WO2021185348A1

WO2021185348A1 - Substituted acrylamide derivative and composition and use thereof

Info

Publication number: WO2021185348A1
Application number: PCT/CN2021/081756
Authority: WO
Inventors: 王义汉; 赵九洋; 邢青峰; 李焕银; 艾义新
Original assignee: 深圳市塔吉瑞生物医药有限公司
Priority date: 2020-03-20
Filing date: 2021-03-19
Publication date: 2021-09-23
Also published as: CN113493439A; CN113493439B

Abstract

Provided are a substituted acrylamide derivative, a composition comprising said compound, and a use thereof. The substituted acrylamide derivative is a compound represented by formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof. The compound and the composition thereof can be used to prepare a drug for treating and/or preventing tumors mediated by wild and/or mutant EGFR and/or HER2 kinase.

Description

Substituted acrylamide derivatives and their compositions and uses

Technical field

The present invention belongs to the field of medical technology, and particularly relates to substituted acrylamide derivatives that have inhibitory effects on wild and/or mutant EGFR and/or HER2, pharmaceutical compositions containing them, and their preparation methods and uses.

Background technique

EGFR is a receptor tyrosine kinase that binds to epidermal growth factor (hereinafter also referred to as EGF) as a ligand to exert its physiological functions in normal tissues, and contributes to the inhibition of epithelial tissue growth and apoptosis . Somatic mutations of the EGFR gene are known to be carcinogenic: for example, the EGFR and exon 21 regions where amino acids 746 to 750 in the exon 19 region are deleted (hereinafter also referred to as "exon 19 deletion mutations") EGFR whose amino acid at position 858 is mutated from leucine to arginine (hereinafter also referred to as "L858R mutation") continuously induces EGF-independent kinase activity and leads to the growth and survival of cancer cells. For example, these mutations are observed in about 30%-50% of non-small cell lung cancers in East Asia, and these mutations are also observed in about 10% of non-small cell lung cancers in Europe and the United States, so they are considered to be one of the causes of cancer. .

Therefore, research and development of EGFR inhibitors as antitumor agents have been actively carried out and used in the treatment of EGFR mutation-positive lung cancer. For example, gefitinib, erlotinib, and afatinib have high anti-tumor effects in EGFR-positive lung cancers with exon 19 deletion mutations and L858R mutations, but they can cause digestive tract diseases when used in their therapeutic doses. And skin diseases and other side effects.

Recent studies have found that some cancers have new mutations in EGFR, in which one or more amino acids are inserted into the exon 20 region (hereinafter also referred to as "exon 20 insertion mutations"), and these cancers are relatively EGFR inhibitors have low sensitivity.

On the other hand, there have been reports that point mutations or deletion mutations in exon 18 and point mutations in exon 21 are several rarer EGFR mutations. For example, a new EGFR point mutation of lung cancer has been discovered, in which the 719th glycine in the exon 18 region is replaced by any amino acid (hereinafter referred to as the G719X mutation), and the 861th leucine in the exon 21 region is replaced by glutathione. Aminoamide substitution (hereinafter referred to as L861Q mutation).

HER2 (also known as ErbB2) is a receptor tyrosine kinase belonging to the ErbB2 family. HER2 is considered to be a proto-oncogene, and gene amplification, mutation, and overexpression of HER2 have been reported in various cancers. In these cancer cells with abnormal and overexpression of HER2 gene, the signal activation of HER2 and downstream pathways enhances the survival and proliferation signals of cancer cells.

HER2 mutation is one of the common driver mutation genes in lung cancer, mainly manifested as gene amplification, point mutation, exon 20 insertion mutation and other mutation types (such as deletion insertion mutation, frameshift mutation, etc.), of which exon 20 Insertion mutations are the most common. For example, the HER2 mutant contains a YVMA inserted into exon 20 (hereinafter referred to as ex20insYVMA). Mutant HER2 activates signal transduction, phosphorylates EGFR, and induces tumor formation and spread more effectively than wild-type HER2.

Therefore, it can be presumed that an inhibitor capable of controlling the kinase activity of HER2 exerts an antitumor effect by inhibiting the signal transduction of HER2 and downstream pathways in cancer cells, and therefore, it can be considered that it can be effectively used as a cancer therapeutic agent.

Therefore, it is necessary to further develop new EGFR inhibitors and HER2 inhibitors in order to effectively inhibit wild EGFR and/or exon 20 insertion mutation EGFR, exon 18 point mutation EGFR, and exon 21 point. Mutant EGFR, wild HER2 and/or mutant HER2.

Summary of the invention

The present invention provides a new acrylamide derivative and a composition containing the compound and uses thereof, which include exon 20 ins mutant EGFR, exon 18 point mutant EGFR, and exon 21 point mutant EGFR, exon 19 del mutant EGFR, L858R mutant EGFR, exon 19 deletion/T790M mutant EGFR, L858R/T790M mutant EGFR, etc. have better inhibitory activity and High selectivity and inhibitory activity to wild HER2 and/or mutant HER2, thus providing an anti-tumor drug with low toxicity and side effects.

In this regard, the present invention adopts the following technical solutions:

In one aspect, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

Ring A is an aromatic ring;

Ring C is C _6-10 aryl or 5-10 membered heteroaryl;

A ₁ is CR _A1 or N;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

Wherein R _A1 and R _A4 are each independently selected from H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, and are optionally substituted with one or more R″;

B ₁ is CR ₁ or N;

B ₂ is CR ₂ or N;

B ₃ is CR ₃ or N;

B ₄ is CR ₄ or N;

Wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6} Alkynyl, -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C (O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _{3 -7} cycloalkyl, 3 to 7 membered heterocyclyl, C _6-10 aryl or 5 to 10 membered heteroaryl, and is optionally substituted by one or more R″;

L is selected from O, S or NR _L;

Wherein R _{L is} selected from H or C _1-6 alkyl, and is optionally substituted with one or more R*;

V is (CR _V1 R _V2 ) _o ;

Wherein R _V1 and R _V2 are each independently selected from H, D, halogen or C _1-6 alkyl, and are optionally substituted with one or more R*;

o = 1, 2, 3, 4, 5 or 6;

R ₆ is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C _6-10 aryl or 5 To 10-membered heteroaryl groups, and the above groups are optionally substituted by one or more R*;

R ₅ and R ₇ are each independently selected from H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl, and the above groups are optionally substituted by one or more R*; or , R ₅ and R ₇ together with the double bond they are connected to form a triple bond;

R is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C (O )R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to A 7-membered heterocyclic group, a C _6-10 aryl group, or a 5- to 10-membered heteroaryl group; or, two R groups on the same atom or adjacent atoms can form a C _3-7 cycloalkyl group, 3 to 7 Membered heterocyclic group, C _6-10 aryl group or 5 to 10-membered heteroaryl group; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;

m=0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

R'is each independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C (O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7 members Heterocyclyl, C _6-10 aryl or 5 to 10 membered heteroaryl, and is optionally substituted with one or more R″;

n=0, 1, 2, 3 or 4;

p=0, 1 or 2;

R" is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C( O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b ,- NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 To 7-membered heterocyclic group, C _6-10 aryl group or 5 to 10-membered heteroaryl group, or two R" groups on the same atom or adjacent atoms can form a C _3-7 cycloalkyl group, 3 To 7-membered heterocyclic group, C _6-10 aryl group or 5 to 10-membered heteroaryl group; wherein each group in the definition of R" is optionally substituted with one or more D until fully deuterated;

R* are each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C( O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b ,- NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 To 7-membered heterocyclic group, C _6-10 aryl group or 5 to 10-membered heteroaryl group; or, two R* groups on the same atom or adjacent atoms can form a C _3-7 cycloalkyl group, 3 To 7-membered heterocyclic group, C _6-10 aryl group or 5 to 10-membered heteroaryl group; wherein each group in the definition of R* is optionally substituted with one or more D until fully deuterated;

R _a , R _b and R _c are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl , 3 to 7 membered heterocyclic group, C _6-10 aryl group or 5 to 10 membered heteroaryl group, or R _b and R _c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R _a, R _b and R _{c are} defined in each group is optionally substituted by one or more D, until completely deuterated.

In another aspect, the present invention provides a pharmaceutical composition containing the compound of the present invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent Compound, and pharmaceutically acceptable excipients. In a specific embodiment, the compound of the invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the invention is provided in a prophylactically effective amount.

In another aspect, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention Use of the pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of wild-type or mutant EGFR kinase-mediated tumors.

In another aspect, the present invention provides a method of treating and/or preventing a disease in a subject, such as a wild and/or mutant EGFR kinase-mediated tumor, comprising administering to the subject The compound of the invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of the invention.

In a specific embodiment, the mutant EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR.

In a specific embodiment, the exon 20 insertion mutation is a mutation in which one or more amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is a mutation in which 1 to 7 amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is a mutation in which 1 to 4 amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, D770>GY, N771_P772insN, P772_R773insPR, H773_V774ins_V774ins, H773insPR, H773_V774ins_V774ins, H773_H773_H773HinsPR, H773_V774ins_V774ins, H773_VH774ins, H773_H773_H774ins_V774ins, H773_H774ins, H773_H773_H774ins_V774ins, H773_VH774ins In a specific embodiment, the exon 20 insertion mutation is V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH.

In a specific embodiment, the exon 18 point mutation is selected from the G719X mutation of exon 18 or the E709X mutation of exon 18. In a specific embodiment, the G719X mutation is selected from at least one mutation of G719A, G719S and G719C. In a specific embodiment, the E709X mutation is selected from at least one mutation of E709K and E709A.

In a specific embodiment, the exon 21 point mutation is selected from the L861X mutation of exon 21. In a specific embodiment, the L861X mutation is a L861Q mutation.

In a specific embodiment, the mutated EGFR has a T790M mutation and is selected from the group consisting of exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation, or L858R mutation. At least one mutation.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 20 Tumor patients with inserted mutated EGFR.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with exon 20 insertion mutation of EGFR.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 18 Tumor patients with point mutant EGFR.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with exon 18 point mutation EGFR.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 21 Tumor patients with point mutant EGFR.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Cancer patients with exon 21 point mutant EGFR.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 19 Tumor patients with deletion of mutant EGFR.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Cancer patients with exon 19 deletion mutant EGFR.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expressing the L858R mutant EGFR Of cancer patients.

In a specific embodiment, the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with L858R mutant EGFR.

In a specific embodiment, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention The use of the pharmaceutical composition of the invention in the preparation of a medicament for the treatment and/or prevention of the following tumors, or the invention provides a method for the treatment and/or prevention of the following tumors in a subject, comprising: The person administers the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention: lung cancer, breast cancer , Head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.

In another aspect, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention The pharmaceutical composition is used in the preparation of a medicament for the treatment and/or prevention of wild and/or mutant HER2 kinase-mediated tumors.

In another aspect, the present invention provides a method of treating and/or preventing a disease in a subject, such as a wild and/or mutant HER2 kinase-mediated tumor, comprising administering to the subject The compound of the invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of the invention.

In a specific embodiment, the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C Mutant HER2, L755S mutant HER2 or ex20insYVMA mutant HER2.

In a specific embodiment, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.

In a specific embodiment, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention Use of the pharmaceutical composition of the invention in the preparation of a medicament for the treatment and/or prevention of the following tumors, or the invention provides a method for the treatment and/or prevention of the following tumors in a subject, comprising providing Administration of the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention: lung cancer, gastric cancer or breast cancer.

From the following specific embodiments, examples and claims, other objects and advantages of the present invention will be apparent to those skilled in the art.

definition

Chemical definition

The definitions of specific functional groups and chemical terms are described in more detail below.

When listing numerical ranges, it is intended to include each value and sub-ranges within the stated range. For example, "C _1-6 alkyl" includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1 -2} , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and C _{5 -6} alkyl.

The "C _1-6 alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and is also referred to herein as a "lower alkyl group". In some embodiments, C _1-4 alkyl is particularly preferred. Examples of the alkyl group include but are not limited to: methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert Butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butyl (C ₅ ), tert-amyl (C ₅ ) and n-hexyl (C ₆ ). Regardless of whether or not the alkyl group is modified with "substituted", each of the alkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. The appropriate substituents are as follows definition.

The "C _2-6 alkenyl group" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C _2-4 alkenyl is preferred. Examples of C _2-6 alkenyl groups include: vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), etc. The term "C _2-6 alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. Regardless of whether the alkenyl group is modified with "substituted", each of the alkenyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are as follows definition.

"C _2-6 alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C _2-4 alkynyl is preferred. Examples of C _2-6 alkynyl groups include but are not limited to: ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), pentynyl (C ₅ ), hexynyl (C ₆ ), and so on. The term "C _2-6 alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. Regardless of whether the alkynyl group is modified with "substituted" in front of it, each of the alkynyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. Suitable substituents are as follows definition.

"C _1-6 alkoxy" refers to the group -OR, where R is a substituted or unsubstituted C _1-6 alkyl group. In some embodiments, C _1-4 alkoxy is particularly preferred. Specific alkoxy groups include but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, N-hexyloxy and 1,2-dimethylbutoxy. Regardless of whether the alkoxy group is modified with "substituted", each of the alkoxy groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate. The basis is defined as follows.

"C _1-6 alkylamino" refers to the group -NHR or -NR ₂ , where R is a substituted or unsubstituted C _1-6 alkyl group. In some embodiments, C _1-4 alkylamino is particularly preferred. The specific alkylamino group includes but is not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, methylethylamino and diethylamino. Regardless of whether the alkylamino group is modified with "substituted" before it, each of the alkylamino groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. The appropriate substituents are as follows definition.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

Therefore, "C _1-6 haloalkyl" and "C _1-6 haloalkoxy" refer to the above-mentioned "C _1-6 alkyl" and "C _1-6 alkoxy", which are substituted by one or more halogen groups. The group replaces. In some embodiments, C _1-4 haloalkyl is particularly preferred, and C _1-2 haloalkyl is more preferred. In some embodiments, C _1-4 haloalkoxy is particularly preferred, and C _1-2 haloalkoxy is more preferred. Exemplary haloalkyl groups include, but the are not limited _{_{to: -CF 3, -CH 2 F,}} -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl ₂ , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Exemplary halogenated alkoxy groups include, but are not limited to: -OCH ₂ F, -OCHF ₂ , -OCF ₃ , and the like.

"C _3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C _3-7 cycloalkyl is preferred, C _3-6 cycloalkyl is particularly preferred, and C _5-6 cycloalkyl is more preferred. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to indicate The number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include but are not limited to: cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl ( C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptene Group (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1] Heptyl (C ₇ ), bicyclo[2.2.2]octyl (C ₈ ), cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthyl (C ₁₀ ), spiro[4.5]decyl (C ₁₀ ), and so on. Regardless of whether the cycloalkyl group is modified with "substituted", each of the cycloalkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate. The basis is defined as follows.

"3 to 10 membered heterocyclic group" or a group of 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen and oxygen , Sulfur, boron, phosphorus and silicon. In a heterocyclic group containing one or more nitrogen atoms, as long as the valence permits, the point of attachment may be a carbon or nitrogen atom. In some embodiments, a 3 to 7 membered heterocyclic group is preferred, which is a 3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3 to 6 The membered heterocyclic group is particularly preferred, which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5 to 6 membered heterocyclic group, which is a ring system having ring carbon atoms and A 5- to 6-membered non-aromatic ring system with 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl ring is fused with one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in this case, the ring The number of members continues to indicate the number of ring members in the heterocyclyl ring system. Regardless of whether the heterocyclic group is modified with "substituted" in front of it, each of the heterocyclic groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitably substituted The basis is defined as follows.

Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxasulfuranyl. Oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiacyclohexyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl, and thieppanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azacyclooctyl, oxetanyl, and thietanyl. Exemplary _{5-membered heterocyclic groups fused to a C 6} aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: indolinyl, isoindolinyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc. Exemplary _{6-membered heterocyclic groups fused to a C 6} aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.

"C _6-14 aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6-14 ring carbon atoms and zero heteroatoms) The shared 6, 10, or 14 π electrons) groups are arranged in a ring. In some embodiments, an aryl group having six ring carbon atoms ( "C ₆ aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C ₁₀ aryl"; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C ₁₄ aryl"; for example, anthryl). In some embodiments, C _6-10 aryl groups are particularly preferred, and C ₆ aryl groups are more preferred. The aryl group also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring. In this case, the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is modified with "substituted", each of the aryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. The appropriate substituents are as follows definition.

"5 to 10 membered heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (for example, having a shared ring arrangement 6 or 10 π electrons), where each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, as long as the valence allows, the point of attachment may be a carbon or nitrogen atom. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case, the carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5- to 6-membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Regardless of whether the heteroaryl group is modified with "substituted" in front of it, each of the heteroaryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitably substituted The basis is defined as follows.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , Benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indenazinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pterridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .

