CN113493439A

CN113493439A - Substituted acrylamide derivative, composition and application thereof

Info

Publication number: CN113493439A
Application number: CN202110293647.8A
Authority: CN
Inventors: 王义汉; 赵九洋; 邢青峰; 李焕银; 艾义新
Original assignee: Shenzhen Targetrx Inc
Current assignee: Shenzhen Targetrx Inc
Priority date: 2020-03-20
Filing date: 2021-03-19
Publication date: 2021-10-12
Anticipated expiration: 2041-03-19
Also published as: CN113493439B; WO2021185348A1

Abstract

The invention provides a substituted acrylamide derivative, a composition containing the same and application thereof, wherein the substituted acrylamide derivative is a compound shown as a formula (I) or a tautomer, a stereoisomer, a prodrug, a crystal form and a pharmaceutical aspect thereofAn acceptable salt, hydrate or solvate. The compounds of the invention and compositions thereof are useful for the treatment and/or prevention of tumors mediated by the wild type and/or mutant EGFR and/or HER2 kinase.

Description

Substituted acrylamide derivative, composition and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to substituted acrylamide derivatives with an inhibitory effect on wild and/or mutant EGFR and/or HER2, pharmaceutical compositions containing the same, and preparation methods and applications of the same.

Background

EGFR is a receptor tyrosine kinase that exerts its physiological function in normal tissues by binding to epidermal growth factor (hereinafter also referred to as EGF) as a ligand, and contributes to growth and apoptosis inhibition of epithelial tissues. Somatic mutations in the EGFR gene are known to be carcinogenic: for example, EGFR lacking 746 th to 750 th amino acids in the exon 19 region (hereinafter also referred to as "exon 19 deletion mutation") and EGFR lacking the leucine th to arginine in the exon 21 region (hereinafter also referred to as "L858R mutation") continuously induce EGF-independent kinase activity and cause 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 also in about 10% of non-small cell lung cancers in europe and the united states, and thus 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 applied to 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 side effects such as digestive tract diseases and skin diseases when used in therapeutic doses thereof.

Recent studies have found that EGFR of some cancers has a novel mutation in which one or more amino acids are inserted into the exon 20 region (hereinafter also referred to as "exon 20 insertion mutation"), and these cancers have low sensitivity to previously known EGFR inhibitors.

On the other hand, a number of rare EGFR mutations, such as point mutations or deletion mutations of exon 18 and point mutations of exon 21, have been reported. For example, a novel EGFR point-mutated lung cancer has been found in which glycine at position 719 in the exon 18 region is substituted with an arbitrary amino acid (hereinafter referred to as G719X mutation) and leucine at position 861 in the exon 21 region is substituted with glutamine (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 protooncogene, and gene amplification, mutation, overexpression, and the like of HER2 have been reported in various cancers. In these cancer cells with abnormal and excessive expression of HER2 gene, signals of HER2 and downstream pathways are activated, and thus survival, proliferation signals, and the like of cancer cells are enhanced.

The HER2 mutation is one of the common driver mutations in lung cancer, and is mainly manifested by gene amplification, point mutation, exon 20 insertion mutation and other mutation types (such as deletion insertion mutation, frame shift mutation, etc.), wherein the insertion mutation of exon 20 is the most common. For example, the HER2 mutant contains a YVMA insert into exon 20 (hereinafter referred to as ex20 insYVMA). Mutant HER2 activated signaling, phosphorylated EGFR, induced tumor formation and spread more efficiently than wild-type HER 2.

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

Therefore, there is a need to further develop new EGFR inhibitors and HER2 inhibitors in hopes of being effective in inhibiting wild EGFR and/or exon 20 insertion mutated EGFR, exon 18 point mutated EGFR, exon 21 point mutated EGFR, wild HER2 and/or mutated HER 2.

Summary of The Invention

The invention provides a novel acrylamide derivative, a composition containing the same and application thereof, wherein the acrylamide derivative has better inhibitory activity and high selectivity on exon 20 insertion (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 and the like, and has inhibitory activity on wild HER2 and/or mutant HER2, so that the acrylamide derivative provides an antitumor drug with low toxic and side effects.

