (m, 2H), 7.03 (dd, J = 8.7, 14.7 Hz, 1H), 3.46-3.37 ( m, 2H), 3.33 (brd, J = 11.5 Hz, 2H), 3.29 (s, 1H), 3.14 (s, 1H), 3.11-2.93 (m, 2H), 2.72 (dd, J = 4.8, 11.0 Hz) , 3H), 2.53 (d, J = 1.8 Hz, 2H), 2.00-1.84 (m, 4H), 1.82 (s, 3H), 1.79 (s, 3H). LC-MS (ESI) (0-60AB) :m/z: 559.1[M+1].

Example 39

Compound 39A:

The material 1-chloro-2,3-difluoro-benzene (1.00 g, 6.73 mmol, 1.00 equiv) was dissolved in concentrated sulfuric acid (3.30 g, 33.7 mmol, 1.79 mL, 5.00 eq.). After 0 ° C, nitric acid (652 mg, 6.73 mmol, 65% purity, 1.00 eq.) was added dropwise, and the mixture was reacted at 0 ° C for 2 h. The mixture was poured into ice water (EtOAc) (EtOAc) The combined organic phases were washed twice with aq. aq. sodium hydrogen sulfate (30 mL) and brine (30 mL). The residue obtained was purified using column chromatography ( petroleum ether) to afford compound 39A (550 mg, 2.84 mmol, 42.2% yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 7.89 - 7.80 (m, 1H), 7.34 - 7.26 (m, 1H).

Compound 39B:

Prepared according to the procedure of compound 4A, 3-bromo-4-fluoronitrobenzene was replaced by compound 39A to afford compound 39B (350 mg, 732 um, 47.3% yield, 71.5% purity). ¹ H NMR (300 MHz, CHLOROFORM-d) δ = 8.00 (s, 1H), 7.82 (dd, J = 1.9, 9.2 Hz, 1H), 3.28-3.21 (m, 4H), 2.41-2.34 (m, 4H) , 2.28 (s, 3H), 1.61 (td, J = 5.6, 13.8 Hz, 8H).

Compound 39C:

The title compound 39C (210 mg, 673 umol, 91.9% yield) was obtained from the title compound. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 6.78 (t, J = 8.8Hz, 1H), 6.49 (dd, J = 1.9,8.7Hz, 1H), 2.97-2.81 (m, 4H), 2.46 (brs , 4H), 2.34 (s, 3H), 1.69-1.59 (m, 8H).

Compound 39

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 39D to give Compound 39 (41.1 mg, 64.7 umol, 20.1% yield, 98.9% purity). ^{1 H NMR (400MHz, METHANOL-} d4) δ = 8.21 (s, 1H), 8.08 (brdd, J = 3.8,7.9Hz, 1H), 7.65 (dd, J = 7.4,13.8Hz, 1H), 7.53-7.46 (m, 1H), 7.45-7.33 (m, 3H), 3.39 (brd, J = 5.3 Hz, 4H), 3.27 (t, J = 1.6 Hz, 2H), 3.19 (brt, J = 12.5 Hz, 2H) , 2.87 (s, 3H), 2.15-2.00 (m, 4H), 1.86 (s, 3H), 1.82 (s, 3H), 1.82-1.66 (m, 4H).

Example 40

Compound 40A:

Prepared according to the method of Compound 4A, 3-bromo-4-fluoronitrobenzene was replaced by 2-chloro-1-fluoro-4-nitrobenzene to give Compound 40A (660 mg, crude). ¹ H NMR (400 MHz, CHLOROFORM-d) 8.14 (d, J = 2.5 Hz, 1H), 8.01 (dd, J = 2.5, 9.2 Hz, 1H), 6.35 (d, J = 9.2 Hz, 1H), 4.06 ( s, 4H), 1.86-1.78 (m, 4H), 1.61 (s, 4H), 1.52-1.44 (m, 9H). LC-MS (ESI) (5-95CD): m/z: 326.0 [M- 55].

