CN113493439B - Substituted acrylamide derivative, composition and application thereof - Google Patents

Abstract

The present invention provides a substituted acrylamide derivative, a composition comprising the compound and use thereof, wherein the substituted acrylamide derivative is a compound represented by formula (I) or its tautomer, stereoisomer Conforms, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates. The compounds of the present invention and compositions thereof are useful in the treatment and/or prevention of wild-type and/or mutated EGFR and/or HER2 kinase-mediated tumors.

Description

Substituted acrylamide derivatives, compositions and uses thereof

technical field

The present invention belongs to the technical field of medicine, and particularly relates to substituted acrylamide derivatives having inhibitory effect on wild and/or mutated EGFR and/or HER2, pharmaceutical compositions containing them, and their preparation methods and uses.

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 . Somatic mutations of the EGFR gene are known to be oncogenic: for example, deletion of amino acids 746 to 750 in the exon 19 region (hereinafter also referred to as "exon 19 deletion mutations") in the EGFR and exon 21 regions EGFR in which amino acid 858 is mutated from leucine to arginine (hereinafter also referred to as "L858R mutation") continuously induces EGF-independent kinase activity and leads to the growth and survival of cancer cells. For example, these mutations are observed in about 30%-50% of non-small cell lung cancers in East Asia, and 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-mutated and L858R-mutated EGFR-positive lung cancers, but they cause gastrointestinal disease at their therapeutic doses and dermatological side effects.

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 719th glycine in the exon 18 region is substituted by any amino acid (hereinafter referred to as the G719X mutation), and the 861st leucine in the exon 21 region is replaced by a glutamate Aminoamide substitution (hereinafter referred to as L861Q mutation).

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

HER2 mutation is one of the common driver mutation genes in lung cancer, mainly manifested as gene amplification, point mutation, exon 20 insertion mutation and other mutation types (such as deletion insertion mutation, frameshift mutation, etc.), among which exon 20 mutation. Insertional mutations are the most common. For example, HER2 mutants contain a YVMA insertion into exon 20 (hereafter referred to as ex20insYVMA). Mutant HER2 activates signaling, phosphorylates EGFR, and induces tumor formation and spread more efficiently than wild-type HER2.

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 wild-type EGFR and/or exon 20 insertion mutation EGFR, exon 18 mutated EGFR, exon 21 Mutated EGFR, wild-type HER2 and/or mutated HER2.

SUMMARY OF THE INVENTION

The present invention provides a novel acrylamide derivative, a composition comprising the compound and use thereof, which are inserted into exon 20 (exon 20ins) mutant EGFR, exon 18 point mutant EGFR, exon 21 Point mutant EGFR, exon 19 deletion (exon 19del) mutant EGFR, L858R mutant EGFR, exon 19 deletion/T790M mutant EGFR, L858R/T790M mutant EGFR, etc. have better inhibitory activity and high selection and has inhibitory activity against wild-type HER2 and/or mutated HER2, thus providing an anti-tumor drug with low toxicity and side effects.

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

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

in,

Ring A is an aromatic ring;

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

A1 is CR _A1 or N _;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

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

B ₁ is CR ₁ or N;

B ₂ is CR ₂ or N;

B ₃ is CR ₃ or N;

B ₄ is CR ₄ or N;

wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6alkynyl} , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O) R _b , -NR _a C (O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _{3 -7} cycloalkyl, 3 to 7 membered heterocyclyl, _C6-10 aryl or 5 to 10 membered heteroaryl, optionally substituted with one or more R";

L is selected from O, S or NR _L ;

wherein R _L is selected from H or C _1-6 alkyl, and is optionally substituted with one or more R*;

V is (CR _V1 R _V2 ) _o ;

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

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

R ₆ is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl, or 5 to 10-membered heteroaryl groups optionally substituted with one or more R*;

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

R is each independently selected from H, D, halogen, -CN, =O, _C1-6 alkyl, _C1-6 haloalkyl, _C2-6 alkenyl, _C2-6 alkynyl, -C(O )R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl; alternatively, two R groups on the same or adjacent atoms can be taken together to form a _C3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;

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

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

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

p=0, 1 or 2;

R" is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C ( O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , - NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl, alternatively, two R" groups on the same or adjacent atoms can be taken together to form a _C3-7 cycloalkyl, 3 to 7 membered heterocyclyl, _C6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the R" definition is optionally substituted with one or more D until fully deuterated;

R* is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C ( O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , - NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl; alternatively, two R* groups on the same or adjacent atoms can be taken together to form _{C3-7cycloalkyl} , 3 to 7 membered heterocyclyl, _C6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the R* definition is optionally substituted with one or more D until fully deuterated;

R _a , R _b and R _c are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl , 3 to 7 membered heterocyclyl, _C6-10 aryl or 5 to 10 membered heteroaryl, or R and R together with the N atom to which they are attached form _{a 3} to 7 membered heterocyclyl or 5 to 10 A membered heteroaryl; wherein each group in the definitions of R _a , R _b and R _c is optionally substituted with one or more D until fully deuterated.

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 treating and/or preventing a tumor mediated by a wild-type or mutant EGFR kinase.

In another aspect, the present invention provides a method of treating and/or preventing a disease, such as a wild-type and/or mutated EGFR 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 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_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH.

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

In a specific embodiment, the exon 21 point mutation is selected from the L861X mutation of exon 21. In 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 treating and/or preventing the following tumors, or the present invention provides a method for treating and/or preventing the following tumors in a subject, comprising administering to the subject or tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate of the present invention, or the pharmaceutical composition of the present invention: lung cancer, breast cancer , head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.

In another aspect, the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, 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 _2-6 alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C _2-4 alkenyl groups are preferred. Examples of C _2-6 alkenyl groups include: vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. The term "C _2-6 alkenyl" also includes heteroalkenyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. Whether or not the alkenyl group is modified with "substituted" or not, each of the alkenyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are as follows definition.

"C _2-6 alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, _C2-4alkynyl groups are preferred. Examples of C _2-6 alkynyl groups include, but are not limited to: ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. The term "C _2-6 alkynyl" also includes heteroalkynyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. Each of the alkynyl groups, whether or not modified with "substituted" before the alkynyl group, 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. Whether or not the alkoxy group is modified with "substituted" or not, each of the alkoxy 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.

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

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

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, hydroxide, formate, sulfate, phosphate, 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 suffers from 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 an aromatic ring;

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

A1 is CR _A1 or N _;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

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

B ₁ is CR ₁ or N;

B ₂ is CR ₂ or N;

B ₃ is CR ₃ or N;

B ₄ is CR ₄ or N;

wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6alkynyl} , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O) R _b , -NR _a C (O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _{3 -7} cycloalkyl, 3 to 7 membered heterocyclyl, _C6-10 aryl or 5 to 10 membered heteroaryl, optionally substituted with one or more R";

L is selected from O, S or NR _L ;

wherein R _L is selected from H or C _1-6 alkyl, and is optionally substituted with one or more R*;

V is (CR _V1 R _V2 ) _o ;

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

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

R ₆ is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl, or 5 to 10-membered heteroaryl groups optionally substituted with one or more R*;

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

R is each independently selected from H, D, halogen, -CN, =O, _C1-6 alkyl, _C1-6 haloalkyl, _C2-6 alkenyl, _C2-6 alkynyl, -C(O )R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl; alternatively, two R groups on the same or adjacent atoms can be taken together to form a _C3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;

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

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

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

p=0, 1 or 2;

R" is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C ( O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , - NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl, alternatively, two R" groups on the same or adjacent atoms can be taken together to form a _C3-7 cycloalkyl, 3 to 7 membered heterocyclyl, _C6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the R" definition is optionally substituted with one or more D until fully deuterated;

R* is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C ( O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , - NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl; alternatively, two R* groups on the same or adjacent atoms can be taken together to form _{C3-7cycloalkyl} , 3 to 7 membered heterocyclyl, _C6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the R* definition is optionally substituted with one or more D until fully deuterated;

R _a , R _b and R _c are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl , 3 to 7 membered heterocyclyl, _C6-10 aryl or 5 to 10 membered heteroaryl, or R and R together with the N atom to which they are attached form _{a 3} to 7 membered heterocyclyl or 5 to 10 A membered heteroaryl; wherein each group in the definitions of R _a , R _b and R _c is optionally substituted with one or more D until fully deuterated.

Ring C

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

A ₁ , A ₂ , A ₄ and A ₅

_{In one} embodiment, A1 is CR _A1 ; in another embodiment, A1 is CH _; in another embodiment, A1 is N.

_In one embodiment, A2 is C _; in another embodiment, A2 is N.

_In one embodiment, A4 is CR _A4 ; in another embodiment, _A4 is CH; in another embodiment, _A4 is N.

_In one embodiment, A5 is C; in another embodiment, _A5 is N.

选自以下结构：In one embodiment,

Choose from the following structures:

选自以下结构：Preferably,

Choose from the following structures:

选自以下结构：Preferably,

Choose from the following structures:

B ₁ , B ₂ , B ₃ and B ₄

_{In one} embodiment, B1 is CR1 _; in another embodiment, B1 is N.

