CN112574208A - Substituted fused tricyclic derivatives, compositions and uses thereof - Google Patents

Abstract

The present invention provides a substituted condensed tricyclic derivative, a composition comprising the compound and use thereof, wherein the substituted condensed tricyclic derivative is a compound represented by formula (I) or its tautomerism isomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates. The compounds and compositions of the present invention are useful in the treatment and/or prevention of mutated EGFR kinase-mediated tumors, as well as wild-type and/or mutated HER2 kinase-mediated tumors.

Description

Substituted fused tricyclic derivatives, compositions and uses thereof

technical field

The present invention belongs to the technical field of medicine, and particularly relates to substituted fused tricyclic derivatives having inhibitory effect on mutant epidermal growth factor receptor (EGFR), wild and/or mutant HER2, pharmaceutical compositions comprising them, and their preparation and use.

Background technique

EGFR is a receptor tyrosine kinase that exerts its physiological functions in normal tissues by binding to epidermal growth factor (hereinafter also referred to as EGF) as a ligand, and contributes to the growth and apoptosis inhibition of epithelial tissues . In addition, somatic mutations of the EGFR gene are known to be oncogenes: for example, EGFR and exon deletions of amino acids 746 to 750 in the exon 19 region (hereinafter also referred to as "exon 19 deletion mutations") The EGFR mutation at amino acid 858 in region 21 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 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 conducted and used in the treatment of EGFR mutation-positive lung cancer. For example, gefitinib, erlotinib, and afatinib have high antitumor effects on exon 19 deletion mutant and L858R mutant EGFR-positive lung cancers, but their administration at their therapeutic doses causes gastrointestinal Disease and dermatological side effects are generally believed to be attributable to wild-type EGFR.

Recent studies have found that some cancers have novel 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, several rare EGFR mutations have been reported, such as point mutations or deletion mutations in exon 18 and point mutations in exon 21. For example, a new EGFR point mutation in lung cancer has been discovered, in which the glycine encoded by codon 719 in exon 18 has been replaced by any amino acid (hereinafter referred to as the G719X mutation), and the glycine encoded by codon 861 in exon 21 has been Leucine has been replaced by glutamine (hereafter 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. It is reported that in these cancer cells with abnormal and overexpressed HER2 genes, the signal activation of HER2 and downstream pathways enhances the survival and proliferation signals of cancer cells.

Therefore, it is presumed that an inhibitor capable of controlling the kinase activity of HER2 exerts an antitumor effect by inhibiting the signaling of HER2 and downstream pathways in cancer cells, and thus can be considered to be effective as a cancer therapeutic drug.

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

SUMMARY OF THE INVENTION

The present invention provides a novel condensed tricyclic derivative, a composition comprising the compound, and use thereof, wherein the exon 20 insertion (exon 20ins) mutant EGFR, exon 18 point mutant EGFR, exon 20 insertion (exon 20ins) mutant EGFR, exon 18 point mutant EGFR, Sub-21 mutant EGFR, exon 19 deletion (exon 19del) mutant EGFR, L858R mutant EGFR, exon 19 deletion/T790M mutant EGFR, L858R/T790M mutant EGFR have better inhibitory activity and high Selectivity, no or little inhibitory activity against wild-type EGFR, and inhibitory activity against wild-type HER2 and/or mutated HER2, thus providing an anti-tumor inhibitor with low toxicity.

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, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

Ring A is selected from C _6-14 aryl or 5 to 10 membered heteroaryl;

R is each independently selected from H, D, halogen, -OH, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy;

p is selected from 0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl or 3- to 7-membered heterocyclyl, wherein said C _{1 -6} alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, and 3- to 7-membered heterocyclyl are each independently optionally selected by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution;

R ₂ is selected from H, D, 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 , wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C _6-10 -membered aryl group and 5- to 10-membered heteroaryl group are each independently optionally replaced by a or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond ;

R ₃ is selected from H, D, 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 , wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C _6-10 -membered aryl group or 5- to 10-membered heteroaryl group are each independently optionally replaced by a or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy;

R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy;

X is C(R ₄ )(R ₄ ');

Y is C(R ₅ )(R ₅ ');

表示单键或双键；

Indicates a single bond or a double bond;

表示R或S的立体构型；

Represents the stereo configuration of R or S;

表示双键时，X为C(R₄)；when

When representing a double bond, X is C(R ₄ );

m is 0, 1 or 2;

n is 1, 2 or 3;

When m is 0, the carbon atom connected to R ₁ and the carbon atom connected to the N atom of the amide directly form a chemical bond;

R ₄ and R ₄ ' are each independently selected from H, D, halogen, -CN or C _1-6 alkyl; or R ₄ and R ₄ ' form carbonyl, C _3-7 cycloalkane with the carbon atom to which they are attached wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected from D by one or more , halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution;

R ₅ and R ₅ ' are each independently selected from H, D, halogen, -CN or C _1-6 alkyl; or R ₅ and R ₅ ' form carbonyl, C _3-7 cycloalkane with the carbon atom to which they are attached wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected from D by one or more , halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution;

R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; wherein said C _1-6 alkyl, C _3-7 cycloalkyl and 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, C _1-6 alkyl or C _1-6 alkoxy group substitution;

表示单键且m为1时，R₁不为H。The condition is that when

When it represents a single bond and m is 1, R ₁ is not H.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof of the present invention compound, and a pharmaceutically acceptable excipient. In specific embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In specific embodiments, the compounds of the present invention are provided in a prophylactically effective amount.

In another aspect, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystalline 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 mutated EGFR kinase-mediated tumors.

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

In a specific embodiment, the mutated EGFR is selected from exon 20 insertion mutant EGFR, exon 18 mutant EGFR, exon 21 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.在具体实施方案中，所述的外显子20插入突变为A763_Y764insFQEA、V769_D770insASV、D770_N771insSVD、D770_N771insNPG、D770_N771insG、D770>GY、N771_P772insN、P772_R773insPR、H773_V774insNPH、H773_V774insPH、H773_V774insAH、H773_V774insH、H774_C774insHV、A761_E762insEAFQ。 In a specific embodiment, the exon 20 insertion mutation is V769_D770insASV, D770_N771insSVD, 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 E790X 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 E790X mutation is selected from at least one mutation of E790K and E790A.

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

In specific embodiments, the mutated EGFR has a T790M mutation and has a mutation 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, a compound of the invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of expression having exon 20 Tumor patients with insertional mutated EGFR.

In a specific embodiment, a compound of the invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, is used for the treatment of expression having the T790M mutation and having Tumor patients with exon 20 insertion mutations in EGFR.

In a specific embodiment, a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of an expression having exon 18 Tumor patients with point-mutated EGFR.

In a specific embodiment, a compound of the invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, is used for the treatment of expression having the T790M mutation and having Tumor patients with exon 18 mutant EGFR.

In a specific embodiment, a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of an expression having exon 21 Tumor patients with point-mutated EGFR.

In a specific embodiment, a compound of the invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, is used for the treatment of expression having the T790M mutation and having Cancer patients with exon 21 mutant EGFR.

In a specific embodiment, a compound of the invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of an expression having exon 19 Patients with tumors lacking mutant EGFR.

In a specific embodiment, a compound of the invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, is used for the treatment of expression having the T790M mutation and having Cancer patients with exon 19 deletion mutant EGFR.

In a specific embodiment, a compound of the invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof is used for the treatment of expressing EGFR having the L858R mutation of tumor patients.

In a specific embodiment, a compound of the invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, is used for the treatment of expression having the T790M mutation and having Tumor patients with L858R mutant EGFR.

In specific embodiments, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present 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 present invention provides a method for the treatment and/or prevention of the following tumors in a subject, comprising administering to the subject Administration of the compound of the present invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of the present invention: lung cancer, breast cancer, Cancer of the head and neck, brain, uterus, hematopoietic system, or skin.

In another aspect, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention Use of the pharmaceutical composition in the manufacture of a medicament for the treatment and/or prevention of wild-type and/or mutated HER2 kinase-mediated tumors.

In another aspect, the present invention provides a method of treating and/or preventing a disease, such as a wild-type and/or mutated HER2 kinase mediated tumor in a subject, comprising administering to the subject the present invention Compounds of the present invention or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions of the present invention.

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

In specific embodiments, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present 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 present invention provides a method for the treatment and/or prevention of the following tumors in a subject, comprising administering to the subject Administration of the compound of the present invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of the present invention: lung cancer, gastric cancer or breast cancer cancer.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the ensuing detailed description, examples and claims.

definition

chemical definition

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

When numerical ranges are listed, each value and subranges within the range are intended to be included. 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} , _C2-6 , _C2-5 , _C2-4 , _C2-3 , _C3-6 , _C3-5 , _C3-4 , _C4-6 , _C4-5 , and _{C5 -6} alkyl.

"C _1-6 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C _1-4 alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tertiary 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 ). Whether or not the alkyl group is modified with "substituted" or not, each of the alkyl groups is independently optionally substituted, eg, 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, wherein R is a substituted or unsubstituted C _1-6 alkyl group. In some embodiments, C _1-4 alkoxy is particularly preferred. The 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.

"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.

Thus, "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 replaced by one or more halo groups group replaced. In some embodiments, C _1-4 haloalkyl is particularly preferred, more preferably C _1-2 haloalkyl. In some embodiments, C _1-4 haloalkoxy is particularly preferred, more preferably C _1-2 haloalkoxy. Exemplary such _haloalkyl groups include, but are not limited to _{: -CF3} , _-CH2F , _-CHF2 , _-CHFCH2F , _-CH2CHF2 , _-CF2CF3 , _-CCl3 , _-CH2Cl , -CHCl ₂ , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Exemplary such haloalkoxy groups include, but are not limited to: _-OCH2F , _-OCHF2 , _-OCF3 , 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, _C3-7 cycloalkyl is preferred, _C3-6 cycloalkyl is particularly preferred, and _C5-6 cycloalkyl is more preferred. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to 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 a cycloalkyl system. Exemplary such 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 radical (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 the like. Whether or not the cycloalkyl group is modified with "substituted" or not, each of the cycloalkyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate The basis is defined as follows.

"3- to 10-membered heterocyclyl" alternatively refers to a group of 3- to 10-membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen , sulfur, boron, phosphorus and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence allows. In some embodiments, 3- to 7-membered heterocyclyl groups are preferred, which are 3- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3-6 A 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 carbon atom and A 5- to 6-membered non-aromatic ring system of 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the aforementioned heterocyclyl ring is fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the ring The number of members continues to indicate the number of ring members in a heterocyclyl ring system. Whether or not the heterocyclyl group is modified with "substituted" or not, each of the heterocyclyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate The basis is defined as follows.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridine, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-diketone. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxa oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiahexyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azacyclooctyl, oxacyclooctyl, and thiacyclooctyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyl groups) fused to a _C6 aryl ring include, but are not limited to: indoline, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary ₆ -membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.

"C _6-14 aryl" refers to a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 aromatic ring system (eg, having 6-14 ring carbon atoms and zero heteroatoms) 6, 10 or 14 pi electrons shared by a cyclic arrangement). In some embodiments, an aryl group has six ring carbon atoms (" _C6 aryl"; eg, phenyl). In some embodiments, aryl groups have ten ring carbon atoms (" _C10 aryl"; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C ₁₄ aryl"; eg, anthracenyl). In some embodiments, _C6-10 aryl groups are particularly preferred, and _C6 aryl groups are more preferred. Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system. Whether or not the aryl group is modified with "substituted" or not, each of the aryl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are as follows definition.

"5- to 10-membered heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (eg, having shared in a cyclic arrangement 6 or 10 pi electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence allows. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom is The numbers continue to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Whether or not the heteroaryl group is modified with "substituted" or not, each of the heteroaryl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate 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, azacyclotrienyl, oxeptrienyl, and thiacyclotrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indanyl and purine groups. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .

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

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, _-NO2 , _-N3 , _-SO2H , _-SO3H , -OH, ^-ORaa , -ON( ^Rbb ) 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 heterocyclyl Aryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups ;

Or two geminal hydrogens on a carbon atom are surrounded by groups =O, =S, =NN( ^Rbb ) ₂ , = ^NNRbbC (=O) ^Raa , = ^NNRbbC (=O) ^ORaa , = NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc substitution;

Each of R ^aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^aa groups are combined to form a heterocyclyl or Heteroaryl rings in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced 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 radical, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^bb groups combined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkyne radyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each of ^Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rcc groups are combined to form a heterocycle yl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R ^dd group substitution;

Each of ^Rdd is independently selected from: halogen, -CN, _-NO2 , _-N3 , -SO2H, _-SO3H , -OH, ^-ORee , -ON( ^Rff _{)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 ^Ree , -OC(=O) ^Ree , -OCO ₂ ^Ree , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , - ^NRff C(=O) ^{Ree,-NRffCO2Ree , -NRffC} (=O)N( ^Rff ) ₂ , _-C (= ^NRff ) ^ORee , ^{-OC(=NRff ) Ree} , -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 ^Ree , -SO ₂ N(R ^ff ) ₂ , -SO ₂ ^Ree , -SO ₂ OR ^ee , -OSO ₂ ^Ree , -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 Re ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle aryl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two gem R ^dd substituents may combine 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 cyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

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

Each of Rgg is independently: halogen, -CN, _-NO2 , _-N3 , ^-SO2H , _-SO3H , _-OH , _-OC1-6 alkyl, -ON( _C1-6 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 carbocyclyl , C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, C ₅ -C ₁₀ heteroaryl; or two gem R ^gg substituents can be combined to form =O or =S; wherein, X ^- is trans ion.

Exemplary substituents on nitrogen 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 )( ^NRcc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rcc groups attached to a nitrogen atom combine to form a heterocycle yl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced 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.

"Deuterated" or "D" refers to the replacement of one or more hydrogens in a compound or group with deuterium; deuterated substitution can be mono-, di-, poly- or per-substitution. The term "one or more deuterated" and "one or more deuterated" are used interchangeably.