Compound 40B:

Prepared according to the procedure of Compound 16B, Compound 16A was replaced with Compound 40A to give Compound 40B (1.3 g, crude). ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.44 (brs, 1H), 8.16 (d, J = 2.5 Hz, 1H), 8.04 (dd, J = 2.6, 9.1 Hz, 1H), 6.40 (d, J) = 9.2 Hz, 1H), 4.14 (s, 4H), 3.31 (brs, 4H), 2.81 (s, 3H), 2.24-2.16 (m, 4H). LCMS (ESI) (5-95CD): m/z :282.0[M+1].

Compound 40C:

Prepared according to the method of Compound 16C, Compound 16B was replaced with Compound 40B to give Compound Compound 40C (620 mg, 2.10 mmol, 45.5% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.61 (brs, 1H), 8.12 (s, 1H), 6.38 (d, J = 9.2 Hz, 1H), 3.55 (s, 4H), 2.17-2. m, 4H), 1.80 (s, 3H), 1.78-1.76 (m, 4H). LCMS (ESI) (5-95CD): m/z: 296.0 [M+1].

Compound 40D:

Prepared according to the method of Compound 2B, Compound 2A was replaced with Compound 40C to give Compound 40D (480 mg, crude). ^{1 H NMR (400MHz, DMSO-} d 6) δ = 11.12 (s, 1H), 9.09 (s, 1H), 8.61 (brs, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.58 ( Dd, J = 7.2, 13.8 Hz, 1H), 7.46 (brt, J = 7.8 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.16 (brt, J = 7.4 Hz, 1H), 6.38 (d, J = 8.9 Hz, 1H), 3.57 (s, 8H), 2.31 (s, 3H), 2.10 (s, 3H), 1.78 (brd, J = 13.4 Hz, 10H). LCMS (ESI) (5-95CD): m/z: 266.0 [M+1].

Compound 40:

Prepared according to the procedure of Compound 2, Compound 2B was replaced with Compound 40D to give Compound 40 (41 mg, 74.7 rnmol, 19.8% yield, 99.4% purity). ^{1 H NMR (400MHz, DMSO-} d 6) δ = 11.16 (s, 1H), 9.28 (s, 1H), 8.57 (brs, 1H), 8.22 (s, 2H), 8.17 (s, 1H), 7.67- 7.49 (m, 3H), 7.35 (dd, J = 2.2, 8.6 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 8.9 Hz, 1H), 3.67 (s, 4H) ), 2.43-2.29 (m, 4H), 2.20 (s, 3H), 1.82-1.74 (m, 10H). LCMS (ESI) (5-95CD): m/z: 545.1 [M+1].

Example 41

Prepared according to the method of compound 15, replacing (2-((2,5-dichloro-pyrimidin-4-yl)amino)phenyl) dimethylphosphine oxide with (2-((5-bromo-2-) Pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide afforded the hydrochloride salt of compound 41 (35.8 mg, 52.4 micromoles, 29.3% yield, 93.8% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ=11.53-11.37 (m, 1H), 10.65-10.48 (m, 1H), 10.29-10.11 (m, 1H), 8.39 (s, 1H), 8.36-8.24 ( m,1H), 7.70-7.60 (m, 2H), 7.58-7.49 (m, 1H), 7.36-7.24 (m, 2H), 7.06-6.95 (m, 1H), 3.44 - 3.36 (m, 2H), 3.36-3.29 (m, 2H), 3.28 (s, 1H), 3.13 (s, 1H), 3.11-2.93 (m, 2H), 2.73 (dd, J = 4.8, 11.0 Hz, 3H), 2.53 (d, J=1.8 Hz, 2H), 1.98-1.84 (m, 4H), 1.81 (s, 3H), 1.77 (s, 3H). LC-MS (ESI) (0-60AB): m/z: 604.9 [M +1].

Test Example 1: Cell anti-proliferation experiment

Experimental Materials:

RPMI 1640, DMEM, fetal calf serum, L-glutamine, IL3, were purchased from Life Technology (USA).

Double antibody (penicillin/streptomycin solution) and blasticidin purchased from Merck (Germany)

Cell Titer-Glo luminescent cell viability reagents were purchased from Promega (USA).

Ba/F3, A431 cell line and NCI-H1975 cell line were purchased from the European Collection of Cell Cultures (ECACC).

