CN111836819A

CN111836819A - Arylamine-substituted pyrrolopyrimidine compound, and preparation method and application thereof

Info

Publication number: CN111836819A
Application number: CN201980017096.3A
Authority: CN
Inventors: 张强; 王中祥; 冯守业; 张宏波; 杨海龙; 周利凯; 徐占强
Original assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Current assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Priority date: 2018-05-24
Filing date: 2019-05-24
Publication date: 2020-10-27
Also published as: WO2019223777A1

Abstract

The invention provides an arylamine group-substituted pyrrolopyrimidine compound, a preparation method and application thereof, and particularly relates to a compound shown in a formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt and a prodrug thereof, a preparation method and application thereof in preparation of a drug serving as a kinase inhibitor.

Description

Arylamine-substituted pyrrolopyrimidine compound, and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to an arylamine-substituted pyrrolopyrimidine compound, and a preparation method and application thereof.

Background

Protein kinases are important signaling agents for cell life activities and catalyze the transfer of the gamma phosphate group at the end of ATP to hydroxyl acceptors in the amino acid residues of substrates (serine, threonine, tyrosine) to activate the target protein (Johnson l.n., and Lewis r.j., Structural basis for control by phosphorylation, Cheminform,2001,101,2209.). Protein kinases are involved in numerous physiological processes including cell proliferation, survival, apoptosis, metabolism, transcription and differentiation etc. (Adams j.a., Kinetic and catalytic mechanisms of protein kinases, Chemical reviews,2001,101,2271.). Protein kinase family members account for up to 10% of the existing Drug targets in humans (Santos r., Ursu o., Gaulton a., et al., a comprehensive map of molecular Drug targets, Nature Reviews Drug Discovery,2017,16, 19.).

Epidermal growth factor receptor (ErbB) tyrosine kinase can regulate cell proliferation, migration, differentiation, apoptosis, and cell movement in a variety of ways. In many forms of malignancy, ErbB family members, as well as some of their ligands, are often overexpressed, amplified, or mutated, making them important therapeutic targets. The family of protein kinases includes: ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER 4. Wherein EGFR is an important target for the development of Non-Small Cell Lung Cancer (Dienstmann R., et. al., Personating Therapy with Targeted Agents in Non-Small Cell Lung Cancer, ONCOTARGET,2001,2(3), 165.).

Gefitinib (Gefitinib), Erlotinib (Erlotinib) and Erlotinib (Icotinib) are the first generation reversible kinase inhibitors targeting EGFR and are used for the treatment of non-small cell cancers. The inhibitor has an inhibiting effect on wild type EGFR and activation mutant EGFR simultaneously, and has great clinical success, but the occurrence of drug resistance of a receptor patient after taking the inhibitor for a period of time, particularly the drug resistance caused by T790M mutation reduces or loses the curative effect. The second generation EGFR inhibitor Afatinib (Afatinib) is a non-reversible inhibitor, which contains michael receptor, can be covalently bound to cysteine residue (Cys797) at the entrance of ATP binding pocket, and has very strong activity against both T790M mutant EGFR kinase and wild-type EGFR kinase, and has higher inhibitory activity against T790M mutant EGFR kinase than wild-type EGFR kinase, which makes the therapeutic window of the drug in Clinical application narrower and the use effect not ideal (camide, d.r., et al., Acquired resistance TKIs in soluble patients: free from cancer. The third generation EGFR kinase inhibitors oxitinib (Osimetinib) and imatinib (Olmutinib) realize high selective inhibition on T790M mutant EGFR kinase compared with wild type EGFR kinase, enlarge the clinical application window and realize effective treatment on T790M mutant patients. Unfortunately, third-generation EGFR kinase inhibitors also develop resistance after some period of clinical use. One of the reasons for this is that EGFR has developed a secondary mutation of C797S. The action mechanism of the existing third-generation small molecule EGFR inhibitor and target is that the drug molecule and Cys797 of EGFR form covalent binding. However, in patients with secondary mutations in C797S, the covalent binding of the drug molecule to Cys797 is lost, leading to failure of the drug (Harun patel, et al, 2017, Recent updates on third generation EGFR inhibitors and emergencies of fourth generation EGFR inhibitors to combat C797S resistance, Eur J Med chem.,2017,142, 32). Based on the above, it is of great significance to develop novel drug molecules having good inhibitory activity against T790M mutant EGFR kinase and good inhibitory activity against C797S mutant EGFR kinase.

Brigatinib, a targeted ALK inhibitor, was developed by Ariad pharmaceutical and approved by the U.S. FDA in 2017 for the treatment of ALK-positive non-small cell lung cancer. According to the report of the literature, Brigatinib has certain inhibitory effect on C797S mutant EGFR kinase.

Disclosure of Invention

In view of the above discussion, the present invention aims to provide an arylamino-substituted pyrrolopyrimidine compound, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a pharmaceutical composition thereof, and use thereof in the preparation of a medicament as a kinase inhibitor.

One aspect of the present invention provides a compound represented by formula (I), isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof,

in the formula (I), the compound is shown in the specification,

x is CH or N;

y is CH or N;

R¹is-NHR⁵，R⁵Is unsubstituted or substituted aryl, heteroaryl, cycloalkyl bridged ring structures, fused ring structures,

R⁵wherein the substituent in the substituted aryl, heteroaryl, cycloalkyl bridged ring structure, and fused ring structure is-CF₃、-OCF₃Hydroxy, cyano, halogen, C_1-C₆Alkyl radical, C_3-C₅Cycloalkyl radical, C_1-C₆Alkoxy radical, C_3-C₅Cycloalkyloxy, -S (═ O)₂R⁶、-C(＝O)R⁶、-P(＝O)R⁶R⁷、-S(＝O)₂NR⁶R⁷，

R⁶And R⁷Are each independently-H, C_1-C₆Alkyl radical, C_3-C₆A cycloalkyl group,

the fused ring structure is selected from aromatic ring and 5-6 membered heteroaromatic ring group, 5-6 membered heteroaromatic ring and 5-6 membered heteroaromatic ring group, aromatic ring and 5-6 membered cycloalkyl, aromatic ring and 5-6 membered heterocyclic group, 5-6 membered heteroaromatic ring and 5-6 membered heterocycloalkyl or 5-6 membered heteroaromatic ring and 5-6 membered heterocyclic group;

R²is-H, -CF₃、-CH₂CF₃、C_1-C₆Alkyl radical, C_3-C₆Cycloalkyl radical, C_3-C₄Cycloalkyl-substituted C_1-C₂Alkyl, 4-6 membered heterocyclic group containing one oxygen atom, or- (CH)₂)_mR⁸Wherein m is an integer of 1,2, 3,

R⁸is-OH, -CN, -C (O) NH₂、-S(＝O)₂CH₃、C_1-C₃Alkoxy radical, C_1-C₃An alkylthio group;

R³and R⁴Are each independently-H, C_1-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-to 6-membered heterocyclic ring containing one nitrogen or one oxygen atomRadical or- (CH)₂)_nR⁹Wherein n is an integer of 1,2, 3,

the 4-6 membered heterocyclic ring containing one nitrogen atom or one oxygen atom is unsubstituted or substituted by C₁-C₃Is substituted with an alkyl group of (a) or (b),

R⁹is-OH, -CN, -C (O) NH₂、-S(＝O)₂CH₃、-NR'R”、C_1-C₃Alkoxy radical, C_1-C₃An alkylthio group is a group of one or more,

r 'and R' are each independently H or C₁-C₃The alkyl group of (a) is,

or, R³、R⁴The nitrogen atom to which it is attached constitutes a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O or S or a group-C (═ O) -or-S (═ O), or a 6-9 membered spirocyclic ring₂-as a ring member,

the R is³、R⁴The 4-6 membered heterocyclic ring formed by the nitrogen atom connected with the heterocyclic ring is unsubstituted or respectively substituted by 1-2 groups selected from halogen, cyano, hydroxyl, amino and C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halo C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl radical, C₁-C₃Alkoxy-substituted C₁-C₃The alkyl group is substituted by the alkyl group,

the R is³、R⁴The 6-to 9-membered spirocyclic ring composed of the nitrogen atom to which it is attached is a monospirocyclic ring containing one nitrogen atom.

In some of the preferred embodiments, the first and second,

R¹is-NHR⁵，R⁵Selected from the following groups:

q is N or CH, and Q is N or CH,

t is NH, O or S,

R¹⁰selected from the group consisting of-H, -OH, -F, -Cl, -Br, -CN, -CF₃、-OCF₃Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or the following groups:

R¹¹is-H, methyl, ethyl, propyl, isopropyl,

R¹²is-H, -F, -Cl, -Br, hydroxyl, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some preferred embodiments herein, X is CH; y is CH.

In some preferred embodiments of the present application, R¹Is composed of

In some preferred embodiments, R²Selected from-H, -CF₃、-CH₂CF₃Methyl, ethyl, propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, methylsulfonylpropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl.

In other preferred embodiments, R²Selected from n-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl.

Preferably, R³And R⁴Each independently selected from-H, methyl, ethylAlkyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, prop-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylazetan-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, methylsulfonylpropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, methylaminoethyl, dimethylaminoethyl, cyclopentadien-3-yl, tetrahydropyran-3-yl, N-methyloxa-3-yl, methylthioethyl, ethoxyethyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, methylsulfonylpropyl, hydroxyethyl, hydroxypropyl, cyano, Methylaminopropyl, dimethylaminopropyl, or R³、R⁴The nitrogen atom connected with the compound forms a 4-6-membered heterocyclic ring or a 6-9-membered spirocyclic ring, the 4-6-membered heterocyclic ring is a substituted or unsubstituted heterocyclic ring,

the R is³、R⁴The substituted or unsubstituted 4-6 membered heterocyclic ring constituted by the nitrogen atom to which it is attached is selected from the following ring structures:

R¹³selected from-H, methylamino, ethylamino, dimethylamino,

R¹⁴selected from-H, methyl, ethyl, propyl, isopropyl, formyl, acetyl or methylsulfonyl,

R¹⁵and R¹⁶Each independently selected from-H, -F, -CF₃Hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyanomethyl, cyanoethyl, methoxymethyl, methoxyethyl, methoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl,

the R is³、R⁴The 6-to 9-membered spiro ring, constituted by the nitrogen atom to which it is attached, is selected from the following spiro ring structures:

preferably, the following scheme can be included, R³Selected from the group consisting of-H, methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, isopentyl, neopentyl, N-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylaze (hetero) cyclobutane-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, N-methyloxa (hetero) cyclobutane-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, methylsulfonylpropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, methylaminoethyl, dimethylaminoethyl, methylaminopropyl, dimethylaminopropyl,

R⁴selected from n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl.

In another aspect of the present invention, there is provided a compound represented by formula (I), isomers, hydrates, solvates, pharmaceutically acceptable salts thereof, and prodrugs thereof,

in the formula (I), the compound is shown in the specification,

x is CH or N; y is CH or N; preferably, X is CH; y is CH;

R¹is-NHR⁵，R⁵Selected from the following groups:

q is N or CH, and Q is N or CH,

t is NH, O or S,

R¹⁰is selected from-H、-OH、-F、-Cl、-Br、-CN、-CF₃、-OCF₃Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or the following groups:

R¹¹is-H, methyl, ethyl, propyl, isopropyl,

R¹²is-H, -F, -Cl, -Br, hydroxy, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

preferably, R¹Is composed of

R²Selected from-H, -CF₃、-CH₂CF₃Methyl, ethyl, propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, methylsulfonylpropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl;

R³selected from the group consisting of-H, methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, isopentyl, neopentyl, N-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl,N-methyl aza (hetero) cyclobutane-3-yl;

R⁴is selected from- (CH)₂)_nR¹⁷Wherein n is an integer of 1,2, 3,

R¹⁷is composed of

Or C_3-C₆Cycloalkyl radical, R¹⁸is-OH, -CN, -C (O) NH₂、

-S(＝O)₂CH₃、C_1-C₃Alkoxy radical, C_1-C₃An alkylthio group.

in the formula (I), the compound is shown in the specification,

x is CH or N;

y is CH or N;

R¹is-NHR⁵，R⁵Selected from the following groups:

q is N or CH, and Q is N or CH,

t is NH, O or S,

R¹¹is-H, methyl, ethyl, propyl, isopropyl,

R²is-H, C_1-C₆Alkyl radical, C_3-C₆Cycloalkyl, halo C_1-C₆An alkyl group;

R³and R⁴Are each independently-H, C₃-C₈Cycloalkyl or from 1 to 3 substituents selected from C₁-C₆Alkoxy, hydroxy, halogen, C₃-C₆C substituted or unsubstituted by a substituent of cycloalkyl_1-C₉An alkyl group, a carboxyl group,

or, R³、R⁴The nitrogen atom to which it is attached forms a 4-to 8-membered heterocyclic ring which also contains 1-2 heteroatoms selected from N, O or S or contains the group-C (═ O) -or-S (═ O)₂-as a ring member,

the R is³、R⁴The 4-to 8-membered heterocyclic ring formed by the nitrogen atom to which it is attached is unsubstituted or substituted by 1 to 2 substituents selected from halogen, cyano, hydroxy, amino, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halo C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl radical, C₁-C₃Alkoxy-substituted C₁-C₃Alkyl groups are substituted.

In some preferred embodiments, X is CH; y is CH;

R¹is composed of

R²is-H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, isopentyl, pentyl, neopentyl, hexylIsohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, fluoroethyl;

R³and R⁴Each independently selected from the group consisting of-H, methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, isopentyl, neopentyl, N-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylaze (hetero) cyclobutane-3-yl, methylthioethyl, methylthiopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, isopropoxymethyl, tert-butyl, tert-pentyl, isopentyl, neopentyl, hexyl, cyclohexyl, oxetan-3-yl, N-methylpiperidin-3-yl, N-methylaze, Isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, methylsulfonylpropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, methylaminoethyl, dimethylaminoethyl, methylaminopropyl, dimethylaminopropyl, cyclopropylmethyl, cyclopropylethyl, trifluoromethyl, fluoroethyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methyl, ethyl, isopropyl,

or R³、R⁴The nitrogen atom connected with the heterocyclic ring forms a 4-8 membered heterocyclic ring, the 4-8 membered heterocyclic ring is a substituted or unsubstituted heterocyclic ring,

the R is³、R⁴The substituted or unsubstituted 4-to 8-membered heterocyclic ring formed by the nitrogen atom to which it is attached is selected from the following ring structures:

R¹³selected from-H, methylamino, ethylamino, dimethylamino,

R¹⁵and R¹⁶Each independently selected from-H, -F, -CF₃Hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyanomethyl, cyanoethyl, methoxymethyl, methoxyethyl, methoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl.