"Non-deuterated compound" refers to a compound containing deuterium atoms in a proportion 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, within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergy, etc., and with reasonable benefit/risk those salts in commensurate proportions. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in J. Pharmaceutical Sciences (1977) 66: 1-19 describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or salts formed with organic acids such as acetic, oxalic, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using methods conventional in the art, eg, ion exchange methods. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphor acid salt, camphorsulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl Sulfate , malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, Pectin Acetate, 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 or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations with counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrates, lower alkyl sulfonates and aryl sulfonates.

"Subjects" for administration include, but are not limited to, humans (i.e., male or female of any age group, e.g., 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, eg, mammals, eg, primates (eg, 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 has a particular disease, disorder or condition, which reduces the severity of, or delays or slows down, the disease, disorder or condition or development of a disorder ("therapeutic treatment"), and also includes effects that occur before a subject begins to suffer from a particular 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, a compound of the present invention may be administered concurrently or sequentially with another therapeutic agent in separate unit dosage forms, or concurrently with another therapeutic agent in a single unit dosage form.

Detailed ways

compound

As used herein, "compounds of the present invention" refers to compounds of formula (I) below (including subsets 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, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

Ring A is selected from C _6-14 aryl or 5 to 10 membered heteroaryl;

R is each independently selected from H, D, halogen, -OH, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy;

p is selected from 0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl or 3- to 7-membered heterocyclyl, wherein said C _{1 -6} alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, and 3- to 7-membered heterocyclyl are each independently optionally selected by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution;

R ₂ is selected from H, D, 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 , wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C _6-10 -membered aryl group and 5- to 10-membered heteroaryl group are each independently optionally replaced by a or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond ;

R ₃ is selected from H, D, 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 , wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C _6-10 -membered aryl group or 5- to 10-membered heteroaryl group are each independently optionally replaced by a or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy;

R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy;

X is C(R ₄ )(R ₄ ');

Y is C(R ₅ )(R ₅ ');

表示单键或双键；

Indicates a single bond or a double bond;

表示R或S的立体构型；

Represents the stereo configuration of R or S;

表示双键时，X为C(R₄)；when

When representing a double bond, X is C(R ₄ );

m is 0, 1 or 2;

n is 1, 2 or 3;

When m is 0, the carbon atom connected to R ₁ and the carbon atom connected to the N atom of the amide directly form a chemical bond;

R ₄ and R ₄ ' are each independently selected from H, D, halogen, -CN or C _1-6 alkyl; or R ₄ and R ₄ ' form carbonyl, C _3-7 cycloalkane with the carbon atom to which they are attached wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected from D by one or more , halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution;

R ₅ and R ₅ ' are each independently selected from H, D, halogen, -CN or C _1-6 alkyl; or R ₅ and R ₅ ' form carbonyl, C _3-7 cycloalkane with the carbon atom to which they are attached wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected from D by one or more , halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution;

R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; wherein said C _1-6 alkyl, C _3-7 cycloalkyl and 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, C _1-6 alkyl or C _1-6 alkoxy group substitution;

表示单键且m为1时，R₁不为H。The condition is that when

When it represents a single bond and m is 1, R ₁ is not H.

Ring A

In one embodiment, Ring A is selected from C _6-14 aryl or 5 to 10 membered heteroaryl; in another embodiment, Ring A is C _6-14 aryl; in another embodiment, Ring A is a 5- to 10-membered heteroaryl; in another embodiment, Ring A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl , furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, quinolinyl or isoquinolinyl; in another embodiment, Ring A is selected from phenyl, naphthyl, pyridine oxazolyl, imidazolyl, oxazolyl, isoxazolyl, quinolinyl or isoquinolinyl; in another embodiment, Ring A is selected from naphthyl, quinolinyl or isoquinolinyl; in another In an embodiment, Ring A is selected from quinolyl or isoquinolyl; in another embodiment, Ring A is quinolyl.

R

In one embodiment, each R is independently selected from H, D, halogen, -OH, -CN, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, or _C1-6 haloalkoxy; in another embodiment, each R is independently H; in another embodiment, each R is independently D; in another embodiment, each R is independently halogen; in another embodiment In one embodiment, each R is independently -OH; in another embodiment, each R is independently -CN; in another embodiment, each R is independently C _1-6 alkyl; in another embodiment , each R is independently C _1-6 haloalkyl; in another embodiment, each R is independently C _1-6 alkoxy; in another embodiment, each R is independently C _1-6 Haloalkoxy.

In another embodiment, each R is independently selected from D, halogen, -OH, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkane oxy; in another embodiment, each R is independently selected from D, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy; In another embodiment, each R is independently selected from D, halogen, _C1-6 alkyl, or _C1-6 haloalkyl; in another embodiment, each R is independently selected from D, halogen, or _{C1 -6} alkyl; in another embodiment, each R is independently selected from D, F, Cl, Br, _-CH3 , _-CF3 , _-CHF2 , _-CH2F , _-OCH3 , -CH( _CH3 ) ₂ or -OCH( _CH3 ) ₂ ; in another embodiment, each R is independently selected from D, F, _-CH3 , _-CF3 , _-OCH3 or -CH( _CH3 ) ₂ ; In another embodiment, each R is independently selected from D, F or _-CH3 .

p

In one embodiment, p is selected from 0, 1, 2, 3, 4, or 5; in another embodiment, p is 0; in another embodiment, p is 1; in another embodiment, p is 2; in another embodiment, p is 3; in another embodiment, p is 4; in another embodiment, p is 5.

R ₁

In one embodiment, R ₁ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, wherein said C _1-6 alkyl group, C _1-6 alkoxy group, C _3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected by one or more selected from D, halogen , -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; in another embodiment, R ₁ is H; in another embodiment, R ₁ is D; in another embodiment, R1 is halogen _; in another embodiment, R1 is -CN _; in another embodiment, R1 is _C1-6 alkyl _; in another embodiment In, R ₁ is C _1-6 alkoxy; In another embodiment, R ₁ is C _3-7 cycloalkyl; In another embodiment, R ₁ is 3- to 7-membered heterocyclyl; in In another embodiment, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, and 3- to 7-membered heterocyclyl in R ₁ are each independently optionally replaced by one or more substituted with a group selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy.

In another embodiment, R ₁ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein said C _{1- 6} alkyl, C _3-7 cycloalkyl and 3 to 7 membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkane In another embodiment, R ₁ is selected from H, D, halogen, C _{1-6 alkyl} , C _3-7 cycloalkyl or 3-7 membered Heterocyclyl, wherein said C _1-6 alkyl, C _3-7 cycloalkyl and 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; in another embodiment, R ₁ is selected from H, D or C _1-6 alkyl, wherein the The C _1-6 alkyl is optionally substituted with one or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; in In another embodiment, R ₁ is selected from H, D or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH or -NR group substitution of _a R _b ; in another embodiment, R ₁ is selected from H, D or C _1-6 alkyl; in another embodiment, R ₁ is selected from H, D, methyl, ethyl or isopropyl _; in another embodiment, R1 is selected from H, D or methyl _; in another embodiment, R1 is selected from H or methyl.

In another embodiment, R ₁ is selected from halogen, -CN, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl, wherein the The C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl and 3- to 7-membered heterocyclic groups are each independently optionally selected by one or more selected from D, halogen, -OH , -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; in another embodiment, R ₁ is selected from C _1-6 alkyl, C _1-6 alkoxy group, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl and 3- to 7-membered heterocyclic groups The cyclic groups are each independently optionally substituted with one or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; in another In embodiments, R ₁ is selected from C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _{1 -6} alkyl or C _1-6 alkoxy groups; in another embodiment, R ₁ is C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted by one or Multiple groups selected from D, halogen, -OH, -NR _a R _b are substituted; in another embodiment, R ₁ is C _1-6 alkyl; in another embodiment, R ₁ is selected from methyl radical, ethyl, or isopropyl; in another embodiment, R ₁ is methyl.

R ₂

In one embodiment, R ₂ is selected from H, D, 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, wherein said C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl, or C _1-6 alkoxy; or R ₂ and the attached The _double bonds together form a triple bond; in another embodiment, R2 is H; in another embodiment, R2 is D _; in another embodiment, R2 is halogen _; in another embodiment, R ₂ is -CN; in another embodiment, R ₂ is C _1-6 alkyl; in another embodiment, R ₂ is C _3-7 cycloalkyl; in another embodiment, R ₂ is 3- to 7-membered heterocyclyl; in another embodiment, R ₂ is C _6-10 aryl; in another embodiment, R ₂ is 5- to 10-membered heteroaryl; in another embodiment , C _1-6 alkyl group, C _3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C _6-10 -membered aryl group and 5- to 10-membered heteroaryl group in R ₂ are each independently optionally replaced by a or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy groups; in another embodiment, R ₂ and the attached Double bonds together form triple bonds.

In another embodiment, R ₂ is independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl, 3 to 7 membered heterocyclyl, C _6-10 aryl or a 5- to 10-membered heteroaryl group, wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C _6-10 -membered aryl group and 5- to 10-membered heteroaryl group groups are each independently optionally substituted with one or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; in another implementation In the scheme, R ₂ is independently selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally selected from one or more of D, halogen, -OH, - NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; in another embodiment, R ₂ is independently selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more groups selected from D, halogen, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; in In another embodiment, R ₂ is independently selected from H, D, halogen, or C _1-6 alkyl; in another embodiment, R ₂ is independently selected from H, D, F, Cl, or methyl.

_R3

In one embodiment, _R3 is selected from H, D, halogen, -CN, _C1-6 alkyl, _C3-7 cycloalkyl, 3 to 7 membered heterocyclyl, _C6-10 aryl or 5 to 10-membered heteroaryl, wherein said C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl, or 5- to 10-membered heteroaryl are each independently optionally substituted with one or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; in another embodiment, In another embodiment, _R3 is H; in another embodiment, _R3 is D; in another embodiment, _R3 is halogen; in another embodiment, _R3 is -CN; in another embodiment, R3 ₃ is C _1-6 alkyl; in another embodiment, R ₃ is C _3-7 cycloalkyl; in another embodiment, R ₃ is 3- to 7-membered heterocyclyl; in another embodiment In, R ₃ is C _6-10 aryl; In another embodiment, R ₃ is 5- to 10-membered heteroaryl; In another embodiment, R ₃ in C _1-6 alkyl, C _{3 -7} cycloalkyl, 3- to 7-membered heterocyclyl, _C6-10 -membered aryl, or 5- to 10-membered heteroaryl, each independently optionally by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substituted.

在另一个实施方案中，R₃为H。In another embodiment, _R 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, wherein said C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl or 5- to 10-membered heteroaryl are each independently optionally substituted with one or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; in another embodiment, R ₃ is selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl or 5- to 10-membered heteroaryl, wherein the C _{1- 6} alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 -membered aryl, or 5- to 10-membered heteroaryl are each independently optionally selected from D, halogen , -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; in another embodiment, R ₃ is selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl or 5- to 10-membered heteroaryl, wherein the C _1-6 alkyl, C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, C _6-10 aryl, or 5 to 10-membered heteroaryl, each independently optionally by one or more selected from D, halogen, -NR _a R _b or C _1-6 alkyl In another embodiment, _R is selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl, or 5- to 10-membered heteroaryl, wherein said C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl or 5- to 10-membered heteroaryl are each independently Optionally substituted with one or more groups selected from -NR _a R _b ; in another embodiment, R ₃ is selected from H or C _1-6 alkyl, wherein said C _1-6 alkyl is any optionally substituted with one or more groups selected from _-NRaRb ; in another embodiment, _R3 is selected from H, methyl, ethyl, _{-CH2N ( CH3} ) ₂ , _-CH2 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, _R3 is H.

R’

In one embodiment, R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein each of said C _1-6 alkyl and C _1-6 haloalkyl is independently optionally Substituted with one or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; in another embodiment, R' is H; In another embodiment, R' is C _1-6 alkyl; in another embodiment, R' is C _1-6 haloalkyl; in another embodiment, C _1-6 alkane in R' and C _1-6 haloalkyl are each independently optionally replaced by one or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group replaced.

In another embodiment, R' is selected from H or C _1-6 alkyl; in another embodiment, R' is selected from H, methyl, ethyl or isopropyl; in another embodiment, R' is selected from H or methyl.

m

In one embodiment, m is 0, 1, or 2; in another embodiment, m is 0; in another embodiment, m is 1; in another embodiment, m is 2.

n

In one embodiment, n is 1, 2, or 3; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3.

Any technical solution in any of the above specific embodiments or any combination thereof may be combined with any technical solution in other specific embodiments or any combination thereof. For example, any technical solution of ring A or any combination thereof can be combined with any technical solution of R, R ₁ to R ₃ , R′, X, Y, m, n and p or any combination thereof. The present invention is intended to include all the combinations of these technical solutions, and is not listed one by one due to space limitations.

In a more specific embodiment, the present invention relates to the compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It 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 compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It is a compound of the following general formula:

wherein each group is as defined above;

Preferably,

R ₁ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , Group substitution of C _1-6 alkyl or C _1-6 alkoxy;

R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy;

R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond;

R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy;

R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl;

Preferably,

R ₁ is C _1-6 alkyl, preferably methyl;

R' is H;

R ₂ is H;

_R3 is H.

In a more specific embodiment, the present invention relates to the compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It is a compound of the following general formula:

wherein each group is as defined above;

Preferably,

R ₁ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , Group substitution of C _1-6 alkyl or C _1-6 alkoxy;

R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; preferably, R' is selected from C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _{1 -6} alkyl and C _1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C _1-6 alkyl or C _1-6 alkoxy;

R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond;

R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy;

R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl;

Preferably,

R ₁ is C _1-6 alkyl, preferably methyl;

R' is H; or R' is selected from C _1-6 alkyl or C _1-6 haloalkyl;

R ₂ is H;

_R3 is H.