Ba/F3 EGFRΔ19del/T790M/C797S and Ba/F3 EGFRΔ19del/T790M cells were constructed by WuXi itself.

A431 medium: 88% DMEM + 10% fetal bovine serum + 1% L-glutamine + 1% double antibody

H1975 medium: 88% DMEM + 10% fetal bovine serum + 1% L-glutamine + 1% double antibody

Ba/F3 medium: 87.9% DMEM + 10% fetal bovine serum + 1% L-glutamine + 1% double antibody + 0.1% IL3

Ba/F3Δ19del/T790M&Δ19del/T790M/C797S medium: 87.9% DMEM + 10% fetal bovine serum + 1% L-glutamine + 1% double antibody + 0.1% blasticidin

Plate reading instrument: Envision (PerkinElmer).

experimental method:

For Ba/F3, Ba/F3Δ19del/T790M and Ba/F3Δ19del/T790M/C797S three suspension cells

The test compound was diluted 3-fold with Echo to obtain 10 dose concentrations from 10 uM to 0.508 nM, and the compound was transferred to a 384-well plate at 125 nL per well. The cell density was adjusted to 2000 Ba/F3, Ba/F3Δ19del/T790M or Ba/F3Δ19del/T790M/C797S cells per well, 50ul volume. Incubate for 3 days in a 37 ° C incubator in a CO ₂ incubator. After 3 days, 25 ul of detection reagent was added. Incubate for 10 minutes at room temperature and Envision reads the plate.

Two kinds of adherent cells: A431 and NCI-H1975:

384-well plates, 2500 A431 cells and 1000 NCI-H1975 cells per well, 50 ul volume. Incubate overnight at 37 ° C in a CO 2 incubator. The compound was subjected to gradient dilution and transfer using Echo, and the test compound was subjected to 3-fold gradient dilution to obtain a concentration of 10 doses from 10 uM to 0.508 nM, and 125 nL of the compound was added per well. The cells were further cultured for 3 days in a CO ₂ incubator. After 3 days, 25 ul of detection reagent was added. Incubate for 10 minutes at room temperature and Envision reads the plate.

data analysis:

The reading is converted to inhibition rate (%) by the following formula (Max-Sample) / (Max-Min) * 100% . IC50 data was measured by Model 205in Activity Base (IDBS).

test results:

The EGFR Ba/F3 (Δ19del/T790M) cell activity of the compound of the present invention inhibits IC50, H1975 (T790M/L858R) cell activity inhibits IC50, EGFR Ba/F3 (Δ19del/T 790M/C797S) cell activity inhibits IC50, Ba/F3 Parent cell activity inhibition IC50, A431 (EGFR WT) cell activity inhibition IC50 data is shown in Table 1 below. Compounds with IC50 between 1-100 nm are identified by +++, compounds with IC50 between 101-1000 nm are identified by ++, and compounds with IC50 greater than 1000 nm are identified by +.

in conclusion:

It can be seen from Table 1 that most of the compounds of the present invention have a very good inhibitory effect on cells of the EGFR Ba/F3 (Δ19del/T 790M/C797S) triple mutation, and the antiproliferative activity is below 100 nm. EGFR Ba/F3 (Δ19del/T790M) is a cell model of EGFR double mutation, which is the main target of the third generation of EGFR TKIs, mainly for the tolerance of the second mutation of T790M which occurs in the ATP receptor part. From the test, we found that most of the compounds of the present invention have a good cell anti-proliferative effect on the double mutation of EGFR Ba/F3 (Δ19del/T790M), indicating that the compound of the present invention has triple mutation and double mutation of EGFR Ba/F3. It has a dual inhibition effect. The cellular antiproliferative activity test of Ba/F3 parent and A431 (EGFR WT) is a test for normal cells, mainly to determine the selective effect of compounds on normal cells, when paired with Ba/F3 parent and A431 (EGFR WT) When the cytostatic effect is good, the compound may have a greater toxic effect on normal cells and affect the selectivity of the compound. As can be seen from Table 1, the compound of the present invention also has a certain inhibitory effect on normal cells when it has a very good inhibitory effect in the triple mutation and the double mutation, indicating that the compound of the present invention is in the cell. There is a certain improvement in the selectivity.