The present application includes, but is not limited to, the following typical compounds:

according to still another aspect of the present invention, there is provided a method for preparing the compound, its isomer, hydrate, solvate, pharmaceutically acceptable salt thereof and prodrug thereof, comprising the steps of,

PG is selected from: trimethylsilyl ethoxymethyl, t-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl, trifluoroacetyl, fluorenylmethyloxycarbonyl, benzyl; preferably trisilylethoxymethyl (SEM-base),

wherein R is¹、R²、R³、R⁴As described previously.

Further, the present application provides a pharmaceutical composition for treating diseases associated with mutation or overexpression of the tyrosine kinases EGFR, HER2, or ALK, which consists of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

According to a further aspect of the present application there is provided a pharmaceutical composition comprising a compound of formula (I) as described or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as active ingredient, one or more further therapeutic agents, and one or more pharmaceutically acceptable carriers or excipients.

The application also relates to application of the compound of formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof in preparing a medicament for treating cancers related to mutation or overexpression of tyrosine kinase EGFR, HER2 or ALK and autoimmune diseases, wherein the cancers and the autoimmune diseases comprise eyeground diseases, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, bone marrow fibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, Thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract carcinosarcoma, and cholangiocarcinoma.

The present application also relates to a method of treating a kinase-mediated disease or disorder, such as EGFR, HER2 or ALK, including those mentioned above, comprising administering to a patient (human or other mammal, especially human) in need thereof a therapeutically effective amount of a compound of formula (I) or a salt thereof.

Detailed Description

Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. In this application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the terms "including" and other forms, such as "including", "comprising", and "having", are not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

The term "substituted" as used herein includes complex substituents (e.g., aryl (e.g., phenyl), heteroalkyl, heteroaryl), suitably 1 to 5 substituents, preferably 1 to 3 substituents, and most preferably 1 to 2 substituents, which are freely selectable from the list of substituents.

Unless otherwise specified, alkyl represents a saturated straight-chain, branched-chain hydrocarbon radical having the indicated number of carbon atoms, the term C₁-C₁₀Alkyl represents an alkyl moiety containing from 1 to 10 carbon atoms, as with C₁-C₃Alkyl represents an alkyl moiety containing 1 to 3 carbon atoms, e.g. C₁-C₆Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl groups and the like.

When substituent terms such as "alkyl" are used in combination with other substituent terms, for example, in the term "C₁-C₃Alkoxy radical C₁-C₆Alkylthio "or" hydroxy-substituted C₁-C₁₀In alkyl, "the linking substituent term (e.g., alkyl or alkylthio) is intended to encompass divalent moieties wherein the point of attachment is through the linking substituent. "C₁-C₃Alkoxy radical C₁-C₆Examples of alkylthio "include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio, and the like. "hydroxy substituted C₁-C₁₀Examples of alkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, and the like.

Alkoxy is an alkyl-O-group formed from a straight or branched chain alkyl group previously described with-O-, for example, methoxy, ethoxy, and the like. Similarly, an alkylthio group is an alkyl-S-group formed from a straight or branched chain alkyl group previously described with-S-, for example, methylthio, ethylthio, and the like.

Alkenyl and alkynyl groups include straight chain, branched alkenyl or alkynyl groupsTerm C₂-C₆Alkenyl or C₂-C₆Alkynyl represents a straight or branched hydrocarbon group having at least one alkenyl or alkynyl group.

"cycloalkyl" means a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term "(C3-C6) cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from 3 to 6 ring carbon atoms. Exemplary "(C3-C6) cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted aromatic radical, such as phenyl, naphthyl, anthracenyl. The term "aroyl" refers to-C (O) -aryl.

The term "heterocyclyl", as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, wherein the N, S heteroatoms may be optionally oxidized and the N heteroatoms may be optionally quaternized. The heterocyclic ring may be bonded to any heteroatom or carbon atom, thereby forming a stable structure. Examples of such heterocycles include, but are not limited to, azacyclohexane, pyrrolidinyl, piperidinyl, piperazinyl oxide, piperidinyl oxide, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, thiazolidinyl, tetrahydrooxazolyl, tetrahydropyranyl, morphininyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

The term "heteroaryl" as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9-or 10-membered fused benzene heteroaromatic ring system or bicyclic heteroaromatic ring system consisting of carbon atoms and from 1 to 4 heteroatoms selected from N, O, S, wherein the N, S heteroatoms may be optionally oxidized and the N heteroatoms may also be optionally quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom, thereby forming a stable structure. Examples of heteroaryl groups include, but are not limited to, thianthrenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzpyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl or isoquinolinyl.

The term "carbonyl" refers to a C (O) group.

Whenever the term "alkyl" or "aryl" or any of their prefix roots appear in the name of a substituent (e.g., aralkyl, dialkylamino), it is to be considered as encompassing those limitations given above for "alkyl" and "aryl". The specified number of carbon atoms (e.g., C1-C6) will independently represent the number of carbon atoms in an alkyl moiety or in an alkyl moiety in a larger substituent group in which the alkyl group is the prefix root.

It is clear that the compounds of formula I, isomers, crystalline forms or prodrugs, and pharmaceutically acceptable salts thereof, may exist in solvated as well as unsolvated forms. For example, the solvated form may be water soluble. The present invention includes all such solvated and unsolvated forms.

The compounds of the invention may have asymmetric carbon atoms and, depending on their physicochemical differences, such diastereomeric mixtures may be separated into the individual diastereomers by methods well known in the art, for example, chromatography or fractional crystallization. Enantiomers can be separated by first converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitably optically active compound, separating the diastereomers, and then converting (hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.

The compounds of the present invention as active ingredients, as well as methods for preparing the compounds, are the subject of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and as such may be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.

The compounds of the invention may be used in therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives. As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salts may be formed by reacting a compound of the invention with a suitable free base or acid. Including, but not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, caproates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoate, pectinates, persulfates, per3-phenylpropionates, phosphates, picrates, propionates, stearates, sulfates, thiocyanates, P-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include the appropriate non-toxic ammonium, quaternary ammonium, and amine-based cations formed using such salts as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

In addition, the term "prodrug" as used herein means a compound which can be converted in vivo to a compound of the formula (I) of the present invention. This conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent compound in the blood or tissue.

The pharmaceutical compositions of the invention comprise a compound of structural formula (I) as described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic, or an additional active agent that is an anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.

The compounds of the present invention may be used alone or in combination with one or more other compounds of the present invention or with one or more other agents. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or for sequential administration at different times, or the therapeutic agents may be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention in combination with another agent, either by co-administration of each agent simultaneously or by sequential administration of each agent, in either case, for the purpose of achieving optimal effect of the drug. Co-administration includes simultaneous delivery dosage forms, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention may be used concurrently with other therapies known in the art, for example, radiation therapy or adjunctive therapies such as cytostatic agents, cytotoxic agents, other anti-cancer agents, etc. in the treatment of cancer to ameliorate the symptoms of the cancer. The present invention is not limited to the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anti-cancer or cytotoxic agents.

To prepare the pharmaceutical compositions of this invention, one or more compounds or salts of formula (I) as the active ingredient may be intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation designed for administration by any convenient route, e.g. oral or parenteral. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the handbook of pharmaceutical excipients, which is published by the United states society of pharmacy and British pharmaceutical society.

The pharmaceutical compositions of the invention may be in a form, for example, suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injection such as clear solutions, suspensions, emulsions; or for topical application such as creams; or as suppositories for rectal administration. The pharmaceutical compositions may also be in unit dosage form suitable for single use administration of the precise dosage. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the compound as an active ingredient prepared in accordance with the present invention, and may also include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.

Therapeutic compounds may also be administered to mammals other than humans. The dosage of the drug administered to a mammal will depend on the species of the animal and its disease state or disorder in which it is suffering. The therapeutic compound may be administered to the animal in the form of a capsule, bolus, tablet or solution. Therapeutic compounds may also be administered into the animal by injection or infusion. We prepared these pharmaceutical forms according to conventional means which meet the criteria of veterinary practice. Alternatively, the pharmaceutical composition may be mixed with animal feed for feeding to the animal, and thus, the concentrated feed supplement or premix may be prepared for mixing with conventional animal feed.

It is a further object of the present invention to provide a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of the present invention.

The invention also comprises the application of the compound or the pharmaceutically acceptable derivative thereof in preparing medicines for treating cancers and autoimmune diseases related to tyrosine kinases EGFR, HER2 and ALK. Such cancers (including non-solid tumors, primary or metastatic cancers, as noted elsewhere herein and including one or more other treatments for which the cancer is resistant or refractory) as well as other diseases (including but not limited to ocular fundus disease, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, etc.). Such cancers include, but are not limited to: non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, bile duct cancer.

The present invention also provides methods for preparing the corresponding compounds, and the compounds described herein can be prepared using a variety of synthetic methods, including the methods described below, and the compounds of the present invention, or pharmaceutically acceptable salts, isomers, or hydrates thereof, can be synthesized using the methods described below, and synthetic methods known in the art of organic chemical synthesis, or by variations on these methods as understood by those skilled in the art, with preferred methods including, but not limited to, the methods described below.

A process for preparing the compounds of the present invention, isomers, hydrates, solvates, pharmaceutically acceptable salts thereof, and prodrugs thereof, comprising the steps of:

wherein R is¹、R²、R³、R⁴As defined hereinbefore.

Reaction conditions are as follows:

fully contacting the compound shown in the formula (IV) and the compound shown in the formula (III) in the step 1) to obtain a compound shown in a formula (II);

preferably, the reaction may be carried out in an organic solvent including, but not limited to: one or a combination of two or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), ethylene glycol dimethyl ether, isopropanol, N-butanol, 2-butanol (sec-butanol) and tert-butanol;

preferably, the reaction may be carried out in the presence of a base, including but not limited to: one or more of potassium carbonate, sodium acetate, triethylamine, diisopropylethylamine, triethylenediamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or N-methylmorpholine;

preferably, the reaction may be carried out in the presence of an acid, including but not limited to: trifluoroacetic acid, p-toluenesulfonic acid;

preferably, the reaction can be carried out under palladium metal catalytic coupling reaction conditions, wherein the palladium metal catalytic coupling reaction conditions are a palladium ligand, a solvent and a base used in a common Buchward-Hartwig reaction;

and 2) obtaining the compound shown in the formula (I) by the compound shown in the formula (II) in the step 2) in the presence of tetrabutylammonium fluoride.

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. The examples provided below are intended to better illustrate the invention, all temperatures being in degrees centigrade unless otherwise indicated.

For the synthesis of some of the intermediates used in this application, see chinese patent application No. WO 2016000581A.

EXAMPLE 1 preparation of (2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Step 1) preparation of (2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine 249 mg (1mmol), (2- ((2-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) dimethyl oxyphosphor 450 mg (1mmol) and p-toluenesulfonic acid 17 mg (0.1mmol) are placed in a reaction bottle, 10 ml sec-butyl alcohol is added, heating and stirring are carried out until the reaction is finished, and column chromatography is carried out after rotary evaporation and concentration to obtain 330 mg of product with 50 percent of yield. MS:664[ M + H]⁺.

Step 2) preparation of (2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

(2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide 330 mg (0.5mmol) were placed in a reaction flask, dissolved by adding tetrahydrofuran, followed by the addition of 1 mol/l of tetrabutyl phosphoniumAnd 2ml of ammonium fluoride tetrahydrofuran solution is stirred until the reaction is finished, the solvent is distilled off, and column chromatography is carried out to obtain 265 mg of a product with 50% yield.¹H NMR(400MHz,DMSO-d6)11.62 (s,1H),11.24(s,1H),9.15(d,J＝5.3Hz,1H),8.76(s,1H),7.63–7.53(m,1H),7.48(s,2H),7.35(d,J＝8.7Hz,1H),7.06(t,J＝7.2Hz,1H),6.96–6.90(m,1H),6.81(d,J＝8.5Hz,1H),6.37(d,J＝2.6Hz,1H),3.78(s,3H),3.14–2.82(m,4H),2.22(s,6H),2.18–2.13(m,1H),1.83(d,J＝13.5Hz,6H),1.81–1.77(m,2H),1.58–1.47(m,2H)；MS:534[M+H]⁺.

EXAMPLE 2 preparation of (2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-ethoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

Reference example 1 preparation, 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine was replaced with an equimolar amount of 1- (4-amino-2-ethoxyphenyl) -N, N-dimethylpiperidin-4-amine in the starting material.¹H NMR(400MHz,DMSO-d6)11.61(s,1H),11.22(s,1H),9.24–9.06(m,1H),8.73(s,1H),7.63–7.52(m,1H),7.52–7.42(m,2H),7.33(d,J＝8.5Hz,1H),7.13–7.00(m,1H),6.98–6.89(m,1H),6.79(d,J＝8.6Hz,1H),6.36(d,J＝2.9Hz,1H),4.12–3.92(m,2H),3.37(d,J＝11.3Hz,2H),3.20–2.79(m,2H),2.22(s,6H),2.19–2.12(m,1H),1.90–1.76(m,8H),1.60–1.45(m,2H),1.38–1.35(m,3H)；MS:548[M+H]⁺.

EXAMPLE 3 preparation of (2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Preparation of reference example 1 starting with 1- (4-amino-2-isopropoxyphenyl) -N, N-dimethylpiperidin-4-amine in equimolar amountsInstead of 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine.¹H NMR(400MHz,DMSO-d6)11.60(s,1H),11.21(s,1H),9.14(s,1H),8.72(s,1H),7.63–7.47(m,2H),7.38(d,J＝12.5Hz,2H),7.07(t,J＝7.3Hz,1H),6.96–6.90(m,1H),6.80(d,J＝8.3Hz,1H),6.38–6.33(m,1H),4.68–4.48(m,1H),3.43–3.35(m,2H),3.02–2.93(m,2H),2.22(s,6H),2.03–1.94(m,1H),1.87–1.78(m,8H),1.59–1.43(m,2H),1.29(d,J＝6.0Hz,6H)；MS:562[M+H]⁺.

EXAMPLE 4 preparation of (2- ((2- ((3-ethoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

With reference to the preparation of example 1, an equimolar amount of 3-ethoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline was substituted for 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine in the starting material.¹H NMR(400MHz,DMSO-d6)11.60(s,1H),11.22(s,1H),9.21–9.04(m,1H),8.72(s,1H),7.63–7.52(m,1H),7.52–7.41(m,2H),7.39–7.27(m,1H),7.06(t,J＝7.5Hz,1H),7.00–6.88(m,1H),6.79(d,J＝8.6Hz,1H),6.36(d,J＝2.9Hz,1H),4.08–3.93(m,2H),3.42–3.34(m,2H),3.22–2.74(m,2H),2.49–2.43(m,4H),2.43–2.28(m,4H),2.28–2.21(m,1H),2.17(s,3H),1.90–1.73(m,8H),1.63–1.46(m,2H),1.36(t,J＝6.8Hz,3H)；MS:603[M+H]⁺.