In a more specific embodiment, the present invention relates to the compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It 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 compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It is a compound of the following general formula:

wherein each group is as defined above;

Preferably,

R ₁ is selected from D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _{1 -6} alkyl group or C _1-6 alkoxy group substitution; preferably, R ₁ is S configuration; preferably, R ₁ is R configuration;

R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy;

R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond;

R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy;

R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl;

Preferably,

R ₁ is C _1-6 alkyl, preferably methyl; preferably, R ₁ is S configuration; preferably, R ₁ is R configuration;

R' is H;

R ₂ is H;

_R3 is H.

In a more specific embodiment, the present invention relates to the compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It is a compound of the following general formula:

wherein each group is as defined above;

Preferably,

R ₁ is selected from D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _{1 -6} alkyl or C _1-6 alkoxy group substitution;

R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; preferably, R' is selected from C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _{1 -6} alkyl and C _1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C _1-6 alkyl or C _1-6 alkoxy;

R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond;

R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy;

R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl;

Preferably,

R ₁ is C _1-6 alkyl, preferably methyl;

R' is H; or R' is selected from C _1-6 alkyl or C _1-6 haloalkyl;

R ₂ is H;

_R3 is H.

In a more specific embodiment, the present invention relates to the compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It 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 compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It is a compound of the following general formula:

wherein each group is as defined above;

Preferably,

R ₁ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , Group substitution of C _1-6 alkyl or C _1-6 alkoxy;

R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy;

R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond;

R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy;

R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl;

Preferably,

R ₁ is C _1-6 alkyl, preferably methyl;

R' is H;

R ₂ is H;

_R3 is H.

In a more specific embodiment, the present invention relates to the compounds described above, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, It is a compound of the following general formula:

wherein each group is as defined above;

Preferably,

R ₁ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , Group substitution of C _1-6 alkyl or C _1-6 alkoxy;

R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; preferably, R' is selected from C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _{1 -6} alkyl and C _1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C _1-6 alkyl or C _1-6 alkoxy;

R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond;

R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy;

R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl;

The condition is that R ₁ is not H;

Preferably,

R ₁ is C _1-6 alkyl, preferably methyl;

R' is H; or R' is selected from C _1-6 alkyl or C _1-6 haloalkyl;

R ₂ is H;

_R3 is H.

In a more specific embodiment, the present invention relates to compounds selected from the group consisting of tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof :

The compounds of the present invention may contain one or more asymmetric centers, and thus may exist in various stereoisomeric, eg, enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (eg, cis and trans isomers), or may be in the form of a mixture of stereoisomers, Include racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferred isomers can be separated by prepared by asymmetric synthesis.

"Tautomer" means that one functional group in some compounds changes its structure into another functional group isomer, and can rapidly convert into each other, becoming two isomers in dynamic equilibrium, and the two isomers are in dynamic equilibrium. isomers are called tautomers.

Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

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

The term "hydrate" refers to a compound that is combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general formula R×xH ₂ O, where R is the compound and x is a number greater than zero. A given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R x 0.5H2 ₎ O)) and polyhydrates (x is a number greater than 1, eg, dihydrate ( _Rx2H2O ) and hexahydrate ( _Rx6H2O )).

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

The present invention also includes isotopically-labeled compounds that are equivalent to those described in formula (I), but with one or more atoms replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of ^hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, ^3H , ^13C , ^11C , ^14C , ^15N , ¹⁸ , respectively O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, such as those into which radioactive isotopes (eg, ^{3H and14C} ) have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium, ie ³ H, and carbon-14, ie ¹⁴ C isotopes are particularly preferred because of their ease of preparation and detection. Furthermore, substitution with heavier isotopes, such as deuterium, ie, 2H, may be preferred in some circumstances because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half ^- life or reduced dosage requirements. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in carrying out the processes disclosed in the following Schemes and/or Examples and Preparations labeled reagents.

Furthermore, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo to its active form having a medical effect by, for example, hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, 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 limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each incorporated herein as refer to.

A prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include, for example, compounds of the present invention wherein a hydroxyl, amino or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxy, sulfhydryl and amino functional groups of compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. The esters themselves may be active and/or hydrolyzable under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups which are readily cleaved in humans to release the parent acid or salt thereof.

treat

The present invention provides a method of treating and/or preventing a disease, such as mutated EGFR kinase-mediated cancer, in a subject, comprising administering to said subject a compound of the present invention or a tautomer thereof, Stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutical compositions of the present invention.

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

In specific embodiments, the mutated EGFR has a T790M mutation and has a mutation 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.

As used herein, "EGFR" refers to the human epidermal growth factor receptor protein and is referred to as ErbB-1 or HER1.

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

As used herein, "exon 20 insertion mutation" refers to a region in which one or more amino acids (preferably 1 to 7, more preferably 1 to 4) are inserted into the exon 20 region of EGFR (eg amino acids 761 to 823) sequence); preferably, a mutation in which the amino acid sequence FQEA (in the order phenylalanine, glutamine, glutamic acid and alanine from the N-terminus) is inserted at position 763 in the exon 20 region Mutation between alanine and tyrosine 764 (A763_Y764insFQEA); preferably, a mutation in which the amino acid sequence ASV (in the order alanine, serine and valine from the N-terminus) is inserted into an exon A mutation between valine 769 and aspartic acid 770 in region 20 (V769_D770insASV); preferably, a mutation in which the amino acid sequence SVD (starting from the N-terminus with serine, valine and aspartic acid) This sequence) inserts a mutation between aspartate 770 and asparagine 771 in the exon 20 region (D770_N771insSVD); preferably, a mutation in which the amino acid sequence NPG (starting from the N-terminus with asparagine) amide, proline and glycine in this sequence) into a mutation in the exon 20 region between aspartic acid 770 and asparagine 771 (D770_N771insNPG); preferably, a mutation in which the amino acid G (glycine ) a mutation inserted between aspartic acid at position 770 and asparagine at position 771 (D770_N771insG); preferably, a mutation in which aspartic acid at position 770 in the exon 20 region is deleted, and the amino acid is inserted thereby Mutation (D770>GY) of the sequence GY (in the order of glycine and tyrosine from the N-terminus); preferably, a mutation in which the amino acid N (asparagine) is inserted into aspart 771 in the exon 20 region Mutation between amide and proline at position 772 (N771_P772insN); preferably, a mutation in which the amino acid sequence PR (in the order of proline and arginine from the N-terminus) is inserted in the exon 20 region Mutation between proline 772 and histidine 773 (P772_R773insPR); preferably, a mutation in which the amino acid sequence is NPH (in the order of asparagine, proline and histidine from the N-terminus) A mutation inserted between histidine 773 and valine 774 in the exon 20 region (H773_V774insNPH); preferably, a mutation in which the amino acid sequence PH (starting from the N-terminus with proline and histidine) This sequence) inserts a mutation between histidine 773 and valine 774 in the exon 20 region (H773_V774insPH); and histidine in this order) into a mutation in exon 20 region between histidine 773 and valine 774 (H773_V774insAH); preferably, a mutation in which the amino A mutation in which acid H (histidine) is inserted between histidine 773 and valine 774 in the exon 20 region (H773_V774insH); preferably, a mutation in which the amino acid sequence HV (from the N-terminus to The sequence of histidine and valine) is inserted into a mutation between valine 774 and cysteine 775 in the exon 20 region (V774_C774insHV); preferably, a mutation in which the amino acid sequence EAFQ ( A mutation in the exon 20 region between alanine 761 and glutamic acid 762 (in the order glutamic acid, alanine, phenylalanine and glutamine) inserted from the N-terminus ( A761_E762insEAFQ). More preferably, the mutation is one in which the amino acid sequence ASV (in the order alanine, serine and valine from the N-terminus) is inserted into the exon 20 region as valine 769 and aspartic acid 770 A mutation between (V769_D770insASV); more preferably, a mutation in which the amino acid sequence SVD (in the order of serine, valine and aspartic acid from the N-terminus) is inserted into aspart 770 in the exon 20 region A mutation between amino acid and asparagine at position 771 (D770_N771insSVD); more preferably, a mutation in which the amino acid G (glycine) is inserted into aspartic acid at position 770 and asparagine at position 771 in the exon 20 region A mutation between (D770_N771insG); more preferably, a mutation in which the amino acid sequence NPH (in the order of asparagine, proline and histidine from the N-terminus) is inserted into group 773 in the exon 20 region A mutation between amino acid and valine at position 774 (H773_V774insNPH); more preferably, a mutation in which the amino acid sequence PH (in the order of proline and histidine from the N-terminus) is inserted into the exon 20 region A mutation between histidine 773 and valine 774 (H773_V774insPH) in sequence) a mutation inserted between aspartic acid 770 and aspartic acid 771 in the exon 20 region (D770_N771insSVD); more preferably, a mutation in which the amino acid G (glycine) is inserted into the exon 20 region Mutation between aspartic acid at position 770 and asparagine at position 771 (D770_N771insG).

Herein, "a cancer patient expressing EGFR with exon 20 insertion mutation" refers to a cancer patient 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. Furthermore, EGFR may also have mutations other than exon 20 insertion mutations (eg, exon 19 deletion mutations, L858R mutations, or T790M mutations).

In the present invention, the method for detecting the expression of EGFR exon 20 insertion mutation in cancer patients is not particularly limited as long as the method can detect the mutation, and any known detection method can be used. The detection target for detecting the exon 20 insertion mutation 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 used for detection of exon 20 insertion mutation is not particularly limited as long as the sample is a biological sample isolated from a cancer patient, particularly a sample obtained from a cancer patient and containing malignant tumor cells. Examples of biological samples include body fluids (eg, blood, urine, etc.), tissues, extracts thereof, and cultures from which tissues are obtained. The method of separating the biological sample can be appropriately selected according to the type of the biological sample.

Biological samples are prepared by appropriate processing according to the detection method. In addition, reagents for detection (eg, reagents containing primers or probes) can be prepared by conventional methods according to the detection method.

In one embodiment of the invention, the step of detecting the presence of an exon 20 insertion mutation of EGFR expressed in a patient with malignancy may be performed prior to administering an anti-tumor agent to the patient with cancer.

As used herein, "exon 18 point mutation" refers to 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 1 amino acid is substituted in the exon 18 region; more preferably, the mutation is a point mutation in exon 18 where the histidine encoded by codon 709 has been replaced by any amino acid A mutation (ie, E790X), and a point mutation in which the glutamic acid encoded by codon 719 in exon 18 has been replaced by any amino acid (ie, G719X). Specifically, E790X can be, for example, a point mutation in which the glutamic acid encoded by codon 709 in the exon 18 region has been replaced by a lysine (ie, E709K), and a point mutation in the exon 18 region encoded by codon 709 A point mutation in which glutamic acid has been replaced by alanine (ie, E709A). G719X can be, for example, a point mutation in the exon 18 region where the glycine encoded by codon 719 has been replaced by alanine (ie G719A), and the point in the exon 18 region where the glycine encoded by codon 719 has been replaced by serine The mutation (ie, G719S), and the point mutation in which the glycine encoded by codon 719 in the exon 18 region has been replaced by a cysteine (ie, G719C), of which G719A is the most common.

As used herein, "exon 21" refers to the region 824-875 in the amino acid sequence of wild-type EGFR.

As used herein, "exon 21 point mutation" refers to a point mutation in an amino acid in the exon 21 region of wild-type EGFR. Preferably, the point mutation in exon 21 is a point mutation in which 1 amino acid is substituted in the exon 21 region; more preferably, the point mutation in exon 21 is leucine encoded by codon 861 in the exon 21 region A point mutation in which the acid has been replaced by any amino acid (ie, L861X), eg, a point mutation in which the leucine encoded by codon 861 in the exon 21 region has been replaced by glutamine (ie, L861Q).

As used herein, "exon 18 mutant EGFR" means EGFR having at least one exon 18 mutation; preferably the EGFR means having two or more relevant exon 18 mutations; more preferably, the EGFR EGFR is indicated with 1 exon 18 point mutation. In addition, the EGFR may also have other mutations other than exon 18 point mutation (eg, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).

As used herein, "exon 21 mutant EGFR" refers to EGFR having at least one exon 21 mutation; preferably, the EGFR refers to having two or more relevant exon 21 mutations; more preferably, the EGFR EGFR is indicated with 1 exon 21 point mutation. In addition, the EGFR may have other mutations other than the exon 21 point mutation (eg, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).

In a specific embodiment, the mutated EGFR has a T790M mutation and has a mutation 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, in the present invention, there is a T790M mutation and is selected from exon 18 point mutant EGFR, exon 21 point mutant EGFR is any one of the following: has a T790M mutation and has an exon 18 region E709X and /or G719X mutant EGFR; with T790M mutation and with L861X mutant EGFR in exon 21 region. Specifically, it is any one of the following: having T790M mutation and having E709K or E709A mutant EGFR; having T790M mutation and having G719A, G719S or G719C mutant EGFR; having T790M mutation and having L861Q mutant EGFR; wherein, having T790M Mutated EGFR with G719A and with T790M mutation with L861Q mutation is more common.

Herein, the detection method for the point mutation of exon 18 and/or exon 21 in the EGFR expressed by the cancer patient can be used as long as the above mutation can be detected, and a known detection method can be used.

The sample used for detection of exon 18 and/or exon 21 point mutation 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 (eg, blood, urine, etc.), tissues, extracts thereof, and cultures from which tissues are obtained. The method of separating the biological sample can be appropriately selected according to the type of the biological sample.

Biological samples are prepared by appropriate processing according to the detection method. In addition, reagents for detection (eg, reagents containing primers or probes) can be prepared by conventional methods according to the detection method.

In one embodiment of the invention, the step of detecting the presence of a point mutation in exon 18 and/or exon 21 expressed in a patient with malignancy may be performed prior to administering an antineoplastic agent to the patient with cancer.