Test Example 2: Cell EGFR phosphorylation inhibition experiment

Experimental Materials:

RPMI 1640, DMEM, fetal bovine serum, L-glutamine, and EGF were purchased from Life Technology (USA).

Double antibody (penicillin/streptomycin solution) and blasticidin purchased from Merck

BSA solution was purchased from SIGMA

Phospho-EGFR (Tyr 1068) Cellular Assay Kit was purchased from Cis-Bio International.

Ba/F3 EGFRΔ19del/T790M/C797S cells were constructed by WuXi itself.

Ba/F3Δ19del/T790M/C797S medium: 87.9% DMEM + 10% fetal bovine serum + 1% L-glutamine + 1% double antibody + 0.1% blasticidin

Plate reading instrument: Envision (PerkinElmer).

experimental method:

The test compound and the reference compound were diluted to 10 mM or 1 mM with 100% DMSO, respectively, and then diluted with Echo as designed, 150 nL per well, three-fold dilution, ten-point dose reaction curve, and the final concentration of the compound was 100 uM or 10 uM. The suspension cells were centrifuged at 1000 rpm for 5 minutes, and the Hanks balanced salt solution was suspended, added to a 384-well plate containing the compound at 10 uL/120 K/well (cell density of 1.2e7), centrifuged at 1200 rpm for 30 s, and incubated at 37 ° C for 30 minutes. 5 ul of EGF diluted with 0.1% BSA Hanks balanced salt solution was added to each well, and the final concentration of EGF was 1 uM. Centrifuge at 1200 rpm for 30 s and incubate at 37 ° C for 20 minutes. 5 uL of 4X lysis buffer containing blocking solution was added to each well, centrifuged at 1200 rpm for 30 s, and incubated at 37 ° C for 30 minutes. Add 5 ul of 0.25X Eu and D2 mixture to each well, centrifuge at 1200 rpm for 30 s, seal the plate with light-proof membrane, incubate at room temperature (22-26 °C for 4h-24h, and read the signal at 665nm/620nm fluorescence signal by microplate reader.

Experimental Results: The IC50 data for inhibition of pEGFR Ba/F3 (Δ19del/T 790M/C797S) cell viability of the compounds of the present invention are shown in Table 1 below. Compounds with IC50 between 1-100 nm are identified by +++, compounds with IC50 between 101-1000 nm are identified by ++, and compounds with IC50 greater than 1000 nm are identified by +.

in conclusion:

Since autophosphorylation of EGFR, ie, dimerization, activates its intracellular kinase pathway, and many tumors are highly expressed or abnormally expressed in EGFR, they play a very important role in the progression of malignant tumors. The inhibition of pEGFR Ba/F3 (Δ19del/T 790M/C797S) cell activity is the most intuitive expression of the phosphorylation inhibition of the Ba/F3 (Δ19del/T 790M/C797S) triple mutant cell model, thus targeting the compound In vitro screening. As can be seen from Table 1, the compounds of this patent have a very good inhibitory effect on the phosphorylation activity of Ba/F3 (Δ19del/T 790M/C797S) cells.

Table 1

Test Example 3: In vivo pharmacodynamic study

experimental method:

In vivo pharmacodynamic experiments were performed subcutaneously implanted with Ba/F3 (exon19del/T790m/C797S)-derived xenograft (CDX) BALB/c nude mice. BALB/c nude mice, female, 6-8 weeks, weighing approximately 18-22 grams, were housed in SPF-grade environment, and each cage was individually ventilated (5 mice per cage). All cages, bedding and water are disinfected prior to use. All animals are free to access a standard certified commercial laboratory diet. A total of 54 mice purchased from Beijing Vital Lihua were used for the study. Each mouse was subcutaneously implanted with cells (5 x 10*5 + Matrigel gel) in the right flank for tumor growth. The experiment was started when the average tumor volume reached approximately 80-120 cubic millimeters. The test compounds were orally administered daily (each compound was administered at 35 mg/kg for 14 consecutive days, and the data is shown in Table 2). The tumor volume was measured twice a week using a two-dimensional caliper, and the volume was measured in cubic millimeters, calculated by the following formula: V = V = 0.5 axb2, where a and b are the long and short diameters of the tumor, respectively. The anti-tumor efficacy is determined by dividing the average tumor-increased volume of the treated animals by the average tumor-increased volume of the untreated animals.