Example 5 preparation of (2- ((2- ((3-isopropoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Preparation of reference example 1, equimolar amounts of 3-isopropoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline in the starting material1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine.¹H NMR(400MHz,DMSO-d6)11.60(s,1H),11.21(s,1H),9.21–9.04(m,1H),8.71(s,1H),7.63–7.43(m,2H),7.38(d,J＝9.2Hz,2H),7.06(t,J＝7.2Hz,1H),6.99–6.89(m,1H),6.79(d,J＝8.4Hz,1H),6.41–6.28(m,1H),4.60–4.50(m,1H),3.38(d,J＝11.0Hz,2H),3.18–2.85(m,2H),2.48–2.39(m,4H),2.38–2.24(m,4H),2.24–2.18(m,1H),2.15(s,3H),1.88–1.69(m,8H),1.60–1.46(m,2H),1.29(d,J＝6.0Hz,6H).MS:617[M+H]⁺.

EXAMPLE 6 preparation of (2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-isobutoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

Step 1) preparation of 1-fluoro-2-isobutoxy-4-nitrobenzene

184 mg (1mmol) of 1-iodo-2-methylpropane and 157 mg (1mmol) of 2-fluoro-5-nitrophenol are placed in a reaction bottle, 2ml of DMF and 138 mg (1mmol) of potassium carbonate are added, the reaction is stirred until the reaction is finished, water is added, and the product 181 mg is obtained by suction filtration, and the yield is 85%. MS:214[ M + H]⁺.

Step 2) preparation of 1- (2-isobutoxy-4-nitrophenyl) -N, N-dimethylpiperazin-4-amine

Putting 108 mg (0.85mmol) of N, N-dimethylpiperazine-4-amine and 181 mg (0.85mmol) of 1-fluoro-2-isobutoxy-4-nitrobenzene into a reaction bottle, adding 2ml of DMF and 138 mg (1mmol) of potassium carbonate, stirring until the reaction is finished, adding water, and performing suction filtration to obtain 245 mg of a product, wherein the yield is 90%.MS:322[M+H]⁺.

Step 3) preparation of 1- (4-amino-2-isobutoxyphenyl) -N, N-dimethylpiperidin-4-amine

Putting 245 mg (0.77mmol) of 1- (2-isobutoxy-4-nitrophenyl) -N, N-dimethylpiperazine-4-amine into a reaction bottle, adding 5ml of methanol, 431 mg (7.7mmol) of iron powder and 407 mg (7.7mmol) of ammonium chloride, heating until the reaction is finished, performing suction filtration, adding potassium carbonate aqueous solution to adjust the solution to be alkaline, extracting with ethyl acetate, and concentrating to obtain 157 mg of a product, wherein the yield is 70%. MS 292[ M + H ]]⁺.

Step 4) and step 5) preparation of (2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-isobutoxyphenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Prepared by reference to step 1) and step 2) of example 1, replacing 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine with an equimolar amount of 1- (4-amino-2-isobutoxyphenyl) -N, N-dimethylpiperidin-4-amine in the starting material.¹H NMR(400MHz,DMSO-d6)11.56(s,1H),11.16(t,J＝2.2Hz,1H),9.23–8.97(m,1H),8.67(s,1H),7.55–7.46(m,1H),7.44–7.37(m,1H),7.30(d,J＝7.9Hz,2H),7.02–6.95(m,1H),6.89–6.82(m,1H),6.71(d,J＝8.4Hz,1H),6.34–6.25(m,1H),3.64(d,J＝6.2Hz,2H),3.35–3.30(m,2H),2.53–2.45(m,2H),2.15(s,6H),2.12–2.04(m,1H),2.04–1.92(m,1H),1.86–1.68(m,8H),1.55–1.36(m,2H),0.96(d,J＝6.7Hz,6H)；MS:576[M+H]⁺.

EXAMPLE 7 preparation of (2- ((2- ((3-cyclobutoxy-4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Preparation of example 7 step 1) to step 5) of reference example 6), 1-iodo-2-methylpropane was replaced with equimolar equivalents of cyclobutane iodide in the starting material in step 1).¹H NMR(400MHz,DMSO-d6)11.54(s,1H),11.13(t,J＝2.2Hz,1H),9.26–8.96(m,1H),8.67(s,1H),7.60–7.38(m,2H),7.33–7.27(m,1H),7.20(d,J＝2.4Hz,1H),7.04–6.96(m,1H),6.89–6.82(m,1H),6.71(d,J＝8.7Hz,1H),6.33–6.24(m,1H),4.61–4.47(m,1H),3.34–3.26(m,4H),2.42–2.36(m,4H),2.16(s,6H),2.06–1.91(m,2H),1.76(d,J＝13.5Hz,8H),1.66–1.53(m,1H),1.52–1.39(m,2H)；MS:574[M+H]⁺.

EXAMPLE 8 preparation of (2- ((2- ((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Preparation of example 8 step 1) to step 5) of the preparation route of reference example 6, wherein in step 1) the starting material is replaced by an equimolar amount of methyl iodide instead of 1-iodo-2-methylpropane and in step 2) an equimolar amount of 1-methyl-4- (piperidin-4-yl) piperazine is replaced by N, N-dimethylpiperazin-4-amine.¹H NMR(400MHz,DMSO-d6)11.56(s,1H),11.18(t,J＝2.0Hz,1H),9.33–8.99(m,1H),8.71(s,1H),7.56–7.46(m,1H),7.42(t,J＝4.6Hz,2H),7.32–7.24(m,1H),7.03–6.94(m,1H),6.90–6.81(m,1H),6.73(d,J＝8.6Hz,1H),6.33– 6.20(m,1H),3.81–3.59(m,6H),3.25–3.17(m,2H),2.59–2.45(m,3H),2.42–2.20(m,4H),2.20–2.13(m,1H),2.09(s,3H),1.76(d,J＝13.5Hz,6H),1.74–1.66(m,2H),1.55–1.40(m,2H).MS:589[M+H]⁺.

EXAMPLE 9 preparation of (2- ((2- ((3-isobutoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Preparation of example 9 reference is made to step 1) to step 5) of the preparation route of example 6, wherein in step 2) the N, N-dimethylpiperazin-4-amine is replaced by an equimolar amount of 1-methyl-4- (piperidin-4-yl) piperazine.¹H NMR(400MHz,DMSO-d6)11.61(s,1H),11.21(s,1H),9.18–9.00(m,1H),8.71(s,1H),7.62–7.51(m,1H),7.47(t,J＝8.0Hz,1H),7.36(d,J＝8.3Hz,2H),7.05(t,J＝7.1Hz,1H),6.92(t,J＝2.8Hz,1H),6.77(d,J＝8.4Hz,1H),6.39–6.28(m,1H),3.70(d,J＝6.2Hz,2H),3.40–3.35(m,4H),2.57–2.52(m,4H),2.39–2.26(m,4H),2.25–2.19(m,1H),2.15(s,3H),2.08–2.01(m,1H),1.89–1.77(m,8H),1.60–1.46(m,2H),1.03(d,J＝6.7Hz,6H)；MS:631[M+H]⁺.

EXAMPLE 10 preparation of (2- ((2- ((3-cyclobutoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Preparation of example 10 reference is made to step 1) to step 5) of the preparation route of example 7, wherein in step 2) the N, N-dimethylpiperazin-4-amine is replaced by an equimolar amount of 1-methyl-4- (piperidin-4-yl) piperazine.¹H NMR(400MHz,DMSO-d6)11.59(s,1H),11.18(s,1H),9.15–9.07(m,1H),8.72(s,1H),7.60–7.46(m,2H),7.39–7.33(m,1H),7.26(d,J＝2.3Hz,1H),7.06(t,J＝7.5Hz,1H),6.92(t,J＝2.8Hz,1H),6.77(d,J＝8.6Hz,1H),6.36(t,J＝2.7Hz,1H),4.67–4.55(m,1H),3.41–3.36(m,4H),2.48–2.41(m,4H),2.39–2.29(m,4H),2.28–2.20(m,2H),2.16(s,3H),2.09–2.01(m,2H),1.87–1.72(m,10H),1.68–1.60(m,1H),1.60–1.50(m,2H)；MS:629[M+H]⁺.

EXAMPLE 11 preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3-isopropylphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Preparation of example 11 reference is made to the preparation route of example 6, steps 1) to 5), wherein in step 1) 1-iodo-2-methylpropane is replaced by an equimolar amount of bromoisopropane and in step 2) N, N-dimethylpiperazin-4-amine is replaced by an equimolar amount of 2-methyl-1- (methyl (piperidin-4-yl) amino) propan-2-ol.¹H NMR(600MHz,DMSO-d6)11.60(s,1H),11.21(s,1H),9.15–9.10(m,1H),8.72(s,1H),7.59–7.53(m,1H),7.49(t,J＝7.9Hz,1H),7.39(s,1H),7.38–7.36(m,1H),7.06(t,J＝7.6Hz,1H),6.93–6.91(m,1H),6.79(d,J＝8.5Hz,1H),6.37–6.35(m,1H),4.60–4.51(m,1H),3.97(s,1H),3.42–3.38(m,2H),3.29(s,2H),2.34(s,3H),2.31–2.26(m,2H),1.83(d,J＝13.5Hz,6H),1.78–1.70(m,2H),1.61–1.51(m,2H),1.29(d,J＝6.0Hz,6H),1.25–1.21(m,1H),1.09(s,6H)；MS:620[M+H]⁺.

EXAMPLE 12 preparation of (2- ((2- ((3-isopropyl-4- (4- ((2-methoxy) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Preparation of example 12 reference is made to the preparation route of example 6, steps 1) to 5), wherein in step 1) 1-iodo-2-methylpropane is replaced by an equimolar amount of bromoisopropane and in step 2) N, N-dimethylpiperazin-4-amine is replaced by an equimolar amount of N- (2-methoxyethyl) -N-methylpiperidin-4-amine.¹H NMR(400MHz,DMSO-d6)11.60(s,1H),11.21(s,1H),9.17–9.10(m,1H),8.72(s,1H),7.61–7.52(m,1H),7.49(t,J＝7.9Hz,1H),7.41–7.35(m,2H),7.10–7.03(m,1H),6.94–6.90(m,1H),6.79(d,J＝8.3Hz,1H),6.38–6.34(m,1H),4.60–4.51(m,1H),3.44–3.35(m,5H),3.25(s,3H),2.60(t,J＝6.2Hz,2H),2.41–2.32(m,2H),2.24(s,3H),1.83(d,J＝13.5Hz,6H),1.78–1.73(m,2H),1.59–1.51(m,2H),1.29(d,J＝6.0Hz,6H)；MS:606[M+H]⁺.

EXAMPLE 13 preparation of (2- ((2- ((4- (4- ((cyclopropylmethyl) (methyl) amino) piperidin-1-yl) -3-isopropylphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Preparation of example 13 reference is made to the preparation route of example 6, steps 1) to 5), wherein in step 1) 1-iodo-2-methylpropane is replaced by an equimolar amount of bromoisopropane and in step 2) N, N-dimethylpiperazin-4-amine is replaced by an equimolar amount of N- (cyclopropylmethyl) -N-methylpiperidin-4-amine.¹H NMR(400MHz,DMSO-d6)11.60(s,1H),11.21(s,1H),9.16–9.09(m,1H),8.72(s,1H),7.61–7.52(m,1H),7.49(t,J＝7.9Hz,1H),7.42–7.34(m,2H),7.06(t,J＝7.3Hz,1H),6.94–6.90(m,1H),6.79(d,J＝8.4Hz,1H),6.38–6.32(m,1H),4.60–4.49(m,1H),3.41–3.36(m,2H),2.47–2.44(m,2H),2.34–2.31(m,2H),2.28(s,3H),1.83(d,J＝13.5Hz,6H),1.78–1.73(m,2H),1.63–1.49(m,3H),1.29(d,J＝6.0Hz,6H),0.84–0.78(m,1H),0.48–0.43(m,2H),0.11–0.05(m,2H)；MS:602[M+H]⁺.

EXAMPLE 14 preparation of (2- ((2- ((3-isopropyl-4- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Preparation of example 14 reference is made to step 1) to step 5) of the preparation route of example 6, wherein in step 2) the N, N-dimethylpiperazin-4-amine is replaced by an equimolar amount of 1-isopropyl-4- (piperidin-4-yl) piperazine.¹HNMR(400MHz,DMSO-d₆)11.64(s,1H),11.31–11.21(m,1H),9.76–9.16(m,1H),9.14–9.09(m,1H),8.87(s,1H),7.64–7.48(m,3H),7.42(d,J＝8.6Hz,1H),7.12–7.05(m,1H),7.00–6.94(m,1H),6.40–6.36(m,1H),4.70–4.53(m,1H),3.54–3.44(m,4H),3.33–3.27(m,4H),3.09–2.88(m,3H),2.79–2.57(m,3H),2.06–1.92(m,2H),1.84(d,J＝13.5Hz,6H),1.78–1.59(m,2H),1.33(d,J＝6.0Hz,6H),1.28–1.16(m,6H)；MS:645[M+H]⁺.

EXAMPLE 15 preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3-methoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Step 1) preparation of tert-butyl (1- (2-methoxy-4-nitrophenyl) piperidin-4-yl) (methyl) carbamate

214 mg (1mmol) of tert-butyl methyl (piperidin-4-yl) carbamate and 171 mg (1mmol) of 1-fluoro-2-methoxy-4-nitrobenzene are placed in a reaction bottle, 2ml of DMF and 138 mg (1mmol) of potassium carbonate are added, stirring is carried out until the reaction is finished, water is added, and suction filtration is carried out to obtain 329 mg of a product, wherein the yield is 90%. MS 366[ M + H]⁺.

Step 2) preparation of 1- (2-methoxy-4-nitrophenyl) -N-methylpiperidin-4-amine

Placing 329 mg (0.9mmol) of tert-butyl (1- (2-methoxy-4-nitrophenyl) piperidin-4-yl) (methyl) carbamate in a reaction bottle, adding 4 ml of dichloromethane and 1ml of trifluoroacetic acid, stirring until the reaction is finished, evaporating the solvent, adding ethyl acetate and aqueous sodium carbonate solution for extraction, and concentrating an organic phase to obtain 239 mg of a product, wherein the yield is 100%. MS 266[ M + H ]]⁺.