Specific examples of mutated EGFR kinase-mediated tumors in the present invention include, but are not limited to, head and neck cancer, gastrointestinal cancer (esophageal, gastric, duodenal, liver, cholangiocarcinoma (eg, gallbladder and bile duct cancer), pancreas cancer, colorectal cancer (eg, colon and rectal cancer), etc.), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancer (eg, ovarian cancer, uterine cancer (eg, breast cancer) cervical cancer and endometrial cancer), etc.), urinary tract cancer (eg, kidney cancer, bladder cancer, prostate cancer, and testicular cancer), hematopoietic system tumors (eg, 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 mutated EGFR is selected from exon 20 insertion mutant EGFR, exon 18 mutant EGFR, exon 21 mutant EGFR, exon 19 deletion mutant EGFR or L858R mutant EGFR.

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

The present invention also provides a method for treating a tumor patient, comprising adding a mutation to an expression 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 The step of administering an effective amount of an anti-tumor agent comprising a 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 for use in the treatment of an expression having a mutation selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, and exon 21 point mutant EGFR , Exon 19 deletion mutant EGFR or L858R mutant EGFR tumor patients.

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

The present invention also provides a method for predicting the therapeutic effect of using an anti-tumor agent in a tumor patient, the anti-tumor agent being a 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) a step of detecting the presence or absence of a mutation in the EGFR gene contained in a biological sample obtained from a patient; and

(2) When the detection 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, Predicting steps that chemotherapy has a high probability of showing adequate therapeutic effect in patients.

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

(1) the step of detecting the presence or absence of the mutation of the EGFR gene contained in the biological sample obtained from the patient;

(2) When the detection 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 of treating the patient with a compound of the present invention or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating and/or preventing a disease, such as a wild-type and/or mutated HER2 kinase mediated tumor in a subject, comprising administering to the subject the present invention Compounds of the present invention or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions of the present invention.

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

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

In the present invention, the HER2 kinase-mediated tumor is preferably a tumor with HER2 overexpression, HER2 gene amplification or HER2 mutation. The above-mentioned "tumor" is not particularly limited, for example, it may be head and neck cancer, esophagus cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder-cholangiocarcinoma, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, and 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. Breast cancer, gastric cancer, esophageal cancer, ovarian cancer, lung cancer, esophageal cancer, gallbladder-cholangiocarcinoma, biliary tract cancer, bladder cancer, colon cancer are preferred, and breast cancer, gastric cancer, esophageal cancer, biliary tract cancer, ovarian cancer, lung cancer, esophageal cancer are more preferred Cancer, more preferably breast cancer, gastric cancer, and lung cancer.

In the treatment methods of the present invention, an "effective amount" refers to an amount or dose sufficient to produce the desired therapeutic benefit in an individual in need of such treatment. An effective amount or dosage of a compound of the invention can be determined by conventional methods (eg, modeling, dose escalation, or clinical trials) and by conventional factors (eg, mode or route of drug delivery, pharmacokinetics of the agent, severity and course of infection, individual health status and weight, and the judgment of the treating physician). 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 (eg, BID, TID, QID).

After the patient's disease has improved, the dose can be adjusted for prophylactic or maintenance therapy. For example, the dose or frequency of administration, or both, can be reduced to an amount that maintains the desired therapeutic or prophylactic effect, depending on symptoms. Of course, treatment can be discontinued if symptoms have been reduced to an appropriate level. However, when either symptom recurs, patients may require intermittent treatment on a long-term basis. Patients may also require long-term slow treatment.

Pharmaceutical compositions, formulations and kits

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

A pharmaceutically acceptable excipient for use 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 compositions 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 phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block segment polymers, polyethylene glycol, and lanolin.

The present invention also includes kits (eg, pharmaceutical packages). Provided kits can include a compound of the present invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packs or other) containing the compounds of the present invention, other therapeutic agents. suitable container). In some embodiments, provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the present invention and/or other therapeutic agent. In some embodiments, a compound of the present invention and other therapeutic agent provided in a first container and a second container are combined to form one unit dosage form.

The pharmaceutical compositions 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 , intrameningeal administration, intralesional administration, and intracranial injection or infusion techniques.

Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by the physician depending on the 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. .

When used to prevent the disorders of the present invention, the compounds provided herein are administered to subjects at risk of developing the disorders, typically on the advice and supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular disorder typically include subjects with a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.

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

Various methods of administration can be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus injection, eg, 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, eg, intramuscular or subcutaneous bolus doses provide slow release of the active ingredient, whereas boluses delivered directly into the vein (eg, by IV infusion) can be more effective. It is delivered rapidly, resulting in a rapid increase in the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the body of the subject. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.

Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the compositions are presented in unit dosage form for ease of precise dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, and the like. In such compositions, the compound will generally be the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.

For oral doses, a typical regimen is one to five oral doses, especially two to four oral doses, typically three oral doses per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg/kg of a compound of the 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 blood levels similar to, or lower than, the use of injectable doses, transdermal doses are typically selected in amounts of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, 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, injection dose levels are in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered. For human patients of 40 to 80 kg, the maximum total dose cannot exceed approximately 2 g/day.

Liquid forms suitable for oral administration can include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds of similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or cornstarch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl cylate or orange flavoring.

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

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.

The compounds of the present invention may also be administered by transdermal devices. Thus, transdermal administration can be accomplished using reservoir or porous membrane types, or patches of various solid matrices.

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

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

The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally include a or more substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, a sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).

drug combination

The compounds of the invention described herein may be used in combination with one or more other active ingredients in pharmaceutical compositions or methods for the treatment of the diseases and disorders described herein. Other additional active ingredients include other therapeutic agents or agents that moderate the adverse effects of the treatment against 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 dose of a compound of the present invention. The additional active ingredients may be formulated in separate pharmaceutical compositions from the compounds of the present invention or may be included with the compounds of the present invention in a single pharmaceutical composition. The additional active ingredient may be administered concurrently with, prior to or subsequent to administration of the compounds of the present invention.

Combination agents include those active ingredients known or observed to be effective in treating the diseases and disorders described herein, including those effective against another target associated with the disease. For example, the compositions and formulations, and methods of treatment of the present invention may further comprise other drugs, such as other agents useful in the treatment or amelioration of the target disease or associated symptoms or conditions. For cancer indications, such other agents include, but are not limited to, kinase inhibitors such as EGFR inhibitors (eg, erlotinib, gefitinib); Raf inhibitors (eg, Verotinib) vemurafenib), VEGFR inhibitors (eg, sunitinib); standard chemotherapeutics such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs , mitotic inhibitors, antibodies, hormone therapy, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory agents such as NSAIDs. Pharmaceutical compositions of the present invention may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.

Example

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples 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 suggested by the manufacturer. Parts and percentages are by weight unless otherwise indicated.

Usually, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (eg, 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.

Abbreviations used herein have the following meanings:

POCl ₃ : Phosphorus oxychloride

DMF: N,N-Dimethylformamide

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

Pd(OAc) ₂ : palladium acetate

NBS: N-bromosuccinimide

TEA: Triethylamine

TFA: trifluoroacetic acid

Na ₂ CO ₃ : sodium carbonate

MeOH: methanol

EtOH: Ethanol

DCM: dichloromethane

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

Dioxane: Dioxane

(Boc) ₂ O: di-tert-butyl dicarbonate

NaHMDS: sodium bis(trimethylsilyl)amide

PPh ₃ : triphenylphosphine

Bu ₄ NOAc: tetrabutylammonium acetate

In: indium powder

Ti(OEt) ₄ : tetraethyl titanate

Allyl bromide: 3-bromopropene

Example 1 N-(4-Amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1,6-a] Preparation of indol-8-yl)acrylamide (compound T-1).

The following synthetic route was used:

Step 1. Synthesis of compound 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde

Pyrrolo[2,1-f][1,2,4]triazin-4-amine (10 g, 74.6 mmol) was dissolved in 150 mL of DMF, and 35 mL of phosphorus oxychloride was added dropwise under ice bath, and the temperature was raised to The reaction was carried out at 60°C overnight. After the reaction was completed, the reaction solution was slowly added to ice water, stirred at room temperature for 30 minutes, adjusted to pH 8-9 with 4N NaOH solution, extracted with ethyl acetate (150 mL*3), the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. , concentrated to obtain 8.65g of pale yellow solid, yield 71.5%. ESI-MS: m/z=163 [M ⁺ +1].

Step 2. Synthesis of compound 4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde

4-Aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (8.65 g, 53.4 mmol) was dissolved in 100 mL of tetrahydrofuran, cooled to -20 °C in an ice bath, and two Bromohydantoin (9.15 g, 32 mmol) was naturally warmed to room temperature after the addition and reacted overnight. 200 mL of water was added to the reaction solution, stirred at room temperature for 30 minutes, filtered, and the filter cake was washed with water, and dried to obtain 8.78 g of a pale yellow solid with a yield of 68%. ESI-MS: m/z=243[M ⁺ +2].

Step 3. Synthesis of compound 4-amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde

4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (8.78 g, 36.3 mmol), (quinolin-3-yl)boronic acid (7.54 g , 43.6 mmol), Pd(dppf)Cl ₂ (0.8 g, 1.09 mmol) and sodium carbonate (11.55 g, 109 mmol) were added to 150 mL of dioxane and 50 mL of water, nitrogen was replaced three times, and the temperature was raised to 100 ° C for 4 hours. TLC detected that the reaction was complete, the reaction solution was rotary evaporated to remove the solvent, 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, and concentrated to obtain 6.5 g of a pale yellow solid , the yield is 62%. ESI-MS: m/z=290[M ⁺ +1].

Step 4. Compound (E)-7-(2-Methoxyvinyl)-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4 -Synthesis of amines

(Methoxymethyl)triphenylphosphine chloride (15.3 g, 44.6 mmol) was dissolved in 100 mL of tetrahydrofuran, and NaHMDS (22 mL, 44 mmol, 2 mol/L of THF solution) was slowly added dropwise at 0 °C, and the addition was completed and continued The reaction was carried out at 0 °C for 30 minutes, and 4-amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (6.44 g, 22.3 g) was slowly added dropwise. mmol) in tetrahydrofuran (20 mL), the ice bath was removed after the dropwise addition, and the reaction was carried out at room temperature for 3 hours. TLC detected that the reaction was complete, the solvent was evaporated by rotary evaporation, 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, and concentrated to obtain a brown solid. The solid was added to 30 mL of ethyl acetate, slurried at room temperature overnight, filtered and dried to obtain 5.01 g of a pale yellow solid with a yield of 71%. ESI-MS: m/z=318[M ⁺ +1].

Step 5. Synthesis of compound 2-(4-amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)acetaldehyde

(E)-7-(2-methoxyvinyl)-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine ( 5.01 g, 15.8 mmol) was dissolved in 60 mL of tetrahydrofuran, 2N hydrochloric acid (20 mL) was added dropwise under an ice bath, and the temperature was raised to 70° C. for 2 hours after the dropwise addition. The reaction solution was cooled to room temperature, diluted with 100 mL of water, adjusted to pH 8-9 with 2N NaOH solution, extracted with ethyl acetate (60 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to 3.64 g of pale yellow solid were obtained by silica gel column separation, and the yield was 76%. ESI-MS: m/z=304 [M ⁺ +1].

Step 6. Compound N-(1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pentan-4 Synthesis of -en-2-yl)-2-methylpropane-2-sulfinamide

2-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)acetaldehyde (3.64 g, 12 mmol), Tert-butylsulfinamide (2.18 g, 18 mmol) and indium powder (2.07 g, 18 mmol) were dissolved in 40 mL of tetrahydrofuran, and tetraethyl titanate (5.47 g, 24 mmol) was slowly added dropwise at 0 °C. The reaction was carried out at room temperature for 2 hours. The reaction solution was moved to an ice bath, 3-bromopropene (3.23 g, 26.7 mmol) was slowly added dropwise, the ice bath was removed after the dropwise addition was completed, and the reaction was performed at 60° C. overnight. TLC detected that the reaction was complete, the reaction solution was diluted with 120 mL of water and 50 mL of ethyl acetate, filtered through celite, the aqueous phase was extracted with ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. , concentrated, and separated by silica gel column to obtain 1.61 g of pale yellow solid with a yield of 30%. ESI-MS: m/z = 449 [M ⁺ +1].

Step 7. Compound (1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pent-4-ene Synthesis of -2-yl) tert-butyl carbamate

N-(1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pent-4-ene- 2-yl)-2-methylpropane-2-sulfinamide (1.39 g, 3.1 mmol) was dissolved in 15 mL of methanol, 7M methanolic hydrogen chloride solution (2.2 mL, 15.3 mmol) was slowly added dropwise at 0°C, and the addition was completed and continued The reaction was carried out at 0°C for 1 hour, the solvent was evaporated by rotary evaporation, the residue was dissolved in 20 mL of dichloromethane, triethylamine (0.94 g, 9.3 mmol) was added, and (Boc) ₂ O (0.81 g, 3.7 mmol) was added dropwise under an ice bath. ), the dropwise addition was completed and the reaction was raised to room temperature overnight. TLC detected that the reaction was complete, the reaction solution was concentrated, and separated on a silica gel column to obtain 1.1 g of a pale yellow solid with a yield of 80%. ESI-MS: m/z=445[M ⁺ +1].

Step 8. Compound (1-(4-Amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pentan Synthesis of tert-butyl-4-en-2-yl)carbamate

(1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pent-4-en-2- tert-butyl)carbamate (400 mg, 0.9 mmol) was dissolved in 10 mL of DMF, NBS (170 mg, 0.95 mmol) was added in portions at 0°C, and the reaction was continued at 0°C for 2 hours after the addition was completed. The reaction solution was diluted with 30 mL of water, extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 390 mg of a pale yellow solid with a yield of 83%. ESI-MS: m/z=525 [M ⁺ +2].