_In one embodiment, B2 is CR2 _; in another embodiment, _B2 is N.

In one embodiment, _B3 is _CR3 ; in another embodiment, _B3 is N.

_In one embodiment, B4 is CR4 _; in another embodiment, _B4 is N.

R ₁ , R ₂ , R ₃ and R ₄

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

In another embodiment, R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 alkoxy, or C _3-7 cycloalkyl; in another embodiment, R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy; In another embodiment, R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D, halogen, or C _1-6 alkyl; in another embodiment, R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D, F, Cl or methyl; in another embodiment, R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H or Cl. _In another embodiment, R2 is halogen, preferably Cl.

In another embodiment, R1, R2, _R3 , and R4 are independently substituted with one or more R", eg, ₁ , ₂ , 3, ₄ , 5, 6, 7, 8, 9, 10 or more R" substitutions.

L

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

V

In one embodiment, V is (CR _V1 R _V2 ) _o ; in another embodiment, V is (CR _V1 R _V2 ) ₁ , (CR _V1 R _V2 ) ₂ , (CR _V1 R _V2 ) ₃ , ( CR _V1 R _V2 ) ₄ , (CR _V1 R _V2 ) ₅ or (CR _V1 R _V2 ) ₆ ; in another embodiment, R _V1 and R _V2 are each independently H, D, halogen, or C _1-6 alkane group; in another embodiment, both R _V1 and R _V2 are H. In another embodiment, V is ( _CH2 ) _o ; preferably _CH2 .

_R6

In one embodiment, R6 is H _; in another embodiment, R6 is D _; in another embodiment, R6 is halogen _; in another embodiment, R6 is -CN _; In one embodiment, R ₆ is C _1-6 alkyl; in another embodiment, R ₆ is C _1-6 haloalkyl; in another embodiment, R ₆ is C _3-7 cycloalkyl; In another embodiment, R ₆ is 3- to 7-membered heterocyclyl; in another embodiment, R ₆ is C _6-10 aryl; in another embodiment, R ₆ is 5- to 10-membered heterocyclyl Aryl.

In another embodiment, R6 is substituted with one or more R*, eg, 1, 2, 3, 4, 5, ₆ , 7, 8, 9, 10 or more R*.

在另一个实施方案中，R₆选自H、F、Cl、甲基或-CH₂N(CH₃)₂；在另一个实施方案中，R₆选自H、甲基或-CH₂N(CH₃)₂；在另一个实施方案中，R₆为H。In another embodiment, R ₆ is selected from H, halogen, -CN, C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl, or 5- to 10-membered heteroaryl; in another embodiment, R ₆ is selected from H, halogen, -CN or C _1-6 alkyl; in another embodiment, R ₆ is selected from H, F, Cl, Br, -CN, methyl, ethyl, isopropyl, -CH2N( _CH3 ) ₂ , _-CH2N ( _CH3 )( _CH2CH3 ), _-CH2N ( _CH3 )( _CH ( _CH3 ) ₃ ) ₂ ), -CH ₂ N(CH ₂ CH ₃ ) ₂ or

_In another embodiment, R6 is selected from H, F, Cl, methyl or _{-CH2N ( CH3} ) ₂ ; in another embodiment, R6 is selected from H, methyl or _-CH2N ( _CH3 ) _{2 ;} in another embodiment, R6 is H.

_R5 and _R7

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

In another embodiment, R ₅ and R ₇ are each independently selected from H, halogen, -CN or C _1-6 alkyl; in another embodiment, R ₅ and R ₇ are each independently selected from H, halogen or CN; in another embodiment, R ₅ and R ₇ are each independently selected from H, F, Cl or CN; in another embodiment, R ₅ and R ₇ are each independently selected from H or CN; _In another embodiment, R5 and _R7 are H.

R and m

In one embodiment, R is H; in another embodiment, R is D; in another embodiment, R is halogen; in another embodiment, R is -CN; in another embodiment , R is =O; in another embodiment, R is C _1-6 alkyl; in another embodiment, R is C _1-6 haloalkyl; in another embodiment, R is C _{2- 6} alkenyl; in another embodiment, R is C _2-6 alkynyl; in another embodiment, R is -C(O)R _a ; in another embodiment, R is -C(O ) OR _a ; in another embodiment, R is -C(O)NR _b R _c ; in another embodiment, R is -NR _b R _c ; in another embodiment, R is -NH ₂ In another embodiment, R is -NRaC(O) _Rb ; In another embodiment, R is _{-NRaC (} O) _ORb ; In another embodiment, R is -NR _a C(O)NR _b R _c ; in another embodiment, R is -OR _a ; in another embodiment, R is -OH; in another embodiment, R is -OC(O)R _a ; in another embodiment, R is -OC(O) _ORa ; in another embodiment, R is -OC(O _{) NRbRc} ; in another embodiment, R is _{C3- 7} cycloalkyl; in another embodiment, R is 3 to 7 membered heterocyclyl; in another embodiment, R is C _6-10 aryl; in another embodiment, R is 5 to 10 membered heteroaryl; in another embodiment, two R groups on the same or adjacent atoms can be taken together to form a _C3-7 cycloalkyl; in another embodiment, on the same or adjacent atoms The two R groups of can be taken together to form a 3- to 7-membered heterocyclic group; in another embodiment, two R groups on the same atom or adjacent atoms can be taken together to form a C _6-10 aryl group; in another In embodiments, two R groups on the same atom or on adjacent atoms can be taken together to form a 5- to 10-membered heteroaryl; wherein each group in the R definition is optionally substituted with one or more D until fully Deuterated.

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

p

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

选自以下结构：In another embodiment,

Choose from the following structures:

Preferably:

R' and n

In one embodiment, R' is H; in another embodiment, R' is D; in another embodiment, R' is halogen; in another embodiment, R' is -CN; In one embodiment, R' is C _1-6 alkyl; in another embodiment, R' is C _1-6 haloalkyl; in another embodiment, R' is C _2-6 alkenyl; in In another embodiment, R' is C _2-6 alkynyl; in another embodiment, R' is -C(O)R _a ; in another embodiment, R' is -C(O)OR _a ; in another embodiment, R' is -C ₍ O) _{NRb Rc} ; in another embodiment, R' is _-NRbRc ; in another embodiment, R' is -NR _aC (O) _Rb ; in another embodiment, R' is _-NRaC (O) _ORb ; in another embodiment, R' is _{-NRaC (} O) _NRbRc ; In another embodiment, R' is -OR _a ; in another embodiment, R' is -OC(O)R _a ; in another embodiment, R' is -OC(O)OR _a ; In another embodiment, R' is -OC(O) _NRbRc ; in another embodiment, R' is _{C3-7cycloalkyl} ; in another embodiment, R' is ₃ to 7 membered heterocyclyl; in another embodiment, R' is _C6-10 aryl; in another embodiment, R' is 5 to 10 membered heteroaryl.

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

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

R”

In one embodiment, R" is H; in another embodiment, R" is D; in another embodiment, R" is halogen; in another embodiment, R" is -CN; In one embodiment, R" is =O; in another embodiment, R" is C _1-6 alkyl; in another embodiment, R" is C _1-6 haloalkyl; in another embodiment In another embodiment, R" is C _{2-6 alkenyl} ; In another embodiment, R " is -C(O)R _a ; In another In one embodiment, R" is -C(O) _ORa ; in another embodiment, R" is -C(O _{) NRbRc} ; in another embodiment, _R " is _-NRbRc In another embodiment, R" is _-NH2 ; In another embodiment, R" is _-NRaC (O) _Rb ; In another embodiment, R" is _-NRaC ( O) OR _b ; in another embodiment, R" is _-NRaC (O) _NRbRc ; in another embodiment, R" is _{-ORa ;} in another embodiment, R" is -OH; in another embodiment, R" is -OC(O)R _a ; in another embodiment, R" is -OC(O)OR _a ; in another embodiment, R" is -OC(O)OR a -OC(O) _NRbRc ; in another embodiment, R" is _{C 3-7} cycloalkyl; in another embodiment, R" is a 3- to 7-membered heterocyclyl; in another embodiment In the scheme, R" is a C _6-10 aryl group; in another embodiment, R" is a 5- to 10-membered heteroaryl group; in another embodiment, two R" on the same atom or adjacent atoms groups can be taken together to form a C _3-7 cycloalkyl; in another embodiment, two R" groups on the same atom or adjacent atoms can be taken together to form a 3- to 7-membered heterocyclyl; in another embodiment In another embodiment, two R" groups on the same or adjacent atoms can form together a C _6-10 aryl group; in another embodiment, two R" groups on the same or adjacent atoms can form together 5 to 10 membered heteroaryl; wherein each group in the R" definition is optionally substituted with one or more D until fully deuterated.