"Carbonyl" refers to the -C(O)- group.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON (R ^bb _{^{) 2, -N (R bb)}} 2, -N (R bb) 3 + X -, -N (OR cc) R bb, -SH, -SR aa, -SSR cc, -C (= O) R aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C (=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) _2. -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa ,- Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(= S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P( =O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ ,- NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and hetero Aryl groups, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl group is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups ；

Or the two geminal hydrogens on the carbon atom are grouped by =0, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , = Replace with NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc ;

^{Each of Raa} is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl, or two ^Raa groups are combined to form a heterocyclic group or Heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^dd groups Group replacement

Each of R ^bb is independently selected from: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) _2. -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O ) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl, haloalkyl, alkene Group, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ^bb groups combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkyne Group, carbocyclic group, heterocyclic group, aryl group and heteroaryl group are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each of R ^cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ^cc groups are combined to form a heterocyclic ring Group or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^dd group substitution;

Each of R ^dd is independently selected from: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N ^{_{(R ff) 2 ,, - N}} (R ff) 3 + X -, -N (OR ee) R ff, -SH, -SR ee, -SSR ee, -C (= O) R ee, -CO 2 H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ ,- NR ^ff C(=O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff ) R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff ) N(R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee ,- SC(=S)SR ^ee , -P(=O) ₂ R ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group The group, the aryl group and the heteroaryl group are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two geminal R ^dd substituents may be combined to form =O or =S;

Each of R ^ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon Cyclic, heterocyclic, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

Each of R ^ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ^ff groups are combined to form a heterocyclic group Or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^gg Group substitution

Each of R ^gg is independently: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON (C _1-6 alkyl) _2, -N (C _1-6 alkyl) _2, -N (C _1-6 _{^{^{alkyl) 3 + X -, -NH (}}} C 1-6 alkyl) _₂ ⁺ X ^-, -NH ₂ (C _1-6 ^{^{_{^{alkyl) + X -, -NH 3 +}}}} X -, -N (OC 1-6 alkyl) (C _1-6 alkyl), - N (OH) ( C 1-6 alkyl ), -NH(OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C(=O) (C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C (=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ ,- NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _{1- 6} alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl) , -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C (=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl , -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl) ₂ , -OP(= O)(C _1-6 alkyl) ₂ , -OP(= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbocyclic group , C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, C ₅ -C ₁₀ heteroaryl; or two geminal R ^gg substituents can be combined to form =O or =S; where X ^- is the opposite ion.

Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) _2. -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O )(NR ^cc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ^cc groups connected to the nitrogen atom combine to form a heterocyclic ring Group or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R ^{The dd} group is substituted, and wherein R ^aa , R ^bb , R ^cc and R ^{dd are} as described above.

"Deuteration" or "D" means that one or more hydrogens in a compound or group are replaced by deuterium; deuteration can be mono-, di-, multi-, or full-substitution. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.

"Non-deuterated compound" refers to a compound that contains a proportion of deuterium atoms not higher than the natural deuterium isotope content (0.015%).

The deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably Greater than 99%.

The term "pharmaceutically acceptable salt" means that within the scope of reliable medical judgment, it is suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and is compatible with reasonable benefits/risks. The salt in proportion. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe the pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. It also includes salts formed using conventional methods in the art, for example, ion exchange methods. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , Malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. If appropriate, other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counter ions such as halide, hydroxide, formate, sulfate, phosphate, Nitrate, lower alkyl sulfonate and aryl sulfonate.

The "subject" to be administered includes, but is not limited to: humans (ie, men or women of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults)) and/or non-human animals, for example, mammals, for example, primates (for example, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , Goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"Disease", "disorder" and "condition" are used interchangeably herein.

Unless otherwise specified, the term "treatment" as used herein includes the effect that occurs when a subject suffers from a specific disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder Or the development of a condition ("therapeutic treatment"), and also includes effects that occur before the subject begins to suffer from a specific disease, disorder, or condition ("prophylactic treatment").

"Combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compound of the present invention can be administered simultaneously or sequentially in separate unit dosage forms with another therapeutic agent, or simultaneously administered in a single unit dosage form with another therapeutic agent.

Detailed ways

Compound

Herein, "the compound of the present invention" refers to the following compound of formula (I) (including a subset of each formula), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In one embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

Ring A is an aromatic ring;

Ring C is C _6-10 aryl or 5-10 membered heteroaryl;

A ₁ is CR _A1 or N;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

B ₁ is CR ₁ or N;

B ₂ is CR ₂ or N;

B ₃ is CR ₃ or N;

B ₄ is CR ₄ or N;

L is selected from O, S or NR _L;

V is (CR _V1 R _V2 ) _o ;

o = 1, 2, 3, 4, 5 or 6;

m=0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

n=0, 1, 2, 3 or 4;

p=0, 1 or 2;

Ring C

In one embodiment, ring C is C _6-10 aryl; in another embodiment, ring C is 5 to 10 membered heteroaryl; in another embodiment, ring C is phenyl or 5 to 6 In another embodiment, ring C is a phenyl group or a 5- to 6-membered heteroaryl group containing 1-3 N, O or S heteroatoms; in another embodiment, ring C is Phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl or thienyl; in In another embodiment, ring C is phenyl or pyridyl; in another embodiment, ring C is pyridyl.

A ₁ , A ₂ , A ₄ and A ₅

In one embodiment, A ₁ is CR _A1 ; in another embodiment, A ₁ is CH; in another embodiment, A ₁ is N.

In one embodiment, A ₂ is C; in another embodiment, A ₂ is N.

In one embodiment, A ₄ is CR _A4; In another embodiment, A ₄ is CH; In another embodiment, A ₄ is N.

In one embodiment, A ₅ are C; In another embodiment, A ₅ is N.

In one embodiment,

Selected from the following structures:

Preferably,

Selected from the following structures:

Preferably,

Selected from the following structures:

B ₁ , B ₂ , B ₃ and B ₄

In one embodiment, B ₁ is CR ₁ ; in another embodiment, B ₁ is N.

In one embodiment, B ₂ is CR ₂ ; in another embodiment, B ₂ is N.

In one embodiment, B ₃ is CR ₃ ; in another embodiment, B ₃ is N.

In one embodiment, B ₄ is CR ₄ ; in another embodiment, B ₄ is N.

R ₁ , R ₂ , R ₃ and R ₄

In one embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently H; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently D; in another embodiment Where R ₁ , R ₂ , R ₃ and R _{4 are} independently halogen; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -CN; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently C _1-6 alkyl; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently C _1-6 haloalkyl; In one embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently C _2-6 alkenyl; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently C _{2- 6} alkynyl; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -C(O)R _a ; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 is} independently -C(O)OR _a ; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -C(O)NR _b R _c ; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -NR _b R _c ; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -NR _a C(O)R _b ; In another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -NR _a C(O)OR _b ; In another embodiment, R ₁ , R ₂ , R ₃ and R ₄ Are independently -NR _a C(O)NR _b R _c ; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -OR _a ; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -OC(O)R _a ; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -OC(O)OR _a ; In one embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently -OC(O)NR _b R _c ; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently C _3-7 cycloalkyl; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently 3 to 7 membered heterocyclyl; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently C _6-10 aryl groups; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently 5- to 10-membered heteroaryl groups.

In another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 alkoxy, or C _3-7 Cycloalkyl; In another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from H, D, halogen, -CN, C _1-6 alkyl, or C _1-6 alkoxy; In another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from H, D, halogen or C _1-6 alkyl; in another embodiment, R ₁ , R ₂ , R ₃ And R _{4 are} independently selected from H, D, F, Cl or methyl; in another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from H or Cl. In another embodiment, R ₂ is halogen, preferably Cl.

In another embodiment, R ₁ , R ₂ , R ₃ and R _{4 are} independently substituted with one or more R", for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Or more R" substitutions.

L

In one embodiment, L is O; In another embodiment, L is S; In another embodiment, L is NR _L; In another embodiment, L is NH.

V

In one embodiment, V is (CR _V1 R _V2 ) _o ; in another embodiment, V is (CR _V1 R _V2 ) ₁ , (CR _V1 R _V2 ) ₂ , (CR _V1 R _V2 ) ₃ , ( CR _V1 R _V2 ) ₄ , (CR _V1 R _V2 ) ₅ or (CR _V1 R _V2 ) ₆ ; In another embodiment, R _V1 and R _V2 are each independently H, D, halogen or C _1-6 alkane In another embodiment, R _V1 and R _V2 are both H. In another embodiment, V is (CH ₂ ) _o ; preferably CH ₂ .

R ₆

In one embodiment, R ₆ is H; in another embodiment, R ₆ is D; in another embodiment, R ₆ is halogen; in another embodiment, R ₆ is -CN; in another embodiment, R 6 is -CN; In one embodiment, R ₆ is C _1-6 alkyl; in another embodiment, R ₆ is C _1-6 haloalkyl; in another embodiment, R ₆ is C _3-7 cycloalkyl; In another embodiment, R ₆ is a 3 to 7 membered heterocyclic group; in another embodiment, R ₆ is a C _6-10 aryl group; in another embodiment, R ₆ is a 5 to 10 membered heterocyclic group; Aryl.

In another embodiment, R ₆ is substituted with one or more R*, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R*.

In another embodiment, R _{6 is} selected from H, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl, 3 to 7 membered heterocyclyl, C _6-10 aryl, or 5 to 10-membered heteroaryl; in another embodiment, R _{6 is} selected from H, halogen, -CN or C _1-6 alkyl; in another embodiment, R _{6 is} selected from H, F, Cl, Br, -CN, methyl, ethyl, isopropyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ N(CH ₃ )(CH(CH ₃ ) ₂ ), -CH ₂ N(CH ₂ CH ₃ ) ₂ or

In another embodiment, R _{6 is} selected from H, F, Cl, methyl, or -CH ₂ N(CH ₃ ) ₂ ; in another embodiment, R _{6 is} selected from H, methyl, or -CH ₂ N (CH ₃ ) ₂ ; In another embodiment, R ₆ is H.

R ₅ and R ₇

In one embodiment, R ₅ and R ₇ are each independently H; in another embodiment, R ₅ and R ₇ are each independently D; in another embodiment, R ₅ and R ₇ are each independently Is halogen; in another embodiment, R ₅ and R ₇ are each independently -CN; in another embodiment, R ₅ and R ₇ are each independently C _1-6 alkyl; in another embodiment In this, R ₅ and R ₇ are each independently C _1-6 haloalkyl; in another embodiment, R ₅ and R ₇ together with the double bond to which they are attached form a triple bond.

In another embodiment, R ₅ and R ₇ are each independently selected from H, halogen, -CN, or C _1-6 alkyl; in another embodiment, R ₅ and R ₇ are each independently selected from H, Halogen or CN; in another embodiment, R ₅ and R ₇ are each independently selected from H, F, Cl, or CN; in another embodiment, R ₅ and R ₇ are each independently selected from H or CN; In another embodiment, R ₅ and R ₇ are H.

R and m

In one embodiment, R is H; in another embodiment, R is D; in another embodiment, R is halogen; in another embodiment, R is -CN; in another embodiment , R is =0; in another embodiment, R is C _1-6 alkyl; in another embodiment, R is C _1-6 haloalkyl; in another embodiment, R is C _{2- 6} alkenyl group; in another embodiment, R is a C _2-6 alkynyl group; in another embodiment, R is -C (O) R _a; in another embodiment, R is -C (O ) OR _a ; in another embodiment, R is -C(O)NR _b R _c ; in another embodiment, R is -NR _b R _c ; in another embodiment, R is -NH ₂ ; In another embodiment, R is -NR _a C(O)R _b ; In another embodiment, R is -NR _a C(O)OR _b ; In another embodiment, R is -NR _a C(O)NR _b R _c ; in another embodiment, R is -OR _a ; in another embodiment, R is -OH; in another embodiment, R is -OC(O)R _a ; In another embodiment, R is -OC(O)OR _a ; In another embodiment, R is -OC(O)NR _b R _c ; In another embodiment, R is C _{3- 7} cycloalkyl; in another embodiment, R is 3 to 7 membered heterocyclyl; in another embodiment, R is C _6-10 aryl; in another embodiment, R is 5 to 10 Membered heteroaryl; in another embodiment, two R groups on the same atom or on adjacent atoms can form a C _3-7 cycloalkyl group together; in another embodiment, on the same atom or on adjacent atoms The two R groups of can together form a 3- to 7-membered heterocyclic group; in another embodiment, two R groups on the same atom or adjacent atoms can together form a C _6-10 aryl group; in another In an embodiment, two R groups on the same atom or adjacent atoms can form a 5- to 10-membered heteroaryl group; wherein each group in the definition of R is optionally substituted by one or more D until completely Deuterated.

In one embodiment, m=0; in another embodiment, m=1; in another embodiment, m=2; in another embodiment, m=3; in another embodiment, m=4; in another embodiment, m=5; in another embodiment, m=6; in another embodiment, m=7; in another embodiment, m=8; in another embodiment In one embodiment, m=9.

p

In one embodiment, p=0; in another embodiment, p=1; in another embodiment, p=2.

In another embodiment,

Selected from the following structures:

Preferably:

R’ and n

In one embodiment, R'is H; in another embodiment, R'is D; in another embodiment, R'is halogen; in another embodiment, R'is -CN; in another embodiment, R'is -CN; In one embodiment, R'is C _1-6 alkyl; in another embodiment, R'is C _1-6 haloalkyl; in another embodiment, R'is C _2-6 alkenyl; in another embodiment, R 'is C _2-6 alkynyl; in another embodiment, R' is -C (O) R _a; in another embodiment, R 'is -C (O) OR _a ; in another embodiment, R'is -C(O)NR _b R _c ; in another embodiment, R'is -NR _b R _c ; in another embodiment, R'is -NR _a C(O)R _b ; in another embodiment, R'is -NR _a C(O)OR _b ; in another embodiment, R'is -NR _a C(O)NR _b R _c ; in another embodiment, R 'is -OR _a; in another embodiment, R' is -OC (O) R _a; in another embodiment, R 'is -OC (O) OR _a; In another embodiment, R′ is -OC(O)NR _b R _c ; in another embodiment, R′ is C _3-7 cycloalkyl; in another embodiment, R′ is 3 to 7-membered heterocyclyl; in another embodiment, _R'is C 6-10 aryl; in another embodiment, R'is 5 to 10-membered heteroaryl.

In another embodiment, R'is substituted with one or more R", for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R".

In one embodiment, n=0; in another embodiment, n=1; in another embodiment, n=2; in another embodiment, n=3; in another embodiment, n=4.

R"

In one embodiment, R” is H; in another embodiment, R” is D; in another embodiment, R” is halogen; in another embodiment, R” is -CN; In one embodiment, R” is =0; in another embodiment, R” is C _1-6 alkyl; in another embodiment, R” is C _1-6 haloalkyl; in another embodiment , R "is as C _2-6 alkenyl; in another embodiment, R" is a C _2-6 alkynyl group; in another embodiment, R "is -C (O) R _a; in another In one embodiment, R" is -C(O)OR _a ; in another embodiment, R" is -C(O)NR _b R _c ; in another embodiment, R "is -NR _b R _c ; In another embodiment, R "is -NH ₂ ; in another embodiment, R" is -NR _a C (O) R _b ; in another embodiment, R "is -NR _a C ( O) OR _b ; in another embodiment, R” is -NR _a C(O)NR _b R _c ; in another embodiment, R” is -OR _a ; in another embodiment, R” is -OH; in another embodiment, R "is -OC (O) R _a; in another embodiment, R" is -OC (O) OR _a; in another embodiment, R "is -OC(O)NR _b R _c ; in another embodiment, R" is C _3-7 cycloalkyl; in another embodiment, R" is 3 to 7 membered heterocyclyl; in another embodiment In the scheme, R" is a C _6-10 aryl group; in another embodiment, R" is a 5- to 10-membered heteroaryl group; in another embodiment, two R" on the same atom or adjacent atoms The groups can together form a C _3-7 cycloalkyl group; in another embodiment, two R" groups on the same atom or adjacent atoms can together form a 3- to 7-membered heterocyclic group; in another embodiment In another embodiment, two R” groups on the same atom or adjacent atoms can form a C _6-10 aryl group together; in another embodiment, two R” groups on the same atom or adjacent atoms can form a C 6-10 aryl group together. 5- to 10-membered heteroaryl; wherein each group in the definition of R" is optionally substituted with one or more D until fully deuterated.

R*

In one embodiment, R* is H; in another embodiment, R* is D; in another embodiment, R* is halogen; in another embodiment, R* is -CN; in another In one embodiment, R* is =0; in another embodiment, R* is C _1-6 alkyl; in another embodiment, R* is C _1-6 haloalkyl; in another embodiment in, R * is a C _2-6 alkenyl group; in another embodiment, R * is a C _2-6 alkynyl group; in another embodiment, R * is -C (O) R _a; in another In one embodiment, R* is -C(O)OR _a ; in another embodiment, R* is -C(O)NR _b R _c ; in another embodiment, R* is -NR _b R _c ; In another embodiment, R* is -NH ₂ ; In another embodiment, R* is -NR _a C(O)R _b ; In another embodiment, R* is -NR _a C( O) OR _b ; in another embodiment, R* is -NR _a C(O)NR _b R _c ; in another embodiment, R* is -OR _a ; in another embodiment, R* Is -OH; in another embodiment, R* is -OC(O)R _a ; in another embodiment, R* is -OC(O)OR _a ; in another embodiment, R* is -OC(O)NR _b R _c ; in another embodiment, R* is C _3-7 cycloalkyl; in another embodiment, R* is 3 to 7 membered heterocyclyl; in another embodiment In the scheme, R* is a C _6-10 aryl group; in another embodiment, R* is a 5- to 10-membered heteroaryl group; in another embodiment, two R* on the same atom or adjacent atoms The groups can together form a C _3-7 cycloalkyl group; in another embodiment, two R* groups on the same atom or adjacent atoms can together form a 3- to 7-membered heterocyclic group; in another embodiment In this, two R* groups on the same atom or adjacent atoms can form a C _6-10 aryl group together; in another embodiment, two R* groups on the same atom or adjacent atoms can form a C 6-10 aryl group together 5- to 10-membered heteroaryl; wherein each group in the definition of R* is optionally substituted with one or more D until fully deuterated.