Step 9. Compound (4-amino-6-methylene-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1, Synthesis of tert-butyl 6-a]indol-8-yl)carbamate

(1-(4-Amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pentan-4- tert-Butyl en-2-yl)carbamate (390 mg, 0.74 mmol), tetrabutylammonium acetate (362 mg, 1.2 mmol), palladium acetate (9 mg, 0.04 mmol) and triphenylphosphine (39 mg, 0.15 mmol) were added In 10 mL of tetrahydrofuran, nitrogen was replaced three times, and the temperature was raised to 90° C. to react for 8 hours. TLC detected that the reaction was complete, the reaction solution was concentrated and separated by silica gel column to obtain 280 mg of pale yellow solid with a yield of 85%. ESI-MS: m/z = 443 [M ⁺ +1].

Step 10. Compound 6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1,6-a]indole-4,8 -Synthesis of diamines

(4-amino-6-methylene-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6-a ] tert-butyl indol-8-yl)carbamate (280 mg, 0.63 mmol) was dissolved in 5 mL of ethanol and 1 mL of 4N hydrochloric acid, and the reaction was refluxed overnight. 1 mL of 4N hydrochloric acid was added, and the reflux reaction was continued for 6 hours. TLC detected that the reaction was basically complete, diluted with 20 mL of water, adjusted the pH to 8-9 with saturated sodium carbonate solution, extracted with ethyl acetate (20 mL*3), washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain Light yellow solid 152 mg, yield 70%. ESI-MS: m/z=343 [M ⁺ +2].

Step 11. Compound N-(4-Amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1,6-a Synthesis of ]indol-8-yl)acrylamide

6-Methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1,6-a]indole-4,8-diamine (152 mg, 0.44 mmol) and triethylamine (114 mg, 0.88 mmol) were dissolved in 10 mL of dichloromethane, cooled to -20°C on an ice bath, slowly added dropwise acryloyl chloride (40 mg, 0.44 mmol), and continued at -20 The reaction was carried out at ℃ for 1 hour, diluted with 10 mL of water, extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 120 mg of a pale yellow solid with a yield of 68%. . ESI-MS: m/z=397[M ⁺ +1]. ¹ H NMR (300MHz, CCl ₃ D) δ 9.05–8.97(m, 1H), 8.27(s, 1H), 8.20(d, J= 8.5Hz, 1H), 7.94–7.77 (m, 3H), 7.66 (t, J=7.6Hz, 1H), 6.31 (d, J=16.9Hz, 1H), 6.04 (ddd, J=16.6, 10.1, 6.0 Hz,1H),5.90(dd,J＝24.5,8.1Hz,1H),5.64(d,J＝10.2Hz,1H),5.60–5.54(m,1H),5.00(d,J＝23.5Hz,3H) ), 3.33(q, J=4.2Hz, 2H), 1.55(s, 3H).

Example 2(R)-N-(4-Amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1, Preparation of 6-a]indol-8-yl)acrylamide (compound T-1-a).

100mg of racemic compound T-1 was dissolved in methanol solution, and the target product T-1-a (retention time: 21.22min, relative content: 40.3%). ¹ H NMR (300MHz, CCl ₃ D) δ 9.05-8.97 (m, 1H), 8.27 (s, 1H), 8.20 (d, J=8.5Hz, 1H), 7.94-7.77 (m, 3H), 7.66 (t, J=7.6Hz, 1H), 6.31 (d, J=16.9Hz, 1H), 6.04 (ddd, J=16.6, 10.1, 6.0Hz, 1H), 5.90 (dd, J=24.5, 8.1Hz, 1H), 5.64(d, J＝10.2Hz, 1H), 5.60–5.54(m, 1H), 5.00(d, J＝23.5Hz, 3H), 3.33(q, J＝4.2Hz, 2H), 1.55( s, 3H).

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

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: dichloromethane:methanol:ethanol (0.1% diethylamine) = 60:30:10

Retention time: 21.22min.

Example 3 (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1, Preparation of 6-a]indol-8-yl)acrylamide (compound T-1-b).

100mg of racemic compound T-1 was dissolved in methanol solution, and the target product T-1-b (retention time: 26.82min, relative content: 54.6%). ¹ H NMR (300MHz, CCl ₃ D) δ 9.05-8.97 (m, 1H), 8.27 (s, 1H), 8.20 (d, J=8.5Hz, 1H), 7.94-7.77 (m, 3H), 7.66 (t, J=7.6Hz, 1H), 6.31 (d, J=16.9Hz, 1H), 6.04 (ddd, J=16.6, 10.1, 6.0Hz, 1H), 5.90 (dd, J=24.5, 8.1Hz, 1H), 5.64(d, J＝10.2Hz, 1H), 5.60–5.54(m, 1H), 5.00(d, J＝23.5Hz, 3H), 3.33(q, J＝4.2Hz, 2H), 1.55( s, 3H).

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

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: dichloromethane:methanol:ethanol (0.1% diethylamine) = 60:30:10

Retention time: 26.82min.

Example 4 N-(4-Amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1, Preparation of 6-a]indol-8-yl)acrylamide (compound T-2).

The following synthetic route was used:

Step 1. Compound (4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6 Synthesis of tert-butyl -a]indol-8-yl)carbamate

(4-amino-6-methylene-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6-a ] tert-butyl indol-8-yl)carbamate (305 mg, 0.69 mmol) was dissolved in 15 mL of methanol, 50 mg of 10% palladium/carbon was added, hydrogen was replaced three times, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere of 1 atmosphere. After the reaction was completed, the palladium/carbon was filtered off, the filtrate was concentrated, and purified by column chromatography to obtain 250 mg of a pale yellow solid with a yield of 82%. ESI-MS: m/z=445 [M ⁺ +1].

Step 2. Compound 6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6-a]indole Synthesis of -4,8-diamine

(4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6-a] Indol-8-yl) tert-butyl carbamate (250 mg, 0.56 mmol) was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 hours. TLC detected that the reaction was complete, the solvent was evaporated by rotary evaporation, diluted with 20 mL of water, adjusted to pH 8-9 with saturated sodium carbonate solution, extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine, and anhydrous sodium sulfate It was dried and concentrated to obtain 134 mg of pale yellow solid with a yield of 70%. ESI-MS: m/z=345 [M ⁺ +2].

Step 3. Compound N-(4-Amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1 Synthesis of ,6-a]indol-8-yl)acrylamide

6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6-a]indole-4, 8-Diamine (134 mg, 0.39 mmol) and triethylamine (79 mg, 0.78 mmol) were dissolved in 10 mL of dichloromethane, cooled to -20°C in an ice bath, and slowly added dropwise acryloyl chloride (35 mg, 0.39 mmol), the dropwise addition was complete Continue to react at -20 °C for 1 hour, add 10 mL of water to dilute, extract with dichloromethane (10 mL*3), wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by silica gel column to obtain 100 mg of pale yellow solid , the yield is 65%. ESI-MS: m/z=399 [M ⁺ +1]. ¹ H NMR (400 MHz, CCl ₃ D) δ 9.02 (d, J=2.2 Hz, 1H), 8.25–8.14 (m, 2H), 7.94 –7.85(m,2H),7.80(ddd,J=8.4,6.8,1.4Hz,1H),7.65(t,J=7.5Hz,1H),6.33(dd,J=17.0,1.4Hz,1H), 6.13(dd,J＝16.9,10.3Hz,1H),5.77(d,J＝8.1Hz,1H),5.68(dd,J＝10.2,1.4Hz,1H),5.11(s,2H),4.48(s ,1H),3.55(dd,J＝15.9,5.5Hz,1H),3.34(s,1H),2.68(ddd,J＝16.0,10.5,1.5Hz,1H),2.29(s,1H),1.48– 1.37(m,1H),0.79(d,J=6.7Hz,3H).

Example 5(6S,8R)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4] Preparation of triazino[1,6-a]indol-8-yl)acrylamide (compound T-2-a).

100mg of racemate compound T-2 was dissolved in methanol solution, and the target product T-2-a (retention time: 22.013min, relative content: 22.9%). ¹ H NMR (400MHz, CCl ₃ D) δ 9.02 (d, J=2.2Hz, 1H), 8.25-8.14 (m, 2H), 7.94-7.85 (m, 2H), 7.80 (ddd, J=8.4, 6.8, 1.4Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 6.33 (dd, J=17.0, 1.4Hz, 1H), 6.13 (dd, J=16.9, 10.3Hz, 1H), 5.77 ( d, J＝8.1Hz, 1H), 5.68(dd, J＝10.2, 1.4Hz, 1H), 5.11(s, 2H), 4.48(s, 1H), 3.55(dd, J＝15.9, 5.5Hz, 1H ), 3.34(s, 1H), 2.68(ddd, J=16.0, 10.5, 1.5Hz, 1H), 2.29(s, 1H), 1.48–1.37(m, 1H), 0.79(d, J=6.7Hz, 3H).

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

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: MTBE: n-hexane: methanol: ethanol (0.1% triethylamine) = 45:42:5:8

Retention time: 22.013min.

Example 6(6R,8R)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4] Preparation of triazino[1,6-a]indol-8-yl)acrylamide (compound T-2-b).

100mg of racemic compound T-2 was dissolved in methanol solution, and the target product T-2-b (retention time: 24.560min, relative content: 25.4%). ¹ H NMR (400MHz, CCl ₃ D) δ 9.02 (d, J=2.2Hz, 1H), 8.25-8.14 (m, 2H), 7.94-7.85 (m, 2H), 7.80 (ddd, J=8.4, 6.8, 1.4Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 6.33 (dd, J=17.0, 1.4Hz, 1H), 6.13 (dd, J=16.9, 10.3Hz, 1H), 5.77 ( d, J＝8.1Hz, 1H), 5.68(dd, J＝10.2, 1.4Hz, 1H), 5.11(s, 2H), 4.48(s, 1H), 3.55(dd, J＝15.9, 5.5Hz, 1H ), 3.34(s, 1H), 2.68(ddd, J=16.0, 10.5, 1.5Hz, 1H), 2.29(s, 1H), 1.48–1.37(m, 1H), 0.79(d, J=6.7Hz, 3H).

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

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: MTBE: n-hexane: methanol: ethanol (0.1% triethylamine) = 45:42:5:8

Retention time: 24.560min.

Example 7(6R,8S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4] Preparation of triazino[1,6-a]indol-8-yl)acrylamide (compound T-2-c).

100mg of racemic compound T-2 was dissolved in methanol solution, and the target product T-2-c (retention time: 28.840min, relative content: 18.5%). ¹ H NMR (400MHz, CCl ₃ D) δ 9.02 (d, J=2.2Hz, 1H), 8.25-8.14 (m, 2H), 7.94-7.85 (m, 2H), 7.80 (ddd, J=8.4, 6.8, 1.4Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 6.33 (dd, J=17.0, 1.4Hz, 1H), 6.13 (dd, J=16.9, 10.3Hz, 1H), 5.77 ( d, J＝8.1Hz, 1H), 5.68(dd, J＝10.2, 1.4Hz, 1H), 5.11(s, 2H), 4.48(s, 1H), 3.55(dd, J＝15.9, 5.5Hz, 1H ), 3.34(s, 1H), 2.68(ddd, J=16.0, 10.5, 1.5Hz, 1H), 2.29(s, 1H), 1.48–1.37(m, 1H), 0.79(d, J=6.7Hz, 3H).

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

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: MTBE: n-hexane: methanol: ethanol (0.1% triethylamine) = 45:42:5:8

Retention time: 28.840min.

Example 8(6S,8S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4] Preparation of triazino[1,6-a]indol-8-yl)acrylamides (compound T-2-d).

100mg of racemic compound T-2 was dissolved in methanol solution, and the target product T-2-d (retention time: 39.140min, relative content: 20.1%). ¹ H NMR (400MHz, CCl ₃ D) δ 9.02 (d, J=2.2Hz, 1H), 8.25-8.14 (m, 2H), 7.94-7.85 (m, 2H), 7.80 (ddd, J=8.4, 6.8, 1.4Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 6.33 (dd, J=17.0, 1.4Hz, 1H), 6.13 (dd, J=16.9, 10.3Hz, 1H), 5.77 ( d, J＝8.1Hz, 1H), 5.68(dd, J＝10.2, 1.4Hz, 1H), 5.11(s, 2H), 4.48(s, 1H), 3.55(dd, J＝15.9, 5.5Hz, 1H ), 3.34(s, 1H), 2.68(ddd, J=16.0, 10.5, 1.5Hz, 1H), 2.29(s, 1H), 1.48–1.37(m, 1H), 0.79(d, J=6.7Hz, 3H).

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

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: MTBE: n-hexane: methanol: ethanol (0.1% triethylamine) = 45:42:5:8

Retention time: 39.140min.

Example 9 N-(4-Amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1 - Preparation of f][1,2,4]triazin-7-yl)acrylamide (compound T-3).

The following synthetic route was used:

Step 1. Compound (E)-N-(2-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl ) ethylene)-2-methylpropane-2-sulfinamide synthesis

2-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)acetaldehyde (3.09 g, 10.2 mmol) and tert-butylsulfinamide (1.85 g, 15.3 mmol) was dissolved in 60 mL of tetrahydrofuran, and tetraethyl titanate (4.65 g, 20.4 mmol) was slowly added dropwise at 0 °C. TLC detected that the reaction was complete, the reaction solution was diluted with 100 mL of water and 100 mL of ethyl acetate, filtered through celite, the aqueous phase was extracted with ethyl acetate (40 mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. , concentrated, and separated by silica gel column to obtain 1.45 g of pale yellow solid with a yield of 35%. ESI-MS: m/z=407[M ⁺ +1].