R*

In one embodiment, R* is H; in another embodiment, R* is D; in another embodiment, R* is halogen; in another embodiment, R* is -CN; In one embodiment, R* is =O; in another embodiment, R* is C _1-6 alkyl; in another embodiment, R* is C _1-6 haloalkyl; in another embodiment , R* is C _2-6 alkenyl; in another embodiment, R* is C _2-6 alkynyl; in another embodiment, R* is -C(O)R _a ; in another In one embodiment, R* is -C(O) _ORa ; in another embodiment, R* is -C(O) _NRbRc ; in another embodiment, _{R *} is _-NRbRc In another embodiment, R* is _-NH2 ; In another embodiment, R* is _-NRaC (O) _Rb ; In another embodiment, R* is _-NRaC ( O) _ORb ; in another embodiment, R* is _-NRaC (O) _NRbRc ; in another embodiment, R* is _{-ORa ;} in another embodiment, R* is -OH; in another embodiment, R* is -OC(O)R _a ; in another embodiment, R* is -OC(O)OR _a ; in another embodiment, R* is -OC(O) _NRbRc ; in another embodiment, R* is _{C3-7cycloalkyl} ; in another embodiment, R* is ₃ to 7 membered heterocyclyl; in another embodiment In one embodiment, R* is a C _6-10 aryl group; in another embodiment, R* is a 5- to 10-membered heteroaryl group; in another embodiment, two R* on the same atom or adjacent atoms groups can be taken together to form a C _3-7 cycloalkyl; in another embodiment, two R* groups on the same atom or adjacent atoms can be taken together to form a 3- to 7-membered heterocyclyl; in another embodiment In another embodiment, two R* groups on the same or adjacent atoms can form together a C _6-10 aryl group; in another embodiment, two R* groups on the same or adjacent atoms can form together 5 to 10 membered heteroaryl; wherein each group in the R* definition is optionally substituted with one or more D until fully deuterated.

R _a , R _b and R _c

In one embodiment, _Ra , _Rb , and _Rc are independently H; in another embodiment, _Ra , _Rb , and _Rc are independently _C1-6 alkyl; in one embodiment, R _a , R _b and R _c are independently C _1-6 haloalkyl; in one embodiment, R _a , R _b and R _c are independently C _3-7 cycloalkyl; in one embodiment, R _a , _Rb , and _Rc are independently 3- to 7-membered heterocyclyl; in one embodiment, _Ra , _Rb , and _Rc are independently _C6-10 aryl; in one embodiment, R _a , _Rb , and _Rc are independently 5- to 10-membered heteroaryl groups; wherein each group in the definitions of _Ra , _Rb , and _Rc is optionally substituted with one or more D until fully deuterated.

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, rings C, A ₁ , A ₂ , A ₄ , A ₅ , B ₁ , B ₂ , B ₃ , B ₄ , L, V, R ₅ , R ₆ , R ₇ , R, m, R′, n Combine with any technical solution of p or any combination thereof. The present invention is intended to include all the combinations of these technical solutions, and is not listed one by one due to space limitations.

In a more specific embodiment, the present invention relates to a compound of formula (I) as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvates, wherein,

选自以下结构：

Choose from the following structures:

Preferably,

选自以下结构：

Choose from the following structures:

Preferably,

选自以下结构：

Choose from the following structures:

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

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

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

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

In a more specific embodiment, the present invention relates to a compound of formula (I) as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvates, wherein,

选自以下结构：

Choose from the following structures:

Preferably:

In a more specific embodiment, the present invention relates to a compound of formula (I) as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvates, which are compounds of the general formula:

wherein each group is as defined above.

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

in,

Ring A is an aromatic ring;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

wherein R _A4 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, which is optionally substituted with one or more R";

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

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

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

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

o=1, 2, 3 or 4;

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

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

p=0, 1 or 2;

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

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

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

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

R" is each independently selected from H, D, halogen, _-CN , =O, _-ORa or _-NRbRc ;

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

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

in,

Ring A is an aromatic ring;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

wherein R _A4 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, which is optionally substituted with one or more R";

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

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

o=1, 2, 3 or 4;

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

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

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

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

R" is each independently selected from H, D, halogen, _-CN , =O, _-ORa or _-NRbRc ;

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

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

in,

A1 is CR _A1 or N _;

wherein R _A1 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, which is optionally substituted with one or more R";

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

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

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

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

o=1, 2, 3 or 4;

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

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

p=0, 1 or 2;

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

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

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

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

R" is each independently selected from H, D, halogen, _-CN , =O, _-ORa or _-NRbRc ;

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

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

in,

A1 is CR _A1 or N _;

wherein R _A1 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, which is optionally substituted with one or more R";

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

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

o=1, 2, 3 or 4;

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

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

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

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

Each R" is independently selected from H, D, halogen, _-CN , =O, _-ORa , or _-NRbRc ;

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

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

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 type of hydrate, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R 0.5H2 ₎ O)) and polyhydrates (x is a number greater than 1, eg, dihydrate ( _R.2H2O ) and hexahydrate ( _R.6H2O )).

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 formic acid (-COOH), esters such as methyl esters, ethyl esters, and the like may 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 wild-type and/or mutated EGFR kinase-mediated cancer, 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 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, also known 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, positions 761 to 823) amino acid sequence); preferably, a mutation in which the amino acid sequence FQEA (in the order of phenylalanine, glutamine, glutamic acid and alanine from the N-terminus) is inserted in the exon 20 region A mutation between alanine 763 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 outside the A mutation between valine 769 and aspartic acid 770 in the exon 20 region (V769_D770insASV); preferably, a mutation in which the amino acid sequence SVD (starting from the N-terminus with serine, valine and aspartic acid) amino acid sequence) into a mutation in the exon 20 region between aspartic acid 770 and asparagine 771 (D770_N771insSVD); preferably, a mutation in which the amino acid sequence NPG (starting from the N-terminal to asparagine, proline and glycine in this order) into a mutation in the exon 20 region between aspartic acid 770 and asparagine 771 (D770_N771insNPG); preferably, a mutation in which 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 thus A mutation (D770>GY) inserting the amino acid sequence GY (in this order of glycine and tyrosine from the N-terminus); preferably, a mutation in which the amino acid N (asparagine) is inserted at position 771 in the exon 20 region Mutation between asparagine 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 into the exon 20 region A mutation between proline 772 and histidine 773 (P772_R773insPR) in ; sequence) a mutation inserted between histidine 773 and valine 774 in the exon 20 region (H773_V774insNPH); preferably, a mutation wherein the amino acid sequence PH (starting from the N-terminus with proline and group amino acid sequence) into the exon 20 region between histidine 773 and valine 774 (H773_V774insPH); preferably, a mutation in which the amino acid sequence AH (starting from the N-terminal with C (H773_V774insAH) is inserted into the exon 20 region between histidine 773 and valine 774; A mutation in which the amino 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 (starting from the N-terminal 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 sequence NPG (in the order asparagine, proline and glycine from the N-terminus) is inserted into an exon Mutation between aspartic acid at position 770 and asparagine at position 771 in region 20 (D770_N771insNPG); more preferably, a mutation in which the amino acid G (glycine) is inserted into aspartic acid at position 770 in exon 20 region Mutation between acid and asparagine at position 771 (D770_N771insG); more preferably, a mutation in which the amino acid sequence NPH (in the order asparagine, proline and histidine from the N-terminus) is inserted into the exon A mutation between histidine 773 and valine 774 in the sub-20 region (H773_V774insNPH); more preferably, a mutation in which the amino acid sequence PH (from the N-terminal to proline and histidine such as sequence) a mutation inserted between histidine 773 and valine 774 in the exon 20 region (H773_V774insPH); acid and aspartic acid in this sequence) into a mutation in the exon 20 region between aspartic acid at position 770 and aspartic acid at position 771 (D770_N771insSVD); more preferably, a mutation in which amino acid G ( Glycine) is inserted between aspartate 770 and asparagine 771 in the exon 20 region (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 in the exon 18 region is substituted; more preferably, the mutation is a point mutation in which the glutamic acid encoded by codon 709 in exon 18 is replaced by any amino acid (ie, E790X), and a point mutation in which the glycine encoded by codon 719 in exon 18 is replaced by any amino acid (ie, G719X). Specifically, E790X can be, for example, a point mutation in which the glutamic acid encoded by codon 709 in the exon 18 region is replaced by a lysine (ie, E709K), and the glutamic acid encoded by codon 709 in the exon 18 region A point mutation in which amino acid was replaced by alanine (ie, E709A). G719X can be, for example, a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by alanine (ie, G719A), and a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by serine ( That is, G719S), and a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by a cysteine (ie, G719C), of which G719A is the most common.

As used herein, "exon 18 mutant EGFR" refers to EGFR having at least one exon 18 mutation; preferably, the EGFR has two or more relevant exon 18 mutations; more preferably, the EGFR Has 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" 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 is replaced by any amino acid (ie, L861X), eg, a point mutation in which the leucine encoded by codon 861 in the exon 21 region is replaced by glutamine (ie, L861Q).