Step 3) preparation of 1- ((1- (2-methoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol

Putting 1- (2-methoxy-4-nitrophenyl) -N-methylpiperidine-4-amine 239 mg (0.9mmol) and 2, 2-dimethyl ethylene oxide 72 mg (1mmol) in a reaction bottle, adding ethanol, heating and stirring until the reaction is finished, evaporating the solvent, and carrying out column chromatography to obtain a product 213 mg with the yield of 70％。MS:338[M+H]⁺.

Step 4) preparation of 1- ((1- (4-amino-2-methoxyphenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol

213 mg (0.63mmol) of 1- ((1- (2-methoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol is placed in a reaction bottle, methanol and 200 mg of raney nickel are added, the mixture is stirred under hydrogen atmosphere until the reaction is finished, and the mixture is filtered by suction and concentrated to obtain 194 mg of a product, wherein the yield is 100%. MS 308[ M + H ]]⁺.

Step 5) preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3-methoxyphenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

194 mg (0.63mmol) of 1- ((1- (4-amino-2-methoxyphenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol, (2- ((2-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) dimethylphosphide 283 mg (0.63mmol), dibenzylideneacetone dipalladium 91 mg (0.1mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene 58 mg (0.1mmol) and cesium carbonate 325 mg (1mmol) were placed in a reaction flask, dioxane was added, heating and stirring were carried out until the reaction was completed, ethyl acetate and water were extracted, the organic phase was concentrated, and column chromatography was carried out to obtain 227 mg of the product, the yield being 50%. MS:722[ M + H]⁺.

Step 6) preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3-methoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

(2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3-methoxyphenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide (227 mg (0.32mmol) was placed in a reaction flask, 4 ml of dichloromethane and 1ml of trifluoroacetic acid were added, the mixture was stirred until the starting material disappeared, the solvent was evaporated, and 4 ml of methanol was added. 0.5 ml of saturated sodium hydroxide aqueous solution is stirred until the reaction is finished, ethyl acetate and water are used for extraction, and organic phase is concentrated and subjected to column chromatography to obtain151 mg of product, 80% yield.¹H NMR(400MHz,DMSO-d6)11.64(s,1H),11.25(s,1H),9.18–9.13(m,1H),8.79(s,1H),7.60–7.53(m,1H),7.51–7.45(m,2H),7.37–7.34(m,1H),7.09–7.03(m,1H),6.93(dd,J＝3.5,2.2Hz,1H),6.80(d,J＝8.6Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),3.99(s,1H),3.78(s,3H),3.37–3.34(m,2H),3.33–3.30(m,2H),2.48–2.47(m,1H),2.35(t,3H),2.30(s,2H),1.83(d,J＝13.5Hz,6H),1.76–1.70(m,2H),1.63–1.52(m,2H),1.08(s,6H).MS:592[M+H]⁺.

EXAMPLE 16 preparation of (2- ((2- ((4- (4- (ethyl (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Step 1) preparation of 8- (2-isopropoxy-4-nitrophenyl) -1, 4-dioxo-8-azaspiro [4.5] decane

199 mg (1mmol) of 1-fluoro-2-isopropoxy-4-nitrobenzene and 1, 4-dioxo-8-azaspiro [4.5]]143 mg (1mmol) of decane was placed in a reaction flask, 2ml of DMF and 138 mg (1mmol) of potassium carbonate were added, stirring was carried out until the reaction was completed, water was added, and suction filtration was carried out to obtain 290 mg of the product, yield 90%. MS 323M + H]⁺.

Step 2) preparation of 3-isopropoxy-4- (1, 4-dioxo-8-azaspiro [4.5] decan-8-yl) aniline

Reacting 8- (2-isopropoxy-4-nitrophenyl) -1, 4-dioxo-8-azaspiro [4.5]]290 mg (0.9mmol) of decane is placed in a reaction bottle, methanol and 200 mg of raney nickel are added, the mixture is stirred under hydrogen environment till the reaction is finished, and 263 mg of product is obtained after suction filtration and concentration, wherein the yield is 100%. MS 293[ M + H ]]⁺.

Step 3) preparation of (2- ((2- ((3-isopropoxy-4- (1, 4-dioxo-8-azaspiro [4.5] decan-8-yl) phenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

3-isopropoxy-4- (1, 4-dioxo-8-azaspiro [4.5]]Decyl-8-yl) aniline (263 mg)0.9mmol), (2- ((2-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) dimethylphosphorus dimethyloxide 404 mg (0.9mmol), dipalladium tris (dibenzylideneacetone) 91 mg (0.1mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene 58 mg (0.1mmol) and cesium carbonate 325 mg (1mmol) were placed in a reaction flask, dioxane was added, heating and stirring were carried out until the reaction was completed, ethyl acetate and water were extracted, the organic phase was concentrated, and column chromatography was carried out to obtain 318 mg of the product, with a yield of 50%. MS 707[ M + H]⁺.

Step 4) preparation of 1- (4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -2-isopropoxyphenyl) piperidin-4-one

A mixture of (2- ((2- ((3-isopropoxy-4- (1, 4-dioxo-8-azaspiro [ 4.5))]Decan-8-yl) phenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide 318 mg (0.45mmol) is placed in a reaction bottle, trifluoroacetic acid 2ml and water 2ml are added, stirring is carried out until the raw materials disappear, the solvent is evaporated, methanol and saturated sodium hydroxide aqueous solution are added, stirring is carried out until the reaction is finished, ethyl acetate and water are extracted, the organic phase is concentrated, and column chromatography is carried out to obtain the product 120 mg, wherein the yield is 50%. MS:533[ M + H ]]⁺.

Step 5) preparation of (2- ((2- ((4- (4- (ethyl (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

1- (4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -7H-pyrrolo [2, 3-d)]120 mg (0.225mmol) of pyrimidin-2-yl) amino) -2-isopropoxyphenyl) piperidin-4-one is put into a reaction bottle, 13 mg (0.225mmol) of N-methylethylamine and 95 mg (0.45mmol) of sodium triacetoxyborohydride are added, the reaction is stirred until the reaction is finished, ethyl acetate and water are extracted, the organic phase is concentrated, and column chromatography is carried out to obtain 110 mg of a product, wherein the yield is 85%.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.24(s,1H),9.14(dd,J＝8.6,4.3Hz,1H),8.75(s,1H),7.61–7.47(m,2H),7.41–7.37(m,2H),7.09–7.04(m,1H),6.94–6.91(m,1H),6.80(d,J＝8.4Hz,1H),6.38–6.35(m,1H),4.59–4.53(m,1H),3.40(d,J＝11.1Hz,2H),2.65–2.52(m,4H),2.49–2.47(m,1H),2.27(s,3H),1.83(d,J＝13.5Hz,6H),1.79(s,2H),1.65–1.56(m,2H),1.30(d,J＝6.0Hz,6H),1.03(t,J＝7.0Hz,3H).MS:576[M+H]⁺.

EXAMPLE 17 preparation of (2- ((2- ((3-ethoxy-4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Step 1) preparation of tert-butyl (1- (2-hydroxy-4-nitrophenyl) piperidin-4-yl) (methyl) carbamate

214 mg (1mmol) of tert-butylmethyl (piperidin-4-yl) carbamate and 157 mg (1mmol) of 2-fluoro-5-nitrophenol are placed in a reaction flask, 2ml of DMF and 138 mg (1mmol) of potassium carbonate are added, stirring is carried out until the reaction is finished, water is added, and suction filtration is carried out to obtain 315 mg of a product, wherein the yield is 90%. MS 352[ M + H ]]⁺.

Step 2) preparation of tert-butyl (1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) carbamate

315 mg (0.9mmol) of tert-butyl (1- (2-hydroxy-4-nitrophenyl) piperidin-4-yl) (methyl) carbamate and 107 mg (1mmol) of bromoethane are placed in a reaction flask, 2ml of DMF and 138 mg (1mmol) of potassium carbonate are added, stirring is carried out until the reaction is finished, water is added, and suction filtration is carried out to obtain 307 mg of a product, wherein the yield is 90%. MS 380[ M + H ]]⁺.

Step 3) preparation of 1- (2-ethoxy-4-nitrophenyl) -N-methylpiperidin-4-amine

307 mg (0.81mmol) of tert-butyl (1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) carbamate is placed in a reaction flask, 4 ml of dichloromethane and 1ml of trifluoroacetic acid are added, stirring is carried out until the reaction is finished, the solvent is evaporated, ethyl acetate and aqueous sodium carbonate solution are added for extraction, and the organic phase is concentrated to obtain 226 mg of a product with the yield of 100%. MS 280[ M + H ]]⁺.

Step 4) preparation of 1- ((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol

226 mg (0.81mmol) of 1- (2-ethoxy-4-nitrophenyl) -N-methylpiperidine-4-amine and 72 mg (1mmol) of 2, 2-dimethyloxirane are put into a reaction bottle, ethanol is added, heating and stirring are carried out until the reaction is finished, the solvent is distilled off, and column chromatography is carried out to obtain 200 mg of a product, wherein the yield is 70%. MS 352[ M + H ]]⁺.

Step 5) preparation of 1- ((1- (4-amino-2-ethoxyphenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol

Putting 200 mg (0.56mmol) of 1- ((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol into a reaction bottle, adding 200 mg of methanol and 200 mg of raney nickel, stirring under a hydrogen environment until the reaction is finished, performing suction filtration, and concentrating to obtain 180 mg of a product, wherein the yield is 100%. MS 322[ M + H ]]⁺.

Step 6 preparation of) (2- ((2- ((3-ethoxy-4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

180 mg (0.56mmol) of 1- ((1- (4-amino-2-ethoxyphenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol, (2- ((2-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide 252 mg (0.56mmol), dibenzylideneacetone dipalladium 91 mg (0.1mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene 58 mg (0.1mmol) and cesium carbonate 325 mg (1mmol) were placed in a reaction flask, dioxane was added, heating and stirring were carried out until the reaction was completed, ethyl acetate and water were extracted, the organic phase was concentrated, and column chromatography gave 205 mg of product in 50% yield. MS:736[ M + H]⁺.

Step 7 preparation of) (2- ((2- ((3-ethoxy-4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

(2- ((2- ((3-ethoxy-4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) dimethyl205 mg (0.28mmol) of phosphine oxide is put into a reaction bottle, 4 ml of dichloromethane and 1ml of trifluoroacetic acid are added, the mixture is stirred until the raw materials disappear, the solvent is distilled off, and 4 ml of methanol is added. 0.5 ml of saturated sodium hydroxide aqueous solution is stirred until the reaction is finished, ethyl acetate and water are used for extraction, an organic phase is concentrated, and column chromatography is carried out to obtain 131 mg of a product, wherein the yield is 80%. .¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.24(d,J＝2.3Hz,1H),9.17–9.12(m,1H),8.75(s,1H),7.60–7.54(m,1H),7.50–7.44(m,2H),7.36–7.31(m,1H),7.09–7.04(m,1H),6.94–6.92(m,1H),6.78(d,J＝8.6Hz,1H),6.37–6.34(m,1H),4.04–4.02(m,1H),4.00(q,J＝5.8Hz,2H),3.38(d,J＝11.3Hz,2H),2.49–2.43(m,3H),2.35(s,3H),2.30(s,2H),1.83(d,J＝13.5Hz,6H),1.74(d,J＝11.9Hz,2H),1.62–1.54(m,2H),1.37(t,J＝6.9Hz,3H),1.08(s,6H).MS:606[M+H]⁺.

EXAMPLE 18 preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3-propoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

The preparation of example 18 refers to preparation steps 1) to 7) of example 17, in which 1-bromopropane is used in place of bromoethane in step 2) in an equimolar amount.¹H NMR(400MHz,DMSO-d6)11.63(s,1H),11.24(s,1H),9.14(dd,J＝8.6,4.3Hz,1H),8.75(s,1H),7.60–7.53(m,1H),7.48(t,J＝7.9Hz,1H),7.41(d,J＝2.3Hz,1H),7.36–7.32(m,1H),7.09–7.04(m,1H),6.93(dd,J＝3.5,2.2Hz,1H),6.78(d,J＝8.6Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),3.99(s,1H),3.91(d,J＝6.3Hz,2H),3.41–3.36(m,2H),2.44(d,J＝15.4Hz,3H),2.34(s,3H),2.30(s,2H),1.83(d,J＝13.5Hz,6H),1.79–1.71(m,4H),1.63–1.53(m,2H),1.08(s,6H),1.04(t,J＝7.4Hz,3H).MS:620[M+H]⁺.

EXAMPLE 19 preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3-isobutoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

The preparation of example 19 refers to preparation steps 1) to 7) of example 17, in which 1-bromo-2-methylpropane is substituted for ethyl bromide in step 2) in an equimolar amount.¹H NMR(400MHz,DMSO-d6)11.64(s,1H),11.23(s,1H),9.14(dd,J＝8.5,4.3Hz,1H),8.74(s,1H),7.60–7.53(m,1H),7.50–7.45(m,1H),7.40–7.34(m,2H),7.09–7.04(m,1H),6.93(dd,J＝3.5,2.2Hz,1H),6.78(d,J＝8.4Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),4.00(s,1H),3.71(d,J＝6.2Hz,2H),3.39(d,J＝11.0Hz,2H),2.49–2.39(m,3H),2.34(s,3H),2.30(s,2H),2.10–2.02(m,1H),1.83(d,J＝13.5Hz,6H),1.74(d,J＝11.8Hz,2H),1.58(q,J＝10.7Hz,2H),1.08(s,6H),1.03(d,J＝6.7Hz,6H).MS:634[M+H]⁺.

EXAMPLE 20 preparation of (2- ((2- ((3-butoxy-4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

The preparation of example 20 refers to preparation steps 1) to 7) of example 17, wherein 1-bromobutane is used in place of bromoethane in step 2) in an equimolar amount.¹H NMR(400MHz,DMSO-d6)11.63(s,1H),11.23(d,J＝2.6Hz,1H),9.14(dd,J＝8.6,4.3Hz,1H),8.74(s,1H),7.60–7.53(m,1H),7.50–7.45(m,1H),7.41(d,J＝2.3Hz,1H),7.35(dd,J＝8.5,2.3Hz,1H),7.08–7.04(m,1H),6.93(dd,J＝3.5,2.2Hz,1H),6.78(d,J＝8.6Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),4.00(s,1H),3.96–3.91(m,2H),3.37(d,J＝11.6Hz,2H),2.49–2.40(m,3H),2.34(s,3H),2.30(s,2H),1.83(d,J＝13.5Hz,6H),1.77–1.70(m,4H),1.61–1.47(m,4H),1.08(s,6H),0.96(t,J＝7.4Hz,3H).MS:634[M+H]⁺.