Step 2. Compound N-(1-(4-Amino-5-(quinolin-3-yl))pyrrolo[2,1-f][1,2,4]triazin-7-yl)butan- Synthesis of 3-en-2-yl)-2-methylpropane-2-sulfinamide

(E)-N-(2-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)ethylene base)-2-methylpropane-2-sulfinamide (1.45g, 3.58mmol) was dissolved in 40mL of dichloromethane, cooled to -20°C, and slowly added dropwise vinylmagnesium bromide (10mL, 1mol/L THF solution ), the dropwise addition was completed and the reaction was continued at -20°C for 2 hours. TLC detected that the reaction was complete, 20 mL of saturated ammonium chloride solution was dropped into the reaction to quench, extracted with dichloromethane (20 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid 1.01 g, the yield is 65%. ESI-MS: m/z=435 [M ⁺ +2].

Step 3. Compound (1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)but-3-ene Synthesis of -2-yl) tert-butyl carbamate

N-(1-(4-Amino-5-(quinolin-3-yl))pyrrolo[2,1-f][1,2,4]triazin-7-yl)but-3-ene -2-yl)-2-methylpropane-2-sulfinamide (1.01 g, 2.33 mmol) was dissolved in 15 mL of methanol, 7M methanolic hydrogen chloride solution (1.7 mL, 11.9 mmol) was slowly added dropwise at 0°C, and the dropwise addition was completed. The reaction was continued at 0°C for 1 hour, the solvent was evaporated by rotary evaporation, the residue was dissolved in 20 mL of dichloromethane, triethylamine (0.71 g, 7 mmol) was added, and (Boc) ₂ O (0.61 g, 2.8 mmol) was added dropwise under an ice bath. ), the dropwise addition was completed and the reaction was raised to room temperature overnight. TLC detected that the reaction was complete, the reaction solution was concentrated, and separated on a silica gel column to obtain 0.72 g of a pale yellow solid with a yield of 72%. ESI-MS: m/z = 431 [M ⁺ +1].

Step 4. Compound (1-(4-Amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)butane Synthesis of tert-butyl-3-en-2-yl)carbamate

(1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)but-3-en-2- base) tert-butyl carbamate (720 mg, 1.67 mmol) was dissolved in 15 mL of DMF, NBS (312 mg, 1.75 mmol) was added in portions at 0 °C, and the reaction was continued at 0 °C for 2 hours after the addition was completed. The reaction solution was diluted with 50 mL of water, extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 600 mg of pale yellow solid with a yield of 70%. ESI-MS: m/z=511 [M ⁺ +2].

Step 5. Compound (4-amino-6-methylene-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1 Synthesis of -f][1,2,4]triazin-7-yl)carbamate tert-butyl ester

(1-(4-Amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)butan-3- tert-Butyl en-2-yl)carbamate (600 mg, 1.18 mmol), tetrabutylammonium acetate (573 mg, 1.9 mmol), palladium acetate (13 mg, 0.06 mmol) and triphenylphosphine (63 mg, 0.24 mmol) were added In 10 mL of tetrahydrofuran, nitrogen was replaced three times, and the temperature was raised to 90° C. to react for 8 hours. TLC detected that the reaction was complete, the reaction solution was concentrated and separated by silica gel column to obtain 430 mg of pale yellow solid with a yield of 85%. ESI-MS: m/z = 429 [M ⁺ +1].

Step 6. Compound (4-amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1- Synthesis of f][1,2,4]triazin-7-yl)carbamate tert-butyl ester

(4-Amino-6-methylene-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1-f] [1,2,4]Triazin-7-yl)carbamate tert-butyl ester (430 mg, 1 mmol) was dissolved in 20 mL of methanol, 50 mg of 10% palladium/carbon was added, hydrogen was replaced three times, and the room temperature was under 1 atmosphere of hydrogen. Stir overnight. After the reaction was completed, the palladium/carbon was filtered off, the filtrate was concentrated, and purified by column chromatography to obtain 360 mg of a pale yellow solid with a yield of 84%. ESI-MS: m/z=431 [M ⁺ +1].

Step 7. Compound 6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1-f][1, Synthesis of 2,4]triazine-4,7-diamine

(4-amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1-f][ 1,2,4]T-butyl triazin-7-yl)carbamate (360 mg, 0.84 mmol) was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 hours. TLC detected that the reaction was complete, the solvent was evaporated by rotary evaporation, diluted with 20 mL of water, adjusted to pH 8-9 with saturated sodium carbonate solution, extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine, and anhydrous sodium sulfate It was dried and concentrated to obtain 205 mg of pale yellow solid with a yield of 74%. ESI-MS: m/z=331 [M ⁺ +2].

Step 8. Compound N-(4-Amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2, Synthesis of 1-f][1,2,4]triazin-7-yl)acrylamide

6-Methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1-f][1,2,4 ] Triazine-4,7-diamine (205 mg, 0.62 mmol) and triethylamine (125 mg, 1.24 mmol) were dissolved in 10 mL of dichloromethane, cooled to -20 °C in an ice bath, and slowly added dropwise acryloyl chloride (56 mg, 0.62 mmol), continue to react at -20 ° C for 1 hour after the dropwise addition, add 20 mL of water to dilute, extract with dichloromethane (10 mL*3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate on a silica gel column 150 mg of light yellow solid was obtained, and the yield was 63%. ESI-MS: m/z=3385 [M ⁺ +1]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.04 (d, J=2.2 Hz, 1H), 8.25–8.15 (m, 2H), 7.93– 7.84(m,2H),7.82(ddd,J=8.3,6.8,1.4Hz,1H),7.66(t,J=7.6Hz,1H),6.31(dd,J=16.9,1.4Hz,1H),6.16 (dd,J=16.9,10.1Hz,1H),5.82(d,J=8.3Hz,1H),5.65(d,J=10.2,1H),5.11(s,2H),4.54(s,1H), 4.05(m, 1H), 3.58(s, 1H), 3.43(m, 1H), 0.86(d, J=6.7Hz, 3H).

Example 10 (6R,7S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H cyclopentano[4,5]pyrrole Preparation of [2,1-f][1,2,4]triazin-7-yl)acrylamide (Compound T-3-a).

100mg of racemic compound T-3 was dissolved in methanol solution, and the target product T-3-a (retention time: 15.52min, relative content: 20.5%). ESI-MS: m/z=3385 [M ⁺ +1]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.04 (d, J=2.2 Hz, 1H), 8.25–8.15 (m, 2H), 7.93– 7.84(m,2H),7.82(ddd,J=8.3,6.8,1.4Hz,1H),7.66(t,J=7.6Hz,1H),6.31(dd,J=16.9,1.4Hz,1H),6.16 (dd,J=16.9,10.1Hz,1H),5.82(d,J=8.3Hz,1H),5.65(d,J=10.2,1H),5.11(s,2H),4.54(s,1H), 4.05(m, 1H), 3.58(s, 1H), 3.43(m, 1H), 0.86(d, J=6.7Hz, 3H).

Chiral preparative 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:methanol:ethanol (0.1% diethylamine) = 75:10:15

Retention time: 15.52min.

Example 11 (6S,7S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H cyclopentano[4,5]pyrrole Preparation of [2,1-f][1,2,4]triazin-7-yl)acrylamide (Compound T-3-b).

100mg of racemic compound T-3 was dissolved in methanol solution, and the target product T-3-b (retention time: 27.54min, relative content: 30.4%). ESI-MS: m/z=3385 [M ⁺ +1]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.04 (d, J=2.2 Hz, 1H), 8.25–8.15 (m, 2H), 7.93– 7.84(m,2H),7.82(ddd,J=8.3,6.8,1.4Hz,1H),7.66(t,J=7.6Hz,1H),6.31(dd,J=16.9,1.4Hz,1H),6.16 (dd,J=16.9,10.1Hz,1H),5.82(d,J=8.3Hz,1H),5.65(d,J=10.2,1H),5.11(s,2H),4.54(s,1H), 4.05(m, 1H), 3.58(s, 1H), 3.43(m, 1H), 0.86(d, J=6.7Hz, 3H).

Chiral preparative 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:methanol:ethanol (0.1% diethylamine) = 75:10:15

Retention time: 27.54min.

Example 12 (6S,7R)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H cyclopentano[4,5]pyrrole Preparation of [2,1-f][1,2,4]triazin-7-yl)acrylamide (Compound T-3-c).

100mg of racemic compound T-3 was dissolved in methanol solution, and the target product T-3-c (retention time: 19.25min, relative content: 18.3%). ESI-MS: m/z=3385 [M ⁺ +1]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.04 (d, J=2.2 Hz, 1H), 8.25–8.15 (m, 2H), 7.93– 7.84(m,2H),7.82(ddd,J=8.3,6.8,1.4Hz,1H),7.66(t,J=7.6Hz,1H),6.31(dd,J=16.9,1.4Hz,1H),6.16 (dd,J=16.9,10.1Hz,1H),5.82(d,J=8.3Hz,1H),5.65(d,J=10.2,1H),5.11(s,2H),4.54(s,1H), 4.05(m, 1H), 3.58(s, 1H), 3.43(m, 1H), 0.86(d, J=6.7Hz, 3H).

Chiral preparative 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:methanol:ethanol (0.1% diethylamine) = 75:10:15

Retention time: 19.25min.

Example 13 (6R,7R)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H cyclopentano[4,5]pyrrole Preparation of [2,1-f][1,2,4]triazin-7-yl)acrylamide (Compound T-3-d).

100mg of racemic compound T-3 was dissolved in methanol solution, and the target product T-3-d (retention time: 33.22min, relative content: 25.1%). ESI-MS: m/z=3385 [M ⁺ +1]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.04 (d, J=2.2 Hz, 1H), 8.25–8.15 (m, 2H), 7.93– 7.84(m,2H),7.82(ddd,J=8.3,6.8,1.4Hz,1H),7.66(t,J=7.6Hz,1H),6.31(dd,J=16.9,1.4Hz,1H),6.16 (dd,J=16.9,10.1Hz,1H),5.82(d,J=8.3Hz,1H),5.65(d,J=10.2,1H),5.11(s,2H),4.54(s,1H), 4.05(m, 1H), 3.58(s, 1H), 3.43(m, 1H), 0.86(d, J=6.7Hz, 3H).

Chiral preparative 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:methanol:ethanol (0.1% diethylamine) = 75:10:15

Retention time: 33.22min.

Example 14 (R)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1, Preparation of 6-a]indol-8-yl)acrylamide (compound T-1-a).

The following synthetic route was used:

Step 1. Compound (R)-N-((S)-1-(4-amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine Synthesis of -7-yl)pent-4-en-2-yl)-2-methylpropane-2-sulfinamide

2-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)acetaldehyde (7.2 g, 24 mmol), (R)-tert-butylsulfinamide (4.36 g, 36 mmol) and indium powder (4.14 g, 36 mmol) were dissolved in 60 mL of tetrahydrofuran, and tetraethyl titanate (10.5 g, 48 mmol) was slowly added dropwise at 0° C. After completion, the reaction was naturally raised to room temperature for 2 hours. The reaction solution was moved to an ice bath, 3-bromopropene (6.46 g, 52.4 mmol) was slowly added dropwise, the ice bath was removed after the dropwise addition was completed, and the reaction was performed at 60° C. overnight. TLC detected that the reaction was complete, the reaction solution was diluted with 200 mL of water and 150 mL of ethyl acetate, filtered through celite, the aqueous phase was extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. , concentrated, and separated by silica gel column to obtain 3.25 g of pale yellow solid with a yield of 29.6%. ESI-MS: m/z = 449.1 [M ⁺ +1].

Step 2. Compound (S)-(1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pentane Synthesis of tert-butyl-4-en-2-yl)carbamate

(R)-N-((S)-1-(4-amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7- yl)pent-4-en-2-yl)-2-methylpropane-2-sulfinamide (2.8g, 6.2mmol) was dissolved in 30mL methanol, and 7M hydrogen chloride methanol solution (4.4mL, 30.6 mmol), continue to react at 0 °C for 1 hour after the dropwise addition, the solvent was evaporated by rotary evaporation, the residue was dissolved in 40 mL of dichloromethane, triethylamine (2.0 g, 19.0 mmol) was added, and (Boc) was added dropwise under an ice bath. ₂ O (1.62 g, 7.4 mmol) was added dropwise, and the mixture was warmed to room temperature and reacted overnight. TLC detected that the reaction was complete, the reaction solution was concentrated, and separated on a silica gel column to obtain 2.3 g of a pale yellow solid with a yield of 80.6%. ESI-MS: m/z = 445.1 [M ⁺ +1].

Step 3. Compound (S)-(1-(4-Amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7 Synthesis of -yl)pent-4-en-2-yl)carbamic acid tert-butyl ester

(S)-(1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pentan-4- En-2-yl)carbamate tert-butyl ester (808 mg, 1.8 mmol) was dissolved in 20 mL of DMF, NBS (340 mg, 1.9 mmol) was added in portions at 0°C, and the reaction was continued at 0°C for 2 hours after the addition was completed. The reaction solution was diluted with 50 mL of water, extracted with ethyl acetate (30 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 770 mg of pale yellow solid with a yield of 82.5%. ESI-MS: m/z = 525.2 [M ⁺ +1].

Step 4. Compound (S)-(4-Amino-6-methylene-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazine Synthesis of tert-butyl [1,6-a]indol-8-yl)carbamate

(S)-(1-(4-Amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) tert-butyl pent-4-en-2-yl)carbamate (770 mg, 1.46 mmol), tetrabutylammonium acetate (720 mg, 2.4 mmol), palladium acetate (18 mg, 0.08 mmol) and triphenylphosphine (80 mg, 0.3 mmol) was added to 20 mL of tetrahydrofuran, nitrogen was replaced three times, and the temperature was raised to 90° C. to react for 8 hours. TLC detected that the reaction was complete, the reaction solution was concentrated and separated by silica gel column to obtain 550 mg of pale yellow solid with a yield of 84.5%. ESI-MS: m/z = 443.1 [M ⁺ +1].