R _a , R _b and R _c

In one embodiment, R _a, R _b and R _{c are} independently H; In another embodiment, R _a, R _b and R _{c are} independently C _1-6 alkyl; In one embodiment, R _a , R _b and R _{c are} independently C _1-6 haloalkyl; in one embodiment, R _a , R _b and R _{c are} independently C _3-7 cycloalkyl; in one embodiment, R _a , R _b and R _{c are} independently 3 to 7 membered heterocyclic groups; in one embodiment, R _a , R _b and R _{c are} independently C _6-10 aryl groups; in one embodiment, R _a , R _b and R _{c are} independently 5- to 10-membered heteroaryl groups; wherein _{each group in the definition of R a} , R _b and R _c is optionally substituted with one or more D until fully deuterated.

Any technical solution or any combination of any of the above specific embodiments can be combined with any technical solution or any combination of other specific embodiments. For example, ring C, A ₁ , A ₂ , A ₄ , A ₅ , B ₁ , B ₂ , B ₃ , B ₄ , L, V, R ₅ , R ₆ , R ₇ , R, m, R', n Combine with any technical solution of p or any combination thereof. The present invention is intended to include all the combinations of these technical solutions, limited to space, and will not be listed one by one.

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvates, in which,

Selected from the following structures:

Preferably,

Selected from the following structures:

Preferably,

Selected from the following structures:

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, wherein ring C is phenyl or 5- to 6-membered heteroaryl; preferably phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxalin Azolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl or thienyl; preferably phenyl or pyridyl.

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, wherein V is (CH ₂ ) _o ; preferably CH ₂ .

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, where L is O.

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, wherein B ₁ is CR ₁ , B ₂ is CR ₂ , B ₃ is CR ₃ , and B ₄ is CR ₄ ; preferably, R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from H, D. Halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl.

Selected from the following structures:

Preferably:

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, which is a compound of the following general formula:

Wherein each group is as defined above.

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, which is a compound of formula (II-1), (III-1) or (IV-1):

in,

Ring A is an aromatic ring;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

Wherein R _A4 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, which is optionally substituted by one or more R″;

R ₁ is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl, and is optionally substituted with one or more R″;

R ₂ is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl, and is optionally substituted with one or more R″;

R ₃ is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl, and is optionally substituted with one or more R″;

R ₄ is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl, and is optionally substituted with one or more R″;

o = 1, 2, 3 or 4;

Each R is independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; wherein R is in the definition Each group of is optionally substituted with one or more D until fully deuterated;

m=0, 1, 2, 3, 4 or 5;

p=0, 1 or 2;

Each R'is independently selected from H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl, and is optionally substituted with one or more R″;

n=0, 1, 2, 3 or 4;

R ₅ , R ₆ and R ₇ are each independently selected from H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl, and the above groups are optionally substituted by one or more R* Substitution; or, R ₅ and R ₇ together with the double bond to which they are connected form a triple bond;

R* is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; wherein R* Each group in the definition is optionally substituted with one or more D until it is fully deuterated;

R" is each independently selected from H, D, halogen, -CN, =O, -OR _a or -NR _b R _c ;

R _a , R _b and R _c are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, or R _b and R _c together The N atoms to which they are attached together form a 3 to 7 membered heterocyclic group or a 5 to 10 membered heteroaryl group; wherein _{each group in the definition of R a} , R _b and R _c is optionally substituted by one or more D , Until fully deuterated.

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, which is a compound of formula (II-2), (III-2) or (IV-2):

in,

Ring A is an aromatic ring;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

o = 1, 2, 3 or 4;

m=0, 1, 2, 3, 4 or 5;

n=0, 1, 2, 3 or 4;

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, which is a compound of formula (V-1) or (VI-1):

in,

A ₁ is CR _A1 or N;

Wherein R _A1 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, which is optionally substituted by one or more R″;

o = 1, 2, 3 or 4;

m=0, 1, 2, 3, 4 or 5;

p=0, 1 or 2;

n=0, 1, 2, 3 or 4;

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, which is a compound of formula (V-2) or (VI-2):

in,

A ₁ is CR _A1 or N;

o = 1, 2, 3 or 4;

m=0, 1, 2, 3, 4 or 5;

n=0, 1, 2, 3 or 4;

Each R" is independently selected from H, D, halogen, -CN, =0, -OR _a or -NR _b R _c ;

Each R _a , R _b and R _{c is} independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, or R _b and R _c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or a 5 to 10 membered heteroaryl group; wherein _{each group in the definition of R a} , R _b and R _c is optionally substituted by one or more D substitution, until fully deuterated.

In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvates, wherein the compound is selected from:

The compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, Including racemate mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be separated by Prepared by asymmetric synthesis.

"Tautomers" means that a functional group in some compounds changes its structure to become another functional group isomer, and can quickly convert between each other, and the two isomers are in dynamic equilibrium. This kind of isomer is called tautomer.

Those skilled in the art will understand that an organic compound can form a complex with a solvent, which reacts in the solvent or precipitates or crystallizes out of the solvent. These complexes are called "solvates". When the solvent is water, the complex is called "hydrate". The present invention covers all solvates of the compounds of the present invention.

The term "solvate" refers to a compound or a salt form thereof combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes a solvate in a solution state and an isolable solvate. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, a hydrate of a compound can be represented by, for example, the general formula R·x H ₂ O, where R is the compound, and x is a number greater than zero. A given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5 H ₂ O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R·2 H ₂ O) and hexahydrate (R·6 H ₂ O)).

The compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic). In addition, the compounds of the present invention may exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to a crystalline form (or a salt, hydrate or solvate thereof) of a compound in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to dominate. Various polymorphs of the compound can be prepared by crystallization under different conditions.

The present invention also includes isotopically-labeled compounds, which are equivalent to those described in formula (I), but one or more atoms are replaced by atoms having an atomic mass or mass number different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, and ^{18 respectively.} O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. The compounds of the present invention containing the above-mentioned isotopes and/or other isotopes of other atoms, their prodrugs, and the compounds or pharmaceutically acceptable salts of the prodrugs all fall within the scope of the present invention. Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes (e.g. ³ H and ¹⁴ C), can be used for drug and/or substrate tissue distribution assays. Tritium, i.e. ³ H and carbon-14, i.e. ¹⁴ C isotopes are particularly preferred because they are easy to prepare and detect. Further, substituted with heavier isotopes such as deuterium, i.e. ² H, may provide greater metabolic stability, since the therapeutic benefit, such as increased in vivo half-life or reduced dosage requirements, which in some cases may be preferred. Isotopically-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in this way. When performing the processes disclosed in the following procedures and/or examples and preparation examples, readily available isotope-labeled reagents are used instead of non-isotopes. Labeled reagents.

In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted into its active form with a medical effect by, for example, hydrolysis in the blood in the body. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ASSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limits overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduced This article serves as a reference.

A prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in the body. Prodrugs are usually prepared by modifying functional groups in such a way that the modification can be performed by conventional operations or cleavage in vivo to produce the parent compound. Prodrugs include, for example, the compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group, which can be cleaved to form a hydroxyl, amino, or sulfhydryl group when administered to a patient. Therefore, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of the compound of formula (I). In addition, in the case of formic acid (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. The ester itself can be active and/or can be hydrolyzed under conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or salt thereof.

treatment

The present invention provides a method for treating and/or preventing diseases in a subject, such as wild and/or mutant EGFR kinase-mediated cancer, comprising administering to the subject a compound of the present invention or its interaction Tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention.

In this article, "EGFR" refers to human epidermal growth factor receptor protein, also known as ErbB-1 or HER1.

As used herein, "wild-type EGFR" refers to EGFR without somatic cell mutation.

As used herein, "exon 20 insertion mutation" means that one or more amino acids (preferably 1 to 7, more preferably 1 to 4) are inserted into the exon 20 region of EGFR (such as the 761st to the 823th position). Amino acid sequence); preferably, the mutation is in which the amino acid sequence FQEA (in the order of phenylalanine, glutamine, glutamic acid and alanine from the N-terminus) is inserted into the exon 20 region The mutation between alanine 763 and tyrosine 764 (A763_Y764insFQEA); preferably, the mutation is in which the amino acid sequence ASV (in the order of alanine, serine and valine from the N-terminus) is inserted outside The mutation between the 769th valine and the 770th aspartic acid in the region of exon 20 (V769_D770insASV); preferably, the mutation is wherein the amino acid sequence SVD (from the N-terminus with serine, valine and aspartic acid) The sequence of amino acid) is inserted into the mutation between aspartic acid at position 770 and asparagine at position 771 in the region of exon 20 (D770_N771insSVD); preferably, the mutation is in which the amino acid sequence NPG (from the N-terminus The sequence of asparagine, proline and glycine) is inserted into the mutation between asparagine at position 770 and asparagine at position 771 in the region of exon 20 (D770_N771insNPG); preferably, the mutation is wherein amino acid G (Glycine) A mutation (D770_N771insG) inserted between aspartic acid at position 770 and asparagine at position 771; preferably, the mutation is in which the aspartic acid at position 770 in the exon 20 region is deleted, and thus A mutation (D770>GY) into the amino acid sequence GY (in the order of glycine and tyrosine from the N-terminus); preferably, the mutation is where the amino acid N (asparagine) is inserted at position 771 in the exon 20 region The mutation between asparagine and proline at position 772 (N771_P772insN); preferably, the mutation is in which the amino acid sequence PR (in the order of proline and arginine from the N-terminus) is inserted into the exon 20 region The mutation between proline at position 772 and histidine at position 773 (P772_R773insPR); preferably, the mutation is wherein the amino acid sequence NPH (from the N-terminus to asparagine, proline and histidine) Sequence) inserted into the mutation between histidine 773 and valine 774 in the exon 20 region (H773_V774insNPH); preferably, the mutation is the amino acid sequence PH (from the N-terminus with proline and group The sequence of amino acid) is inserted into the mutation between histidine at position 773 and valine at position 774 in the exon 20 region (H773_V774insPH); preferably, the mutation is in which the amino acid sequence AH (from the N-terminus to C The sequence of amino acid and histidine) is inserted into the mutation between histidine at position 773 and valine at position 774 in the exon 20 region (H773_V774insAH); preferably, the mutation is The amino acid H (histidine) is inserted into the mutation between the 773th histidine and the 774th valine in the exon 20 region (H773_V774insH); preferably, the mutation is wherein the amino acid sequence HV (from the N-terminal In the order of histidine and valine) insert the mutation between the 774th valine and the 775th cysteine in the exon 20 region (V774_C774insHV); preferably, the mutation is wherein the amino acid sequence EAFQ (From the N-terminus in the order of glutamic acid, alanine, phenylalanine and glutamine) Insert the mutation between the 761st alanine and the 762nd glutamate in the exon 20 region (A761_E762insEAFQ). More preferably, the mutation is in which the amino acid sequence ASV (in the order of alanine, serine and valine from the N-terminus) is inserted into the 769th valine and the 770th aspartic acid in the exon 20 region (V769_D770insASV); More preferably, the mutation is in which the amino acid sequence SVD (in the order of serine, valine and aspartic acid from the N-terminus) is inserted into the aspartic acid at position 770 in the exon 20 region Mutation between amino acid and asparagine at position 771 (D770_N771insSVD); more preferably, the mutation is in which the amino acid sequence NPG (from the N-terminus in the order of asparagine, proline and glycine) is inserted into the exon The mutation between aspartic acid at position 770 and asparagine at position 771 in region 20 (D770_N771insNPG); more preferably, the mutation is in which amino acid G (glycine) is inserted into aspartic acid at position 770 in region of exon 20 The mutation between acid and asparagine at position 771 (D770_N771insG); more preferably, the mutation is in which the amino acid sequence NPH (from the N-terminus in the order of asparagine, proline and histidine) is inserted into the exon The mutation between the 773th histidine and the 774th valine in the sub20 region (H773_V774insNPH); more preferably, the mutation is wherein the amino acid sequence PH (proline and histidine from the N-terminus) Sequence) inserted into the mutation between histidine 773 and valine 774 in the exon 20 region (H773_V774insPH); more preferably, the mutation is the amino acid sequence SVD (from the N-terminus with serine, valine) Acid and aspartic acid) inserted into the mutation between aspartic acid at position 770 and aspartic acid at position 771 in the region of exon 20 (D770_N771insSVD); more preferably, the mutation is where the amino acid G ( Glycine) was inserted into the mutation between aspartic acid at position 770 and asparagine at position 771 in the region of exon 20 (D770_N771insG).

As used herein, "cancer patients expressing EGFR with exon 20 insertion mutation" refers to cancer patients expressing EGFR with exon 20 insertion mutation in at least a part of the exon 20 region of EGFR. EGFR may have exon 20 insertion mutations in two or more different parts, but one part is preferred. Moreover, EGFR may also have mutations other than the insertion mutation in exon 20 (such as exon 19 deletion mutation, L858R mutation, or T790M mutation).

In the present invention, the method for detecting insertion mutations in exon 20 expressing EGFR in cancer patients is not particularly limited, as long as the method can detect mutations, and any known detection method can be used. The detection target for detecting the insertion mutation of exon 20 can be any one of the gene sequence of the EGFR gene, the transcription product of the EGFR gene, and the EGFR protein.

The sample for detecting the insertion mutation of exon 20 is not particularly limited, as long as the sample is a biological sample isolated from a cancer patient, especially a sample obtained from a cancer patient and containing malignant tumor cells. Examples of biological samples include body fluids (for example, blood, urine, etc.), tissues, extracts thereof, and cultures obtained from tissues. The method of separating the biological sample can be appropriately selected according to the type of the biological sample.

Prepare biological samples through appropriate treatments according to the detection method. In addition, reagents used for detection (for example, reagents containing primers or probes) can be prepared by conventional methods according to the detection method.

In one embodiment of the present invention, the step of detecting the presence of insertion mutations in exon 20 of EGFR expressed in patients with malignant tumors may be performed before administering anti-tumor agents to patients with cancer.

As used herein, "exon 18 point mutation" means a point mutation in an amino acid in the exon 18 region of wild-type EGFR. Preferably, the mutation is a point mutation or deletion mutation in which one amino acid in the exon 18 region is replaced; more preferably, the mutation is a point mutation in which the glutamic acid encoded by codon 709 in exon 18 is replaced by any amino acid (Ie E790X), and a point mutation in which the glycine encoded by codon 719 in exon 18 is replaced by any amino acid (ie G719X). Specifically, E790X can be, for example, a point mutation in which the glutamic acid coded by codon 709 in the exon 18 region is replaced by lysine (ie E709K), and the valley coded by codon 709 in the exon 18 region A point mutation in which the amino acid is replaced by alanine (ie E709A). G719X can be, for example, a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by alanine (ie G719A), and a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by serine ( That is G719S), and the point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by cysteine (namely G719C), of which G719A is the most common.

Herein, "exon 18 point mutant EGFR" means EGFR with at least one exon 18 point mutation; preferably, the EGFR has more than two related exon 18 point mutations; more preferably, the EGFR It has an 18-point mutation in one exon. In addition, the EGFR may also have mutations other than exon 18 point mutations (for example, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).

Here, "exon 21" represents the region 824-875 in the amino acid sequence of wild-type EGFR.

As used herein, "exon 21 point mutation" means a point mutation in an amino acid in the exon 21 region of wild-type EGFR. Preferably, the 21 point mutation of exon is a point mutation in which one amino acid in the region of exon 21 is replaced; more preferably, the 21 point mutation of exon is a leucine encoded by codon 861 in the region of exon 21. A point mutation in which an acid is replaced by any amino acid (ie L861X), for example, a point mutation in which the leucine encoded by codon 861 in the exon 21 region is replaced by glutamine (ie, L861Q).

As used herein, "exon 21 point mutant EGFR" means EGFR with at least one exon 21 point mutation; preferably, the EGFR has more than two related exon 21 point mutations; more preferably, the EGFR There is a 21-point mutation in one exon. In addition, the EGFR may also have mutations other than exon 21 point mutations (for example, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).

In a specific embodiment, the mutant EGFR has a T790M mutation and is selected from the group consisting of exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation, or L858R mutation. At least one mutation in.

Specifically, the present invention has a T790M mutation and is selected from exon 18 point mutant EGFR, exon 21 point mutant EGFR is any one of the following: has T790M mutation and has exon 18 region E709X and / Or G719X mutant EGFR; L861X mutant EGFR with T790M mutation and exon 21 region. Specifically, it is any one of the following: T790M mutation and E709K or E709A mutant EGFR; T790M mutation and G719A, G719S, or G719C mutant EGFR; T790M mutation and L861Q mutant EGFR; among them, T790M Mutations with G719A and T790M mutations with L861Q mutant EGFR are more common.

In this article, the detection method for EGFR expressed by cancer patients with exon 18 and/or exon 21 point mutations should only be able to detect the above-mentioned mutations, and known detection methods can be used.

The sample used for detecting exon 18 and/or exon 21 point mutations is not particularly limited, as long as the sample is a biological sample isolated from a cancer patient, especially a sample obtained from a cancer patient and containing malignant tumor cells. Examples of biological samples include body fluids (for example, blood, urine, etc.), tissues, extracts thereof, and cultures obtained from tissues. The method of separating the biological sample can be appropriately selected according to the type of the biological sample.

In one embodiment of the present invention, the step of detecting the presence of exon 18 and/or exon 21 point mutations expressed in patients with malignant tumors may be performed before administering the anti-tumor agent to the cancer patients.