EXAMPLE 21 preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3- (isopentoxy) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

The preparation of example 21 refers to preparation steps 1) to 7) of example 17, wherein 1-bromo-3-methylbutane is substituted for ethyl bromide in step 2) in an equimolar amount.¹H NMR(400MHz,DMSO-d6)11.64(s,1H),11.24(s,1H),9.14(dd,J＝8.5,4.2Hz,1H),8.74(s,1H),7.60–7.53(m,1H),7.50–7.45(m,1H),7.42–7.34(m,2H),7.09–7.03(m,1H),6.93(dd,J＝3.5,2.2Hz,1H),6.78(d,J＝8.5Hz,1H),6.37–6.35(m,1H),4.01–3.94(m,3H),3.40–3.33(m,5H),2.34(d,J＝4.5Hz,3H),2.29(s,2H),1.83(d,J＝13.5Hz,6H),1.77–1.70(m,2H),1.70–1.61(m,3H),1.60–1.52(m,2H),1.08(s,6H),0.95(d,J＝6.7Hz,6H).MS:648[M+H]⁺.

EXAMPLE 22 preparation of (2- ((2- ((4- (4- (isobutyl (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphino

Reference example 16 preparation method steps 1) to 5), wherein in step 5) N, 2-dimethylpropan-1-amine is replaced by N-methylethylamine in equimolar amounts.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.22(s,1H),9.14(dd,J＝8.6,4.3Hz,1H),8.74(s,1H),7.60–7.47(m,2H),7.41–7.36(m,2H),7.09–7.04(m,1H),6.92(dd,J＝3.5,2.2Hz,1H),6.80(d,J＝8.5Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),4.60–4.52(m,1H),3.43–3.36(m,3H),2.64–2.57(m,2H),2.21(s,3H),2.16(d,J＝7.2Hz,2H),1.83(d,J＝13.5Hz,6H),1.77–1.69(m,3H),1.62–1.53(m,2H),1.30(d,J＝6.0Hz,6H),0.86(d,J＝6.6Hz,6H).MS:604[M+H]⁺.

EXAMPLE 23 preparation of (2- ((2- ((3-isopropoxy-4- (4- (methyl (propyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Reference example 16 preparation method steps 1) to 5), wherein in step 5) N-methylethylamine was replaced by equimolar amounts of N-methylpropan-1-amine.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.23(d,J＝2.3Hz,1H),9.14(dd,J＝8.5,4.2Hz,1H),8.74(s,1H),87.60–7.47(m,2H),7.41–7.36(m,2H),7.09–7.04(m,1H),6.92(dd,J＝3.5,2.2Hz,1H),6.80(d,J＝8.5Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),4.61–4.53(m,1H),3.39(d,J＝11.4Hz,3H),2.46(d,J＝9.2Hz,2H),2.44–2.40(m,2H),2.23(s,3H),1.83(d,J＝13.5Hz,6H),1.80–1.74(m,2H),1.64–1.55(m,2H),1.47–1.39(m, 2H),1.30(d,J＝6.0Hz,6H),0.86(t,J＝7.3Hz,3H).MS:590[M+H]⁺.

EXAMPLE 24 preparation of (2- ((2- ((4- (4- (diethylamino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Reference example 16 preparation method steps 1) to 5), wherein in step 5) N-methylethylamine was replaced by equimolar amounts of diethylamine.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.23(s,1H),9.14(dd,J＝8.6,4.3Hz,1H),8.74(s,1H),7.60–7.48(m,2H),7.41–7.37(m,2H),7.06(t,J＝7.6Hz,1H),6.94–6.91(m,1H),6.80(d,J＝9.2Hz,1H),6.37–6.35(m,1H),4.59–4.54(m,1H),3.39(d,J＝11.4Hz,2H),2.59–2.52(m,6H),2.47(s,1H),1.83(d,J＝13.5Hz,6H),1.75(d,J＝12.0Hz,2H),1.60–1.52(m,2H),1.29(d,J＝6.0Hz,6H),0.98(t,J＝7.0Hz,6H).MS:590[M+H]⁺.

EXAMPLE 25 preparation of (2- ((2- ((4- (4- (dipropylamino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Reference example 16 preparation method steps 1) to 5), wherein N-methylethylamine was replaced with an equimolar amount of dipropylamine in step 5).¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.22(t,J＝2.1Hz,1H),9.14(dd,J＝8.5,4.3Hz,1H),8.74(s,1H),7.60–7.47(m,2H),7.38(d,J＝6.9Hz,2H),7.10–7.03(m,1H),6.92(dd,J＝3.5,2.2Hz,1H),6.79(d,J＝9.3Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),4.59–4.53(m,1H),3.42–3.37(m,2H),2.49–2.45(m,3H),2.43–2.38(m,4H),1.83(d,J＝13.5Hz,6H),1.72(d,J＝12.0Hz,2H),1.61–1.52(m,2H),1.43–1.35(m,4H),1.29(d,J＝6.0Hz,6H),0.86(t,J＝7.3Hz,6H).MS:618[M+H]⁺.

EXAMPLE 26 preparation of (2- ((2- ((3-isopropoxy-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Reference example 16 preparation method steps 1) to 5), wherein in step 5) N-methylethylamine was replaced by an equimolar amount of pyrrolidine.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.23(s,1H),9.14(dd,J＝8.4,4.3Hz,1H),8.74(s,1H),7.60–7.47(m,2H),7.39(d,J＝7.3Hz,2H),7.09–7.04(m,1H),6.92(dd,J＝3.5,2.2Hz,1H),6.80(d,J＝9.0Hz,1H),6.37–6.35(m,1H),4.59–4.53(m,1H),3.31(s,2H),2.57–2.52(m,7H),1.97–1.90(m,2H),1.83(d,J＝13.5Hz,6H),1.69(s,4H),1.60–1.49(m,2H),1.29(d,J＝6.0Hz,6H).MS:588[M+H]⁺.

EXAMPLE 27 preparation of (2- ((2- ((4- ([1,4 '-bipiperidin ] -1' -yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Reference example 16 preparation method steps 1) to 5), wherein in step 5) the N-methylethylamine is replaced by an equimolar amount of piperidine.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.23(s,1H),9.14(dd,J＝8.5,4.2Hz,1H),8.74(s,1H),7.60–7.47(m,2H),7.38(d,J＝7.1Hz,2H),7.09–7.04(m,1H),6.92(dd,J＝3.4,2.2Hz,1H),6.79(d,J＝9.2Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),4.59–4.52(m,1H),3.42–3.37(m,2H),2.50–2.44(m,7H),1.83(d,J＝13.5Hz,6H),1.80–1.76(m,2H),1.63–1.55(m,2H),1.53–1.47(m,4H),1.40(d,J＝6.6Hz,2H),1.29(d,J＝6.0Hz,6H).MS:602[M+H]⁺.

EXAMPLE 28 preparation of (2- ((2- ((3-cyclobutoxy-4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

The preparation of example 28 refers to preparation steps 1) to 7) of example 17, wherein in step 2) an equimolar amount of bromocyclobutane is substituted for bromoethane.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.21(s,1H),9.15–9.10(m,1H),8.75(s,1H),7.61–7.48(m,2H),7.40–7.36(m,1H),7.26(d,J＝2.4Hz,1H),7.08(d,J＝7.5Hz,1H),6.93(dd,J＝3.5,2.2Hz,1H),6.77(d,J＝8.7Hz,1H),6.38–6.34(m,1H),4.65–4.58(m,1H),3.99(s,1H),3.42–3.35(m,5H),2.35(s,3H),2.30(s,2H),2.09–2.00(m,3H),1.83(d,J＝13.5Hz,6H),1.79–1.71(m,3H),1.69–1.52(m,4H),1.08(s,6H).MS:632[M+H]⁺.

EXAMPLE 29 preparation of (2- ((2- ((4- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Reference example 16 preparation method steps 1) to 5), wherein in step 5) N-methylethylamine was replaced by an equimolar amount of N-methylcyclobutylamine.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.23(s,1H),9.14(dd,J＝8.3,4.2Hz,1H),8.74(s,1H),7.60–7.47(m,2H),7.39(dd,J＝4.6,2.4Hz,2H),7.06(dd,J＝8.4,6.5Hz,1H),6.92(dd,J＝3.5,2.2Hz,1H),6.79(d,J＝9.2Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),4.58–4.52(m,1H),3.39(d,J＝12.7Hz,3H),3.32–3.28(m,2H),3.16(t,J＝7.9Hz,1H),2.08(s,3H),2.00–1.94(m,2H),1.83(d,J＝13.5Hz,6H),1.79(s,2H),1.66–1.56(m,6H),1.29(d,J＝6.0Hz,6H).MS:602[M+H]⁺.

EXAMPLE 30 preparation of (2- ((2- ((3- (cyclopentyloxy) -4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

The preparation of example 30 refers to preparation steps 1) to 7) of example 17, in which bromoethane is replaced by equimolar amounts of bromocyclopentane in step 2).¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.22(s,1H),9.14(dd,J＝8.5,4.2Hz,1H),8.74(s,1H),7.60–7.47(m,2H),7.42–7.34(m,2H),7.09–7.04(m,1H),6.93(dd,J＝3.5,2.2Hz,1H),6.77(d,J＝8.6Hz,1H),6.36(dd,J＝3.5,1.9Hz,1H),4.78(d,J＝5.8Hz,1H),4.01(s,1H),3.39–3.36(m,2H),3.32–3.29(m,2H),2.45–2.43(m,1H),2.35(s,3H),2.30(s,2H),1.94–1.86(m,2H),1.83(d,J＝13.5Hz,6H),1.79–1.71(m,5H), 1.67–1.50(m,5H),1.08(s,6H).MS:646[M+H]⁺.

EXAMPLE 31 preparation of (2- ((2- ((4- (4- (ethyl (2-hydroxy-2-methylpropyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

Step 1) preparation of N-ethyl-1- (2-isopropoxy-4-nitrophenyl) piperidin-4-amine

Placing 45 mg (1mmol) of ethylamine and 278 mg (1mmol) of 1- (2-isopropoxy-4-nitrophenyl) piperidin-4-one in a reaction bottle, adding 10 ml of dichloromethane, adding 424 mg (2mmol) of sodium triacetoxyborohydride, stirring till the reaction is finished, extracting dichloromethane and water, and concentrating an organic phase to obtain 308 mg of a product with the yield of 100%. MS 308[ M + H ]]⁺.

Step 2) preparation of 1- (ethyl (1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) amino) -2-methylpropan-2-ol

Putting 308 mg (1mmol) of N-ethyl-1- (2-isopropoxy-4-nitrophenyl) piperidine-4-amine and 87 mg (1.2mmol) of 2, 2-dimethyl oxirane in a reaction bottle, adding ethanol, heating and stirring until the reaction is finished, evaporating the solvent, and carrying out column chromatography to obtain 256 mg of a product with the yield of 70%. MS 380[ M + H ]]⁺.

Step 3) to step 5) (preparation of 2- ((2- ((4- (4- (ethyl (2-hydroxy-2-methylpropyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Step 3) to step 5) referring to step 5) to step 7) in the preparation method of example 17, the starting material was substituted with equimolar amounts of 1- (ethyl (1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) amino) -2-methylpropan-2-ol instead of 1- ((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol.¹H NMR(400MHz,DMSO-d6)11.61(s,1H),11.22(s,1H),9.14(dd,J＝8.4,4.2Hz,1H),8.73(s,1H),7.60–7.53(m,1H),7.50(t,J＝8.0,8.0Hz,1H),7.40–7.37(m,2H),7.06(t,J＝7.3,7.3Hz,1H),6.93–6.91(m,1H),6.81–6.78(m,1H),6.37–6.35(m,1H),4.59–4.52(m,1H),3.40(d,J＝11.0Hz,2H),2.64–2.58(m,4H),2.47–2.43(m,2H),2.36–2.33(m,2H),1.83(d,J＝13.5Hz,6H),1.74(d,J＝11.8Hz,2H),1.60–1.53(m,2H),1.30(s,3H),1.29(s,3H),1.08(s,6H),0.99(t,J＝7.0,7.0Hz,3H).MS:634[M+H]⁺.

EXAMPLE 32 preparation of (2- ((2- ((3- (cyclohexyloxy) -4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

The preparation of example 32 refers to preparation steps 1) to 7) of example 17, wherein bromocyclohexane in step 2) is replaced by an equimolar amount.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.21(s,1H),9.16–9.11(m,1H),8.72(s,1H),7.60–7.47(m,2H),7.42–7.34(m,2H),7.09–7.03(m,1H),6.93(dd,J＝3.5,2.2Hz,1H),6.79(d,J＝8.6Hz,1H),6.36(dd,J＝3.4,1.9Hz,1H),4.37–4.29(m,1H),4.02(s,1H),3.41(d,J＝11.1Hz,2H),2.58–2.52(m,2H),2.48–2.45(m,1H),2.35(s,3H),2.31(s,2H),1.93–1.86(m,2H),1.83(d,J＝13.5Hz,6H),1.79–1.71(m,4H),1.62–1.48(m,5H),1.39–1.31(m,3H),1.09(s,6H).MS:660[M+H]⁺.

EXAMPLE 33 preparation of (2- ((2- ((4- (4- (azacyclooctan-1-yl) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Step 1) preparation of 1- (1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) azocane

113 mg (1mmol) of azocane and 278 mg (1mmol) of 1- (2-isopropoxy-4-nitrophenyl) piperidin-4-one are placed in a reaction bottle, 10 ml of dichloromethane is added, 424 mg (2mmol) of sodium triacetoxyborohydride is added, stirring is carried out until the reaction is finished, dichloromethane and water are extracted, and an organic phase is concentrated to obtain 300 mg of a product with the yield of 80%. MS 376[ M + H]⁺.

Step 2) to step 4 preparation of) (2- ((2- ((4- (4- (azocan-1-yl) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Step 2) to step 4) steps 5) to 7) of the preparation process of reference example 17) were repeated, starting material was substituted with 1- ((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol in equimolar amounts of 1- (1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) azocane.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.23–11.21(m,1H),9.16–9.12(m,1H),8.74(s,1H),7.60–7.53(m,1H),7.52–7.47(m,1H),7.40–7.36(m,2H),7.08–7.04(m,1H),6.93–6.91(m,1H),6.81–6.78(m,1H),6.37–6.35(m,1H),4.59–4.53(m,1H),3.40–3.36(m,2H),2.59(t,J＝5.4,5.4Hz,4H),2.47–2.43(m,1H),1.83(d,J＝13.5Hz,6H),1.77–1.72(m,2H),1.65–1.50(m,14H),1.30(s,3H),1.29(s,3H).MS:630[M+H]⁺.