As used herein, "exon 21 mutant EGFR" refers to EGFR having at least one exon 21 mutation; preferably, the EGFR has two or more relevant exon 21 mutations; more preferably, the EGFR Has 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:

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

Na ₂ CO ₃ : sodium carbonate

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

HOBT: 1-Hydroxybenzotriazole

NIS: N-Iodosuccinimide

DMF: N,N-Dimethylformamide

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

MTBE: methyl tert-butyl ether

DME: ethylene glycol dimethyl ether

NBS: N-Bromosuccinimide

Cbz: benzyloxycarbonyl

TEA: Triethylamine

DCM: dichloromethane

ACN: Acetonitrile

POCl ₃ : Phosphorus oxychloride

tert-Butyl nitrite: tert-butyl nitrite

TPP: triphenylphosphine

DIAD: Diisopropyl azodicarboxylate

NH ₄ OAc: Ammonium Acetate

DMSO: Dimethyl sulfoxide

B ₂ pin ₂ : Pinacol Biborate

KOAc: Potassium acetate

Dioxane: Dioxane

NaNO ₂ : sodium nitrite

EtOH: Ethanol

NaOH: sodium hydroxide

DIPEA: N,N-Diisopropylethylamine

TFAA: trifluoroacetic anhydride

H ₂ O ₂ : hydrogen peroxide

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

NaH: sodium hydride

THF: Tetrahydrofuran

i-PrOH: isopropanol

PtO ₂ : platinum dioxide

EA: Ethyl acetate

EtOH: Ethanol

Tosmic: p-Toluenesulfonylmethylisonitrile

PdCl ₂ : Palladium dichloride

TESiH: Triethylsilane

NaIO ₄ : sodium periodate

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

The following synthetic route was used:

To the reaction flask was added 3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (1.2g, 4.6mmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.1 g, 6.9 mmol), tetrakis(triphenylphosphine) ) palladium (53mg, 0.05mmol) and sodium carbonate (975mg, 9.2mmol), add 20ml dioxane and 2ml water to dissolve, be heated to 90 ℃ of stirring reaction 6 hours under nitrogen protection, TLC monitoring reaction is completed, after concentrating and removing solvent The product was purified by silica gel column chromatography to obtain 1.17 g, yield: 80.7%. LC-MS (APCI): m/z=317.2 (M+1) ⁺ .

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

The following synthetic route was used:

To the reaction flask was added 3-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.17 g, 3.7mmol), catalytic amount of palladium on carbon, add 20ml methanol to dissolve, fill with hydrogen balloon, stir the reaction at room temperature for 5 hours, TLC detects the completion of the reaction, removes the catalyst by filtration, and purifies by silica gel column chromatography after concentration to obtain 1.05g of product, which is collected Rate: 89%. LC-MS (APCI): m/z=319.5 (M+1) ⁺ .

Intermediate A3(R)-3-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester preparation

The following synthetic route was used:

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

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

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

To the reaction flask was added (R)-3-(((3-chloropyrazin-2-yl)methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.82 mmol), under nitrogen protection 25ml of anhydrous ethyl acetate was added to dissolve, then 3.7ml of anhydrous DMF was added, and phosphorus oxychloride (2.6g, 17.0mmol) was slowly added dropwise under an ice-salt bath. After the addition was completed, the reaction was stirred at room temperature for 1h, and the reaction was monitored by TLC. After completion, 20 ml of saturated aqueous sodium carbonate solution was added dropwise under an ice bath to quench the reaction, the organic phase was separated, the aqueous phase was extracted 3-4 times with ethyl acetate, the organic phases were combined, washed with saturated brine, and concentrated by silica gel column chromatography (petroleum Ether:ethyl acetate 2:1) was purified to give 0.89 g of oily product, yield: 93.8%. LC-MS (APCI): m/z=337.8 (M+1) ⁺ .

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

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

Step 4 Synthesis of (R)-3-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

To the reaction flask was added (R)-3-(8-chloro-1-iodoimidazo[1,5-α]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (1.06 g, 2.29 mmol ), add 8ml 2-butanol, then add ammonia water (6.7ml, 176mmol), heat to 90°C under airtight conditions to react overnight, drop to room temperature, monitor the completion of the reaction by TLC, add excess water to dilute, extract with ethyl acetate for 3 -4 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and purified by adding MTBE to obtain 0.89 g of product, yield: 87.6%. LC-MS (APCI): m/z=444.3 (M+1) ⁺ .

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

The following synthetic route was used:

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

4-Amino-7-bromopyrrolo[2,1-f][1,2,4]triazine (4.69 g, 13.6 mmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (5.04 g, 16.3 mmol), Pd(dppf)Cl ₂ (0.5 g, 0.68 mmol) and Na ₂ CO ₃ (4.35 g, 41 mmol) were added to 70 mL of DME and 15 mL of water, nitrogen was replaced three times, and the temperature was raised to 90° C. to react overnight. The reaction solution was cooled to room temperature, 100 mL of water was added, extracted with ethyl acetate (60 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 3.21 g of a pale yellow solid, which was collected. rate 75%. ESI-MS: 316[M ⁺ +1].

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

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

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

3-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (2.9 g, 9.16 mmol) was dissolved in 30 mL DMF , NBS (1.78 g, 10 mmol) was added in batches under an ice bath, and the mixture was naturally warmed to room temperature and reacted overnight. After the reaction was completed, 100 mL of water was added to the reaction solution, extracted with ethyl acetate (40 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 2.54 g of a pale yellow solid, Yield 70%. ESI-MS: 398[M ⁺ +2].

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

The following synthetic route was used:

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

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

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

(R)-Piperidine-1,3-dicarboxylic acid (1-benzyl)(3-succinimidyl)ester (10.15 g, 28.2 mmol) and 3-amino-6-(aminomethyl)- 1,2,4-Triazin-5(4H)-one acetate (5.67 g, 28.2 mmol) was dissolved in 100 mL of acetonitrile, triethylamine (8.54 g, 84.6 mmol) was added, and the temperature was raised to 50° C. to react overnight. After the reaction was cooled, 150 mL of water was added to dilute it, extracted with ethyl acetate (80 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 8.07 g of a pale yellow solid with a yield of 74%. . ESI-MS: 387[M ⁺ +1].

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

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

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

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

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

(R)-3-(2-Amino-5-bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl) Benzyl piperidine-1-carboxylate (5.77 g, 12.9 mmol) was dissolved in 50 mL of tetrahydrofuran, tert-butyl nitrite (2 g, 19.4 mmol) was slowly added, and the temperature was raised to 60° C. to react for 3 hours. After the reaction was completed, 100 mL of water was added to dilute it, extracted with ethyl acetate (100 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 4.79 g of a pale yellow solid with a yield of 86%. . ESI-MS: 434[M ⁺ +2].

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

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

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

The following synthetic route was used:

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

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

The following synthetic route was used:

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

To the reaction flask were added tert-butyl 3-oxopiperidine-1-carboxylate (5.0 g, 25 mmol), methyl 2-cyanoacetate (2.5 g, 25 mmol) and ammonium acetate (0.25 g, 3.25 mmol), and added 25ml of toluene, then 0.5ml of glacial acetic acid was added, heated to reflux (water separation) and stirred for 7 hours. After the reaction was monitored by TLC, the solvent was concentrated and removed, and purified by silica gel column chromatography to obtain 6.75g of colorless oily liquid, yield: 96.4% . LC-MS (APCI): m/z=281.1 (M+1) ⁺ .

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

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

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

The following synthetic route was used:

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

2-Chloro-4-nitrophenol (5.2g, 30mmol), 2-chloromethylpyridine hydrochloride (5.42g, 33mmol) and anhydrous sodium carbonate (7.95g, 75mmol) were added to the reaction flask, and 20ml was added. Anhydrous DMF was dissolved, heated to 80 °C and stirred for 4 hours. After the reaction was monitored by TLC, it was lowered to room temperature, diluted with excess water, extracted with ethyl acetate for 3-4 times, combined with the organic phases, washed with saturated brine, and concentrated with silica gel. Column chromatography gave 4.5 g of product, yield: 56.8%. LC-MS (APCI): m/z=265.7 (M+1) ⁺ .

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

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

Preparation of Intermediate B3 2-((4-Bromo-2-chlorophenoxy)methyl)pyridine

The following synthetic route was used:

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

Intermediate B4 2-((2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy Preparation of base)methyl)pyridine

The following synthetic route was used:

Combine 2-((4-bromo-2-chlorophenoxy)methyl)pyridine (3.98 g, 13.3 mmol), pinacol biboronate (4.06 g, 16 mmol), Pd(dppf)Cl ₂ (0.49 g) , 0.67 mmol) and potassium acetate (3.92 g, 40 mmol) were added to 60 mL of dioxane, nitrogen was replaced three times, and the temperature was raised to 90° C. to react for 3 hours. The reaction solution was cooled to room temperature, 100 mL of water was added, extracted with ethyl acetate (60 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 3.45 g of a pale yellow solid, which was collected. rate 75%. ESI-MS: 346[M ⁺ +1].

Example 1 3-(1-Acryloylpiperidin-3-yl)-4-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)benzene yl)-1H-pyrazole-5-carbonitrile preparation

The following synthetic route was used:

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

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

Step 2 2-(1-(tert-Butoxycarbonyl)piperidin-3-yl)-2-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazono) Synthesis of Acetic Acid

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

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

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

Step 4 tert-butyl 3-(1-cyano-1-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazono)methyl)piperidine-1-carboxylic acid Synthesis of Esters

Add 3-(2-amino-1-(2-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)hydrazono)-2-oxoethyl)piperidine to the reaction flask tert-butyl pyridine-1-carboxylate (392mg, 0.8mmol) and pyridine (0.5ml, 5.6mmol) were added with 10ml of dichloromethane to dissolve, the temperature was lowered to 0°C under nitrogen protection, and trifluoroacetic anhydride (0.6ml, 4.0 mmol), stirred and reacted at room temperature for 1 hour, after the completion of TLC monitoring reaction, a small amount of dichloromethane was added for dilution, washed with 1N dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine successively, dried over anhydrous sodium sulfate and concentrated To dryness, it was directly used in the next reaction without purification.