Specific examples of tumors mediated by mutant EGFR kinase in the present invention include, but are not limited to: head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, cholangiocarcinoma (eg, gallbladder and bile duct cancer), pancreas Cancer, colorectal cancer (for example, colon cancer and rectal cancer), lung cancer (for example, non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (for example, child Cervical cancer and endometrial cancer), urinary tract cancer (for example, kidney cancer, bladder cancer, prostate cancer, and testicular cancer), hematopoietic tumors (for example, leukemia, malignant lymphoma and multiple myeloma), osteosarcoma , Soft tissue sarcoma, skin cancer, brain tumor, etc. Preferred examples include lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.

In a specific embodiment, the mutant EGFR has a T790M mutation and is selected from the group consisting of exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR .

The present invention also provides a method for treating tumor patients, including expressing a mutant EGFR selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, and exon 19 deletion mutant type. The step of administering an effective amount of an antitumor agent including the compound of the present invention or a pharmaceutically acceptable salt thereof to a tumor patient with EGFR or L858R mutant EGFR.

The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof, which is used for therapeutic expression of a compound selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, and exon 21 point mutant EGFR , Tumor patients with exon 19 deletion mutant EGFR or L858R mutant EGFR.

The present invention also provides that the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 Use in tumor patients with deletion of mutant EGFR or L858R mutant EGFR.

The present invention also provides a method for predicting the therapeutic effect of using an antitumor agent in a tumor patient, the antitumor agent being the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, the method comprising the following steps (1) and ( 2):

(1) Steps to detect the presence or absence of the mutation of the EGFR gene contained in the biological sample obtained from the patient; and

(2) When the test result in step (1) finds that the EGFR gene has a mutation selected from exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation or L858R mutation, A step that predicts that chemotherapy is highly likely to show a sufficient therapeutic effect on the patient.

The present invention also provides a method for treating tumor patients, the method comprising the following steps (1) to (2):

(1) Steps to detect the presence or absence of the mutation of the EGFR gene contained in the biological sample obtained from the patient;

(2) When the test result in step (1) finds that the EGFR gene has a mutation selected from exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation or L858R mutation, Steps of using the compound of the present invention or a pharmaceutically acceptable salt thereof to treat the patient.

As used herein, "HER2" includes HER2 of human or non-human mammals. Also, the term "HER2" includes subtypes.

In the present invention, HER2 kinase-mediated tumors are preferably tumors with HER2 overexpression, HER2 gene amplification or HER2 mutation. The above-mentioned "tumor" is not particularly limited, and may be, for example, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder-biliary duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer , Uterine cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone-soft tissue sarcoma, blood cancer, multiple myeloma, skin cancer, brain tumor, mesothelial cancer, etc. Preferably breast cancer, gastric cancer, esophageal cancer, ovarian cancer, lung cancer, esophageal cancer, gallbladder-cholangiocarcinoma, biliary tract cancer, bladder cancer, colon cancer, more preferably breast cancer, stomach cancer, esophageal cancer, biliary cancer, ovarian cancer, lung cancer, esophagus Cancer, breast cancer, stomach cancer, and lung cancer are more preferable.

In the treatment method of the present invention, "effective amount" refers to an amount or dose sufficient to produce the desired therapeutic benefit in the individual in need of the treatment. The effective amount or dosage of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation, or clinical trials) and conventional factors (e.g., the mode or route of drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, and the individual Health status and weight, and the judgment of the treating physician) to determine. Exemplary dosages are in the range of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day. The total dose can be administered in a single dose or in divided dose units (e.g., BID, TID, QID).

After the patient's disease has improved, the dosage can be adjusted for preventive or maintenance treatment. For example, the dosage or frequency of administration or both can be reduced to an amount that maintains the desired therapeutic or preventive effect based on symptoms. Of course, if the symptoms have alleviated to an appropriate level, then treatment can be stopped. However, when either symptom recurs, the patient may require long-term intermittent treatment. Patients may also require long-term slow treatment.

Pharmaceutical compositions, preparations and kits

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains an effective amount of active ingredient. In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition includes a prophylactically effective amount of the active ingredient.

The pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-inlay Segment polymers, polyethylene glycol and lanolin.

The present invention also includes kits (e.g., pharmaceutical packaging). The kit provided may include the compound of the present invention, other therapeutic agents, and first and second containers (for example, vials, ampoules, bottles, syringes, and/or dispersible packages or other Suitable container). In some embodiments, the provided kit may also optionally include a third container, which contains pharmaceutical excipients for diluting or suspending the compound of the present invention and/or other therapeutic agents. In some embodiments, the compound of the present invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.

The pharmaceutical composition provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration Drugs, administration via implants or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , Intracerebrospinal membrane administration, intralesional administration, and intracranial injection or infusion technology.

Generally, an effective amount of the compound provided herein is administered. According to the relevant circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient’s symptoms, etc., the doctor can determine the amount of the compound actually administered .

When used to prevent the condition of the present invention, the compound provided herein is administered to a subject at risk of developing the condition, typically based on the doctor's recommendation and under the supervision of the doctor, and the dosage level is as described above. Subjects at risk of developing a particular disorder generally include subjects with a family history of the disorder, or those subjects who are particularly sensitive to the development of the disorder as determined by genetic testing or screening.

The pharmaceutical compositions provided herein can also be administered chronically ("long-term administration"). Long-term administration refers to the administration of the compound or its pharmaceutical composition over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the rest of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.

Various administration methods can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, for example, in order to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient. For example, an intramuscular or subcutaneous bolus dose releases the active ingredient slowly, while a bolus injection delivered directly to a vein (for example, via IV infusion) can be more effective. The rapid delivery allows the concentration of the active ingredient in the blood to rise rapidly to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.

Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate precise dosing, the composition is provided in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined number of active substances suitable for producing the desired therapeutic effect and suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In this composition, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remaining part is useful for forming the desired administration form. Kinds of carriers or excipients and processing aids.

For oral doses, the representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing modes, each dose provides about 0.01 to about 20 mg/kg of the compound of the present invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.

In order to provide a blood level similar to or lower than the injected dose, the transdermal dose is usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, and preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.

From about 1 to about 120 hours, especially 24 to 96 hours, the injection dose level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. In order to obtain a sufficient steady-state level, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be given. For human patients of 40 to 80 kg, the maximum total dose cannot exceed approximately 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The solid form may include, for example, any of the following components, or compounds with similar properties: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, mint, water Methyl salicylate or orange flavoring agent.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As mentioned earlier, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

The transdermal composition is typically formulated as a topical ointment or cream containing the active ingredients. When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art, and generally include other components for enhancing the active ingredient or stable skin penetration of the formulation. All such known transdermal preparations and components are included within the scope provided by the present invention.

The compounds of the invention can also be administered via transdermal devices. Therefore, transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.

The above-mentioned components of the composition for oral administration, injection or topical administration are only representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania in Part 8, which is incorporated herein by reference.

The compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.

The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation contains water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins composed of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or multiple substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

Drug combination

The compounds of the invention described herein can be used in pharmaceutical compositions or methods in combination with one or more other active ingredients to treat the diseases and conditions described herein. Other additional active ingredients include other therapeutic agents or agents that mitigate the adverse effects of the treatment on the intended disease target. The combination can be used to increase efficacy, improve symptoms of other diseases, reduce one or more side effects, or reduce the required dosage of the compound of the present invention. The additional active ingredient may be formulated into a pharmaceutical composition separate from the compound of the present invention or may be included in a single pharmaceutical composition with the compound of the present invention. The additional active ingredient may be administered at the same time, before or after the administration of the compound of the invention.

Combination agents include those active ingredients that are known or observed to be effective in the treatment of the diseases and conditions described herein, including those that are effective against another target associated with the disease. For example, the compositions and preparations and treatment methods of the present invention may further include other drugs, such as other drugs that can be used to treat or alleviate the target disease or related symptoms or conditions. For cancer indications, the other agents include (but are not limited to) kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib); Raf inhibitors (e.g., Vero Vemurafenib), VEGFR inhibitors (for example, sunitinib); standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs , Mitosis inhibitors, antibodies, hormone therapy or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory agents, such as NSAIDs. The pharmaceutical composition of the present invention may additionally include one or more of the active agents, and the treatment method may additionally include administering an effective amount of one or more of the active agents.

Example

The present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, parts and percentages are parts by weight and percentages by weight.

Generally, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1-60 hours, preferably 0.5-24 hours.

The abbreviations used in this article have the following meanings:

Pd(PPh ₃ ) ₄ : Tetra(triphenylphosphine) palladium

Na ₂ CO ₃ : Sodium carbonate

EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

HOBT: 1-Hydroxybenzotriazole

NIS: N-iodosuccinimide

DMF: N,N-Dimethylformamide

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

MTBE: methyl tert-butyl ether

DME: Ethylene Glycol Dimethyl Ether

NBS: N-Bromosuccinimide

Cbz: Benzyloxycarbonyl

TEA: Triethylamine

DCM: Dichloromethane

ACN: Acetonitrile

POCl ₃ : Phosphorus oxychloride

tert-Butyl nitrite: tert-butyl nitrite

TPP: Triphenylphosphine

DIAD: Diisopropyl azodicarboxylate

NH ₄ OAc: Ammonium acetate

DMSO: Dimethyl sulfoxide

B ₂ pin ₂ : pinacol diboronic acid ester

KOAc: potassium acetate

Dioxane: Dioxane

NaNO ₂ : Sodium nitrite

EtOH: ethanol

NaOH: Sodium hydroxide

DIPEA: N,N-Diisopropylethylamine

TFAA: Trifluoroacetic anhydride

H ₂ O ₂ : hydrogen peroxide

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

NaH: Sodium hydride

THF: Tetrahydrofuran

i-PrOH: isopropanol

PtO ₂ ：platinum dioxide

EA: ethyl acetate

EtOH: ethanol

Tosmic: p-toluenesulfonyl methyl isonitrile

PdCl ₂ : Palladium dichloride

TESiH: Triethylsilane

NaIO ₄ : Sodium Periodate

Intermediate A1 Preparation of 3-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

The following synthetic route is adopted:

Add 3-iodo-1H-pyrazolo[4,3-d]pyrimidine-7-amine (1.2g, 4.6mmol), 3-(4,4,5,5-tetramethyl-1) to the reaction flask ,3,2-Dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.1g, 6.9mmol), tetrakis(triphenylphosphine) ) Palladium (53mg, 0.05mmol) and sodium carbonate (975mg, 9.2mmol), add 20ml of dioxane and 2ml of water to dissolve, heat to 90°C under nitrogen protection and stir for 6 hours. TLC monitors the completion of the reaction. After concentration to remove the solvent The product was purified by silica gel column chromatography to obtain 1.17 g, with a yield of 80.7%. LC-MS (APCI): m/z=317.2(M+1) ⁺ .

Intermediate A2 Preparation of tert-butyl 3-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidine-1-carboxylate

The following synthetic route is adopted:

Add 3-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.17 g, 3.7mmol), catalytic amount of palladium on carbon, dissolved in 20ml methanol, filled with hydrogen balloon, stirred for 5 hours at room temperature, TLC detection of the reaction is complete, filtered to remove the catalyst, after concentration, silica gel column chromatography purification to obtain the product 1.05g, yield Rate: 89%. LC-MS (APCI): m/z=319.5(M+1) ⁺ .

Preparation of intermediate A3 (R)-3-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

The following synthetic route is adopted:

Step 1 Synthesis of tert-butyl (R)-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)piperidine-1-carboxylate

Add 2-aminomethyl-3-chloropyrazine hydrochloride (1.0g, 4.62mmol), (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1.11g, 4.85 mmol) and HOBT (0.94g, 6.93mmol), dissolved in 20ml of anhydrous DMF, add triethylamine (2.34g, 23.1mmol), reduce the temperature to 0℃ under nitrogen protection, add EDCI (1.33g, 6.93mmol) in batches After the reaction was heated to room temperature, the reaction was stirred overnight. After the reaction was monitored by TLC, excess water was added to quench the reaction, extracted with ethyl acetate 3-4 times, the organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried in vacuo to obtain a colorless Oily product 1.11g, yield: 67.8%. LC-MS (APCI): m/z=355.3 (M+1) ⁺ .

Step 2 Synthesis of tert-butyl (R)-3-(8-chloroimidazo[1,5-α]pyrazin-3-yl)piperidine-1-carboxylate

Add tert-butyl (R)-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)piperidine-1-carboxylate (1.0g, 2.82mmol) to the reaction flask, protected by nitrogen Add 25ml of anhydrous ethyl acetate to dissolve it, then add 3.7ml of anhydrous DMF, slowly add phosphorus oxychloride (2.6g, 17.0mmol) in an ice-salt bath, after the addition, warm up to room temperature and stir for 1h. TLC monitors the reaction After completion, add dropwise 20ml saturated sodium carbonate aqueous solution to quench the reaction under ice bath, separate the organic phase, extract the aqueous phase with ethyl acetate 3-4 times, combine the organic phases, wash with saturated brine, concentrate and then silica gel column chromatography (petroleum Ether: ethyl acetate 2:1) Purification to obtain 0.89 g of oily product, yield: 93.8%. LC-MS (APCI): m/z=337.8(M+1) ⁺ .

Step 3 Synthesis of tert-butyl (R)-3-(8-chloro-1-iodoimidazo[1,5-α]pyrazin-3-yl)piperidine-1-carboxylate

Add (R)-3-(8-chloroimidazo[1,5-α]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (0.89g, 2.64mmol) into the reaction flask, add 10ml DMF was dissolved, and NIS (0.62g, 2.77mmol) was added at room temperature. The temperature was raised to 50°C and the reaction was stirred overnight. After the reaction was monitored by TLC, saturated sodium bicarbonate solution was slowly added to quench the reaction, and extracted with ethyl acetate 3-4 times The organic phases were combined, washed with saturated brine, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 2:1) to obtain 1.06 g of beige solid, yield: 86.9%. LC-MS (APCI): m/z=463.2(M+1) ⁺ .

Step 4 Synthesis of tert-butyl (R)-3-(8-amino-1-iodoimidazole[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

Add (R)-3-(8-chloro-1-iodoimidazo[1,5-α]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (1.06g, 2.29mmol ), add 8ml 2-butanol, then add ammonia (6.7ml, 176mmol), heat to 90°C under airtight conditions and react overnight, and then cool to room temperature. TLC monitors the completion of the reaction, add excess water to dilute, and extract 3 with ethyl acetate. -4 times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate to remove the solvent, add MTBE for pulping and purification to obtain 0.89 g of product, yield: 87.6%. LC-MS (APCI): m/z=444.3 (M+1) ⁺ .

Intermediate A4 Preparation of tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

The following synthetic route is adopted:

Step 1 3-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester synthesis

The 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine (4.69g, 13.6mmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (5.04g, 16.3mmol), Pd(dppf)Cl ₂ (0.5 g, 0.68 mmol) and Na ₂ CO ₃ (4.35 g, 41 mmol) were added to 70 mL of DME and 15 mL of water, replaced with nitrogen three times, and heated to 90° C. to react overnight. The reaction solution was cooled to room temperature, 100 mL of water was added, and it was extracted with ethyl acetate (60 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 3.21 g of a pale yellow solid. The rate is 75%. ESI-MS:316[M ⁺ +1].

Step 2 Synthesis of tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

The 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.21 g, 10.2 mmol) was dissolved in 30 mL of absolute ethanol, 300 mg of 10% palladium on carbon was added, hydrogen was replaced three times, and the mixture was stirred overnight under a hydrogen atmosphere of one atmosphere. After the reaction was completed, the palladium-carbon was filtered off, the filtrate was concentrated, and 2.9 g of light yellow oil was obtained through silica gel column separation, with a yield of 90%. ESI-MS:318[M ⁺ +1].

Step 3 Synthesis of tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

Dissolve tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (2.9g, 9.16mmol) in 30mL DMF In the middle, NBS (1.78g, 10mmol) was added in batches under ice bath, and the reaction was allowed to rise to room temperature overnight. After the reaction was completed, 100 mL of water was added to the reaction solution, extracted with ethyl acetate (40 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 2.54 g of light yellow solid. The yield was 70%. ESI-MS:398[M ⁺ +2].

Intermediate A5 (R)-3-(4-Amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid benzyl ester preparation

The following synthetic route is adopted:

Step 1 Synthesis of (R)-piperidine-1,3-dicarboxylic acid (1-benzyl)(3-succinimidyl) ester

(R)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (8g, 30.4mmol), N-hydroxysuccinimide (4.26g, 37mmol) and triethylamine (6.14g, 60.8mmol) was dissolved in 50mL of dichloromethane, EDCI (8.68g, 45.3mmol) was added under ice bath, and reacted at room temperature overnight. The reaction solution was diluted with 50 mL of dichloromethane, washed with water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 10.15 g of light yellow oil with a yield of 93%. ESI-MS:361[M ⁺ +1].

Step 2 (R)-3-(((3-Amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl)carbamoyl)piperidine- Synthesis of benzyl 1-formate

Combine (R)-piperidine-1,3-dicarboxylic acid (1-benzyl)(3-succinimidyl) ester (10.15g, 28.2mmol) and 3-amino-6-(aminomethyl)- 1,2,4-Triazine-5(4H)-one acetate (5.67g, 28.2mmol) was dissolved in 100mL of acetonitrile, triethylamine (8.54g, 84.6mmol) was added, and the temperature was raised to 50°C to react overnight. After the reaction was cooled, diluted with 150 mL of water, extracted with ethyl acetate (80 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 8.07 g of light yellow solid, the yield was 74% . ESI-MS:387[M ⁺ +1].