EXAMPLE 34 preparation of (2- ((2- ((4- (4- (((1-hydroxycyclopropyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Step 1) to step 3) preparation of 1- (2-isopropoxy-4-nitrophenyl) -N-methylpiperidin-4-amine

Preparation of 1- (2-isopropoxy-4-nitrophenyl) -N-methylpiperidin-4-amine reference is made to preparation steps 1) to 3) of example 17, in which 2) instead of bromoethane, 2-bromopropane is used in equimolar amounts. MS 294[ M + H]⁺.

Step 4) preparation of 1-hydroxy-N- (1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) -N-methylcyclopropane-1-carboxamide

1- (2-isopropoxy-4-nitro-group293 mg (1mmol) of phenyl) -N-methylpiperidine-4-amine, 102 mg (1mmol) of 1-hydroxycyclopropane-1-carboxylic acid and 456 mg (1.2mmol) of 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) are placed in a reaction bottle, 258 mg (2mmol) of N, N-Diisopropylethylamine (DIEA) are added, the reaction is stirred until the reaction is finished, ethyl acetate and water are extracted, an organic phase is concentrated, column chromatography is carried out to obtain 302 mg of a product, and the yield is 80%. MS:378[ M + H]⁺.

Step 5) preparation of 1- (((1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) methyl) cyclopropane-1-ol

302 mg (0.8mmol) of 1-hydroxy-N- (1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) -N-methylcyclopropane-1-formamide is placed in a reaction bottle, 10 ml (1.2mmol) of toluene and 2M borane dimethyl sulfide tetrahydrofuran solution are added, heating and stirring are carried out until the reaction is finished, methanol is added for quenching, column chromatography is carried out after concentration to obtain 174 mg of a product, and the yield is 60%. MS:364[ M + H]⁺.

Step 6) preparation of 1- (((1- (4-amino-2-isopropoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) cyclopropane-1-ol

174 mg (0.48mmol) of 1- (((1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) methyl) cyclopropane-1-ol is placed in a reaction bottle, 10 ml of methanol and 200 mg of raney nickel are added, the mixture is stirred under a hydrogen environment until the reaction is finished, the mixture is filtered by suction, and the product is obtained by column chromatography after concentration, wherein the yield is 160 mg. MS:334[ M + H]⁺.

Step 7 preparation of) (2- ((2- ((4- (4- (((1-hydroxycyclopropyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

The preparation process is referred to step 6) in example 17, in which 1- ((1- (4-amino-2-ethoxyphenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol is replaced by an equimolar amount of 1- (((1- (4-amino-2-isopropoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) cyclopropane-1-ol. MS 748M + H]⁺.

Step 8) preparation of (2- ((2- ((4- (4- (((1-hydroxycyclopropyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

The preparation method is the same as that of step 7) in example 17.¹H NMR(400MHz,DMSO-d6)11.73(s,1H),11.65(s,1H),9.09–9.04(m,1H),7.62–7.51(m,3H),7.20–7.18(m,1H),7.06(t,J＝7.4,7.4Hz,1H),6.59–6.54(m,1H),6.44–6.42(m,1H),6.21–6.17(m,1H),6.10–6.04(m,1H),4.64(s,1H),4.48–4.41(m,1H),3.18–3.13(m,2H),3.03(s,4H),2.68–2.66(m,1H),2.40–2.32(m,4H),2.21(s,3H),1.83(d,J＝13.5Hz,6H),1.73–1.68(m,2H),1.51–1.44(m,2H),1.23(s,3H),1.21(s,3H).MS:618[M+H]⁺.

EXAMPLE 35 preparation of (2- ((2- ((4- (4- (((1-hydroxycyclobutyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

Step 1) preparation of 1- (((1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) amino) methyl) cyclobutan-1-ol

101 mg (1mmol) of 1- (aminomethyl) cyclobutan-1-ol, 278 mg (1mmol) of 1- (2-isopropoxy-4-nitrophenyl) piperidin-4-one, 278 mg (1mmol) were placed in a reaction flask, 10 ml of dichloromethane was added, 424 mg (2mmol) of sodium triacetoxyborohydride was added, the reaction was stirred until the reaction was completed, dichloromethane and water were extracted, and the organic phase was concentrated to obtain 364 mg of a product, 100% yield. MS:364[ M + H]⁺.

Step 2) preparation of 1- (((1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) methyl) cyclobutan-1-ol

364 mg (1mmol) of 1- (((1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) amino) methyl) cyclobutan-1-ol was placed in a reaction flask, 2ml of DMF and 138 mg (1mmol) of potassium carbonate were added, 142 mg (1mmol) of iodomethane was then added, the reaction was stirred until completion, ethyl acetate and water were extracted, and the organic phase was concentrated to give 321 mg of product in 85% yield. MS:378[ M + H]⁺.

Step 3) preparation of 1- (((1- (4-amino-2-isopropoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) cyclobutan-1-ol

Reference example 34 preparation method, step 6), 1- (((1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) methyl) cyclopropane-1-ol was replaced with equimolar amounts of 1- (((1- (2-isopropoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) methyl) cyclobutane-1-ol in the starting material. MS:348[ M + H]⁺.

Step 4) preparation of (2- ((2- ((4- (4- (((1-hydroxycyclobutyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

The preparation process is referred to step 6) in example 17, in which 1- ((1- (4-amino-2-ethoxyphenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol is replaced by an equimolar amount of 1- (((1- (4-amino-2-isopropoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) cyclobutan-1-ol. MS:762[ M + H]⁺.

Step 5) preparation of (2- ((2- ((4- (4- (((1-hydroxycyclobutyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

The preparation method is the same as that of step 7) in example 17.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.22(s,1H),9.16–9.12(m,1H),8.74(s,1H),7.60–7.54(m,1H),7.50(t,J＝7.9,7.9Hz,1H),7.40–7.36(m,2H),7.09–7.04(m,1H),6.94–6.91(m,1H),6.80(d,J＝8.4Hz,1H),6.37–6.35(m,1H),4.71(s,1H),4.59–4.53(m,1H),3.42–3.38(m,2H),2.49–2.45(m,5H),2.34(s,3H),2.05–1.99(m,2H),1.94–1.88(m,2H),1.83(d,J＝13.5Hz,6H),1.80–1.75(m,2H),1.66–1.55(m,3H),1.47–1.40(m,1H),1.31(s,3H),1.29(s,3H).MS:632[M+H]⁺.

EXAMPLE 36 preparation of (2- ((2- ((4- (4- (cyclopropyl (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Step 1) preparation of N-cyclopropyl-1- (2-isopropoxy-4-nitrophenyl) -N-methylpiperidin-4-amine

Reference example 33 preparation method step 1), substituting N-methylcyclopropylamine in an equimolar amount for azocane. MS:334[ M + H]⁺.

Step 2) to step 4 preparation of) (2- ((2- ((4- (4- (cyclopropyl (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Step 2) to step 4) steps 5) to 7) of the preparation process of reference example 17) starting material was substituted with equimolar amounts of N-cyclopropyl-1- (2-isopropoxy-4-nitrophenyl) -N-methylpiperidin-4-amine instead of 1- ((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.23(t,J＝2.1,2.1Hz,1H),9.14(dd,J＝8.6,4.3Hz,1H),8.74(s,1H),7.60–7.53(m,1H),7.50(t,J＝7.8,7.8Hz,1H),7.40–7.37(m,2H),7.09–7.04(m,1H),6.93–6.92(m,1H),6.82–6.79(m,1H),6.37–6.35(m,1H),4.59–4.53(m,1H),3.41–3.37(m,2H),2.55–2.52(m,2H),2.47–2.44(m,1H),2.29(s,3H),1.89–1.86(m,2H),1.83(d,J＝13.5Hz,6H),1.81–1.78(m,1H),1.67–1.59(m,2H),1.30(s,3H),1.29(s,3H),0.49–0.45(m,2H),0.33–0.29(m,2H).MS:588[M+H]⁺.

EXAMPLE 37 preparation of (2- ((2- ((4- (4- (((1-hydroxycyclopentyl) methyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Preparation of example 37 reference is made to step 1) to step 5) of the preparation of example 35) substituting an equimolar amount of 1- (aminomethyl) cyclopent-1-ol for 1- (aminomethyl) cyclobutan-1-ol in the starting material.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.22(s,1H),9.16–9.12(m,1H),8.74(s,1H),7.60–7.53(m,1H),7.50(t,J＝7.9,7.9Hz,1H),7.40–7.36(m,2H),7.06(t,J＝7.2,7.2Hz,1H),6.94–6.91(m,1H),6.80(d,J＝8.4Hz,1H),6.37–6.35(m,1H),4.59–4.52(m,1H),3.98(s,1H),3.40(d,J＝11.0Hz,2H),2.48–2.47(m,1H),2.46–2.45(m,2H),2.35(s,3H),1.83(d,J＝13.5Hz,6H),1.77–1.68(m,4H),1.62–1.46(m,10H),1.30(s,3H),1.29(s,3H).MS:646[M+H]⁺.

EXAMPLE 38 preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Step 1) preparation of tert-butyl (1- (4-amino-2- (trifluoromethoxy) phenyl) piperidin-4-yl) (methyl) carbamate

214 mg (1mmol) of tert-butylmethyl (piperidin-4-yl) carbamate, 255 mg (1mmol) of 4-bromo-3- (trifluoromethoxy) aniline, 91 mg (0.1mmol) of dibenzylideneacetone dipalladium, 45 mg (0.1mmol) of 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl and 650 mg (2mmol) of cesium carbonate were placed in a reaction flask, dioxane was added, heating and stirring were carried out until the reaction was completed, ethyl acetate and water were extracted, the organic phase was concentrated, and column chromatography was carried out to obtain 195 mg of the product, with a yield of 50%. MS 390[ M + H ]]⁺.

Step 2) preparation of tert-butyl (1- (4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -2- (trifluoromethoxy) phenyl) piperidin-4-yl) (methyl) carbamate

Tert-butyl (1- (4-amino-2- (trifluoromethyl)) is reacted withOxy) phenyl) piperidin-4-yl) (methyl) carbamate 195 mg (1mmol), (2- ((2-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide 225 mg (0.5mmol), dibenzylideneacetone dipalladium 91 mg (0.1mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene 58 mg (0.1mmol) and cesium carbonate 325 mg (1mmol) were placed in a reaction flask, dioxane was added, heating and stirring were carried out until the reaction was completed, ethyl acetate and water were extracted, the organic phase was concentrated, and column chromatography was carried out to obtain 200 mg of the product, with a yield of 50%. MS:804[ M + H ]]⁺.

Step 3) preparation of dimethyl (2- ((2- ((4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) phosphine oxide

Tert-butyl (1- (4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-2-yl) amino) -2- (trifluoromethoxy) phenyl) piperidin-4-yl) (methyl) carbamate (200 mg (0.25mmol) was placed in a reaction flask, 4 ml of dichloromethane and 1ml of trifluoroacetic acid were added, and stirring was carried out until the starting material disappeared, the solvent was distilled off, and 4 ml of methanol was added. 0.5 ml of saturated sodium hydroxide aqueous solution is stirred until the reaction is finished, ethyl acetate and water are used for extraction, an organic phase is concentrated, and column chromatography is carried out to obtain 114 mg of a product, wherein the yield is 80%. MS:574[ M + H]⁺.

Step 4) preparation of (2- ((2- ((4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Dimethyl (2- ((2- ((4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) amino) -7H-pyrrolo [2, 3-d)]114 mg (0.2mmol) of pyrimidine-4-yl) amino) phenyl) phosphine oxide and 15 mg (0.2mmol) of 2, 2-dimethyl oxirane are placed in a reaction bottle, ethanol is added, heating and stirring are carried out until the reaction is finished, the solvent is distilled off, and the column chromatography is carried out to obtain 90 mg of a product, wherein the yield is 70%.¹H NMR(400MHz,DMSO-d6)11.67(s,1H),11.32(t,J＝2.2Hz,1H),9.10(d,J＝11.0Hz,2H),7.92–7.84(m,1H),7.78–7.70(m,1H),7.61–7.54(m,1H),7.54–7.47(m,1H),7.13–7.03(m,2H),6.99–6.92(m,1H),6.40–6.35(m,1H),4.01(s,1H),3.25(d,J＝11.0Hz,2H),2.68–2.56(m,2H),2.48–2.39(m,1H),2.34(s,3H),2.29(s,2H),1.83(d,J＝13.5Hz,6H),1.80–1.71(m,2H),1.61–1.46(m,2H),1.08(s,6H).MS:646[M+H]⁺.

EXAMPLE 39 preparation of (2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) -3- (trifluoromethoxy) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

The preparation of example 39 the preparation of example 38, steps 1) to 3), wherein in step 1) tert-butylmethyl (piperidin-4-yl) carbamate is replaced with an equimolar amount of N, N-dimethylpiperidin-4-amine.¹H NMR(400MHz,DMSO-d6)11.67(s,1H),11.33(d,J＝2.2Hz,1H),9.10(d,J＝5.7Hz,2H),7.91–7.86(m, 1H),7.76–7.70(m,1H),7.62–7.54(m,1H),7.54–7.48(m,1H),7.12–7.02(m,2H),6.99–6.91(m,1H),6.41–6.34(m,1H),3.24(d,J＝11.4Hz,2H),2.69–2.59(m,2H),2.22(s,6H),2.20–2.14(m,1H),1.91–1.76(m,8H),1.55–1.45(m,2H).MS:588[M+H]⁺.

EXAMPLE 40 preparation of (2- ((2- ((4- (4- ((2-fluoroethyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

Step 1) preparation of 1- (2-isopropoxy-4-nitrophenyl) -N-methylpiperidin-4-amine

Reference example 35 preparation method step 1), 1- (aminomethyl) cyclobutan-1-ol was replaced with equimolar amount of methylamine. MS 294[ M + H]⁺.

Step 2) preparation of N- (2-fluoroethyl) -1- (2-isopropoxy-4-nitrophenyl) -N-methylpiperidin-4-amine

294 mg (1mmol) of 1- (2-isopropoxy-4-nitrophenyl) -N-methylpiperidine-4-amine are placed in a reaction flask, 2ml of DMF and 138 mg (1mmol) of potassium carbonate are added, followed by 126 mg (1mmol) of 1-bromo-2-fluoroethane, the reaction is stirred until complete, ethyl acetate and water are extracted, and the organic phase is concentrated to give 289 mg of product, 85% yield. MS 340[ M + H ]]⁺.