Experimental results: See Table 2.

in conclusion:

The compounds of the present invention showed potent anti-tumor activity in a subcutaneously implanted Ba/F3 (exon19del/T790m/C797S)-derived xenograft (CDX) BALB/c nude mouse resistance model.

Table 2

Claims (24)

a compound of formula (I) or a pharmaceutically acceptable salt thereof,

among them, R _{1 is} selected from the group consisting of H and methyl; R _{2 is} selected from the group consisting of halogen, CN, C _1-5 alkyl, C _1-5 heteroalkyl, C _1-5 alkenyl, C _1-5 heteroalkenyl, C _1-5 alkynyl, C _1-5 hetero Alkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl, said C _1-5 alkyl, C _1-5 heteroalkyl, C _{1 -5} alkenyl, C _1-5 heteroalkenyl, C _1-5 alkynyl, C _1-5 heteroalkynyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl and 5- The 6-membered heteroaryl is optionally substituted by 1, 2 or 3 R; Or R ₁ and R _{2 are} bonded to form a 5- to 6-membered ring, and the 5- to 6-membered ring is optionally substituted by 1, 2 or 3 R; R ₃ and R ₄ are each independently selected from H and halogen; R _{5 is} selected from the group consisting of H, halogen, CN, C _1-3 alkyl, C _1-3 heteroalkyl, C _1-3 alkenyl, C _1-3 heteroalkenyl, C _3-6 cycloalkyl, 3~ a 6-membered heterocycloalkyl group, a phenyl group and a 5- to 6-membered heteroaryl group, said C _1-3 alkyl group, a C _1-3 heteroalkyl group, a C _1-3 alkenyl group, a C _1-3 heteroalkenyl group, C _3-6 cycloalkyl, 3-6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 R; R _{6 is} selected from H, C _1-3 alkyl and C _1-3 heteroalkyl, and the C _1-3 alkyl and C _1-3 heteroalkyl are optionally substituted by 1, 2 or 3 R; m, n, m', n' are each independently selected from 1 and 2; R ₇ and R ₈ are each independently selected from the group consisting of H, CN, halogen, C _1-3 alkyl, C _1-3 heteroalkyl, cyclopropyl, phenyl and 5- to 6-membered heteroaryl, said C _{1 -3} alkyl, C _1-3 heteroalkyl, cyclopropyl, phenyl and 5- to 6-membered heteroaryl optionally substituted by 1, 2 or 3 R; M is selected from C _1-3 alkyl; Or, M and M are joined to form a 4-8 membered ring, and the 4-8 membered ring is optionally substituted by 1, 2 or 3 R; R is selected from the group consisting of halogen, OH, CN, NH ₂ , C _1-3 alkyl and C _1-3 heteroalkyl, the C _1-3 alkyl and C _1-3 heteroalkyl optionally being 1, 2 or 3 R'substitutions; R' is selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , CH ₃ , CH ₃ CH ₂ , CF ₃ , CHF ₂ and CH ₂ F; "C _1-5 heteroalkyl", "C _1-5 heteroalkenyl", "C _1-5 heteroalkynyl", "3- to 6-membered heterocycloalkyl", "5 to 6-membered heteroaryl" , "C _1-3 heteroalkyl", "C _1-3 alkenyl heteroaryl group" of the "heteroaryl" represents a hetero atom or hetero atom groups, each independently selected from -O -, - S -, = O, = S, -ON=, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) ₂ -, -C (=O) NH-, -NH-, -C(=NH)-, -S(=O) ₂ NH-, -S(=O)NH-, and -NHC(=O)NH-; any of the above In this case, the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH ₂ , CH ₃ , CH ₃ CH ₂ , CF ₃ , CHF _{2 , CH 2 F, NH 2 CH} 2, (NH 2) 2 CH, CH 3 O, CH 3 CH 2 O, CH 3 OCH 2, CH 3 NH , and (CH _{3) 2} N. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from the group consisting of H and methyl. The compound according to claim 1 or 2, wherein R _{2 is} selected from the group consisting of halogen, CN, C _1-3 alkyl, C _1-3 heteroalkyl, C _1-3 alkenyl, or a pharmaceutically acceptable salt thereof a C _1-3 alkynyl group, a C _3-6 cycloalkyl group and a phenyl group, the C _1-3 alkyl group, a C _1-3 heteroalkyl group, a C _1-3 alkenyl group, a C _1-3 alkynyl group, The C _3-6 cycloalkyl group and the phenyl group are optionally substituted by 1, 2 or 3 R groups. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from the group consisting of F, Cl, Br, CN, CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH ₂ , CH ₃ O, CH ₃ CH ₂ O, CH ₃ OCH ₂ , CH ₃ NH, NH ₂ CH ₂ , (NH ₂ ) ₂ CH, (CH ₃ ) ₂ N, CH ₂ =CH, CH ₂ = CHCH ₂ , CH ₃ CH ₂ =CH, CH ₂ =C(CH ₃ ),