Step 3 (R)-3-(2-Amino-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine- Synthesis of benzyl 1-formate

(R)-3-(((3-Amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl)carbamoyl)piperidine-1 -Benzyl formate (8.07 g, 20.9 mmol) was dissolved in 80 mL of acetonitrile, phosphorus oxychloride (6.4 g, 41.8 mmol) was slowly added, and the temperature was raised to 60° C. to react overnight. The reaction solution was cooled and quenched with water, adjusted to pH=7 with 2N sodium hydroxide solution, extracted with ethyl acetate (60mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column. Pale yellow solid 5.78g, yield 75.2%. ESI-MS:369[M ⁺ +1].

Step 4 (R)-3-(2-Amino-5-bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl ) Synthesis of benzyl piperidine-1-carboxylate

(R)-3-(2-Amino-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1 -Benzyl formate (5.78g, 15.7mmol) was dissolved in 40mL DMF, NBS (2.94g, 16.5mmol) was added in batches under ice bath, and the reaction was allowed to rise to room temperature overnight. After the reaction was completed, 100 mL of water was added to the reaction solution, extracted with ethyl acetate (50 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 5.77 g of pale yellow solid. The yield was 82%. ESI-MS:449[M ⁺ +2].

Step 5 (R)-3-(5-Bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine- Synthesis of benzyl 1-formate

(R)-3-(2-Amino-5-bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl) Benzyl piperidine-1-carboxylate (5.77 g, 12.9 mmol) was dissolved in 50 mL of tetrahydrofuran, tert-butyl nitrite (2 g, 19.4 mmol) was slowly added, and the temperature was raised to 60° C. to react for 3 hours. After the reaction was completed, it was diluted with 100 mL of water, extracted with ethyl acetate (100 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 4.79 g of light yellow solid, with a yield of 86% . ESI-MS:434[M ⁺ +2].

Step 6 Synthesis of (R)-3-(4-amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate benzyl ester

(R)-3-(5-Bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1 -Benzyl formate (4.79g, 11.1mmol) and 1,2,4-triazole (2.3g, 33.3mmol) were dissolved in 40mL pyridine, and phosphorus oxychloride (5.1g, 33.3 mmol), after the addition, move to room temperature and react for 2 hours. An ammonia-ethanol solution (15 mL, 7 mol/L) was slowly added dropwise to the reaction solution under an ice bath, and the addition was completed and stirred at room temperature for 2 hours. TLC detected the completion of the reaction, the reaction solution was quenched with water, extracted with ethyl acetate (80mL*3), the organic phase was washed with 2N hydrochloric acid to pH=5-6, then washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated. The silica gel column separated 3.6 g of a light yellow solid with a yield of 75.5%. ESI-MS:433[M ⁺ +2].

Intermediate A6 Preparation of (R)-3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester

The following synthetic route is adopted:

Add 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.50g, 8.95mmol) and anhydrous tetrahydrofuran (40mL) to a 50mL three-necked flask equipped with magnetic stirring in sequence, and stir to dissolve. , Add tert-butyl (S)-3-hydroxypiperidine-1-carboxylate (1.80g, 8.95mmol), cool to 0°C under nitrogen atmosphere, add triphenylphosphine (3.05g, 11.63mmol), and stir for 5 minutes , DIAD (2.35g, 11.63mmol) was slowly added dropwise, after the addition, the ice bath was removed, and the reaction was stirred overnight at room temperature under nitrogen atmosphere. The reaction solution was diluted by adding ethyl acetate (100 mL), washed with water (50 mL*2), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was passed through a silica gel column to obtain 500 mg of white solid with a yield of 12.08%. LC-MS(APCI): m/z=463.1(M+1) ⁺ . ¹ H NMR(400MHz, CDCl ₃ )δ(ppm): 8.64(s,1H),7.49(s,1H),4.83-4.76 (m,1H),4.24-4.15(m,1H),3.97(d,J=13.2Hz,1H),3.35-3.29(m,1H),3.09-3.02(m,1H),2.21-2.04(m ,2H),1.87-1.70(m,2H),1.48(s,9H).

Intermediate B1 Preparation of tert-butyl 3-(1-cyano-2-methoxy-2-oxoethyl)piperidine-1-carboxylate

The following synthetic route is adopted:

Step 1 Synthesis of tert-butyl 3-(1-cyano-2-methoxy-2-oxoethylene)piperidine-1-carboxylate

Add tert-butyl 3-oxopiperidine-1-carboxylate (5.0g, 25mmol), methyl 2-cyanoacetate (2.5g, 25mmol) and ammonium acetate (0.25g, 3.25mmol) into the reaction flask, add 25ml of toluene, then add 0.5ml of glacial acetic acid, heat to reflux (separate water) and stir for 7 hours. After the reaction is monitored by TLC, concentrate to remove the solvent. Purify by silica gel column chromatography to obtain 6.75g of colorless oily liquid. Yield: 96.4% . LC-MS (APCI): m/z=281.1(M+1) ⁺ .

Step 2 Synthesis of tert-butyl 3-(1-cyano-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (Intermediate B1)

Add tert-butyl 3-(1-cyano-2-methoxy-2-oxoethylene)piperidine-1-carboxylate (6.75g, 24mmol), a catalytic amount of palladium on carbon into the reaction flask, and add 100ml of ethanol was dissolved, filled with a hydrogen balloon, heated to 50°C and stirred overnight. After the reaction was monitored by TLC, the catalyst was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 6.51g of light yellow oily liquid. Yield: 96.3%. LC-MS (APCI): m/z=283.4(M+1) ⁺ .

Intermediate B2 Preparation of 3-chloro-4-(pyridin-2-ylmethoxy)aniline

The following synthetic route is adopted:

Step 1 Synthesis of 2-((2-chloro-4-nitrophenoxy)methyl)pyridine

Add 2-chloro-4-nitrophenol (5.2g, 30mmol), 2-chloromethylpyridine hydrochloride (5.42g, 33mmol) and anhydrous sodium carbonate (7.95g, 75mmol) into the reaction flask, add 20ml Dissolve anhydrous DMF, heat to 80°C and stir for 4 hours. After the reaction is monitored by TLC, the reaction is lowered to room temperature, diluted with excess water, extracted with ethyl acetate 3-4 times, the organic phases are combined, washed with saturated brine, and concentrated on silica gel Purified by column chromatography to obtain 4.5 g of product, yield: 56.8%. LC-MS (APCI): m/z=265.7(M+1) ⁺ .

Step 2 Synthesis of 3-chloro-4-(pyridin-2-ylmethoxy)aniline (Intermediate B2)

Add 2-((2-chloro-4-nitrophenoxy)methyl)pyridine (4.5g, 17mmol), catalytic amount of palladium on carbon to the reaction flask, add 50ml ethanol to dissolve, fill with hydrogen balloon, and stir at room temperature The reaction was carried out overnight. After the reaction was monitored by TLC, the catalyst was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 3.76 g of light yellow oily liquid. Yield: 94.1%. LC-MS (APCI): m/z=235.4(M+1) ⁺ .

Preparation of intermediate B3 2-((4-bromo-2-chlorophenoxy)methyl)pyridine

The following synthetic route is adopted:

Dissolve 4-bromo-2-chlorophenol (3.4g, 16.4mmol) and 2-chloromethylpyridine hydrochloride (3.49g, 21.3mmol) in 30mL DMSO, add triethylamine (5.05g, 50mmol), 80 The reaction was heated at °C for 3 hours. The reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (50 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 4 g of light yellow solid with a yield of 82%. ESI-MS: 300[M ⁺ +2].

Intermediate B4 2-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methane Base) pyridine preparation

The following synthetic route is adopted:

Combine 2-((4-bromo-2-chlorophenoxy)methyl)pyridine (3.98g, 13.3mmol), pinacol diboronic acid ester (4.06g, 16mmol), Pd(dppf)Cl ₂ (0.49g , 0.67 mmol) and potassium acetate (3.92 g, 40 mmol) were added to 60 mL of dioxane, replaced with nitrogen three times, and heated to 90° C. to react for 3 hours. The reaction solution was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (60 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 3.45 g of light yellow solid. The rate is 75%. ESI-MS:346[M ⁺ +1].

Example 1 3-(1-Acryloylpiperidin-3-yl)-4-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazole- Preparation of 5-nitrile

The following synthetic route is adopted:

Step 1 3-(1-(2-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazino)-2-methoxy-2-oxoethyl)piperidine Synthesis of tert-butyl -1-carboxylate

Add Intermediate B2 (468mg, 2mmol) to the reaction flask, add 1N aqueous hydrochloric acid (5ml, 5mmol) to dissolve, then add sodium nitrite (230mg, 3.33mmol), stir and react at room temperature for half an hour to obtain solution A; Add Intermediate B1 (470mg, 1.67mmol) to the reaction flask, add 10ml of ethanol to dissolve it, add 5ml of saturated ammonium chloride aqueous solution under ice bath, and then slowly add dropwise the obtained A solution, stir at room temperature and react overnight, TLC monitors after the reaction is complete , Diluted with a small amount of water, extracted 3-4 times with ethyl acetate, combined the organic phases, washed once with saturated ammonium chloride and saturated brine, concentrated and purified by silica gel column chromatography to obtain 340 mg of oily liquid, yield: 40.6%. LC-MS (APCI): m/z=503.1(M+1) ⁺ .

Step 2 2-(1-(tert-Butoxycarbonyl)piperidin-3-yl)-2-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazino) Synthesis of acetic acid

Add 3-(1-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazino)-2-methoxy-2-oxoethyl to the reaction flask ) Tert-butyl piperidine-1-carboxylate (340mg, 0.68mmol), add 15ml of tetrahydrofuran to dissolve, add 3ml aqueous solution of sodium hydroxide (1.2g, 30mmol), stir the reaction at room temperature overnight, TLC monitoring the reaction is completed, add 1N Adjust the pH to acidic with dilute hydrochloric acid, extract 3-4 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain 310 mg of product, which is directly put into the next reaction without purification.

Step 3 3-(2-Amino-1-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazino)-2-oxoethyl)piperidine-1 -Synthesis of tert-butyl formate

Add 2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-2-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)into the reaction flask Hydrazino) acetic acid (310mg, 0.63mmol), EDCI (243mg, 1.26mmol) and HOBT (171mg, 1.26mmol), add 10ml of dichloromethane to dissolve, add ammonia (0.05ml, 1.26mmol) and DIPEA (0.31) under nitrogen protection ml, 1.89mmol), stirred at room temperature for 2 hours, TLC monitoring after the reaction is complete, add a small amount of dichloromethane to dilute, and wash with 1N dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine successively, and concentrate and purify by silica gel column chromatography Obtain 301 mg of product, yield: 98%. LC-MS (APCI): m/z=488.5(M+1) ⁺ .

Step 4 tert-Butyl 3-(1-cyano-1-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazino)methyl)piperidine-1-carboxylate Synthesis of esters

Add 3-(2-amino-1-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazino)-2-oxoethyl)piper in the reaction flask Tert-butyl pyridine-1-carboxylate (392mg, 0.8mmol) and pyridine (0.5ml, 5.6mmol), add 10ml of dichloromethane to dissolve, reduce the temperature to 0℃ under nitrogen protection, slowly add trifluoroacetic anhydride (0.6ml, 4.0mmol), after the addition, the reaction was stirred at room temperature for 1 hour. After the reaction was monitored by TLC, a small amount of dichloromethane was added to dilute, washed with 1N dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine successively, dried over anhydrous sodium sulfate and concentrated When it is dry, it is directly put into the next reaction without purification.

Step 5 3-(4-Amino-5-cyano-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazol-3-yl)piperidine-1 -Synthesis of tert-butyl formate

The intermediate obtained in the previous step was directly dissolved in 15ml tert-butanol, bromoacetonitrile (0.11ml, 1.61mmol) was added, potassium tert-butoxide (270mg, 2.41mmol) was added in batches under nitrogen protection, and the reaction was stirred at room temperature for 2 hours. After the reaction was monitored by TLC, the reaction was quenched by adding a small amount of water, extracted with ethyl acetate 3-4 times, the organic phases were combined, washed with saturated brine, concentrated and purified by silica gel column chromatography to obtain 250 mg of light yellow solid, yield: 61.1% . LC-MS (APCI): m/z=509.7(M+1) ⁺ .

Step 6 3-(1-Acryloylpiperidin-3-yl)-4-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazole-5 -Synthesis of Nitriles

Add 3-(4-amino-5-cyano-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazol-3-yl)piper to the reaction flask Tert-butyl pyridine-1-carboxylate (120mg, 0.24mmol), add 4N hydrogen chloride ethyl acetate solution (2.5ml, 10mmol) under nitrogen protection, stir the reaction at room temperature for 1h, TLC monitors the reaction and concentrate to dryness after the reaction is complete, and put it directly into Go to the next step.

Add 5ml of anhydrous dichloromethane and triethylamine (0.07ml, 0.47mmol) to the above-mentioned intermediate, add acryloyl chloride (22.4mg, 0.25mmol) dropwise under ice bath, after the addition is stirred and react for 10 minutes, TLC monitors the completion of the reaction , Diluted with dichloromethane, washed with water and saturated brine successively, concentrated and purified by silica gel column chromatography to obtain 80 mg of off-white solid, yield: 73.4%. LC-MS (APCI): m/z=463.5(M+1) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.53 (d, J = 2.3 Hz, 1H), 8.13 (t, J = 4.6 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J = 4.6Hz, 1H), 7.41 (d, J = 3.4 Hz, 1H), 7.32 (t, J = 4.6 Hz, 1H), 6.88 (d, J = 3.4 Hz, 1H), 6.63 (m, 1H), 6.12 (d,J=6.8Hz,1H),6.04(s,2H),5.63(d,J=6.8Hz,1H),5.51(s,2H),3.81(m,1H),3.66(m,3H) ,3.04(m,1H),2.01(m,2H),1.66(m,2H).

Example 2 3-(1-Acryloylpiperidin-3-yl)-4-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrrole-5 -Formamide preparation

The following synthetic route is adopted:

Step 1 3-(4-Amino-5-carbamoyl-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazol-3-yl)piperidine- Synthesis of tert-butyl 1-formate

Add 3-(4-amino-5-cyano-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazol-3-yl)piper in the reaction flask Tert-butyl pyridine-1-carboxylate (150mg, 0.29mmol), add 5ml methanol to dissolve, add 3ml aqueous solution of sodium hydroxide (240mg, 6mmol), add 30% hydrogen peroxide (1ml) dropwise under ice bath, warm to room temperature and stir After reacting for 3 hours and monitoring by TLC, after the reaction was completed, ethyl acetate was added for extraction 3-4 times, the organic phases were combined, washed with saturated brine, and concentrated and purified by silica gel column chromatography to obtain 113 mg of the target product. Yield: 74.1%. LC-MS (APCI): m/z=527.9 (M+1) ⁺ .

Step 2 3-(1-Acryloylpiperidin-3-yl)-4-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazole-5 -Synthesis of formamide

Add 3-(4-amino-5-carbamoyl-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazol-3-yl) to the reaction flask Piperidine-1-carboxylic acid tert-butyl ester (113mg, 0.22mmol), add 4N hydrogen chloride ethyl acetate solution (2.5ml, 10mmol) under nitrogen protection, stir the reaction at room temperature for 1h, TLC monitors the reaction and concentrate to dryness after the reaction is complete, directly Move to the next step.

Add 5ml of anhydrous dichloromethane and triethylamine (0.06ml, 0.43mmol) to the above intermediate. Add acryloyl chloride (20.4mg, 0.23mmol) dropwise under ice bath. After the addition is complete, the reaction is stirred for 10 minutes and the reaction is monitored by TLC. , Diluted with dichloromethane, washed sequentially with water and saturated brine, concentrated and purified by silica gel column chromatography to obtain 82 mg of off-white solid, yield: 79.5%. LC-MS (APCI): m/z=481.3(M+1) ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ10.47(s,2H), 8.33(d,J=2.4Hz,1H), 8.10(t,J=4.6Hz,1H), 7.75(s,1H) , 7.70 (d, J = 4.6 Hz, 1H), 7.41 (d, J = 3.6 Hz, 1H), 7.30 (t, J = 4.6 Hz, 1H), 6.81 (d, J = 3.4 Hz, 1H), 6.63 (m, 1H), 6.12 (d, J = 6.8 Hz, 1H), 6.00 (s, 2H), 5.63 (d, J = 6.8 Hz, 1H), 5.52 (s, 2H), 3.81 (m, 1H) , 3.66 (m, 3H), 3.04 (m, 1H), 1.98 (m, 1H), 1.75 (m, 3H).

Example 3 1-(3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidine- 3-yl)-5,6-dihydropyridine Preparation of pyridin-1(2H)-yl)prop-2-en-1-one

The following synthetic route is adopted:

Step 1 3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl) -5,6-dihydropyridine-1(2H)-formic acid tert-butyl ester synthesis

Intermediate A1 (60mg, 0.2mmol), intermediate B3 (120mg, 0.4mmol), N,N-dimethylglycine (13mg, 0.12mmol) and cuprous iodide (8mg, 0.04mmol) were added to the reaction flask Under the protection of nitrogen, 3ml of anhydrous DMF was added, and then DBU (92mg, 0.6mmol) was added. After the addition, the temperature was increased to 110°C and the reaction was stirred for 20 hours. After the reaction was monitored by TLC, saturated ammonium chloride was added to quench the reaction. The ester was extracted 3-4 times, the organic phases were combined, washed with saturated brine, and concentrated and purified by silica gel column chromatography to obtain 74 mg of product. Yield: 69.4%. LC-MS (APCI): m/z=534.7 (M+1) ⁺ .