In contrast, the invention adopts the following technical scheme:

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:

wherein the content of the first and second substances,

ring A is an aromatic ring;

ring C is C_6-10Aryl or 5 to 10 membered heteroaryl;

A₁is CR_A1Or N;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

wherein R is_A1And R_A4Each independently selected from H, D, halogen, -CN, C_1-6Alkyl or C_1-6Alkoxy, and optionally substituted with one or more R ";

B₁is CR₁Or N;

B₂is CR₂Or N;

B₃is CR₃Or N;

B₄is CR₄Or N;

wherein R is₁、R₂、R₃And R₄Each independently selected from H, D, halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) R_a、-C(O)OR_a、-C(O)NR_bR_c、-NR_bR_c、-NR_aC(O)R_b、-NR_aC(O)OR_b、-NR_aC(O)NR_bR_c、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_bR_c、C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl, and optionally substituted with one or more R ";

l is selected from O, S or NR_L；

Wherein R is_LIs selected from H or C_1-6Alkyl, and optionally substituted with one or more R;

v is (CR)_V1R_V2)_o；

Wherein R is_V1And R_V2Each independently selected from H, D, halogen or C_1-6Alkyl, and optionally substituted with one or more R;

o ═ 1,2, 3,4, 5, or 6;

R₆is H, D, halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5-to 10-membered heteroaryl, optionally substituted with one or more R;

R₅and R₇Each independently selected from H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and the aforementioned groups are optionally substituted with one or more R; or, R₅And R₇Together with the double bond to which they are attached form a triple bond;

each R is independently selected from H, D, halo, -CN, ═ O, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) R_a、-C(O)OR_a、-C(O)NR_bR_c、-NR_bR_c、-NR_aC(O)R_b、-NR_aC(O)OR_b、-NR_aC(O)NR_bR_c、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_bR_c、C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl; alternatively, two R groups on the same atom or on adjacent atoms may together form C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D, up to complete deuteration;

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

r' is independently selected from H, D, halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) R_a、-C(O)OR_a、-C(O)NR_bR_c、-NR_bR_c、-NR_aC(O)R_b、-NR_aC(O)OR_b、-NR_aC(O)NR_bR_c、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_bR_c、C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl, and optionally substituted with one or more R ";

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

p is 0, 1 or 2;

each R "is independently selected from H, D, halo, -CN, ═ O, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) R_a、-C(O)OR_a、-C(O)NR_bR_c、-NR_bR_c、-NR_aC(O)R_b、-NR_aC(O)OR_b、-NR_aC(O)NR_bR_c、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_bR_c、C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5-to 10-membered heteroaryl, or two R' groups on the same atom or on adjacent atoms may together form C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl; wherein each group in the definition of R "is optionally substituted with one or more D, up to complete deuteration;

each R is independently selected from H, D, halogen, -CN, ═ O, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) R_a、-C(O)OR_a、-C(O)NR_bR_c、-NR_bR_c、-NR_aC(O)R_b、-NR_aC(O)OR_b、-NR_aC(O)NR_bR_c、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_bR_c、C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl; alternatively, two R groups on the same atom or on adjacent atoms may together form C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D, up to complete deuteration;

R_a、R_band R_cEach independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5-to 10-membered heteroaryl, or R_bAnd R_cTogether with the N atom to which they are attached form a 3-to 7-membered heterocyclyl or 5-to 10-membered heteroaryl; wherein R is_a、R_bAnd R_cEach group in the definition is optionally substituted with one or more D, up to complete deuteration.

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 solvate thereof, and a pharmaceutically acceptable excipient. In particular embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In particular embodiments, the compounds of the present invention are provided in a prophylactically effective amount.

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

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

In specific embodiments, the mutant 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.