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

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

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

Add 3-(4-amino-5-cyano-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazol-3-yl)piperidine to the reaction flask tert-butyl pyridine-1-carboxylate (120 mg, 0.24 mmol), 4N hydrogen chloride in ethyl acetate solution (2.5 ml, 10 mmol) was added under nitrogen protection, the reaction was stirred at room temperature for 1 h, the reaction was monitored by TLC, and then concentrated to dryness, and directly put into to the next step.

5ml of anhydrous dichloromethane and triethylamine (0.07ml, 0.47mmol) were added to the above intermediate, and acryloyl chloride (22.4mg, 0.25mmol) was added dropwise under an ice bath, and the reaction was monitored by TLC after the addition was stirred for 10 minutes. , diluted with dichloromethane, washed with water and saturated brine successively, concentrated and purified by silica gel column chromatography to obtain 80 mg of off-white solid, yield: 73.4%. LC-MS (APCI): m/z=463.5 (M+1) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (d, J=2.3 Hz, 1H), 8.13 (t, J=4.6 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J= 4.6Hz, 1H), 7.41 (d, J=3.4Hz, 1H), 7.32 (t, J=4.6Hz, 1H), 6.88 (d, J=3.4Hz, 1H), 6.63 (m, 1H), 6.12 (d, J=6.8Hz, 1H), 6.04(s, 2H), 5.63(d, J=6.8Hz, 1H), 5.51(s, 2H), 3.81(m, 1H), 3.66(m, 3H) ,3.04(m,1H),2.01(m,2H),1.66(m,2H).

Example 2 3-(1-Acryloylpiperidin-3-yl)-4-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)benzene yl)-1H-pyrrole-5-carboxamide

The following synthetic route was used:

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

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

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

Add 3-(4-amino-5-carbamoyl-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazol-3-yl) to the reaction flask Piperidine-1-carboxylate tert-butyl ester (113mg, 0.22mmol), 4N hydrogen chloride ethyl acetate solution (2.5ml, 10mmol) was added under nitrogen protection, the reaction was stirred at room temperature for 1h, TLC monitored the reaction and concentrated to dryness, directly Invest in the next step.

5ml of anhydrous dichloromethane and triethylamine (0.06ml, 0.43mmol) were added to the above intermediate, and acryloyl chloride (20.4mg, 0.23mmol) was added dropwise under an ice bath, and the reaction was monitored by TLC after 10 minutes of stirring. , diluted with dichloromethane, washed with water and saturated brine successively, concentrated and purified by silica gel column chromatography to obtain 82 mg of off-white solid, yield: 79.5%. LC-MS (APCI): m/z=481.3 (M+1) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.47(s, 2H), 8.33(d, J=2.4Hz, 1H), 8.10(t, J=4.6Hz, 1H), 7.75(s, 1H) ,7.70(d,J＝4.6Hz,1H),7.41(d,J＝3.6Hz,1H),7.30(t,J＝4.6Hz,1H),6.81(d,J＝3.4Hz,1H),6.63 (m,1H),6.12(d,J=6.8Hz,1H),6.00(s,2H),5.63(d,J=6.8Hz,1H),5.52(s,2H),3.81(m,1H) ,3.66(m,3H),3.04(m,1H),1.98(m,1H),1.75(m,3H).

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

The following synthetic route was used:

Step 1 3-(7-Amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl) Synthesis of -5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester

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

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

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

Step 3 1-(3-(7-Amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-3 Synthesis of -yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one

5ml of anhydrous dichloromethane and triethylamine (42.5mg, 0.42mmol) were added to the above intermediate, acryloyl chloride (12.7mg, 0.14mmol) was added dropwise under ice bath, and the reaction was monitored by TLC after the addition was stirred for 10 minutes. , diluted with dichloromethane, washed with water and saturated brine successively, concentrated and purified by silica gel column chromatography to obtain 41 mg of pale yellow solid, yield: 60.1%. LC-MS (APCI): m/z=488.1 (M+1) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.77(s, 1H), 8.64(d, J=3.6Hz, 1H), 8.23(t, J=4.2Hz, 1H), 8.05(s, 1H) ,7.72(d,J＝4.2Hz,1H),7.41(d,J＝3.6Hz,1H),7.32(t,J＝4.4Hz,1H),6.89(d,J＝5.5Hz,1H),6.63 (m, 1H), 6.21 (d, J=7.7Hz, 1H), 6.11 (s, 1H), 5.63 (d, J=7.7Hz, 1H), 3.81 (t, J=4.8Hz, 2H), 3.55 (s, 2H), 2.07(t, J=4.8Hz, 2H).

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

The following synthetic route was used:

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

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

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

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

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

10 ml of anhydrous dichloromethane and triethylamine (189 mg, 1.87 mmol) were added to the above intermediate, acryloyl chloride (49 mg, 0.54 mmol) was added dropwise under an ice bath, and the reaction was monitored by TLC after stirring for 10 minutes. It was diluted with dichloromethane, washed with water and saturated brine successively, concentrated and purified by silica gel column chromatography to obtain 120 mg of yellow solid, yield: 45.5%. LC-MS (APCI): m/z=490.6 (M+1) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.71(s, 1H), 8.68(d, J=4.8Hz, 1H), 8.15(t, J=4.4Hz, 1H), 7.92(s, 1H) ,7.72(d,J＝4.4Hz,1H),7.45(d,J＝4.8Hz,1H),7.30(t,J＝4.4Hz,1H),6.82(d,J＝5.5Hz,1H),6.51 (m,1H),6.00(d,J=8.4Hz,1H),5.52(d,J=8.4Hz,1H),5.37(s,2H),3.82(m,1H),3.79(m,3H) ,2.96(m,1H),2.07(m,1H),1.88(m,3H).

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

120 mg of the racemate compound of Example 4 was dissolved in methanol solution, and separated under the following chiral preparative chromatography column and chiral resolution conditions to obtain 43 mg of the target product (retention time: 27.79 min, defined as R configuration). LC-MS (APCI): m/z=490.6 (M+1) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.69(s, 1H), 8.52(d, J=4.8Hz, 1H), 8.13(t, J=4.4Hz, 1H), 7.92(s, 1H) ,7.72(d,J＝4.4Hz,1H),7.41(d,J＝4.8Hz,1H),7.32(t,J＝4.4Hz,1H),6.82(d,J＝5.5Hz,1H),6.51 (m,1H),6.01(d,J=8.4Hz,1H),5.52(d,J=8.4Hz,1H),5.37(s,2H),3.82(m,1H),3.79(m,3H) ,3.11(m,1H),2.07(m,1H),1.88(m,3H).

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

Column temperature: 30℃

Flow rate: 4.0mL/min

UV detection wavelength: 254nm

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

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

120 mg of the racemate compound of Example 4 was dissolved in methanol solution, and separated under the following chiral preparative chromatography column and chiral resolution conditions to obtain 45 mg of the target product (retention time: 22.48 min, defined as S configuration). LC-MS (APCI): m/z=490.6 (M+1) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.71(s, 1H), 8.69(d, J=4.8Hz, 1H), 8.16(t, J=4.4Hz, 1H), 7.94(s, 1H) ,7.72(d,J＝4.4Hz,1H),7.45(d,J＝4.8Hz,1H),7.31(t,J＝4.4Hz,1H),6.82(d,J＝5.5Hz,1H),6.51 (m,1H),6.00(d,J=8.4Hz,1H),5.52(d,J=8.4Hz,1H),5.37(s,2H),3.82(m,1H),3.79(m,3H) ,2.86(m,1H),2.17(m,1H),1.89(m,3H)

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: n-hexane: ethanol = 70:20:10

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

The following synthetic route was used:

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

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

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

Add (R)-3-(8-amino-1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[1,5-α]pyrazine- 3-yl)piperidine-1-carboxylate tert-butyl ester (132mg, 0.25mmol), 4N hydrogen chloride ethyl acetate solution (5ml, 20mmol) was added, the reaction was stirred at room temperature for 1h, the completion of the reaction was monitored by TLC, concentrated to dryness, directly into the next reaction.