Step 2 1-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrazolo Synthesis of [4,3-d]pyrimidine-7-amine

Add 3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-3 to the reaction flask -Yl)-5,6-dihydropyridine-1(2H)-tert-butyl formate (74mg, 0.14mmol), add 4N hydrogen chloride dioxane solution (3ml, 12mmol) under nitrogen protection, and stir the reaction at room temperature After 1h, TLC monitored the reaction and concentrated to dryness, and put it directly into the next step.

Step 3 1-(3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-3 -Yl)-5,6-dihydropyridine-1(2H)-yl)prop-2-en-1-one

Add 5ml of anhydrous dichloromethane and triethylamine (42.5mg, 0.42mmol) to the above intermediate, add acryloyl chloride (12.7mg, 0.14mmol) dropwise under ice bath, after the addition, stir and react for 10 minutes, and TLC monitors the completion of the reaction. , Diluted with dichloromethane, washed sequentially with water and saturated brine, concentrated and purified by silica gel column chromatography to obtain 41 mg of pale yellow solid, yield: 60.1%. LC-MS (APCI): m/z=488.1 (M+1) ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H), 8.64(d,J=3.6Hz,1H), 8.23(t,J=4.2Hz,1H), 8.05(s,1H) , 7.72 (d, J = 4.2 Hz, 1H), 7.41 (d, J = 3.6 Hz, 1H), 7.32 (t, J = 4.4 Hz, 1H), 6.89 (d, J = 5.5 Hz, 1H), 6.63 (m, 1H), 6.21 (d, J = 7.7 Hz, 1H), 6.11 (s, 1H), 5.63 (d, J = 7.7 Hz, 1H), 3.81 (t, J = 4.8 Hz, 2H), 3.55 (s,2H),2.07(t,J=4.8Hz,2H).

Example 4 1-(3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidine- 3-yl)piperidin-1-yl)propan Preparation of -2-en-1-one

The following synthetic route is adopted:

Step 1 3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl) Synthesis of tert-butyl piperidine-1-carboxylate

Intermediate A2 (432mg, 1.36mmol), intermediate B3 (807mg, 2.72mmol), N,N-dimethylglycine (84mg, 0.82mmol) and cuprous iodide (52mg, 0.27mmol) were added to the reaction flask Under the protection of nitrogen, 5ml of anhydrous DMF was added, and then DBU (620mg, 4.08mmol) was added. After the addition, the temperature was raised to 110°C and the reaction was stirred for 15 hours. After the reaction was monitored by TLC, saturated ammonium chloride was added to quench the reaction. The ester was extracted 3-4 times, the organic phases were combined, washed with saturated brine, and concentrated and purified by silica gel column chromatography to obtain 290 mg of product. Yield: 39.9%. LC-MS (APCI): m/z=536.7(M+1) ⁺ .

Step 2 1-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-3-(piperidin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine- Synthesis of 7-amine

Add 3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-3 to the reaction flask -Yl) piperidine-1-carboxylic acid tert-butyl ester (290 mg, 0.54 mmol), 4N hydrogen chloride dioxane solution (5 ml, 20 mmol) was added under nitrogen protection, and the reaction was stirred at room temperature for 1 h. After the reaction was monitored by TLC, the reaction was concentrated to Do it and go directly to the next step.

Step 3 1-(3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-3 -Yl)piperidin-1-yl)prop-2-en-1-one synthesis

Add 10ml of anhydrous dichloromethane and triethylamine (189mg, 1.87mmol) to the above intermediate. Add acryloyl chloride (49mg, 0.54mmol) dropwise under ice bath. After the addition, the reaction is stirred for 10 minutes and TLC monitors the completion of the reaction. Add Dilute with dichloromethane, wash with water and saturated brine in turn, concentrate and purify by silica gel column chromatography to obtain 120 mg of yellow solid, yield: 45.5%. LC-MS (APCI): m/z=490.6(M+1) ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71(s,1H),8.68(d,J=4.8Hz,1H), 8.15(t,J=4.4Hz,1H),7.92(s,1H) , 7.72 (d, J = 4.4 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.30 (t, J = 4.4 Hz, 1H), 6.82 (d, J = 5.5 Hz, 1H), 6.51 (m,1H),6.00(d,J=8.4Hz,1H),5.52(d,J=8.4Hz,1H),5.37(s,2H),3.82(m,1H),3.79(m,3H) , 2.96 (m, 1H), 2.07 (m, 1H), 1.88 (m, 3H).

Example 5 (R)-1-(3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3- d)pyrimidin-3-yl)piperidine-1- (Base) Preparation of prop-2-en-1-one

120 mg of the racemate compound of Example 4 was dissolved in methanol solution, and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain 43 mg of the target product (retention time: 27.79 min, defined as R configuration). LC-MS (APCI): m/z=490.6(M+1) ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.69(s,1H), 8.52(d,J=4.8Hz,1H), 8.13(t,J=4.4Hz,1H),7.92(s,1H) ,7.72(d,J=4.4Hz,1H),7.41(d,J=4.8Hz,1H),7.32(t,J=4.4Hz,1H),6.82(d,J=5.5Hz,1H),6.51 (m,1H),6.01(d,J=8.4Hz,1H),5.52(d,J=8.4Hz,1H),5.37(s,2H),3.82(m,1H),3.79(m,3H) , 3.11 (m, 1H), 2.07 (m, 1H), 1.88 (m, 3H).

Chiral preparative chromatography column: CHIRALPAK IC (trade name), 10mm×250mm (inner diameter×length), 5μm (filler particle size)

Column temperature: 30℃

Flow rate: 4.0mL/min

UV detection wavelength: 254nm

Mobile phase: dichloromethane: n-hexane: ethanol = 70:20:10

Example 6 (S)-1-(3-(7-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3- d)pyrimidin-3-yl)piperidine-1- (Base) Preparation of prop-2-en-1-one

120 mg of the racemate compound of Example 4 was dissolved in methanol solution, and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain 45 mg of the target product (retention time: 22.48 min, defined as S configuration). LC-MS (APCI): m/z=490.6(M+1) ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71(s,1H),8.69(d,J=4.8Hz,1H), 8.16(t,J=4.4Hz,1H),7.94(s,1H) ,7.72(d,J=4.4Hz,1H),7.45(d,J=4.8Hz,1H),7.31(t,J=4.4Hz,1H),6.82(d,J=5.5Hz,1H),6.51 (m,1H),6.00(d,J=8.4Hz,1H),5.52(d,J=8.4Hz,1H),5.37(s,2H),3.82(m,1H),3.79(m,3H) , 2.86 (m, 1H), 2.17 (m, 1H), 1.89 (m, 3H)

Column temperature: 30℃

Flow rate: 4.0mL/min

UV detection wavelength: 254nm

Mobile phase: dichloromethane: n-hexane: ethanol = 70:20:10

Example 7 (R)-1-(3-(8-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[1,5-a]pyrazine -3-yl)piperidin-1-yl)propan Preparation of -2-en-1-one

The following synthetic route is adopted:

Step 1 (R)-3-(8-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[1,5-α]pyrazin-3-yl ) Synthesis of tert-butyl piperidine-1-carboxylate

Intermediate A3 (220mg, 0.5mmol), intermediate B4 (207mg, 0.6mmol), tetrakis(triphenylphosphine) palladium (30mg, 0.025mmol) and anhydrous sodium carbonate (106mg, 1.0mmol) were added to the reaction flask Under the protection of nitrogen, add 20ml of ethylene glycol dimethyl ether and 5ml of water, react overnight at 90°C and cool to room temperature. After the reaction is monitored by TLC, add excess water to quench the reaction, extract 3-4 times with ethyl acetate, and combine The organic phase was washed with saturated brine, concentrated and purified by silica gel column chromatography to obtain 170 mg of yellow solid, yield: 63.7%. LC-MS (APCI): m/z=535.7(M+1) ⁺ .

Step 2 (R)-1-(3-(8-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[1,5-a]pyrazine- Synthesis of 3-yl)piperidin-1-yl)prop-2-en-1-one

Add (R)-3-(8-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[1,5-α]pyrazine- 3-yl) piperidine-1-carboxylic acid tert-butyl ester (132mg, 0.25mmol), add 4N hydrogen chloride ethyl acetate solution (5ml, 20mmol), stir the reaction at room temperature for 1h, TLC monitors the completion of the reaction, concentrate to dryness, directly Throw into the next reaction.

Add 8ml of anhydrous dichloromethane to the reaction flask of the previous step, add triethylamine (0.1ml, 0.5mmol), reduce the temperature to 0°C under nitrogen protection, add acryloyl chloride (24.5mg, 0.27mmol) dropwise, after the addition, stir After reacting for 0.5h, TLC monitoring the reaction was completed, adding saturated ammonium chloride aqueous solution to quench the reaction, the aqueous phase was extracted with dichloromethane 2-3 times, the organic phases were combined, washed with saturated brine, concentrated and purified by silica gel column chromatography to obtain 66mg Off-white solid, yield: 54.8%. LC-MS (APCI): m/z=489.5(M+1) ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71(d,J=2.3Hz,1H),8.13(m,3H),7.82(m,2H),7.57(d,J=4.6Hz,1H) , 7.34 (t, J = 2.3 Hz, 1H), 7.18 (d, J = 4.6 Hz, 1H), 6.74 (q, J = 6.8 Hz, 1H), 6.15 (d, J = 5.5 Hz, 1H), 5.64 (d,J=5.5Hz,1H),5.58(s,2H),4.01(m,1H),3.81(m,2H),3.72(t,J=7.4Hz,2H),3.02(m,1H) , 2.87 (m, 2H), 2.15 (m, 2H).

Example 8 1-(3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrrolo[2,1-f][1,2,4 ]Triazin-7-yl)piperidin-1-yl) Preparation of prop-2-en-1-one

The following synthetic route is adopted:

Step 1 3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrrolo[2,1-f][1,2,4]triazine- Synthesis of 7-yl) piperidine-1-carboxylic acid tert-butyl ester

Intermediate A4 (645mg, 1.63mmol), intermediate B4 (677mg, 1.96mmol), Pd(dppf)Cl ₂ (58mg, 0.08mmol) and Na ₂ CO ₃ (520mg, 4.9mmol) were added to 12mL DME and 4mL The water was replaced with nitrogen three times, and the temperature was raised to 90°C to react overnight. The reaction solution was cooled to room temperature, 30mL of water was added, and it was extracted with ethyl acetate (20mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain a pale yellow solid 540mg, yield 62%. ESI-MS:536[M+1] ⁺ .

Step 2 5-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)pyrrolo[2,1-f][1,2,4 ] Synthesis of Triazine-4-amine

The 3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrrolo[2,1-f][1,2,4]triazine-7 -Yl)piperidine-1-carboxylic acid tert-butyl ester (535 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated by rotary evaporation, the residue was dissolved in 30 mL of dichloromethane, washed with saturated sodium bicarbonate solution and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 322 mg of light yellow solid. The rate is 74%. ESI-MS:436[M+1] ⁺ .

Step 3 1-(3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrrolo[2,1-f][1,2,4] Synthesis of triazine-7-yl)piperidin-1-yl)prop-2-en-1-one

Put 5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)pyrrolo[2,1-f][1,2,4] Triazine-4-amine (322mg, 0.74mmol) and triethylamine (0.15g, 1.48mmol) were dissolved in 10mL of dichloromethane, cooled to -20°C in an ice bath, and acryloyl chloride (67mg, 0.74mmol) was slowly added, After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. Dilute with 20 mL of water, extract with dichloromethane (15 mL*3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate by silica gel column to obtain 240 mg of light yellow solid with a yield of 65%. ESI-MS: 500[M+1] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ8.61(dt,J=4.8,1.5Hz,1H),7.94(s,1H),7.78(td,J= 7.7, 1.8 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.30-7.28 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 16.7, 10.5 Hz, 1H), 6.46 (s, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.67 (d, J = 10.1 Hz, 1H), 5.37 ( s,1H),5.33(s,2H),4.86(d,J=13.1Hz,0.5H),4.58(d,J=13.3Hz,0.5H), 4.39(d,J=13.1Hz,0.5H) , 4.00 (d, J = 13.2Hz, 0.5H), 3.44 (s, 1H), 3.15 (q, J = 13.0, 11.0 Hz, 1H), 2.99 (t, J = 11.8 Hz, 0.5H), 2.87 ( t,J=11.9Hz,0.5H), 2.25(d,J=10.3Hz,1H), 1.90(d,J=12.1Hz,2H), 1.78–1.71(m,1H).

Example 9 (R)-1-(3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrrolo[2,1-f][1 ,2,4)triazin-7-yl)piperidine-1- (Base) Preparation of prop-2-en-1-one

100mg of the racemate compound of Example 8 was dissolved in methanol solution, and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain the target product (retention time: 61.925min, relative content: 50.04%, named as R configuration). ESI-MS: 500[M+1] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ8.61(dt,J=4.8,1.5Hz,1H),7.94(s,1H),7.78(td,J= 7.7, 1.8 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.30-7.28 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 16.7, 10.5 Hz, 1H), 6.46 (s, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.67 (d, J = 10.1 Hz, 1H), 5.37 ( s,1H),5.33(s,2H),4.86(d,J=13.1Hz,0.5H),4.58(d,J=13.3Hz,0.5H), 4.39(d,J=13.1Hz,0.5H) , 4.00 (d, J = 13.2Hz, 0.5H), 3.44 (s, 1H), 3.15 (q, J = 13.0, 11.0 Hz, 1H), 2.99 (t, J = 11.8 Hz, 0.5H), 2.87 ( t,J=11.9Hz,0.5H), 2.25(d,J=10.3Hz,1H), 1.90(d,J=12.1Hz,2H), 1.78–1.71(m,1H).

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: methyl tert-butyl ether: n-hexane: methanol: isopropanol = 20:58:10:12

Example 10 (S)-1-(3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrrolo[2,1-f][1 ,2,4)triazin-7-yl)piperidine -1-yl) prop-2-en-1-one preparation

100mg of the racemate compound of Example 8 was dissolved in methanol solution, and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain 43mg of the target product (retention time: 65.193min, relative content: 49.96%, named S configuration). ESI-MS: 500[M+1] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ8.61(dt,J=4.8,1.5Hz,1H),7.94(s,1H),7.78(td,J= 7.7, 1.8 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.30-7.28 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 16.7, 10.5 Hz, 1H), 6.46 (s, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.67 (d, J = 10.1 Hz, 1H), 5.37 ( s,1H),5.33(s,2H),4.86(d,J=13.1Hz,0.5H),4.58(d,J=13.3Hz,0.5H), 4.39(d,J=13.1Hz,0.5H) , 4.00 (d, J = 13.2Hz, 0.5H), 3.44 (s, 1H), 3.15 (q, J = 13.0, 11.0 Hz, 1H), 2.99 (t, J = 11.8 Hz, 0.5H), 2.87 ( t,J=11.9Hz,0.5H), 2.25(d,J=10.3Hz,1H), 1.90(d,J=12.1Hz,2H), 1.78–1.71(m,1H).

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Example 11 (R)-1-(3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[5,1-f][1 ,2,4)triazin-7-yl)piperidine -1-yl) prop-2-en-1-one preparation

The following synthetic route is adopted:

Step 1 (R)-3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[5,1-f][1,2,4 ]Triazine-7-yl)piperidine-1-carboxylate benzyl ester

Intermediate A5 (330mg, 0.76mmol), intermediate B4 (342mg, 0.99mmol), Pd(dppf)Cl ₂ (30mg, 0.04mmol) and Na ₂ CO ₃ (244mg, 2.3mmol) were added to 12mL DME and 4mL The water was replaced with nitrogen three times, and the temperature was raised to 90°C to react overnight. The reaction solution was cooled to room temperature, 30mL of water was added, and it was extracted with ethyl acetate (20mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain a light yellow solid of 285mg. Yield 66%. ESI-MS:571[M+1] ⁺ .

Step 2 (R)-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)imidazo[5,1-f][1 ,2,4] Synthesis of Triazine-4-amine

(R)-3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[5,1-f][1,2,4] Triazin-7-yl)piperidine-1-carboxylic acid benzyl ester (285mg, 0.5mmol) was dissolved in 15mL of absolute ethanol, 30mg of 10% palladium on carbon was added, replaced with hydrogen three times, and stirred overnight under an atmosphere of hydrogen at atmospheric pressure . After the reaction was completed, the palladium-carbon was filtered off, the filtrate was concentrated, and 180 mg of pale yellow oil was obtained through silica gel column separation, with a yield of 82%. ESI-MS:437[M ⁺ +1].