Step 3) to step 5 preparation of) (2- ((2- ((4- (4- ((2-fluoroethyl) (methyl) amino) piperidin-1-yl) -3-isopropoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide

Step 3) to step 5) steps 5) to 7) of the preparation process of reference example 17) starting material was substituted with equimolar amounts of N- (2-fluoroethyl) -1- (2-isopropoxy-4-nitrophenyl) -N-methylpiperidin-4-amine instead of 1- ((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol.¹H NMR(400MHz,DMSO-d6)11.62(s,1H),11.23(t,J＝2.2,2.2Hz,1H),9.14(dd,J＝8.4,4.2Hz,1H),8.74(s,1H),7.60–7.53(m,1H),7.52–7.47(m,1H),7.41–7.36(m,2H),7.09–7.04(m,1H),6.94–6.92(m,1H),6.80(d, J＝8.4Hz,1H),6.37–6.35(m,1H),4.59–4.53(m,2H),4.43(t,J＝5.2,5.2Hz,1H),3.39(d,J＝11.2Hz,2H),2.78(t,J＝5.2,5.2Hz,1H),2.71(t,J＝5.2,5.2Hz,1H),2.54–2.52(m,1H),2.48–2.40(m,2H),2.28(s,3H),1.83(d,J＝13.5Hz,6H),1.77(d,J＝11.5Hz,2H),1.61–1.51(m,2H),1.30(s,3H),1.29(s,3H).MS:594[M+H]⁺.

EXAMPLE 41 preparation of (2- ((2- ((3- (2-Fluoroethoxy) -4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphineoxide

Step 1) preparation of 1-benzyl-N-methylpiperidine-4-amine

Putting 378 mg (2mmol) of 1-benzylpiperidin-4-one and 62 mg (2mmol) of methylamine into a reaction bottle, adding 10 ml of dichloromethane, adding 848 mg (4mmol) of sodium triacetoxyborohydride, stirring until the reaction is finished, extracting dichloromethane and water, and concentrating an organic phase to obtain 348 mg of a product, wherein the yield is 85%. MS 205[ M + H ]]⁺.

Step 2) preparation of 1- ((1-benzylpiperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol

Putting 348 mg (1.7mmol) of 1-benzyl-N-methylpiperidine-4-amine and 144 mg (2mmol) of 2, 2-dimethyloxirane in a reaction bottle, adding ethanol, heating and stirring until the reaction is finished, evaporating the solvent, and carrying out column chromatography to obtain 328 mg of a product with the yield of 70%. MS 277[ M + H ]]⁺.

Step 3) preparation of 2-methyl-1- (methyl (piperidin-4-yl) amino) propan-2-ol

Putting 328 mg (1.2mmol) of 1- ((1-benzylpiperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol into a reaction bottle, adding 30 mg of methanol and palladium carbon, stirring under a hydrogen environment until the reaction is finished, performing suction filtration, evaporating a solvent, and concentrating to obtain 224 mg of a product with the yield of 100%. MS 187[ M + H ]]⁺.

Step 4) preparation of 1- ((1- (2- (2-fluoroethoxy) -4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol

157 mg (1mmol) of 2-fluoro-5-nitrophenol is placed in a reaction flask, 2ml of DMF and 276 mg (2mmol) of potassium carbonate are added, 126 mg (1mmol) of 1-bromo-2-fluoroethane is added, 187 mg (1mmol) of 2-methyl-1- (methyl (piperidin-4-yl) amino) propan-2-ol is added after stirring until the starting material disappears, stirring is continued until the reaction is over, ethyl acetate and water are extracted, and the organic phase is concentrated to give 222 mg of product with 60% yield. MS 370[ M + H ]]⁺.

Step 5) to step 7 preparation of) (2- ((2- ((3- (2-fluoroethoxy) -4- (4- ((2-hydroxy-2-methylpropyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

Step 5) to step 7) referring to step 5) to step 7) in the preparation process of example 17, the starting material was substituted with equimolar amounts of 1- ((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol instead of 1- ((1- (2-ethoxy-4-nitrophenyl) piperidin-4-yl) (methyl) amino) -2-methylpropan-2-ol.¹H NMR(400MHz,DMSO-d6)11.63(s,1H),11.25(s,1H),9.17–9.09(m,1H),8.79(s,1H),7.62–7.53(m,1H),7.53–7.41(m,2H),7.39–7.32(m,1H),7.10–7.02(m,1H),6.97–6.91(m,1H),6.83(d,J＝8.7Hz,1H),6.39–6.33(m,1H),4.87–4.79(m,1H),4.75–4.65(m,1H),4.30–4.23(m,1H),4.22–4.15(m,1H),3.41(d,J＝11.1Hz,2H),2.57–2.51(m,2H),2.50–2.46(m,2H),2.46–2.33(m,5H),1.90–1.67(m,8H),1.69–1.55(m,2H),1.11(s,6H).MS:624[M+H]⁺.

Biological activity assay

Main instruments, reagents and cells

TABLE 1 Main instruments, reagents and cells used

Secondly, reagent preparation:

preparation of EDTA (0.5M pH8.0) solution by accurately weighing 14.612g EDTA powder, adding ultrapure water, and adjusting volume to 100mL (if insoluble, heating to 37 deg.C, adjusting pH to 8.0 with NaOH solution)

1 × Kinase Assay Buffer: into a reagent bottle were added 25mL of HEPES solution (1M), 190.175mg of EGTA, and 5mL of MgCl₂The solution (1M), 1mL DTT, 50. mu.L Tween-20, and ultrapure water were added to make a volume of 500mL (pH adjusted to 7.5).

1 × Detection Buffer 1mL of 10 × Detection Buffer was added to 9mL of water and mixed.

4 × stop solution: 0.8mL of the above EDTA (0.5M, pH 8.0.0) solution, 1mL of 10 XDetection Buffer and 8.2mL of ultrapure water were mixed together.

4 × EGFR T790M Kinase solution 1 × Kinase Assay Buffer was used to dilute the Kinase stock solution to a concentration of 0.2nM, mixed well and stored on ice.

4 × substrate solution: substrate ULight was diluted with 1 × Kinase Assay Buffer^TM-PolyGT stock solution to 400nM and mix well.

4 × ATP solution: the ATP stock was diluted with 1 XKinase Assay Buffer to a concentration of 20. mu.M and mixed well.

4 × detection solution: the Detection Antibody Eu-W1024-labeled Anti-Phosphorylazine Antibody (PT66) was diluted with 1 XDeprotection Buffer to a concentration of 8nM, and mixed well.

2 × substrate/ATP mixture: equal amounts of 4 Xsubstrate solution and 4 XATP solution 1:1 were mixed (prepared before use).

EXAMPLE 1 Small molecule Compounds inhibit EGFR^T790MKinase activity was tested as follows:

1) dilution of the Compound

In a 96-well plate a, a compound with a concentration of 10mM is diluted with a DMSO solution by a 3-fold ratio to form 11 gradients, and the 12 th gradient is a pure DMSO solution (as a positive control); a new 96-well plate b was prepared, and the solution was diluted 25-fold with ultrapure water (DMSO concentration: 4%).

2) Rotating Compounds to 384 well plates

The compound solution diluted with ultrapure water in the above 96-well plate b was transferred to the corresponding well of a 384-well plate according to a standard 2-well carousel.

3) Add 4 × kinase solution: mu.l of the 4 Xkinase solution was added to the corresponding reaction well of the 384-well plate using a line gun, and pre-reacted at room temperature for 5 minutes.

4) Add 2 Xsubstrate/ATP mix 5. mu.l of the above 2 Xsubstrate/ATP mix to the corresponding reaction well of a 384 well plate using a discharge gun.

5) Negative control: negative control wells were set in 384-well plates, and 2.5. mu.l of 4 Xsubstrate, 2.5. mu.l of 4 Xenzyme solution, 2.5. mu.l of 1 XKinase Assay Buffer, and 2.5. mu.l of ultrapure water containing 4% DMSO were added to each well.

6) And (4) centrifuging, mixing uniformly, and reacting for 2 hours at room temperature in a dark place.

7) Termination of the enzymatic reaction:

5. mu.l of the above 4 Xstop solution was pipetted into the corresponding well of 384-well plate, centrifuged and mixed, and reacted at room temperature for 5 minutes.

8) And (3) color development reaction:

then, 5. mu.l of the 4X detection solution was pipetted and added to the corresponding well of 384-well plate, and the mixture was centrifuged and mixed and reacted at room temperature for 1 hour.

9) The 384 well plate is placed in a plate reader, and a corresponding program detection signal is called.

10)IC₅₀And (3) analysis:

pore reading 10000 × EU 665/EU 615 values

Inhibition rate ═ 100% (positive control well reading-experimental well reading)/(positive control well reading-negative control well reading)%

The corresponding IC can be calculated by inputting the drug concentration and the corresponding inhibition rate into GraphPad Prism5 for processing₅₀。

EXAMPLE 2 Small molecule Compounds inhibit EGFR^{L858R-T790M-C797S}Kinase activity was tested as follows:

in the in vitro assembled enzymatic reaction, different concentrations of the test compound are added to detect EGFR by the compound^T790M- ^L858R-C797SInhibition of enzymatic reactions by calculation of EGFR^{T790M-L858R-C797S}IC for inhibition of enzymatic reactions₅₀To screen compounds for biochemical inhibitory activity. The specific method of the test is consistent with the method of the experimental example 1, and only the following conditions need to be adjusted: 1) the final concentration of ATP solution in the reaction is 1. mu.M; 2) substrate ULight^TM-final concentration of PolyGT of 50 nM; 3) EGFR^{L858R-T790M-C797S}The final concentration of kinase was 0.5 nM.

Table 2 lists EGFR by the compounds of the examples in this application^T790MKinase and EGFR^{L858R-T790M-C797S}Measurement of tyrosine kinase inhibitory Activity, wherein A represents IC₅₀Less than or equal to 5nM, B represents IC₅₀Greater than 5nM but less than or equal to 50nM, C represents IC₅₀Above 50nM, NT indicates that the corresponding kinase was not tested.

TABLE 2 EGFR treatment with the compounds of the invention^T790MAnd EGFR^{L858R-T790M-C797S}Measurement results of kinase inhibitory Activity

Experimental example 3.

The test of the small molecular compound for inhibiting cell proliferation of Ba/F3 EGFR-L858R/T790M and Ba/F3 EGFR-L858R/T790M/C797S comprises the following specific steps:

1) Ba/F3 EGFR-L858R/T790M and Ba/F3 EGFR-L858R/T790M/C797S cells were cultured in RPMI 1640 complete medium (RPMI 1640 basal medium + 10% FBS).

2) The well-grown cells were collected and transferred to a 15mL centrifuge tube and centrifuged at 1000rpm for 4 minutes.

3) Discarding supernatant, adding the complete culture medium, blowing and beating uniformly, mixing 10 μ L of cell suspension and 10 μ L of 0.4% trypan blue, counting with a cell counter, and recording cell number and survival rate.

4) Each well was seeded with 80 μ L of cell suspension into 96-well plates (different cell seeding cell densities are shown in table 3).

Cell name	Culture medium	Density of inoculation
Ba/F3 EGFR-L858R/T790M	RPMI 1640+10％FBS	5000 per hole
Ba/F3 EGFR-L858R/T790M/C797S	RPMI 1640+10％FBS	5000 per hole

TABLE 3 cell density

5) In a 96-well plate a, a compound with a concentration of 10mM is diluted with a DMSO solution by 3-fold proportion to form 9 gradients, and the 10 th gradient is a pure DMSO solution (as a positive control); a new 96-well plate b was used, and the above solution was diluted 80-fold with RPMI 1640 complete medium to obtain a 5X compound solution (DMSO concentration: 1.25%).

6) mu.L of the above 5X compound solution diluted with the culture medium was added to the experimental well and mixed well.

7) In the presence of 5% CO₂After culturing for 72 hours in an incubator at 37 ℃, adding 10 mu L of CCK-8 reagent into each well, and culturing for 2 hours (the reaction time can be adjusted according to the color depth);

8) the OD value was read at 450nm on a multifunction plate reader.

9) Data processing: cell survival (%) - (As-Ab)/(Ac-Ab) ]. 100%

As: OD value of experimental well (cell-containing medium, CCK-8, compound);

ac: OD of control wells (medium containing cells, CCK-8);

ab: OD of blank wells (medium without cells and compounds, CCK-8).

The values were then introduced into Graphpad Prism5 software for curve fitting and IC was calculated₅₀。

Table 4 shows the results of the activity assay of compounds of the examples of the invention on Ba/F3 EGFR-L858R/T790M and Ba/F3 EGFR-L858R/T790M/C797S cells, wherein A represents IC₅₀Less than or equal to 50nM, B represents IC₅₀Greater than 50nM but less than or equal to 100nM, C represents IC₅₀Greater than 100nM but less than or equal to 200nM, D represents IC₅₀Greater than 200 nM.

TABLE 4 results of the determination of the cellular Activity of some of the Compounds of the invention

Experimental example 4.

The test method for inhibiting ALK kinase activity by the small molecular compound is as follows:

using Perkin Elmer

The Ultra TR-FRET technique measures the activity of ALK kinase by detecting the level of substrate phosphorylation in the reaction. In the LANCE Ultra enzymatic activity assay, Eu-labeled specific anti-phospho antibodies were used to detect phosphorylation of Ulight-substrates. When the detection antibody binds to the phosphorylated substrate, the two groups, Eu and Ulight, are in proximity, and upon exposure to laser radiation at wavelengths of 320 or 340nm, Eu emits energy that is transferred to Ulight and excites a 665nm optical signal. The intensity of the optical signal is positively correlated with the phosphorylation level of the Ulight-substrate in the reaction, enabling quantitative determination of kinase activity.

The enzyme assay was carried out using ALK kinase supplied by Carna Biosciences, ATP supplied by Promega, Perkin Elmer

Ultra Ulight^TM-a Poly GT substrate,

Eu-W1024-anti-phosphotyrosine detection antibody, LANCE^TMDetection Buffer, white OptiPlate-384 well plate, sealing plate membrane and Envison multifunctionalAnd (5) carrying out experiments and detection by a plate reading machine. The preparation method of the kinase buffer solution, the stop solution and the color developing solution and the method for diluting the compound are as follows:

1. preparation of kinase buffer: into a reagent bottle were added 25mL of HEPES solution (1M), 190.175mg of EGTA, and 5mL of MgCl₂The solution (1M), 1mL DTT, 50. mu.L Tween-20, and ultrapure water were added to make a volume of 500mL (pH adjusted to 7.5).