Step 5. Compound (R)-6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1,6-a]indole Synthesis of -4,8-diamine

(S)-(4-Amino-6-methylene-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1 ,6-a]indol-8-yl)carbamate tert-butyl ester (550 mg, 1.24 mmol) was dissolved in 10 mL of ethanol and 4 mL of 4N hydrochloric acid, and the reaction was refluxed overnight. TLC detected that the reaction was complete, diluted with 20 mL of water, adjusted the pH to 8-9 with saturated sodium carbonate solution, extracted with ethyl acetate (20 mL*3), washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain pale 300 mg of yellow solid, yield 71.1%. ESI-MS: m/z = 343.2 [M ⁺ +1].

Step 6. Compound (R)-N-(4-Amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1 Synthesis of ,6-a]indol-8-yl)acrylamide

(R)-6-methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1,6-a]indole-4, 8-Diamine (300 mg, 0.88 mmol) and triethylamine (228 mg, 1.76 mmol) were dissolved in 20 mL of dichloromethane, cooled to -20 °C in an ice bath, slowly added dropwise acryloyl chloride (80 mg, 0.88 mmol), the dropwise addition was complete Continue to react at -20 °C for 1 hour, add 10 mL of water to dilute, extract with dichloromethane (10 mL*3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by silica gel column to obtain 200 mg of pale yellow solid, Yield 61.2%. Chiral purity: 78.6%, separated under the following chiral preparative chromatography column and chiral resolution conditions to obtain 130 mg of off-white solid. ESI-MS: m/z=397 [M ⁺ +1]. ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.05–8.97 (m, 1H), 8.27 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.94–7.77 (m, 3H), 7.66 (t, J=7.6Hz, 1H), 6.31 (d, J=16.9Hz, 1H), 6.04 (ddd, J=16.6, 10.1, 6.0Hz) ,1H),5.90(dd,J＝24.5,8.1Hz,1H),5.64(d,J＝10.2Hz,1H),5.60–5.54(m,1H),5.00(d,J＝23.5Hz,3H) ,3.33(q,J=4.2Hz,2H),1.55(s,3H).

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

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: dichloromethane:methanol:ethanol (0.1% diethylamine) = 60:30:10.

Example 15 N-((8S)-4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazine Preparation of [1,6-a]indol-8-yl)acrylamides (compound T-4) and its stereoisomers (compounds T-4-a and T-4-b).

The following synthetic route was used:

Step 1. Compound ((8S)-4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino Synthesis of tert-butyl [1,6-a]indol-8-yl)carbamate

(S)-(4-Amino-6-methylene-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1 ,6-a] Indol-8-yl) tert-butyl carbamate (1.0 g, 2.25 mmol) was dissolved in 25 mL of methanol, 200 mg of 10% palladium/carbon was added, replaced by hydrogen three times, and stirred at room temperature under a hydrogen atmosphere of 1 atmosphere overnight. After the reaction was completed, the palladium/carbon was filtered off, the filtrate was concentrated, and purified by column chromatography to obtain 850 mg of an off-white solid with a yield of 84.8%. ESI-MS: m/z = 445.1 [M ⁺ +1].

Step 2. Compound (8S)-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6- a]Synthesis of indole-4,8-diamine

((8S)-4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1, 6-a] Indol-8-yl) tert-butyl carbamate (850 mg, 1.91 mmol) was dissolved in 25 mL of dichloromethane, 8 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 hours. TLC detected that the reaction was complete, the solvent was evaporated by rotary evaporation, diluted with 40 mL of water, adjusted to pH 8-9 with saturated sodium carbonate solution, extracted with dichloromethane (40 mL*3), the organic phase was washed with saturated brine, and anhydrous sodium sulfate It was dried and concentrated to obtain 500 mg of pale yellow solid with a yield of 76.1%. ESI-MS: m/z = 345.1 [M ⁺ +1].

Step 3. Compound (8S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]tri Synthesis of azino[1,6-a]indol-8-yl)acrylamides

(8S)-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6-a]indium Indole-4,8-diamine (500mg, 1.45mmol) and triethylamine (360mg, 3.59mmol) were dissolved in 20mL of dichloromethane, cooled to -20°C in an ice bath, and slowly added dropwise acryloyl chloride (140mg, 1.6mmol) , the dropwise addition was completed and the reaction was continued at -20°C for 1 hour. Add 10 mL of water to dilute, and extract with dichloromethane (20 mL*3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 350 mg of pale yellow solid with a yield of 60.6%. ESI-MS: m/z=399 [M ⁺ +1]. ¹ H NMR (400 MHz, CCl ₃ D) δ 9.02 (d, J=2.2 Hz, 1H), 8.25–8.14 (m, 2H), 7.94 –7.85(m,2H),7.80(ddd,J=8.4,6.8,1.4Hz,1H),7.65(t,J=7.5Hz,1H),6.33(dd,J=17.0,1.4Hz,1H), 6.13(dd,J＝16.9,10.3Hz,1H),5.77(d,J＝8.1Hz,1H),5.68(dd,J＝10.2,1.4Hz,1H),5.11(s,2H),4.48(s ,1H),3.55(dd,J＝15.9,5.5Hz,1H),3.34(s,1H),2.68(ddd,J＝16.0,10.5,1.5Hz,1H),2.29(s,1H),1.48– 1.37(m,1H),0.79(d,J=6.7Hz,3H).

Step 4. Chiral Resolution

350 mg of (8S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazine The [1,6-a]indol-8-yl)acrylamide was dissolved in methanol solution and separated under the following chiral preparative chromatography column and chiral separation conditions to obtain 100 mg of off-white solid (retention time: 25.847 min) , defined as T-4-a) and another type of white solid 105 mg (retention time: 36.108 min, as T-4-b).

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

Column temperature: 30℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

Mobile phase: dichloromethane:methanol:ethanol (0.1% diethylamine) = 77:8:15.

Example 16 N-((7R)-4-amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo Preparation of [2,1-f][1,2,4]triazin-7-yl)acrylamide (Compound T-5).

The following synthetic route was used:

Step 1. Compound (R)-N-(2-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl ) ethylene)-2-methylpropane-2-sulfinamide synthesis

2-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)acetaldehyde (6.18 g, 20.4 mmol) and (R)-tert-butylsulfinamide (3.7g, 30.6mmol) was dissolved in 120mL of tetrahydrofuran, tetraethyl titanate (9.3g, 40.8mmol) was slowly added dropwise at 0°C, and the reaction was naturally raised to room temperature after the dropwise addition. 2 hours. TLC detected that the reaction was complete, the reaction solution was diluted with 150 mL of water and 150 mL of ethyl acetate, filtered through celite, the aqueous phase was extracted with ethyl acetate (80 mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. , concentrated, and separated by silica gel column to obtain 3.0 g of pale yellow solid with a yield of 36.1%. ESI-MS: m/z = 407.2 [M ⁺ +1].

Step 2. Compound (R)-N-((R)-1-(4-amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine Synthesis of -7-yl)but-3-en-2-yl)-2-methylpropane-2-sulfinamide

(R)-N-(2-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)ethylene base)-2-methylpropane-2-sulfenamide (2.9g, 6.67mmol) was dissolved in 80mL of dichloromethane, cooled to -20°C, and slowly added dropwise vinylmagnesium bromide (20mL, 1mol/L THF solution ), the dropwise addition was completed and the reaction was continued at -20°C for 2 hours. TLC detected that the reaction was complete, quenched by dropping 20 mL of saturated ammonium chloride solution into the reaction dropwise, extracted with dichloromethane (50 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid 2.1 g, yield 72.4%. ESI-MS: m/z=435.1 [M ⁺ +2].

Step 3. Compound (R)-(1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)butane Synthesis of tert-butyl-3-en-2-yl)carbamate

(R)-N-((R)-1-(4-amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7- yl)but-3-en-2-yl)-2-methylpropane-2-sulfinamide (2.02g, 4.69mmol) was dissolved in 20mL methanol, and 5M hydrogen chloride isopropanol solution (10mL) was slowly added dropwise at 0°C ), continued to react at 0°C for 1 hour after the dropwise addition, the solvent was evaporated by rotary evaporation, the residue was dissolved in 20 mL of dichloromethane, triethylamine (1.4 g, 14.0 mmol) was added, and (Boc) ₂ O was added dropwise under an ice bath. (1.22 g, 5.6 mmol), after the dropwise addition was completed, the mixture was warmed to room temperature and reacted overnight. TLC detected that the reaction was complete, the reaction solution was concentrated, and separated on a silica gel column to obtain 1.5 g of a pale yellow solid with a yield of 74.2%. ESI-MS: m/z = 431.1 [M ⁺ +1].

Step 4. Compound (R)-(1-(4-Amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7 Synthesis of -yl)but-3-en-2-yl)carbamic acid tert-butyl ester

(R)-(1-(4-Amino-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)butan-3- En-2-yl)carbamate tert-butyl ester (1.5 g, 3.48 mmol) was dissolved in 30 mL of DMF, NBS (624 mg, 3.5 mmol) was added in portions at 0 °C, and the reaction was continued at 0 °C for 2 hours after the addition was completed. The reaction solution was diluted with 50 mL of water, extracted with ethyl acetate (40 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 1.3 g of a pale yellow solid with a yield of 73.5%. ESI-MS: m/z = 509.1 [M ⁺ +2].

Step 5. Compound (R)-(4-Amino-6-methylene-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo Synthesis of tert-butyl [2,1-f][1,2,4]triazin-7-yl)carbamate

(R)-(1-(4-Amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) tert-butyl but-3-en-2-yl)carbamate (1.3 g, 2.56 mmol), tetrabutylammonium acetate (1.14 g, 3.8 mmol), palladium acetate (26 mg, 0.12 mmol) and triphenylphosphine ( 126 mg, 0.48 mmol) was added to 10 mL of tetrahydrofuran, nitrogen was replaced three times, and the temperature was raised to 90° C. to react for 8 hours. TLC detected that the reaction was complete, the reaction solution was concentrated and separated by silica gel column to obtain 850 mg of pale yellow solid with a yield of 77.6%. ESI-MS: m/z = 429.1 [M ⁺ +1].

Step 6. Compound (7R)-(4-Amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[ Synthesis of tert-butyl 2,1-f][1,2,4]triazin-7-yl)carbamate

(R)-(4-Amino-6-methylene-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2, 1-f][1,2,4]triazin-7-yl)carbamate tert-butyl ester (850 mg, 1.98 mmol) was dissolved in 20 mL of methanol, 100 mg of 10% palladium/carbon was added, and hydrogen was replaced three times at 1 atm. It was stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was completed, the palladium/carbon was filtered off, the filtrate was concentrated, and purified by column chromatography to obtain 750 mg of a pale yellow solid with a yield of 82.3%. ESI-MS: m/z = 431.1 [M ⁺ +1].

Step 7. Compound (7R)-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1-f Synthesis of ][1,2,4]triazine-4,7-diamine

(7R)-(4-Amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1 -f] tert-butyl [1,2,4]triazin-7-yl)carbamate (750 mg, 1.74 mmol) was dissolved in 20 mL of dichloromethane, 7 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 hours. TLC detected that the reaction was complete, the solvent was evaporated by rotary evaporation, diluted with 20 mL of water, adjusted to pH 8-9 with saturated sodium carbonate solution, extracted with dichloromethane (50 mL*3), the organic phase was washed with saturated brine, and anhydrous sodium sulfate It was dried and concentrated to obtain 420 mg of pale yellow solid with a yield of 73.1%. ESI-MS: m/z=331.1 [M ⁺ +2].

Step 8. Compound (7R)-N-(4-Amino-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrole Synthesis of [2,1-f][1,2,4]triazin-7-yl)acrylamide

(7R)-6-methyl-5-(quinolin-3-yl)-7,8-dihydro-6H-cyclopentano[4,5]pyrrolo[2,1-f][1 ,2,4]Triazine-4,7-diamine (420mg, 1.27mmol) and triethylamine (250mg, 2.48mmol) were dissolved in 20mL of dichloromethane, cooled to -20°C on an ice bath, and slowly added dropwise acryloyl chloride (112 mg, 1.20 mmol), continued to react at -20 ° C for 1 hour after the dropwise addition, diluted with 20 mL of water, extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, 300mg of pale yellow solid was obtained by silica gel column, the yield was 61.5%. ESI-MS: m/z=385.1 [M ⁺ +1]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.04 (d, J=2.2 Hz, 1H), 8.25–8.15 (m, 2H), 7.93– 7.84(m,2H),7.82(ddd,J=8.3,6.8,1.4Hz,1H),7.66(t,J=7.6Hz,1H),6.31(dd,J=16.9,1.4Hz,1H),6.16 (dd,J=16.9,10.1Hz,1H),5.82(d,J=8.3Hz,1H),5.65(d,J=10.2,1H),5.11(s,2H),4.54(s,1H), 4.05(m, 1H), 3.58(s, 1H), 3.43(m, 1H), 0.86(d, J=6.7Hz, 3H).

Biological activity test

Biological Example 1: Kinase Inhibition Assay

1) EGFR (L858R/T790M) and EGFR (D770_N771insNPG) kinase activity inhibition test

The ADP-GloTM Kinase Assay kit (Promega, V9102) was used to determine the effect of the test drug on EGFR (L858R/T790M) (SignalChem, E10-122DG-10) and EGFR (D770_N771insNPG) (SignalChem, E-10-132GG). inhibitory activity.

The highest concentration of the drug to be tested is 1 μM, 3-fold serial dilution, 12 concentrations. In a 384-well plate (Perkin Elmer, 6007290), 0.1 μL of drug solution was added to each well, which was mixed with 5 μL of EGFR (L858R/T790M) and 5 μL of EGFR (D770_N771insNPG), respectively, in double wells. After 15 min incubation at 25°C, 5 μL of substrate was added to initiate the reaction and incubated at 25°C for 60 min. 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 10 μL of ADP Glo reagent was added, and the incubation was continued for 40 min at 25°C. Then 20 μL of detection reagent was added, and after incubation at 25°C for 40 min, reading was performed on an Envision microplate reader (Perkin Elmer, 2104), and the inhibition rates of different concentrations of compounds on the enzyme were calculated. Data were analyzed using GraphPad Prism 6.0 software, and a dose-response curve was fitted to the data using nonlinear curve regression, from which _IC50 values were calculated.