8 ml of anhydrous dichloromethane was added to the reaction flask in the previous step, triethylamine (0.1 ml, 0.5 mmol) was added, the temperature was lowered to 0°C under nitrogen protection, acryloyl chloride (24.5 mg, 0.27 mmol) was added dropwise, the addition was completed and stirred After the reaction was completed for 0.5 h, TLC monitoring was completed, saturated aqueous ammonium chloride solution was added to quench the reaction, the aqueous phase was extracted with dichloromethane 2-3 times, the organic phases were combined, washed with saturated brine, concentrated and purified by silica gel column chromatography to obtain 66 mg Off-white solid, yield: 54.8%. LC-MS (APCI): m/z=489.5 (M+1) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (d, J=2.3 Hz, 1H), 8.13 (m, 3H), 7.82 (m, 2H), 7.57 (d, J=4.6 Hz, 1H) ,7.34(t,J＝2.3Hz,1H),7.18(d,J＝4.6Hz,1H),6.74(q,J＝6.8Hz,1H),6.15(d,J＝5.5Hz,1H),5.64 (d, J＝5.5Hz, 1H), 5.58(s, 2H), 4.01(m, 1H), 3.81(m, 2H), 3.72(t, J＝7.4Hz, 2H), 3.02(m, 1H) ,2.87(m,2H),2.15(m,2H).

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

The following synthetic route was used:

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

Intermediate A4 (645 mg, 1.63 mmol), Intermediate B4 (677 mg, 1.96 mmol), Pd(dppf)Cl2 (58 _mg , 0.08 mmol) and _Na2CO3 (520 _mg , 4.9 mmol) were added to 12 mL of DME and 4 mL In water, nitrogen was replaced three times, and the temperature was raised to 90°C for overnight reaction. The reaction solution was cooled to room temperature, 30 mL of water was added, 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 540 mg of a pale yellow solid with a yield of 540 mg. 62%. ESI-MS:536[M+1] ⁺ .

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

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

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

5-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)pyrrolo[2,1-f][1,2,4] Triazin-4-amine (322 mg, 0.74 mmol) and triethylamine (0.15 g, 1.48 mmol) were dissolved in 10 mL of dichloromethane, cooled to -20°C in an ice bath, and acryloyl chloride (67 mg, 0.74 mmol) was slowly added, After the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. Add 20 mL of water to dilute, extract with dichloromethane (15 mL*3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate through a silica gel column to obtain 240 mg of a pale yellow solid with a yield of 65%. ESI-MS: 500 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (dt, J=4.8, 1.5 Hz, 1H), 7.94 (s, 1H), 7.78 (td, J= 7.7, 1.8Hz, 1H), 7.67 (d, J=7.9Hz, 1H), 7.52 (d, J=2.1Hz, 1H), 7.30–7.28 (m, 1H), 7.07 (d, J=8.4Hz, 1H), 6.69(dd, J＝16.7, 10.5Hz, 1H), 6.46(s, 1H), 6.29(d, J＝16.9Hz, 1H), 5.67(d, J＝10.1Hz, 1H), 5.37( s,1H),5.33(s,2H),4.86(d,J=13.1Hz,0.5H),4.58(d,J=13.3Hz,0.5H),4.39(d,J=13.1Hz,0.5H) ,4.00(d,J＝13.2Hz,0.5H),3.44(s,1H),3.15(q,J＝13.0,11.0Hz,1H),2.99(t,J＝11.8Hz,0.5H),2.87( t, J=11.9Hz, 0.5H), 2.25 (d, J=10.3Hz, 1H), 1.90 (d, J=12.1Hz, 2H), 1.78–1.71 (m, 1H).

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

Dissolve 100 mg of the racemate compound of Example 8 in methanol solution, and separate it under the following chiral preparative chromatography column and chiral separation conditions to obtain the target product (retention time: 61.925 min, relative content: 50.04%, named as R configuration). ESI-MS: 500 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (dt, J=4.8, 1.5 Hz, 1H), 7.94 (s, 1H), 7.78 (td, J= 7.7, 1.8Hz, 1H), 7.67 (d, J=7.9Hz, 1H), 7.52 (d, J=2.1Hz, 1H), 7.30–7.28 (m, 1H), 7.07 (d, J=8.4Hz, 1H), 6.69(dd, J＝16.7, 10.5Hz, 1H), 6.46(s, 1H), 6.29(d, J＝16.9Hz, 1H), 5.67(d, J＝10.1Hz, 1H), 5.37( s,1H),5.33(s,2H),4.86(d,J=13.1Hz,0.5H),4.58(d,J=13.3Hz,0.5H),4.39(d,J=13.1Hz,0.5H) ,4.00(d,J＝13.2Hz,0.5H),3.44(s,1H),3.15(q,J＝13.0,11.0Hz,1H),2.99(t,J＝11.8Hz,0.5H),2.87( t, J=11.9Hz, 0.5H), 2.25 (d, J=10.3Hz, 1H), 1.90 (d, J=12.1Hz, 2H), 1.78–1.71 (m, 1H).

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

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

Dissolve 100 mg of the racemate compound of Example 8 in methanol solution, and separate under the following chiral preparative chromatography column and chiral separation conditions to obtain 43 mg of the target product (retention time: 65.193 min, relative content: 49.96%, named for the S configuration). ESI-MS: 500 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (dt, J=4.8, 1.5 Hz, 1H), 7.94 (s, 1H), 7.78 (td, J= 7.7, 1.8Hz, 1H), 7.67 (d, J=7.9Hz, 1H), 7.52 (d, J=2.1Hz, 1H), 7.30–7.28 (m, 1H), 7.07 (d, J=8.4Hz, 1H), 6.69(dd, J＝16.7, 10.5Hz, 1H), 6.46(s, 1H), 6.29(d, J＝16.9Hz, 1H), 5.67(d, J＝10.1Hz, 1H), 5.37( s,1H),5.33(s,2H),4.86(d,J=13.1Hz,0.5H),4.58(d,J=13.3Hz,0.5H),4.39(d,J=13.1Hz,0.5H) ,4.00(d,J＝13.2Hz,0.5H),3.44(s,1H),3.15(q,J＝13.0,11.0Hz,1H),2.99(t,J＝11.8Hz,0.5H),2.87( t, J=11.9Hz, 0.5H), 2.25 (d, J=10.3Hz, 1H), 1.90 (d, J=12.1Hz, 2H), 1.78–1.71 (m, 1H).

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

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

The following synthetic route was used:

Step 1(R)-3-(4-Amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)imidazo[5,1-f][1,2,4 Synthesis of ]triazin-7-yl)piperidine-1-carboxylic acid benzyl ester

Intermediate A5 (330 mg, 0.76 mmol), Intermediate B4 (342 mg, 0.99 mmol), Pd(dppf)Cl2 (30 _mg , 0.04 mmol) and _Na2CO3 (244 mg, _2.3 mmol) were added to 12 mL of DME and 4 mL In water, nitrogen was replaced three times, and the temperature was raised to 90°C for overnight reaction. The reaction solution was cooled to room temperature, 30 mL of water was added, 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 285 mg of a pale yellow solid with a yield of 285 mg. 66%. ESI-MS:571[M+1] ⁺ .

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

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

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

(R)-5-(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(piperidin-3-yl)imidazo[5,1-f][1, 2,4] Triazin-4-amine (180 mg, 0.41 mmol) and triethylamine (83 mg, 0.82 mmol) were dissolved in 10 mL of dichloromethane, cooled to -20 °C in an ice bath, and acryloyl chloride (37 mg, 0.41 mmol) was slowly added. mmol), the ice bath was removed after the dropwise addition, and the mixture was stirred at room temperature for 1 hour. 20 mL of water was added to dilute, extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 120 mg of pale yellow solid with a yield of 60%. ESI-MS: 491 [M ⁺ +1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (ddd, J=4.9, 1.8, 1.0 Hz, 1H), 7.87 (d, J=12.4 Hz, 1H) ),7.80–7.70(m,2H),7.63(dt,J=7.9,1.1Hz,1H),7.44(dd,J=8.4,2.2Hz,1H),7.28–7.22(m,1H),7.10( d, J=8.5Hz, 1H), 6.62 (dd, J=16.8, 10.6Hz, 1H), 6.27 (t, J=14.6Hz, 1H), 5.67 (dd, J=20.3, 10.5Hz, 1H), 5.34(s, 2H), 4.89(d, J＝13.1Hz, 0.5H), 4.61(d, J＝13.1Hz, 0.5H), 4.27(d, J＝12.5Hz, 0.5H), 4.03(d, J＝14.0Hz, 0.5H), 3.59-3.40(m, 2H), 3.19(t, J＝13.6Hz, 0.5H), 2.85(t, J＝12.5Hz, 0.5H), 2.25(s, 1H) ,2.04(t,J＝6.2Hz,1H),1.92(d,J＝13.8Hz,1H),1.69(d,J＝14.4Hz,1H).

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

The following synthetic route was used:

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

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

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

To a 25 mL single-neck flask equipped with magnetic stirring, add (R)-3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate tert-butyl ester (310mg, 0.58mmol) and dichloromethane (5mL), TFA (1mL) was added, and the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere . Concentrate to dryness under reduced pressure, add dichloromethane (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL), separate the organic phase, extract the aqueous phase with dichloromethane (20 mL*2), combine the organic phases, dry over anhydrous sodium sulfate, Filter and concentrate to dryness to obtain 252 mg of brown solid, yield 99.2%. LC-MS(APCI): m/z=435.2(M+1) ⁺ .