The _{CH 3, CH 3 CH 2,} CH 3 CH 2 CH 2, (CH 3) 2 CH 2, CH 3 O, CH 3 CH 2 O, CH 3 OCH 2, CH 3 NH, NH 2 CH 2, ( NH ₂ ) ₂ CH, (CH ₃ ) ₂ N, CH ₂ =CH, CH ₂ =CHCH ₂ , CH ₃ CH ₂ =CH, CH ₂ =C(CH ₃ ),

Optionally substituted by 1, 2 or 3 R. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein, R ₂ is selected from _{Cl, Br, CN, CH 3} , CF 3, CH 3 CH 2, CH 3 O,

The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the structural unit

selected

The compound according to claim 1 or 2, wherein R ₃ and R ₄ are each independently selected from H and Cl, or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or 2, wherein R _{5 is} selected from the group consisting of H, halogen, CN, C _1-3 alkyl, C _1-3 alkenyl and 5- to 6-membered hetero The aryl group, the C _1-3 alkyl group, the C _1-3 alkenyl group and the 5- to 6-membered heteroaryl group are optionally substituted by 1, 2 or 3 R groups. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R _{5 is} selected from the group consisting of H, F, Cl, Br, CN, CH ₃ ,

And a pyridyl group, the CH ₃ ,

And pyridyl is optionally substituted by 1, 2 or 3 R. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R _{5 is} selected from the group consisting of H, F, Cl, Br, CN, CH ₃ ,

The compound according to claim 1 or 2, wherein R _{6 is} selected from H and C _1-3 alkyl, and the C _1-3 alkyl group is optionally 1, 2 or 3, or a pharmaceutically acceptable salt thereof. Replace with R. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R _{6 is} selected from the group consisting of H, CH ₃ , CH ₃ CH ₂ and

The compound according to claim 1 or 2, wherein R ₇ and R ₈ are each independently selected from the group consisting of H, CN, halogen, CH ₃ , CH ₃ CH ₂ , CH ₃ O, and different, respectively. a propyl group, a cyclopropyl group, a phenyl group and a pyrrolyl group, the CH ₃ , CH ₃ CH ₂ , CH ₃ O, isopropyl, cyclopropyl, phenyl and pyrrolyl groups being optionally 1, 2 or 3 R Replace. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R ₇ and R ₈ are each independently selected from the group consisting of H, CN, F, Cl, Br, CH ₃ , CF ₃ , CH ₃ CH ₂ , CH ₃ O,

The compound according to claim 1 or 2, wherein M is both CH ₃ or both of CH ₃ CH ₂ , or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the structural unit

Selected from

The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the structural unit

Selected from

The compound according to claim 13 or 18, or a pharmaceutically acceptable salt thereof, wherein the structural unit

Selected from

The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the structural unit

Selected from

The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and M are as defined in claims 1 to 20. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23. The use of the substance in the preparation of a medicament for treating cancer.