2. Preparation of detection liquid:

the Eu-W1024-anti-phosphotyrosine Detection antibody was formulated with 1 × Detection Buffer at a concentration of 8 nM.

3. Preparation of a stop solution: 0.8mL of an aqueous EDTA (0.5M, pH 8.0.0) solution, 1mL of 10 XDetection Buffer, and 8.2mL of ultrapure water were mixed together.

4.4 × dilution procedure of intermediate concentration compound: compounds were first diluted to 10mM in neat DMSO and then serially diluted 3-fold in DMSO for 11 concentrations, again with ultrapure H at each concentration point₂Dilution with O25-fold.

ALK kinase, ATP and

Ultra Ulight^TMthe-Poly GT substrate was prepared with a kinase buffer at 4 Xmiddle concentrations of 2.8nM, 4. mu.M, and 200nM, respectively, and the complete enzymatic reaction system consisted of 2.5. mu.L of ALK kinase, 2.5. mu.L of ATP, 2.5. mu.L of diluted 4 Xmiddle concentration compound, and 2.5. mu.L of

Ultra Ulight^TM-a Poly GT substrate. After the assembly enzymatic reaction, the reaction was carried out for 2 hours at room temperature under protection from light. After the completion of the enzymatic reaction, 5. mu.L of a stop solution was added to terminate the enzymatic reaction, and then 5. mu.L of a chromogenic detection solution was added thereto to react for 1 hour. And calling a corresponding program by using an Envison multifunctional plate reading machine to read the plate.

The data processing process is as follows: reading 10000 × EU665 value/EU 615 value

Percent inhibition was 100% (positive control well read-experimental well read)/(positive control well read-negative control well read) ].

The drug concentration and corresponding inhibition rate were input to GraphPad Prism5 for processing to calculate the corresponding IC 50.

Table 5 lists the results of the assays for ALK kinase inhibitory activity of some of the example compounds in this application, where a represents an IC50 of less than or equal to 5nM, B represents an IC50 of greater than 5nM but less than or equal to 50nM, and C represents an IC50 of greater than 50 nM.

TABLE 5 results of measurement of ALK kinase inhibitory Activity of partial Compounds of the present invention

From the crystal structure (5J7H) in the Protein database (RCSB Protein Data Bank), it is known that the piperidine ring in the structure of Brigatinib compound forms a dihedral angle of approximately 90 degrees with the benzene ring to which it is attached in the interaction with ALK Protein. However, the conjugated system formed by the nitrogen atom in the piperidine ring and the benzene ring to which it is attached causes the piperidine ring to tend to form a dihedral angle of approximately 0 degrees with the benzene ring to which it is attached.

As shown in the structure (a), the introduction of a substituent group (such as methyl) at the ortho position of the benzene ring will help the transposition between the piperidine ring and the benzene ring, making the three-dimensional structure of the compound more favorable for the interaction with ALK protein. Therefore, it is likely that such structural modifications will greatly increase the biological activity of compound (a) and similar compounds on the ALK protein. Given the similarity of ALK and EGFR in their three-dimensional structures in the ATP-binding domain, the biological activity of compound (a) and similar compounds on C797S-mutated EGFR is also expected to be greatly improved. Based on the above concept, the inventors designed and synthesized a series of compounds of the present application.

Experimental data show that the compounds of the invention introduce substituents at the ortho-position of a benzene ring (relative to a piperidine ring connected with the benzene ring) to effectively enhance the cell activity of mutant EGFR, the inhibitory activity of partial compounds on EGFR T790M and C797S mutant cells is far higher than that of Brigatinib, and the compounds are hopeful to become fourth generation EGFR mutation-mediated non-small cell lung cancer candidate drug compounds.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims

A compound shown as a formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt and a prodrug thereof,

in the formula (I), the compound is shown in the specification,

x is CH or N;

y is CH or N;

R¹is-NHR⁵，R⁵Is unsubstituted or substituted aryl, heteroaryl, cycloalkyl bridged ring structures, fused ring structures,

R⁵wherein the substituent in the substituted aryl, heteroaryl, cycloalkyl bridged ring structure, and fused ring structure is-CF₃、-OCF₃Hydroxy, cyano, halogen, C₁-C₆Alkyl radical, C₃-C₅Cycloalkyl radical, C₁-C₆Alkoxy radical, C₃-C₅Cycloalkyloxy, -S (═ O)₂R⁶、-C(＝O)R⁶、-P(＝O)R⁶R⁷、-S(＝O)₂NR⁶R⁷，

R⁶And R⁷Are each independently-H, C₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group,

the fused ring structure is selected from aromatic ring and 5-6 membered heteroaromatic ring group, 5-6 membered heteroaromatic ring and 5-6 membered heteroaromatic ring group, aromatic ring and 5-6 membered cycloalkyl, aromatic ring and 5-6 membered heterocyclic group, 5-6 membered heteroaromatic ring and 5-6 membered heterocycloalkyl or 5-6 membered heteroaromatic ring and 5-6 membered heterocyclic group;

R²is-H, -CF₃、-CH₂CF₃、C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₄Cycloalkyl-substituted C₁-C₂Alkyl, 4-6 membered heterocyclic group containing one oxygen atom, or- (CH)₂)_mR⁸Wherein m is an integer of 1,2, 3,

R⁸is-OH, -CN, -C (O) NH₂、-S(＝O)₂CH₃、C₁-C₃Alkoxy radical, C₁-C₃An alkylthio group;

R³and R⁴Are each independently-H, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl containing one nitrogen atom or one oxygen atom or- (CH)₂)_nR⁹Wherein n is an integer of 1,2, 3,

the 4-6 membered heterocyclic ring containing one nitrogen atom or one oxygen atom is unsubstituted or substituted by C₁-C₃Is substituted with an alkyl group of (a) or (b),

R⁹is-OH, -CN, -C (O) NH₂、-S(＝O)₂CH₃、-NR'R”、C₁-C₃Alkoxy radical, C₁-C₃An alkylthio group is a group of one or more,

r 'and R' are each independently H or C₁-C₃The alkyl group of (a) is,

or, R³、R⁴The nitrogen atom to which it is attached constitutes a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O or S or a group-C (═ O) -or-S (═ O), or a 6-9 membered spirocyclic ring₂-as a ring member,

the R is³、R⁴The 4-6 membered heterocyclic ring formed by the nitrogen atom connected with the heterocyclic ring is unsubstituted or respectively substituted by 1-2 groups selected from halogen, cyano, hydroxyl, amino and C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halo C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl radical, C₁-C₃Alkoxy-substituted C₁-C₃The alkyl group is substituted by the alkyl group,

the R is³、R⁴The 6-to 9-membered spirocyclic ring composed of the nitrogen atom to which it is attached is a monospirocyclic ring containing one nitrogen atom.
The compound, isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof according to claim 1, wherein R¹is-NHR⁵，R⁵Selected from the following groups:

q is N or CH, and Q is N or CH,

t is NH, O or S,

R¹⁰selected from the group consisting of-H, -OH, -F, -Cl, -Br, -CN, -CF₃、-OCF₃Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or the following groups:

R¹¹is-H, methyl, ethyl, propyl, isopropyl,

R¹²is-H, -F, -Cl, -Br, hydroxy, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxyAnd (4) a base.
The compound according to claim 1, wherein R is R, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, or a prodrug thereof²Selected from-H, -CF₃、-CH₂CF₃Methyl, ethyl, propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, methylsulfonylpropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl.
The compound according to claim 1, wherein R is R, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, or a prodrug thereof²Selected from n-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl.
The compound according to claim 1, wherein R is R, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, or a prodrug thereof³And R⁴Each independently selected from the group consisting of-H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, prop-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylaze (hetero) cyclobutane-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, methylsulfonylpropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, tert-butylmethyl, isopropylmethyl, methylaminoethyl, dimethylaminoethyl, methylaminopropyl, dimethylaminopropyl,or R³、R⁴The nitrogen atom connected with the compound forms a 4-6-membered heterocyclic ring or a 6-9-membered spirocyclic ring, the 4-6-membered heterocyclic ring is a substituted or unsubstituted heterocyclic ring,

the R is³、R⁴The substituted or unsubstituted 4-6 membered heterocyclic ring constituted by the nitrogen atom to which it is attached is selected from the following ring structures:

R¹³selected from-H, methylamino, ethylamino, dimethylamino,

R¹⁴selected from-H, methyl, ethyl, propyl, isopropyl, formyl, acetyl or methylsulfonyl,

R¹⁵and R¹⁶Each independently selected from-H, -F, -CF₃Hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyanomethyl, cyanoethyl, methoxymethyl, methoxyethyl, methoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl,

the R is³、R⁴The 6-to 9-membered spiro ring, constituted by the nitrogen atom to which it is attached, is selected from the following spiro ring structures:
the compound according to claim 1, wherein R is R, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, or a prodrug thereof³Selected from the group consisting of-H, methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, isopentyl, neopentyl, N-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, prop-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylazetan (hetero) cyclobutane-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methanesulfonylethyl, methanesulfonylpropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, methylaminoethyl, dimethylaminoethyl, methylaminopropyl, dimethylaminopropyl,

R⁴selected from n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl.
A compound shown as a formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt and a prodrug thereof,

in the formula (I), the compound is shown in the specification,

x is CH or N; y is CH or N;

R¹is-NHR⁵，R⁵Selected from the following groups:

q is N or CH, and Q is N or CH,

t is NH, O or S,

R¹⁰selected from the group consisting of-H, -OH, -F, -Cl, -Br, -CN, -CF₃、-OCF₃Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or the following groups:

R¹¹is-H, methyl, ethyl, propyl,The isopropyl group is a group selected from the group consisting of isopropyl,

R¹²is-H, -F, -Cl, -Br, hydroxy, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

R²selected from-H, -CF₃、-CH₂CF₃Methyl, ethyl, propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, methylthioethyl, methylthiopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, aminoacetyl, aminopropionyl, methylsulfonylethyl, methylsulfonylpropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl;

R³selected from-H, methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, isopentyl, neopentyl, N-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylazocyclo (hetero) butan-3-yl;

R⁴is selected from- (CH)₂)_nR¹⁷Wherein n is an integer of 1,2, 3,

R¹⁷is composed of
Or C₃-C₆Cycloalkyl radical, R¹⁸is-OH, -CN, -C (O) NH₂、-S(＝O)₂CH₃、C₁-C₃Alkoxy radical, C₁-C₃An alkylthio group.
A compound shown as a formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt and a prodrug thereof,

in the formula (I), the compound is shown in the specification,

x is CH or N;

y is CH or N;

R¹is-NHR⁵，R⁵Selected from the following groups:

q is N or CH, and Q is N or CH,

t is NH, O or S,

R¹⁰selected from the group consisting of-H, -OH, -F, -Cl, -Br, -CN, -CF₃、-OCF₃Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or the following groups:

R¹¹is-H, methyl, ethyl, propyl, isopropyl,

R¹²is-H, -F, -Cl, -Br, hydroxy, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;

R²is-H, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halo C₁-C₆An alkyl group;

R³and R⁴Are each independently-H, C₃-C₈Cycloalkyl or from 1 to 3 substituents selected from C₁-C₆Alkoxy, hydroxy, halogen, C₃-C₆C substituted or unsubstituted by a substituent of cycloalkyl₁-C₉An alkyl group, a carboxyl group,

or, R³、R⁴The nitrogen atom to which it is attached forms a 4-to 8-membered heterocyclic ring which also contains 1-2 heteroatoms selected from N, O or S or contains the group-C (═ O) -or-S (═ O)₂-as a ring member,

the R is³、R⁴The 4-to 8-membered heterocyclic ring formed by the nitrogen atom to which it is attached is unsubstituted or substituted by 1 to 2 substituents selected from halogen, cyano, hydroxy, amino, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halo C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl radical, C₁-C₃Alkoxy-substituted C₁-C₃Alkyl groups are substituted.
The compound of claim 8, isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof, wherein X is CH; y is CH;

R¹is composed of

R²is-H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, isopentyl, pentyl, neopentyl, hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, fluoroethyl;

R³and R⁴Each independently selected from the group consisting of-H, methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl, isopentyl, neopentyl, N-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, N-methylpiperidin-4-yl, N-methylpyrrolidin-3-yl, N-methylaze (hetero) cyclobutane-3-yl, methylthioethyl, methylthiopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropylpropyl, methylthiopropyl, methoxymethyl, and ethoxypropylbutylA group, isopropoxymethyl group, isopropoxyethyl group, isopropoxypropyl group, aminoacetyl group, aminopropionyl group, methylsulfonylethyl group, methylsulfonylpropyl group, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, cyanomethyl group, cyanoethyl group, cyanopropyl group, methylaminoethyl group, dimethylaminoethyl group, methylaminopropyl group, dimethylaminopropyl group, cyclopropylmethyl group, cyclopropylethyl group, trifluoromethyl group, fluoroethyl group, 2-hydroxy-2-methylpropyl group, 3-hydroxy-3-methylbutyl group, and the like,
Or R³、R⁴The nitrogen atom connected with the heterocyclic ring forms a 4-8 membered heterocyclic ring, the 4-8 membered heterocyclic ring is a substituted or unsubstituted heterocyclic ring,

the R is³、R⁴The substituted or unsubstituted 4-to 8-membered heterocyclic ring formed by the nitrogen atom to which it is attached is selected from the following ring structures:

R¹³selected from-H, methylamino, ethylamino, dimethylamino,

R¹⁴selected from-H, methyl, ethyl, propyl, isopropyl, formyl, acetyl or methylsulfonyl,

R¹⁵and R¹⁶Each independently selected from-H, -F, -CF₃Hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyanomethyl, cyanoethyl, methoxymethyl, methoxyethyl, methoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl.
A compound, isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof, selected from the group consisting of:
a process for preparing a compound of claims 1-9, isomers, hydrates, solvates, pharmaceutically acceptable salts thereof, and prodrugs thereof, comprising the steps of,
a pharmaceutical composition for treating diseases associated with mutation or overexpression of the tyrosine kinases EGFR, HER2 or ALK, which consists of the compound of formula (I) as described in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient.
A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient, one or more further therapeutic agents, and one or more pharmaceutically acceptable carriers or excipients.
Use of a compound of any one of claims 1 to 10, isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof in the manufacture of a medicament for the treatment of cancer and autoimmune diseases associated with mutation or overexpression of the tyrosine kinases EGFR, HER2 or ALK, wherein the cancer and autoimmune diseases include ocular fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, Thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract carcinosarcoma, and cholangiocarcinoma.