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

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

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

The following synthetic route was used:

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

Add intermediate B4 (3.0g, 8.7mmol), acetone (60mL) and water (60mL) to the 250mL single-necked flask equipped with magnetic stirring in turn, stir to dissolve, add ammonium acetate (3.36g, 43.5mmol) and high Sodium iodate (7.92 g, 34.77 mmol), the reaction mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. The acetone was evaporated under reduced pressure, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine (60 mL), dried over colorless sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 2.1 g of a white solid with a yield of 91.8%. LC-MS(APCI): m/z=264.1(M+1) ⁺ .

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

To a 50mL there-necked flask equipped with magnetic stirring, add 3-(5-cyano-4-(1,3-dioxoisoindol-2-yl)-1H-pyrrol-3-yl)piperidine-1 - tert-butyl formate (1.26 g, 3.0 mmol), (3-chloro-4-(pyridin-2-ylmethoxy)phenyl)boronic acid (1.58 g, 6.0 mmol) and copper acetate (546 mg, 3.0 mmol) , evacuated and replaced three times with an oxygen balloon, anhydrous dichloromethane (40 mL) and triethylamine (909 mg, 9.0 mmol) were added dropwise, the addition was completed, and the reaction was stirred at room temperature under an oxygen atmosphere overnight. Water (40 mL) and dichloromethane (40 mL) were added, stirred for 10 minutes, the organic phase was separated, the aqueous phase was extracted with dichloromethane (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain White solid 1.0 g, yield 52.3%. LC-MS (APCI): m/z=638.2 (M+1) ^{+ .1} H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.62-8.61 (m, 1H), 8.01-7.98 (m, 2H) ,7.86-7.81(m,2H),7.79-7.76(m,1H),7.58(d,J=2.7Hz,1H),7.40-7.36(m,1H),7.30-7.28(m,1H),7.10 (d, J=9.0Hz, 1H), 6.99(s, 1H), 5.34(s, 2H), 4.06-4.00(m, 1H), 2.85-2.80(m, 2H), 2.56-2.53(m, 1H) ),2.05-1.97(m,1H),1.71-1.67(m,1H),1.54(s,9H),1.51-1.42(m,3H).

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

To a 50 mL single-neck flask equipped with magnetic stirring, add 3-(1-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-cyano-4-(1,3-di Oxoisoindol-2-yl)-1H-pyrrol-3-yl)piperidine-1-carboxylate tert-butyl ester (0.58g, 0.91mmol) and absolute ethanol (10mL), hydrazine hydrate (0.14g) was added dropwise , 2.92 mmol), and the reaction was stirred at room temperature for half an hour under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and the residue was passed through a silica gel column to obtain 350 mg of a white solid with a yield of 65.9%. LC-MS(APCI): m/z=508.2(M+1) ⁺ .

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

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

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

To a 50 mL single-neck flask equipped with magnetic stirring, add 3-(4-amino-5-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5H-pyrrolo[3,2- d] tert-butyl pyrimidin-7-yl)piperidine-1-carboxylate (290 mg, 0.54 mmol) and dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added, and the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. Concentrate to dryness under reduced pressure, add dichloromethane (30 mL) and saturated aqueous sodium bicarbonate solution (20 mL), separate the organic phase, extract the aqueous phase with dichloromethane (30 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, Concentrated to dryness to obtain 225 mg of brown solid, yield 96.9%. LC-MS(APCI): m/z=435.2(M+1) ⁺ .

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

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

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

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

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

Column temperature: 25℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

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

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

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

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

Column temperature: 25℃

Flow rate: 1.0mL/min

UV detection wavelength: 254nm

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

Biological activity test

Biological Example 1: Kinase Inhibition Assay

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

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

The highest concentration of the drug to be tested is 1 μM, 3-fold serial dilution, 12 concentrations. 0.1 μL of drug solutions of various concentrations were added to each well of a 384-well plate (Perkin Elmer, 6007290), which were mixed with 5 μL of EGFR (WT) or 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 (WT) and HER2 (A775_G776insYVMA) kinase activity inhibition test

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

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 solutions of various concentrations were added to each well, mixed with 5 μL of HER2 (WT) or 5 μL of HER2 (A775_G776insYVMA), 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 concentrations in the system were: 20nM HER2, 5μM 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.

Compounds of the present invention were tested in the above kinase inhibition assays and found to have potent activity against EGFR (WT), EGFR (D770_N771insNPG) and HER2 (WT), HER2 (A775_G776insYVMA) kinases. Results for representative example compounds are summarized in Table 1 below.

Table 1

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

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; H1975 cells are EGFR cells with L858R point mutation and T790M point mutation; HCC827 cells are mutant EGFR cells with deletion of exon 19.

To adjust the concentration of A431 (WT EGFR) cells, A549 cells (WT EGFR), H1975 cells (L858R/T790M EGFR) and HCC827 cells (Ex19del), add 50 μL of cell suspension to a 384-well plate, 37°C, 5% CO ₂ . Incubate overnight. 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 exon 19-deleted mutant EGFR and L858R/T790M mutant EGFR with high specificity. Results for representative example compounds are summarized in Table 2 below.

2) Growth of Ba/F3 parental, Ba/F3 EGFR-D770-N771ins_SVD, Ba/F3 EGFR-L858R, Ba/F3 EGFR-L858R/T790M, Ba/F3 EGFR-Del19/T790M and Ba/F3 EGFR-V769_D770insASV cells Test for Inhibitory Activity

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%. Adjust the concentration of Ba/F3 parental, Ba/F3 EGFR-D770-N771ins_SVD, Ba/F3 EGFR-L858R, Ba/F3 EGFR-L858R/T790M, Ba/F3 EGFR-Del19/T790M and Ba/F3 EGFR-V769_D770ins ASV cells, respectively Add 90 μL of cell suspension to a 96-well plate and incubate overnight at 37°C, 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 solutions of various concentrations were added to each well of the 96-well plate, three replicate wells, 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 invention also have potent activity against Ba/F3 EGFR-D770-N771ins_SVD, Ba/F3 EGFR-L858R, Ba/F3 EGFR-L858R/T790M, Ba/F3 EGFR-Del19/T790M and Ba/F3 EGFR-V769_D770insASV cells and high selectivity, it can be seen that the compound of the present invention can inhibit exon 20 insertion mutant EGFR, L858R mutant EGFR, L858R/T790M mutant EGFR and Del19/T790M mutant EGFR with high specificity. Results for representative example compounds are summarized in Tables 2 and 3 below.

Table 2:

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

table 3:

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

Biological Example 3: Testing of Growth Inhibitory Activity Against Cell Lines Expressing Wild Type HER2

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

SK-BR-3 cells and NCI-N87 cells are wild-type HER2 cells. Adjust the concentration of SK-BR-3 cells and NCI-N87 cells, add 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 potent activities on wild-type HER2 SK-BR-3 cells and NCI-N87 cells, which indicated that the compounds of the present invention could be highly specific. Inhibits wild-type HER2. Results for representative example compounds are summarized in Table 4 below.

2) Test of growth inhibitory activity of Ba/F ₃ parental 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 and Ba/F3 HER2-A775_G776insYVMA cells were adjusted, and 90 μL of cell suspension was added to a 96-well plate, respectively, 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 HER2-A775_G776insYVMA cells, and the results of representative example compounds are summarized in Table 4 below.

Table 4:

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

Biological Example 4: 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 combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field 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.

In summary, the present invention relates to the following technical solutions:

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

in,

Ring A is an aromatic ring;

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

A1 is CR _A1 or N _;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

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

B ₁ is CR ₁ or N;

B ₂ is CR ₂ or N;

B ₃ is CR ₃ or N;

B ₄ is CR ₄ or N;

wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6alkynyl} , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O) R _b , -NR _a C (O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _{3 -7} cycloalkyl, 3 to 7 membered heterocyclyl, _C6-10 aryl or 5 to 10 membered heteroaryl, optionally substituted with one or more R";

L is selected from O, S or NR _L ;

wherein R _L is selected from H or C _1-6 alkyl, and is optionally substituted with one or more R*;

V is (CR _V1 R _V2 ) _o ;

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

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

R ₆ is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C _6-10 aryl, or 5 to 10-membered heteroaryl, optionally substituted with one or more R*;

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

R is each independently selected from H, D, halogen, -CN, =O, _C1-6 alkyl, _C1-6 haloalkyl, _C2-6 alkenyl, _C2-6 alkynyl, -C(O )R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl; alternatively, two R groups on the same or adjacent atoms can be taken together to form a _C3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;

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

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

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

p=0, 1 or 2;

R" is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C ( O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , - NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl, alternatively, two R" groups on the same or adjacent atoms can be taken together to form a _C3-7 cycloalkyl, 3 to 7 membered heterocyclyl, _C6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the R" definition is optionally substituted with one or more D until fully deuterated;

R* is each independently selected from H, D, halogen, -CN, =O, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C ( O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , - NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , C _3-7 cycloalkyl, 3 to 7-membered heterocyclyl, _C6-10 aryl, or 5- to 10-membered heteroaryl; alternatively, two R* groups on the same or adjacent atoms can be taken together to form _{C3-7cycloalkyl} , 3 to 7 membered heterocyclyl, _C6-10 aryl, or 5 to 10 membered heteroaryl; wherein each group in the R* definition is optionally substituted with one or more D until fully deuterated;

R _a , R _b and R _c are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl , 3 to 7 membered heterocyclyl, _C6-10 aryl or 5 to 10 membered heteroaryl, or R and R together with the N atom to which they are attached form _{a 3} to 7 membered heterocyclyl or 5 to 10 A membered heteroaryl; wherein each group in the definitions of R _a , R _b and R _c is optionally substituted with one or more D until fully deuterated.