Step 3 (R)-1-(3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[5,1-f][1, Synthesis of 2,4]triazin-7-yl)piperidin-1-yl)prop-2-en-1-one

(R)-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)imidazo[5,1-f][1, 2,4] Triazine-4-amine (180mg, 0.41mmol) and triethylamine (83mg, 0.82mmol) were dissolved in 10mL of dichloromethane, cooled to -20°C in an ice bath, and slowly added acryloyl chloride (37mg, 0.41 mmol), remove the ice bath after dropping, and stir at room temperature for 1 hour. Dilute with 20 mL of water, extract with dichloromethane (10 mL*3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate by silica gel column to obtain 120 mg of light yellow solid with a yield of 60%. ESI-MS: 491[M ⁺ +1] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ8.59(ddd,J=4.9,1.8,1.0Hz,1H),7.87(d,J=12.4Hz,1H ), 7.80–7.70 (m, 2H), 7.63 (dt, J = 7.9, 1.1 Hz, 1H), 7.44 (dd, J = 8.4, 2.2 Hz, 1H), 7.28–7.22 (m, 1H), 7.10 ( d,J=8.5Hz,1H), 6.62(dd,J=16.8,10.6Hz,1H), 6.27(t,J=14.6Hz,1H), 5.67(dd,J=20.3,10.5Hz,1H), 5.34 (s, 2H), 4.89 (d, J = 13.1Hz, 0.5H), 4.61 (d, J = 13.1Hz, 0.5H), 4.27 (d, J = 12.5 Hz, 0.5H), 4.03 (d, J=14.0Hz, 0.5H), 3.59–3.40(m, 2H), 3.19(t, J=13.6Hz, 0.5H), 2.85(t, J=12.5Hz, 0.5H), 2.25(s, 1H) ,2.04(t,J=6.2Hz,1H),1.92(d,J=13.8Hz,1H),1.69(d,J=14.4Hz,1H).

Example 12 1-(3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-7 -Yl)piperidin-1-yl) Preparation of prop-2-en-1-one

The following synthetic route is adopted:

Step 1 (R)-3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-7 -Yl)piperidine-1-carboxylic acid tert-butyl ester synthesis

Into a 50mL single-necked flask equipped with a magnetic stirring and condenser tube was added Intermediate A6 (350mg, 0.79mmol), Intermediate B4 (300mg, 0.87mmol), sodium carbonate (251mg, 2.37mmol), and ethylene glycol dimethyl ether. (5mL) and water (5mL). Tetrakis(triphenylphosphine)palladium (91mg, 0.079mmol) was added under a nitrogen atmosphere, the temperature was raised to 100°C under a nitrogen atmosphere, and the reaction was maintained overnight with stirring. Cool to room temperature, add water (20mL) and ethyl acetate (30mL), separate the organic phase, extract the aqueous phase with ethyl acetate (30mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and residue It was passed through a silica gel column to obtain 310 mg of a yellow solid with a yield of 73.38%. LC-MS(APCI): m/z=535.2(M+1) ⁺ . ¹ H NMR(500MHz, CDCl ₃ )δ(ppm): 8.62(d,J=5.0Hz,1H),8.33(s,1H ), 7.80-7.77 (m, 1H), 7.68 (d, J = 10.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 9.0 Hz, J = 2.0 Hz, 1H) ), 7.29-7.26 (m, 1H), 7.08 (d, J = 9.0Hz, 1H), 7.01 (s, 1H), 5.34 (s, 2H), 5.15 (br s, 2H), 4.79-4.74 (m ,1H),4.28-4.22(m,1H),4.08-4.00(m,1H),3.29-3.24(m,1H),3.00-2.95(m,1H),2.22-2.19(m,1H),2.06 -1.99(m,1H),1.77-1.68(m,2H),1.46(s,9H).

Step 2 (R)-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)-7H-pyrrolo[2,3-d ] Synthesis of pyrimidine-4-amino

Add (R)-3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (310mg, 0.58mmol) and dichloromethane (5mL), add TFA (1mL), stir and react at room temperature under nitrogen atmosphere for 2 hours . Concentrate to dryness under reduced pressure, add dichloromethane (10mL) and saturated sodium bicarbonate aqueous solution (10mL), separate the organic phase, extract the aqueous phase with dichloromethane (20mL*2), combine the organic phases, and dry with anhydrous sodium sulfate. It was filtered and concentrated to dryness to obtain 252 mg of brown solid with a yield of 99.2%. LC-MS(APCI): m/z=435.2(M+1) ⁺ .

Step 3 1-(3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-7- Synthesis of (yl)piperidin-1-yl)prop-2-en-1-one

(R)-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine -4-amino (252mg, 0.57mmol) was dissolved in acetonitrile (6mL) and water (5mL), triethylamine (116mg, 1.15mmol) was added, cooled to 0℃, and acryloyl chloride (78mg, 0.86mmol) acetonitrile solution (1mL), after dripping, the reaction was stirred at 0°C for 1 hour. Add saturated aqueous sodium bicarbonate (10mL) and ethyl acetate (20mL), stir for 5 minutes, separate the organic phase, extract the aqueous phase with ethyl acetate (15mL*2), combine the organic phases, dry with anhydrous sodium sulfate, and filter. Concentrate and pass through a silica gel column to obtain 120 mg of pale yellow solid, with a yield of 42.69%. LC-MS(APCI): m/z=489.2(M+1) ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ(ppm): 8.63(d,J=5.2Hz,1H),8.34(s,1H ), 7.82-7.78 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.33-7.27 (m, 2H), 7.09 (d, J = 8.8Hz, 1H), 7.01 (s, 1H), 6.67-6.60 (m, 1H), 6.33 (d, J = 16.8 Hz, 1H), 5.78-5.50 (m, 1H), 5.35 (s, 2H), 5.14 (br s, 2H), 4.85-4.61 (m, 2H), 4.35-4.02 (m, 1H), 3.41-2.85 (m, 2H), 2.30-2.14 (m, 2H), 1.98-1.82 (m, 2H).

Example 13 1-(3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7 -Yl)piperidin-1-yl) Preparation of prop-2-en-1-one

The following synthetic route is adopted:

Step 1 Synthesis of (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)boronic acid

Add Intermediate B4 (3.0g, 8.7mmol), acetone (60mL) and water (60mL) to a 250mL single-necked flask equipped with magnetic stirring. Sodium iodate (7.92g, 34.77mmol), the reaction mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The acetone was evaporated under reduced pressure, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine (60 mL), dried with colorless sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 2.1 g of white solid with a yield of 91.8%. LC-MS(APCI): m/z＝264.1(M+1) ⁺ .

Step 2 3-(1-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-cyano-4-(1,3-dioxoisoindol-2-yl )-1H-pyrrol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

Add 3-(5-cyano-4-(1,3-dioxoisoindol-2-yl)-1H-pyrrol-3-yl)piperidine-1 to a 50mL three-neck flask equipped with magnetic stirring. -Tert-butyl formate (1.26g, 3.0mmol), (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)boronic acid (1.58g, 6.0mmol) and copper acetate (546mg, 3.0mmol) , Evacuating and replacing the atmosphere with oxygen gas for three times, adding anhydrous dichloromethane (40 mL) and triethylamine (909 mg, 9.0 mmol) dropwise, after the addition, the reaction was stirred at room temperature under oxygen atmosphere overnight. Add water (40mL) and dichloromethane (40mL), stir for 10 minutes, separate the organic phase, extract the aqueous phase with dichloromethane (20mLx2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 1.0g of white solid, yield 52.3%. LC-MS(APCI): m/z=638.2(M+1) ⁺ . ¹ H NMR(300MHz,CDCl ₃ )δ(ppm):8.62-8.61(m,1H),8.01-7.98(m,2H) ,7.86-7.81(m,2H),7.79-7.76(m,1H),7.58(d,J=2.7Hz,1H),7.40-7.36(m,1H),7.30-7.28(m,1H),7.10 (d,J=9.0Hz,1H),6.99(s,1H),5.34(s,2H),4.06-4.00(m,1H),2.85-2.80(m,2H),2.56-2.53(m,1H) ), 2.05-1.97(m,1H), 1.71-1.67(m,1H), 1.54(s,9H), 1.51-1.42(m,3H).

Step 3 3-(4-Amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-cyano-1H-pyrrol-3-yl)piperidine-1- Synthesis of tert-butyl formate

Add 3-(1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-cyano-4-(1,3-bis Oxoisoindol-2-yl)-1H-pyrrol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (0.58g, 0.91mmol) and absolute ethanol (10mL), add dropwise hydrazine hydrate (0.14g) , 2.92 mmol), and the reaction was stirred at room temperature for half an hour under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and the residue was passed through a silica gel column to obtain 350 mg of white solid with a yield of 65.9%. LC-MS(APCI): m/z=508.2(M+1) ⁺ .

Step 4 3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piper Synthesis of tert-butyl pyridine-1-carboxylate

Add 3-(4-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-cyano-1H to a 50mL single-neck flask equipped with magnetic stirring and condenser. -Pyrrol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (350mg, 0.6mmol) and absolute ethanol, stirred to dissolve, add methyl acetate (620mg, 6.0mmol), heated and refluxed overnight under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was passed through a silica gel column to obtain 290 mg of white solid with a yield of 90.1%. LC-MS(APCI): m/z=535.2(M+1) ⁺ .

Step 5 5-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4 -Synthesis of amines

Add 3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5H-pyrrolo[3,2- d] tert-butyl pyrimidin-7-yl)piperidine-1-carboxylate (290 mg, 0.54 mmol) and dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added, and the reaction was stirred at room temperature for 2 hours under a nitrogen atmosphere. Concentrate to dryness under reduced pressure, add dichloromethane (30mL) and saturated sodium bicarbonate aqueous solution (20mL), separate the organic phase, extract the aqueous phase with dichloromethane (30mLx2), combine the organic phases, dry with anhydrous sodium sulfate, and filter. Concentrate to dryness to obtain 225 mg of brown solid, with a yield of 96.9%. LC-MS(APCI): m/z=435.2(M+1) ⁺ .

Step 6 1-(3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7- (Yl)piperidin-1-yl)prop-2-en-1-one synthesis

5-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (225mg, 0.52mmol) was dissolved in acetonitrile (8mL) and water (4mL), added triethylamine (78mg, 0.78mmol), cooled to 0℃, slowly added dropwise acryloyl chloride (60mg, 0.67mmol) under nitrogen atmosphere Acetonitrile solution (2mL), after dripping, keep at 0°C and stir for 1 hour. Add saturated aqueous sodium bicarbonate (30mL) and ethyl acetate (60mL), stir for 5 minutes, separate the organic phase, extract the aqueous phase with ethyl acetate (15mLx2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and 140 mg of pale yellow solid was obtained through silica gel column with a yield of 55.2%. LC-MS(APCI): m/z=489.2(M+1) ⁺ . ¹ H NMR(500MHz, CDCl ₃ )δ(ppm): 8.62(d,J=5.0Hz,1H), 8.32(s,1H ),7.81-7.7.77(m,1H),7.71(d,J=2.5Hz,1H),7.67(d,J=8.0Hz,1H),7.54(dd,J=8.5Hz,J=2.5Hz ,1H),7.28-7.25(m,1H),7.11(d,J=9.0Hz,1H),6.92(s,1H),6.69-6.64(m,1H),6.45-6.41(m,1H), 6.34(br s,2H),5.83-5.80(m,1H),5.35(s,2H),4.81-4.77(m,1H),4.12-4.10(m,1H),3.28-3.22(m,1H) ,2.55-2.50(m,1H),2.32-2.29(m,1H),2.01-1.98(m,1H),1.94-1.91(m,1H),1.70-1.65(m,1H).

Example 14 (S)-1-(3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5H-pyrrolo[3,2-d ]Pyrimidin-7-yl)piperidine-1- (Base) Preparation of prop-2-en-1-one

140 mg of the racemate compound of Example 13 was dissolved in dichloromethane (10 mL), and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain 51 mg of the target product (retention time: 25.955 min, named as S configuration). LC-MS(APCI): m/z=489.2(M+1) ⁺ . ¹ H NMR(500MHz, CDCl ₃ )δ(ppm): 8.62(d,J=5.0Hz,1H), 8.32(s,1H ),7.81-7.7.77(m,1H),7.71(d,J=2.5Hz,1H),7.67(d,J=8.0Hz,1H),7.54(dd,J=8.5Hz,J=2.5Hz ,1H),7.28-7.25(m,1H),7.11(d,J=9.0Hz,1H),6.92(s,1H),6.69-6.64(m,1H),6.45-6.41(m,1H), 6.34(br s,2H),5.83-5.80(m,1H),5.35(s,2H),4.81-4.77(m,1H),4.12-4.10(m,1H),3.28-3.22(m,1H) ,2.55-2.50(m,1H),2.32-2.29(m,1H),2.01-1.98(m,1H),1.94-1.91(m,1H),1.70-1.65(m,1H).

Column temperature: 25℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: dichloromethane: n-hexane: methanol: ethanol=45:42:5:8 (containing 0.1% diethylamine)

Example 15 (R)-1-(3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5H-pyrrolo[3,2-d ]Pyrimidin-7-yl)piperidine-1- (Base) Preparation of prop-2-en-1-one

140 mg of the racemate compound of Example 13 was dissolved in dichloromethane (10 mL), and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain 48 mg of the target product (retention time: 21.520 min, named as R configuration). LC-MS(APCI): m/z=489.2(M+1) ⁺ . ¹ H NMR(500MHz, CDCl ₃ )δ(ppm): 8.62(d,J=5.0Hz,1H), 8.32(s,1H ),7.81-7.7.77(m,1H),7.71(d,J=2.5Hz,1H),7.67(d,J=8.0Hz,1H),7.54(dd,J=8.5Hz,J=2.5Hz ,1H),7.28-7.25(m,1H),7.11(d,J=9.0Hz,1H),6.92(s,1H),6.69-6.64(m,1H),6.45-6.41(m,1H), 6.34(br s,2H),5.83-5.80(m,1H),5.35(s,2H),4.81-4.77(m,1H),4.12-4.10(m,1H),3.28-3.22(m,1H) ,2.55-2.50(m,1H),2.32-2.29(m,1H),2.01-1.98(m,1H),1.94-1.91(m,1H),1.70-1.65(m,1H).

Chiral preparative chromatography column: CHIRALPAK IC (trade name), 10mm×250mm (inner diameter×length), 50μm (filler particle size)

Column temperature: 25℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Biological activity test

Biological Example 1: Kinase inhibition test

1) EGFR (WT) and EGFR (D770_N771insNPG) kinase activity inhibition test

The ADP-Glo Kinase Assay kit (Promega, V9102) was used to determine the inhibitory activity of the drug to be tested against EGFR (WT) and EGFR (D770_N771insNPG) (SignalChem, E-10-132GG).

The highest concentration of the drug to be tested is 1μM, 3 times dilution, 12 concentrations. In a 384-well plate (Perkin Elmer, 6007290), 0.1 μL of drug solutions of various concentrations were added to each well, and mixed with 5 μL of EGFR (WT) or 5 μL of EGFR (D770_N771insNPG) respectively, and double-replicated. After incubating at 25°C for 15 minutes, add 5 μL of substrate to start the reaction, and incubate at 25°C for 60 minutes. The final reaction concentration in the system is: 0.5nM EGFR, 10μM ATP, 0.03mg/mL Poly(4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl ₂ 10mM, Brij35 0.01%. Then add 10μL ADP Glo reagent and incubate at 25℃ for 40min. Then add 20μL of detection reagent, incubate at 25°C for 40min, read on Envision microplate reader (Perkin Elmer, 2104), and calculate the inhibitory rate of different concentrations of compounds on the enzyme. GraphPad Prism 6.0 software was used to analyze the data, and nonlinear curve regression was used to fit the data to obtain a dose-response curve, and the IC ₅₀ value was calculated from this.

2) HER2 (WT) and HER2 (A775_G776insYVMA) kinase activity inhibition test

The ADP-Glo Kinase Assay kit (Promega, V9102) was used to determine the inhibitory activity of the tested drug on HER2 (WT) and HER2 (A775_G776insYVMA) (SignalChem, E27-13BG).

The highest concentration of the drug to be tested is 1μM, 3 times dilution, 12 concentrations. Each well of a 384-well plate (Perkin Elmer, 6007290) was added with 0.1 μL of drug solutions of various concentrations, mixed with 5 μL of HER2 (WT) or 5 μL of HER2 (A775_G776insYVMA), and double-replicated wells. After incubating at 25°C for 15 minutes, add 5 μL of substrate to start the reaction, and incubate at 25°C for 60 minutes. The final reaction concentration in the system is: 20nM HER2, 5μM ATP, 0.03mg/mL Poly(4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl ₂ 10mM, Brij35 0.01%. Then add 10μL ADP Glo reagent and incubate at 25℃ for 40min. Then add 20μL of detection reagent, incubate at 25°C for 40min, read on Envision microplate reader (Perkin Elmer, 2104), and calculate the inhibitory rate of different concentrations of compounds on the enzyme. GraphPad Prism 6.0 software was used to analyze the data, and nonlinear curve regression was used to fit the data to obtain a dose-response curve, and the IC ₅₀ value was calculated from this.

The compounds of the present invention were tested in the above-mentioned kinase inhibition experiments and found that the compounds of the present invention have potent activity on EGFR (WT), EGFR (D770_N771insNPG), HER2 (WT), and HER2 (A775_G776insYVMA) kinases. The results of representative example compounds are summarized in Table 1 below.

Table 1

*: The control compound is CHMFL-EGFR-202: (R)-1-(3-(4-amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H- Pyrazol[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.

Biological Example 2: Test for growth inhibitory activity of cell lines expressing wild-type and mutant EGFR

1) Test of growth inhibitory activity of A431 cells, A549 cells, H1975 cells and HCC827 cells

A431 cells and A549 cells are wild-type EGFR cells; H1975 cells are EGFR cells with L858R point mutation and T790M point mutation; HCC827 cells are mutant EGFR cells with exon 19 deletion.