2) HER2 (A775_G776insYVMA) kinase activity inhibition test

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

The highest concentration of the drug to be tested is 1 μM, 3-fold serial dilution, 12 concentrations. 0.1 μL of drug solution and 5 μL of EGFR (A775_G776insYVMA) were added to each well of a 384-well plate (Perkin Elmer, 6007290), with double wells. After 15 min incubation at 25°C, 5 μL of substrate was added to initiate the reaction and incubated at 25°C for 60 min. The final reaction concentrations in the system were: 20nM HER2, 5μM ATP, 0.03mg/mL Poly(4:1Glu,Tyr)Peptide, HEPES 50mM, EGTA 1mM, MgCl ₂ 10mM, Brij350.01%. Then 10 μL of ADP Glo reagent was added, and the incubation was continued for 40 min at 25°C. Then 20 μL of detection reagent was added, and after incubation at 25°C for 40 min, reading was performed on an Envision microplate reader (Perkin Elmer, 2104), and the inhibition rates of different concentrations of compounds on the enzyme were calculated. Data were analyzed using GraphPad Prism 6.0 software, and a dose-response curve was fitted to the data using nonlinear curve regression, from which _IC50 values were calculated.

The compounds of the present invention were tested in the above described kinase inhibition experiments and found to have potent activity against EGFR (L858R/T790M) and EGFR (D770_N771insNPG) and HER2 (A775_G776insYVMA) kinases.

Biological Example 2: Testing of growth inhibitory activity against 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; HCC827 cells are mutant EGFR cells with deletion of exon 19; H1975 cells are EGFR cells with L858R point mutation and T790M point mutation.

Adjust the concentration of A431 (EGFR) cells, A549 cells (Ex19del), H1975 cells and HCC827 cells, respectively, add 50 μL of cell suspension to 384-well plates, and culture 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 10 μM, 3-fold gradient dilution, 10 concentrations, double wells, and continue to culture for 72h. The 384-well plate was taken out and equilibrated at room temperature for 30 minutes. 30 μL of CTG (Promega, G7573) reagent was added to each well, and the plate was placed at room temperature for 10 minutes. After the signal was stable, the Luminescence value was read on EnVision (Perkin Elmer 2104). Inhibition rate (%)=(1-Lum _{drug to be tested} /Lum _{negative control} )×100, the negative control group was 0.667% DMSO. _IC50 was calculated using XL-fit software.

The compounds of the present invention were tested in the above cytotoxicity experiments, and it was found that the compounds of the present invention had no inhibitory activity against wild-type EGFR A431 cells and A549 cells, but had potent activity and high selectivity against mutant EGFR H1975 cells and HCC827 cells Therefore, it can be seen that the compound of the present invention can inhibit the mutant EGFR of exon 19 deletion and the mutant EGFR of L858R/T790M with high specificity. Results for representative example compounds are summarized in Table 1 below.

Table 1:

The TAS6417 structure is as follows:

2) Test of growth inhibitory activity of Ba/F ₃ parental, Ba/F ₃ EGFR-D770-N771ins_SVD and Ba/F ₃ HER2-A775_G776insYVMA cells

Cells in logarithmic growth phase were taken, and cell viability was detected by trypan blue exclusion method to ensure that cell viability was above 90%. The concentrations of Ba/F3 parental, Ba/F3 EGFR-D770-N771ins_SVD and Ba/F3 HER2 _- A775_G776insYVMA cells were adjusted, and 90 μL of cell suspension was added to a 96-well plate, and cultured overnight at 37°C and 5% CO ₂ . The highest concentration of the drug to be tested is 1 μM, 3.16-fold gradient dilution, 9 concentrations. 10 μL of drug solution was added to each well of the 96-well plate, three duplicate wells were added, and the culture was continued for 72 h. The 96-well plate was taken out and equilibrated at room temperature for 30 min. An equal volume of CTG reagent was added to each well. The cells were lysed by shaking on an orbital shaker for 5 min. -0010A) to read the luminescence value. Cell survival rate (%)=(luminescence value of drug to be tested-luminescence value of culture solution control)/(luminescence value of cell control-luminescence value of culture solution control)×100%. Data were analyzed using GraphPad Prism 7.0 software, and a dose-response curve was fitted to the data using nonlinear S-curve regression, from which _IC50 values were calculated.

The compounds of the present invention also have potent activity and high selectivity against Ba/F3 EGFR-D770-N771ins_SVD and Ba/F ₃ HER2-A775_G776insYVMA cells, so it can be seen that the compounds of the present invention can inhibit the exon 20 insertion with high specificity. mutant EGFR.

Results for representative example compounds are summarized in Table 2 below.

Table 2:

Biological Example 3: Rats Pharmacokinetic Experiment

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

The rats were fed with standard chow and given water. Fasting was started 16 hours before the test. The drug was dissolved with PEG400 and dimethyl sulfoxide. Orbital blood was collected at 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 inhalation of ether, and 300 μL of blood samples were collected from the orbits in test tubes. The tube contains 30 μL of 1% heparin sodium solution. Tubes were dried at 60°C overnight before use. After the completion of blood sample collection at the last time point, the rats were sacrificed under ether anesthesia.

Immediately after blood sample collection, gently invert the tube at least 5 times to ensure adequate mixing and place on ice. Blood samples were centrifuged at 5000 rpm for 5 minutes at 4°C to separate plasma from red blood cells. Pipette 100 μL of plasma into a clean plastic centrifuge tube with the compound name and time point indicated. Plasma was stored at -80°C until analysis. Plasma concentrations of compounds of the invention were determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentrations of each animal at different time points.

Experiments show that the compounds of the present invention have better pharmacokinetic properties in animals, and thus have better pharmacodynamics and therapeutic effects.

The above content is a further detailed description of the present invention in conjunction 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 of the present invention, without departing from the concept of the present invention, some simple deductions or substitutions can be made, which should be regarded as belonging to the protection scope of the present invention.

Claims (19)

1. A compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in, Ring A is selected from C _6-14 aryl or 5 to 10 membered heteroaryl; R is each independently selected from H, D, halogen, -OH, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy; p is selected from 0, 1, 2, 3, 4 or 5; R ₁ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl or 3- to 7-membered heterocyclyl, wherein said C _{1 -6} alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, and 3- to 7-membered heterocyclyl are each independently optionally selected by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; R ₂ is selected from H, D, 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 , wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C _6-10 -membered aryl group and 5- to 10-membered heteroaryl group are each independently optionally replaced by a or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond ; R ₃ is selected from H, D, 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 , wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C _6-10 -membered aryl group or 5- to 10-membered heteroaryl group are each independently optionally replaced by a or more groups selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy; X is C(R ₄ )(R ₄ '); Y is C(R ₅ )(R ₅ ');

Indicates a single bond or a double bond;

Represents the stereo configuration of R or S; when

When representing a double bond, X is C(R ₄ ); m is 0, 1 or 2; n is 1, 2 or 3; When m is 0, the carbon atom connected to R ₁ and the carbon atom connected to the N atom of the amide directly form a chemical bond; R ₄ and R ₄ ' are each independently selected from H, D, halogen, -CN or C _1-6 alkyl; or R ₄ and R ₄ ' form carbonyl, C _3-7 cycloalkane with the carbon atom to which they are attached wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected from D by one or more , halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; R ₅ and R ₅ ' are each independently selected from H, D, halogen, -CN or C _1-6 alkyl; or R ₅ and R ₅ ' form carbonyl, C _3-7 cycloalkane with the carbon atom to which they are attached wherein said C _1-6 alkyl group, C _3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected from D by one or more , halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkoxy group substitution; R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; wherein said C _1-6 alkyl, C _3-7 cycloalkyl and 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, C _1-6 alkyl or C _1-6 alkoxy group substitution; The condition is that when

When it represents a single bond and m is 1, R ₁ is not H. 2. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Ring A is selected from Naphthyl, quinolyl or isoquinolyl optionally substituted with p R groups. 3. The compound according to claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R ₁ is C _1-6 alkyl, preferably methyl. 4. The compound of any one of claims 1-3, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein, R ₃ is selected from H, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl may be optionally substituted by a -NR _a R _b group; wherein, R _a and R _b are each independently selected from H or C _1-6 alkyl; or R _a , R _b and the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic group; wherein the C _1- The ₆ -alkyl and 3- to 7-membered heterocyclyl groups are each independently optionally substituted with one or more groups selected from D, halogen or -OH. 5. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:

wherein each group is defined as defined in any one of claims 1-4. 6. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:

Wherein, each group definition is as defined in any one of claim 1-4; Preferably, R ₁ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , Group substitution of C _1-6 alkyl or C _1-6 alkoxy; R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond; R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy; R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; Preferably, R ₁ is C _1-6 alkyl, preferably methyl; R' is H; R ₂ is H; _R3 is H. 7. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:

Wherein, each group definition is as defined in any one of claim 1-4; Preferably, R ₁ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , Group substitution of C _1-6 alkyl or C _1-6 alkoxy; R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; preferably, R' is selected from C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _{1 -6} alkyl and C _1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C _1-6 alkyl or C _1-6 alkoxy; R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond; R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein the C _1-6 alkyl, C _{3- 7} -cycloalkyl and 3- to 7-membered heterocyclyl are each independently optionally selected from one or more of D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy; R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; Preferably, R ₁ is C _1-6 alkyl, preferably methyl; R' is H; or R' is selected from C _1-6 alkyl or C _1-6 haloalkyl; R ₂ is H; _R3 is H. 8. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or It is a compound of the following general formula:

wherein each group is defined as defined in any one of claims 1-4. 9. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or It is a compound of the following general formula:

Wherein, each group definition is as defined in any one of claim 1-4; Preferably, R ₁ is selected from D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _{1 -6} alkyl group or C _1-6 alkoxy group substitution; preferably, R ₁ is S configuration; preferably, R ₁ is R configuration; R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond; R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy; R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; Preferably, R ₁ is C _1-6 alkyl, preferably methyl; preferably, R ₁ is S configuration; preferably, R ₁ is R configuration; R' is H; R ₂ is H; _R3 is H. 10. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:

Wherein, each group definition is as defined in any one of claim 1-4; Preferably, R ₁ is selected from D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _{1 -6} alkyl or C _1-6 alkoxy group substitution; R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; preferably, R' is selected from C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _{1 -6} alkyl and C _1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C _1-6 alkyl or C _1-6 alkoxy; R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond; R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy; R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; Preferably, R ₁ is C _1-6 alkyl, preferably methyl; R' is H; or R' is selected from C _1-6 alkyl or C _1-6 haloalkyl; R ₂ is H; _R3 is H. 11. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:

wherein each group is defined as defined in any one of claims 1-4. 12. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:

Wherein, each group definition is as defined in any one of claim 1-4; Preferably, R ₁ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , Group substitution of C _1-6 alkyl or C _1-6 alkoxy; R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond; R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy; R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; Preferably, R ₁ is C _1-6 alkyl, preferably methyl; R' is H; R ₂ is H; _R3 is H. 13. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:

Wherein, each group definition is as defined in any one of claim 1-4; Preferably, R ₁ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , Group substitution of C _1-6 alkyl or C _1-6 alkoxy; R' is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 alkyl and C _1-6 haloalkyl are each independently optionally selected from one or more D. Group substitution of halogen, C _1-6 alkyl or C _1-6 alkoxy; preferably, R' is selected from C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _{1 -6} alkyl and C _1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C _1-6 alkyl or C _1-6 alkoxy; R ₂ is selected from H, D, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is independently optionally surrounded by one or more selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl group or C _1-6 alkoxy group substitution; or R ₂ together with the attached double bond to form a triple bond; R ₃ is selected from H, D, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl or 3- to 7-membered heterocyclic group, wherein said C _1-6 alkyl, C _3- The ₇ -cycloalkyl and the 3- to 7-membered heterocyclyl are each independently optionally selected from D, halogen, -OH, -NR _a R _b , C _1-6 alkyl or C _1-6 alkane group substitution of oxy; R _a and R _b are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; or R _a , R _b and the nitrogen atom to which they are attached form 3 to 7-membered heterocyclyl; The condition is that R ₁ is not H; Preferably, R ₁ is C _1-6 alkyl, preferably methyl; R' is H; or R' is selected from C _1-6 alkyl or C _1-6 haloalkyl; R ₂ is H; _R3 is H. 14. A tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate of a compound selected from the group consisting of:

15. A pharmaceutical composition comprising a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate of the compound of any one of claims 1-14 , and a pharmaceutically acceptable excipient. 16. The compound of any one of claims 1-14, its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or claim 15 Use of a pharmaceutical composition in the manufacture of a medicament for the treatment and/or prevention of mutated EGFR kinase-mediated tumors; Preferably, the mutated EGFR is selected from exon 20 insertion mutant EGFR, exon 18 mutant EGFR, exon 21 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_N771insG, H773_V774insNPH or H773_V774insPH; Preferably, wherein, the exon 18 point mutation is selected from at least one mutation in G719A, G719S, G719C, E790K and E790A; Preferably, wherein, exon 21 point mutation is selected from L861Q mutation; Preferably, the mutated EGFR also has the T790M mutation at the same time. 17. The compound of any one of claims 1-14, its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or claim 15 Use of the pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of the following tumors: lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer. 18. The compound of any one of claims 1-14, its tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate, or claim 15 Use of a pharmaceutical composition in the manufacture of a medicament for the treatment and/or prevention of wild-type and/or mutated HER2 kinase-mediated tumors; Preferably, wherein the mutated 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 type HER2, L755S mutant HER2 or ex20insYVMA mutant HER2; Preferably, wherein, the ex20insYVMA mutant HER2 is selected from A775_G776insYVMA mutant HER2 mutations. 19. The compound of any one of claims 1-14, its tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate, or claim 15 Use of a pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of the following tumors: lung cancer, gastric cancer or breast cancer.