2. The compound according to technical scheme 1, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein,

选自以下结构：

Choose from the following structures:

Preferably,

选自以下结构：

Choose from the following structures:

Preferably,

选自以下结构：

Choose from the following structures:

3. The compound according to technical scheme 1 or 2, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein ring C is phenyl or 5- to 6-membered heteroaryl; preferably phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, Thiazolyl, isothiazolyl, furyl or thienyl; preferably phenyl or pyridyl.

4. The compound according to any one of technical schemes 1-3, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, Wherein, V is (CH ₂ ) _o ; preferably CH ₂ .

5. The compound according to any one of technical solutions 1-4, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, where L is O.

6. The compound according to any one of technical solutions 1-5, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, Wherein, B ₁ is CR ₁ , B ₂ is CR ₂ , B ₃ is CR ₃ , and B ₄ is CR ₄ ; preferably, R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl.

7. The compound according to any one of technical solutions 1-6, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, in,

选自以下结构：

Choose from the following structures:

Preferably:

8. The compound according to any one of technical schemes 1-7, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, It is a compound of the following general formula:

Wherein each group is as defined in any one of technical solutions 1-7.

9. The compound according to technical scheme 8, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, which is of formula (II- 1), (III-1) or (IV-1) compound:

in,

Ring A is an aromatic ring;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

wherein R _A4 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, and is optionally substituted by one or more R";

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

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

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

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

o=1, 2, 3 or 4;

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

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

p=0, 1 or 2;

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

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

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

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

R" is each independently selected from H, D, halogen, _-CN , =O, _-ORa or _-NRbRc ;

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

10. The compound according to technical scheme 9, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, which is of formula (II- 2), (III-2) or (IV-2) compound:

in,

Ring A is an aromatic ring;

A ₂ is C or N;

A ₄ is CR _A4 or N;

A ₅ is C or N;

wherein R _A4 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, and is optionally substituted by one or more R";

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

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

o=1, 2, 3 or 4;

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

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

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

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

R" is each independently selected from H, D, halogen, _-CN , =O, _-ORa or _-NRbRc ;

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

11. The compound according to technical scheme 8, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, which is of formula (V- 1) or (VI-1) compound:

in,

A1 is CR _A1 or N _;

wherein R _A1 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, which is optionally substituted with one or more R";

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

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

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

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

o=1, 2, 3 or 4;

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

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

p=0, 1 or 2;

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

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

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

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

R" is each independently selected from H, D, halogen, _-CN , =O, _-ORa or _-NRbRc ;

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

12. The compound according to technical scheme 11, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, which is of formula (V- 2) or (VI-2) compound:

in,

A1 is CR _A1 or N _;

wherein R _A1 is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 alkoxy, and is optionally substituted with one or more R";

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

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

o=1, 2, 3 or 4;

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

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

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

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

R" is each independently selected from H, D, halogen, _-CN , =O, _-ORa or _-NRbRc ;

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

13. A compound or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, selected from the group consisting of:

14. A pharmaceutical composition comprising the compound of any one of technical solutions 1-13 or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof substances, and pharmaceutically acceptable excipients.

15. The compound of any one of technical solutions 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or technical solution 14 Use of the pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of wild-type and/or mutated EGFR kinase-mediated tumors;

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

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

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

Preferably, wherein the mutated EGFR also simultaneously has the T790M mutation.

16. The compound of any one of technical solutions 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or technical solution 14 Use of the pharmaceutical composition of the invention 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.

17. The compound of any one of technical solutions 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or technical solution 14 Use of the pharmaceutical composition in the preparation 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 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;

Preferably, wherein the ex20insYVMA mutant HER2 is selected from A775_G776insYVMA mutant HER2 mutations.

18. The compound of any one of technical solutions 1-13 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or technical solution 14 Use of the 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.

Claims (39)

1. A compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof:

wherein,

ring A is an aromatic ring;

ring C is phenyl or 5 to 6 membered heteroaryl;

selected from the following structures:

B ₁ is CR ₁ ；

B ₂ Is CR ₂ ；

B ₃ Is CR ₃ ；

B ₄ Is CR ₄ ；

Wherein R is ₁ 、R ₂ 、R ₃ And R ₄ Each independently selected from H, D, halogen or-CN;

l is O;

v is (CR) _V1 R _V2 ) _o ；

Wherein R is _V1 And R _V2 Each independently selected from H, D, halogen or C _1-6 An alkyl group;

o＝1；

R ₆ is H or D;

R ₅ and R ₇ Each is independently selected from H or D;

each R is independently selected from H or D;

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

each R' is independently selected from H or D;

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

p＝1。

2. the compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, wherein,

selected from the following structures:

3. the compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, ring C is phenyl or pyridyl.

4. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, V is CH ₂ 。

5. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, R ₁ 、R ₂ 、R ₃ And R ₄ Independently selected from H or D.

6. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein,

the structure is as follows:

7. the compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, wherein,

the structure is as follows:

8. the compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

9. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

10. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

11. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

12. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

13. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

14. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

15. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

16. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

17. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

18. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of the general formula:

wherein each group is as defined in any one of claims 1 to 7.

19. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II-1):

wherein,

ring A is an aromatic ring;

selected from the following structures:

R ₁ is H, D, halogen or-CN;

R ₂ is H, D, halogen or-CN;

R ₃ is H, D, halogen or-CN;

R ₄ is H, D, halogen or-CN;

o =1; each R is independently selected from H or D;

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

p =1; each R' is independently selected from H or D;

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

R ₅ 、R ₆ and R ₇ Each independently selected from H or D.

20. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (III-1):

wherein,

selected from the following structures:

the remaining groups are as defined in claim 19.

21. The compound of claim 2, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (IV-1):

wherein,

the structure is as follows:

the remaining groups are as defined in claim 19.

22. The compound of claim 2, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II-2):

wherein,

ring A is an aromatic ring;

selected from the following structures:

R ₁ is H, D, halogen or-CN;

R ₂ is H, D, halogen or-CN;

o＝1；

each R is independently selected from H or D;

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

each R' is independently selected from H or D;

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

23. The compound of claim 2, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (III-2):

wherein,

selected from the following structures:

the remaining groups are as defined in claim 22.

24. The compound of claim 2, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (IV-2):

wherein,

the structure is as follows:

the remaining groups are as defined in claim 22.

25. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (V-1):

wherein,

A ₁ is CH or N;

R ₁ is H, D, halogen or-CN;

R ₂ is H, D, halogen or-CN;

R ₃ is H, D, halogen or-CN;

R ₄ is H, D, halogen or-CN;

o＝1；

each R is independently selected from H or D;

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

p＝1；

each R' is independently selected from H or D;

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

R ₅ 、R ₆ and R ₇ Each independently selected from H or D.

26. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (VI-1):

wherein each group is as defined in claim 25.

27. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (V-2):

wherein,

A ₁ is CH or N;

R ₁ is H, D, halogen or-CN;

R ₂ is H, D, halogen or-CN;

o＝1；

each R is independently selected from H or D;

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

each R' is independently selected from H or D;

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

28. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (VI-2):

wherein each group is as defined in claim 27.

29. A compound, or tautomer, stereoisomer, pharmaceutically acceptable salt thereof, selected from the group consisting of:

30. a pharmaceutical composition comprising a compound of any one of claims 1-29, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

31. Use of a compound of any one of claims 1-29, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, for the preparation of a medicament for the treatment and/or prevention of a wild type and/or mutant EGFR kinase-mediated tumor.

32. The use of claim 31, wherein the mutated EGFR is selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR.

33. The use of claim 32, wherein the exon 20 insertion mutation is selected from V769_ D770insASV, D770_ N771insSVD, D770_ N771insNPG, D770_ N771insG, H773_ V774insNPH or H773_ V774insPH;

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

wherein the exon 21 point mutation is selected from the group consisting of the L861Q mutation.

34. The use of claim 32, wherein the mutant EGFR also simultaneously has a T790M mutation.

35. Use of a compound of any one of claims 1-29, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, for the preparation of a medicament for the treatment and/or prevention of: lung cancer, breast cancer, head and neck cancer, brain cancer, uterine cancer, hematopoietic cancer or skin cancer.

36. Use of a compound according to any one of claims 1 to 29, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30, for the preparation of a medicament for the treatment and/or prevention of a wild-type and/or mutant HER2 kinase-mediated tumor.

37. The use of claim 36, 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 HER2, L755S mutant HER2, or ex20 insymva mutant HER2.

38. The use of claim 37, wherein the ex20insYVMA mutant HER2 is selected from a775_ G776insYVMA mutant HER2 mutation.

39. Use of a compound of any one of claims 1-29, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, for the preparation of a medicament for the treatment and/or prevention of: lung cancer, gastric cancer or breast cancer.