Adjust the concentration of A431 (WT EGFR) cells, A549 cells (WT EGFR), H1975 cells (L858R/T790M EGFR) and HCC827 cells (Ex19del), add 50μL of cell suspension to a 384-well plate, 37°C, 5% CO ₂ Cultivate overnight. Set up the Tecan D300E program. Dosing with Tecan D300E instrument, the highest concentration of the drug to be tested is 10μM, 3 times of gradient dilution, 10 concentrations, double multiple wells, and continue to incubate for 72 hours. Take out the 384-well plate and equilibrate at room temperature for 30 minutes, add 30 μL of CTG (Promega, G7573) reagent to each well, and place at room temperature for 10 minutes. After the signal is stable, read the Luminescence value on EnVision (Perkin Elmer 2104). Inhibition rate (%)=(1-Lum _{test drug} /Lum _{negative control} )×100, the negative control group is 0.667% DMSO. The calculation of IC ₅₀ uses XL-fit software.

The compound of the present invention was tested in the above cytotoxicity experiment, and it was found that the compound of the present invention has no inhibitory activity against wild-type EGFR A431 cells and A549 cells, but has strong activity and high selection against H1975 cells and HCC827 cells of mutant EGFR. Therefore, it can be seen that the compound of the present invention can inhibit exon 19 deletion mutant EGFR and L858R/T790M mutant EGFR with high specificity. The results of representative example compounds are summarized in Table 2 below.

2) Ba/F3 parent, Ba/F3EGFR-D770-N771ins_SVD, Ba/F3EGFR-L858R, Ba/F3EGFR-L858R/T790M, Ba/F3EGFR-Del19/T790M and Ba/F3EGFR-V769_D770insASV cell growth inhibitory activity test

Take the logarithmic growth phase cells, use the trypan blue exclusion method to detect the cell viability to ensure that the cell viability is above 90%. Adjust the concentration of Ba/F3 parent, Ba/F3EGFR-D770-N771ins_SVD, Ba/F3EGFR-L858R, Ba/F3EGFR-L858R/T790M, Ba/F3EGFR-Del19/T790M and Ba/F3EGFR-V769_D770insASV cells, and add 90μL cell suspension respectively. Transfer the solution to a 96-well plate and incubate overnight at _{37°C and 5% CO 2.} The highest concentration of the drug to be tested is 1μM, 3.16-fold serial dilution, 9 concentrations. Add 10 μL of drug solutions of various concentrations to each well of the 96-well plate, three replicate wells, and continue to incubate for 72 hours. Take out the 96-well plate and equilibrate at room temperature for 30 minutes, add an equal volume of CTG reagent to each well, shake on an orbital shaker for 5 minutes to lyse the cells, and place it at room temperature for 20 minutes to stabilize the luminescence signal. -0010A) to read the luminescence value. Cell survival rate (%)=(luminescence value of test drug-luminescence value of culture solution control)/(luminescence value of cell control-luminescence value of culture solution control)×100%. Response curves and _IC50 values calculated therefrom IC - data analysis, using a nonlinear regression curve fit data S derived using GraphPad Prism7.0 dose software.

The compounds of the present invention also have potent activity and high selectivity on Ba/F3EGFR-D770-N771ins_SVD, Ba/F3EGFR-L858R, Ba/F3EGFR-L858R/T790M, Ba/F3EGFR-Del19/T790M and Ba/F3EGFR-V769_D770insASV cells Therefore, it can be seen that the compound of the present invention can highly specifically inhibit the mutant EGFR inserted into exon 20, the mutant EGFR of L858R, the mutant EGFR of L858R/T790M, and the mutant EGFR of Del19/T790M. The results of representative example compounds are summarized in Table 2 and Table 3 below.

Table 2:

table 3:

Biological Example 3: Test for growth inhibitory activity of cell lines expressing wild-type HER2

1) Test of growth inhibitory activity of SK-BR-3 cells and NCI-N87 cells

SK-BR-3 cells and NCI-N87 cells are wild-type HER2 cells. Adjust the concentration of SK-BR-3 cells and NCI-N87 cells, add 50μL of cell suspension to a 384-well plate, and incubate overnight at _{37°C and 5% CO 2.} Set up the Tecan D300E program. Dosing with Tecan D300E instrument, the highest concentration of the drug to be tested is 10μM, 3 times of gradient dilution, 10 concentrations, double multiple wells, and continue to incubate for 72 hours. Take out the 384-well plate and equilibrate at room temperature for 30 minutes, add 30 μL of CTG (Promega, G7573) reagent to each well, and place at room temperature for 10 minutes. After the signal is stable, read the Luminescence value on EnVision (Perkin Elmer 2104). Inhibition rate (%)=(1-Lum _{test drug} /Lum _{negative control} )×100, the negative control group is 0.667% DMSO. The calculation of IC ₅₀ uses XL-fit software.

The compound of the present invention was tested in the above-mentioned cytotoxicity experiment, and it was found that the compound of the present invention has potent activity against wild-type HER2 SK-BR-3 cells and NCI-N87 cells. It can be seen that the compound of the present invention has high specificity. Inhibit wild-type HER2. The results of representative example compounds are summarized in Table 4 below.

2) Test of growth inhibitory activity of Ba/F ₃ parents and Ba/F _{3 HER2-A775_G776insYVMA cells}

Take the logarithmic growth phase cells, use the trypan blue exclusion method to detect the cell viability to ensure that the cell viability is above 90%. Adjust the concentration of Ba/F3 parent and Ba/F3HER2-A775_G776insYVMA cells, add 90 μL of cell suspension to 96-well plates, and incubate overnight at _{37°C and 5% CO 2.} The highest concentration of the drug to be tested is 1μM, 3.16-fold serial dilution, 9 concentrations. Add 10μL of the drug solution to each well of the 96-well plate, three replicate wells, and continue to incubate for 72 hours. Take out the 96-well plate and equilibrate at room temperature for 30 minutes, add an equal volume of CTG reagent to each well, shake on an orbital shaker for 5 minutes to lyse the cells, and place it at room temperature for 20 minutes to stabilize the luminescence signal. -0010A) to read the luminescence value. Cell survival rate (%)=(luminescence value of the drug to be tested-luminescence value of the culture solution control)/(luminescence value of the cell control-luminescence value of the culture solution control)×100%. GraphPad Prism 7.0 software was used to analyze the data, and nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC ₅₀ value was calculated from this.

The compounds of the present invention also have potent activity and high selectivity against Ba/F3HER2-A775_G776insYVMA cells. The results of representative example compounds are summarized in Table 4 below.

Table 4:

Biological Example 4: Rat pharmacokinetic experiment

Six male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups, 3 rats in each group, and a single dose of the compound (10 mg/kg orally) was administered intravenously or orally, and their pharmacokinetic differences were compared. .

The rats were fed with standard feed and given water. Fasting was started 16 hours before the test. The drug is dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit. The time points for blood collection were 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration.

The rats were briefly anesthetized after inhaling ether, and 300 μL blood samples were collected from the orbit and placed in a test tube. There is 30μL of 1% heparin sodium solution in the test tube. Before use, the test tube was dried at 60°C overnight. After the blood sample was collected at the last time point, the rats were anesthetized with ether and sacrificed.

Immediately after the blood sample is collected, gently invert the test tube at least 5 times to ensure that it is fully mixed before placing it on ice. The blood sample was centrifuged at 4°C and 5000 rpm for 5 minutes to separate the plasma from the red blood cells. Use a pipette to aspirate 100 μL of plasma into a clean plastic centrifuge tube, and indicate the name and time point of the compound. The plasma is stored at -80°C before analysis. The concentration of the compound of the present invention in plasma was determined by LC-MS/MS. The pharmacokinetic parameters are calculated based on the blood drug concentration of each animal at different time points.

Experiments show that the compound of the present invention has better pharmacokinetic properties in animals, and therefore has better pharmacodynamics and therapeutic effects.

The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as belonging to the protection scope of the present invention.

Claims

The compound of formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate:

in,

Ring A is an aromatic ring;

Ring C is C 6-10 aryl or 5-10 membered heteroaryl;

A 1 is CR A1 or N;

A 2 is C or N;

A 4 is CR A4 or N;

A 5 is C or N;

Wherein R A1 and R A4 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 alkoxy, and are optionally substituted with one or more R″;

B 1 is CR 1 or N;

B 2 is CR 2 or N;

B 3 is CR 3 or N;

B 4 is CR 4 or N;

Wherein R 1 , R 2 , R 3 and R 4 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 Alkynyl, -C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C (O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3 -7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl, and is optionally substituted by one or more R″;

L is selected from O, S or NR L;

Wherein R L is selected from H or C 1-6 alkyl, and is optionally substituted with one or more R*;

V is (CR V1 R V2 ) o ;

Wherein R V1 and R V2 are each independently selected from H, D, halogen or C 1-6 alkyl, and are optionally substituted with one or more R*;

o = 1, 2, 3, 4, 5 or 6;

R 6 is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl or 5 To 10-membered heteroaryl, optionally substituted with one or more R*;

R 5 and R 7 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and are optionally substituted with one or more R*; alternatively, R 5 And R 7 together with the double bond they are connected to form a triple bond;

R is each independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (O )R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to A 7-membered heterocyclic group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group; or, two R groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 to 7 Membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;

m=0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

R'is each independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C (O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to 7 members Heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl, and is optionally substituted with one or more R″;

n=0, 1, 2, 3 or 4;

p=0, 1 or 2;

R" is each independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C( O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b ,- NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 To 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group, or two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; wherein each group in the definition of R" is optionally substituted with one or more D until fully deuterated;

R* are each independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C( O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b ,- NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 To 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; or, two R* groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; wherein each group in the definition of R* is optionally substituted with one or more D until fully deuterated;

R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
The compound according to claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

Selected from the following structures:

Preferably,

Selected from the following structures:

Preferably,

Selected from the following structures:
The compound according to claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring C is benzene Group or 5- to 6-membered heteroaryl group; preferably phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, furyl or thienyl; preferably phenyl or pyridyl.
The compound according to any one of claims 1 to 3, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: V is (CH 2 ) o ; preferably CH 2 .
The compound according to any one of claims 1 to 4, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: L is O.
The compound according to any one of claims 1 to 5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: B 1 is CR 1 , B 2 is CR 2 , B 3 is CR 3 , B 4 is CR 4 ; preferably, R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, -CN , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl.
The compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

Selected from the following structures:

Preferably:
The compound according to any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is Compounds of the following general formula:

Wherein each group is as defined in any one of claims 1-7.
The compound according to claim 8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (II-1) , (III-1) or (IV-1) compound:

in,

Ring A is an aromatic ring;

A 2 is C or N;

A 4 is CR A4 or N;

A 5 is C or N;

Wherein R A4 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 alkoxy, and is optionally substituted by one or more R″;

R 1 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

R 2 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

R 3 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

R 4 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

o = 1, 2, 3 or 4;

Each R is independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; wherein R is in the definition Each group of is optionally substituted with one or more D until fully deuterated;

m=0, 1, 2, 3, 4 or 5;

p=0, 1 or 2;

Each R'is independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

n=0, 1, 2, 3 or 4;

R 5 , R 6 and R 7 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and are optionally substituted with one or more R*; or , R 5 and R 7 together with the double bond they are connected to form a triple bond;

R* is each independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; wherein R* Each group in the definition is optionally substituted with one or more D until it is fully deuterated;

R" is each independently selected from H, D, halogen, -CN, =O, -OR a or -NR b R c ;

R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or R b and R c together The N atoms to which they are attached together form a 3 to 7 membered heterocyclic group or a 5 to 10 membered heteroaryl group; wherein each group in the definition of R a , R b and R c is optionally substituted by one or more D , Until fully deuterated.
The compound according to claim 9, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (II-2) , (III-2) or (IV-2) compound:

in,

Ring A is an aromatic ring;

A 2 is C or N;

A 4 is CR A4 or N;

A 5 is C or N;

Wherein R A4 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 alkoxy, and is optionally substituted by one or more R″;

R 1 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

R 2 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

o = 1, 2, 3 or 4;

Each R is independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; wherein R is in the definition Each group of is optionally substituted with one or more D until fully deuterated;

m=0, 1, 2, 3, 4 or 5;

Each R'is independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

n=0, 1, 2, 3 or 4;

R" is each independently selected from H, D, halogen, -CN, =O, -OR a or -NR b R c ;

R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or R b and R c together The N atoms to which they are attached together form a 3 to 7 membered heterocyclic group or a 5 to 10 membered heteroaryl group; wherein each group in the definition of R a , R b and R c is optionally substituted by one or more D , Until fully deuterated.
The compound according to claim 8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (V-1) Or (VI-1) compound:

in,

A 1 is CR A1 or N;

Wherein R A1 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 alkoxy, which is optionally substituted by one or more R″;

R 1 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

R 2 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

R 3 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

R 4 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

o = 1, 2, 3 or 4;

Each R is independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; wherein R is in the definition Each group of is optionally substituted with one or more D until fully deuterated;

m=0, 1, 2, 3, 4 or 5;

p=0, 1 or 2;

Each R'is independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

n=0, 1, 2, 3 or 4;

R 5 , R 6 and R 7 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and are optionally substituted with one or more R*; or , R 5 and R 7 together with the double bond they are connected to form a triple bond;

R* is each independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; wherein R* Each group in the definition is optionally substituted with one or more D until it is fully deuterated;

R" is each independently selected from H, D, halogen, -CN, =O, -OR a or -NR b R c ;

R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or R b and R c together The N atoms to which they are attached together form a 3 to 7 membered heterocyclic group or a 5 to 10 membered heteroaryl group; wherein each group in the definition of R a , R b and R c is optionally substituted by one or more D , Until fully deuterated.
The compound according to claim 11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (V-2) Or (VI-2) compound:

in,

A 1 is CR A1 or N;

Wherein R A1 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 alkoxy, and is optionally substituted by one or more R″;

R 1 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

R 2 is H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

o = 1, 2, 3 or 4;

Each R is independently selected from H, D, halogen, -CN, =O, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; wherein R is in the definition Each group of is optionally substituted with one or more D until fully deuterated;

m=0, 1, 2, 3, 4 or 5;

Each R'is independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and is optionally substituted with one or more R″;

n=0, 1, 2, 3 or 4;

R" is each independently selected from H, D, halogen, -CN, =O, -OR a or -NR b R c ;

R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or R b and R c together The N atoms to which they are attached together form a 3 to 7 membered heterocyclic group or a 5 to 10 membered heteroaryl group; wherein each group in the definition of R a , R b and R c is optionally substituted by one or more D , Until fully deuterated.
The compound or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, the compounds are selected from:
A pharmaceutical composition containing the compound of any one of claims 1-13 or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, And pharmaceutically acceptable excipients.
The compound of any one of claims 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 14 Use of the composition in the preparation of a medicament for the treatment and/or prevention of wild and/or mutant EGFR kinase-mediated tumors;

Preferably, the mutated EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR;

Preferably, wherein the exon 20 insertion mutation is selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH;

Preferably, wherein the exon 18 point mutation is selected from at least one mutation of G719A, G719S, G719C, E709K and E709A;

Preferably, wherein the exon 21 point mutation is selected from the L861Q mutation;

Preferably, the mutated EGFR also has a T790M mutation at the same time.
The compound of any one of claims 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 14 Use of the composition in the preparation of a medicament for treating and/or preventing the following tumors: lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.
The compound of any one of claims 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 14 Use of the composition in the preparation of a medicament for the treatment and/or prevention of wild and/or mutant HER2 kinase-mediated tumors;

Preferably, the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C mutant HER2, L755S mutant HER2 or ex20insYVMA mutant HER2;

Preferably, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
The compound of any one of claims 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 14 Use of the composition in the preparation of a medicament for treating and/or preventing the following tumors: lung cancer, gastric cancer or breast cancer.
A method for treating and/or preventing wild and/or mutant EGFR kinase-mediated tumors in a subject, comprising administering to the subject the compound of any one of claims 1-13 or Tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 14;

Preferably, the mutated EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR;

Preferably, wherein the exon 20 insertion mutation is selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH;

Preferably, wherein the exon 18 point mutation is selected from at least one mutation of G719A, G719S, G719C, E709K and E709A;

Preferably, wherein the exon 21 point mutation is selected from the L861Q mutation;

Preferably, the mutated EGFR also has a T790M mutation at the same time.
A method for treating and/or preventing the following tumors in a subject: lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, hematopoietic tumor or skin cancer, comprising administering to the subject claim 1 The compound of any one of -13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of claim 14.
A method for treating and/or preventing wild and/or mutant HER2 kinase-mediated tumors in a subject, comprising administering to the subject the compound of any one of claims 1-13 or Tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 14;

Preferably, the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C mutant HER2, L755S mutant HER2 or ex20insYVMA mutant HER2;

Preferably, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
A method of treating and/or preventing the following tumors in a subject: lung cancer, gastric cancer or breast cancer, comprising administering to the subject the compound of any one of claims 1-13 or its tautomers Forms, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 14.
The compound of any one of claims 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 14 A composition for the treatment and/or prevention of wild and/or mutant EGFR kinase-mediated tumors;

Preferably, the mutated EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR;

Preferably, wherein the exon 20 insertion mutation is selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH;

Preferably, wherein the exon 18 point mutation is selected from at least one mutation of G719A, G719S, G719C, E709K and E709A;

Preferably, wherein the exon 21 point mutation is selected from the L861Q mutation;

Preferably, the mutated EGFR also has a T790M mutation at the same time.
The compound of any one of claims 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 14 The composition is used to treat and/or prevent the following tumors: lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.
The compound of any one of claims 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 14 A composition for the treatment and/or prevention of tumors mediated by wild and/or mutant HER2 kinase;

Preferably, the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C mutant HER2, L755S mutant HER2 or ex20insYVMA mutant HER2;

Preferably, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
The compound of any one of claims 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 14 The composition is used to treat and/or prevent the following tumors: lung cancer, gastric cancer or breast cancer.