In a specific embodiment, the exon 20 insertion mutation is a mutation wherein one or more amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is a mutation wherein 1 to 7 amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is a mutation wherein 1 to 4 amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is A763_ Y764insFQEA, V769_ D770insASV, D770_ N771insSVD, D770_ N771insNPG, D770_ N771insG, D770> GY, N771_ P772insN, P772_ R773insPR, H773_ V774insNPH, H773_ V774insPH, H773_ V774insAH, H773_ V774insH, H774_ C774insHV, A761_ E762 insEAFQ. In specific embodiments, the exon 20 insertion mutation is V769_ D770insASV, D770_ N771insSVD, D770_ N771insNPG, H773_ V774insNPH, or H773_ V774 insPH.

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

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

In particular embodiments, the mutant EGFR has a T790M mutation and has at least one mutation selected from an exon 20 insertion mutation, an exon 18 point mutation, an exon 21 point mutation, an exon 19 deletion mutation, or an L858R mutation.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used for treating tumor patients expressing EGFR with an exon 20 insertion mutation.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used for treating tumor patients expressing EGFR with the T790M mutation and with an exon 20 insertion mutation.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used for treating a patient having a tumor expressing EGFR with an exon 18 point mutation.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used for treating a tumor patient expressing EGFR having the T790M mutation and having an exon 18 point mutation.

In a specific embodiment, a compound of the invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, is used to treat a tumor patient expressing EGFR with an exon 21 point mutation.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used to treat cancer patients expressing EGFR having the T790M mutation and having an exon 21 point mutation.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used for treating a tumor patient expressing EGFR having an exon 19 deletion mutant.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used to treat cancer patients expressing EGFR having the T790M mutation and having an exon 19 deletion mutant.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used for treating tumor patients expressing EGFR with L858R mutation.

In a specific embodiment, the compounds of the present invention, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, are used for treating tumor patients expressing EGFR with the T790M mutation and with the L858R mutation.

In a specific embodiment, the present invention provides a use of a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of the present invention for the preparation of a medicament for the treatment and/or prevention of the following tumors, or a method for the treatment and/or prevention of the following tumors in a subject, comprising administering a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of the present invention to the subject: lung cancer, breast cancer, head and neck cancer, brain cancer, uterine cancer, hematopoietic cancer or skin cancer.

In another aspect, the present invention provides a use of a compound of the present invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of the present invention, for the preparation of a medicament for the treatment and/or prevention of a tumor mediated by wild-type and/or mutant HER2 kinase.

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

In specific embodiments, the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_ T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C mutant HER2, L755S mutant HER2, or ex20 insymva mutant HER 2.

In particular embodiments, the ex20insYVMA mutant HER2 is selected from a775_ G776insYVMA mutant HER2 mutation.

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

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

Definition of

Chemical definition

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

When a range of values is recited, it is intended to include each value and every subrange within the range. E.g. "C_1-6Alkyl "includes C₁、C₂、C₃、C₄、C₅、C₆、C_1-6、C_1-5、C_1-4、C_1-3、C_1-2、C_2-6、C_2-5、C_2-4、C_2-3、C_3-6、C_3-5、C_3-4、C_4-6、C_4-5And C_5-6An alkyl group.

“C_1-6Alkyl "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_1-4Alkyl 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) Tert-butyl (C)₄) Sec-butyl (C)₄) Isobutyl (C)₄) N-pentyl group (C)₅) 3-pentyl radical (C)₅) Pentyl group (C)₅) Neopentyl (C)₅) 3-methyl-2-butyl (C)₅) Tert-amyl (C)₅) And n-hexyl (C)₆). Each of the alkyl groups is independently optionally substituted, whether or not the alkyl group is pre-modified with "substituted", for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined below.

“C_2-6Alkenyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C_2-4Alkenyl groups are preferred. C_2-6Examples of alkenyl groups include: vinyl radical (C)₂)、1-propenyl (C)₃) 2-propenyl (C)₃) 1-butenyl (C)₄) 2-butenyl (C)₄) Butadienyl radical (C)₄) Pentenyl (C)₅) Pentadienyl (C)₅) Hexenyl (C)₆) And so on. The term "C_2-6Alkenyl "also includes heteroalkenyl groups in which one or more (e.g., 1,2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Each of the alkenyl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents being defined below, whether or not the alkenyl group is modified "substituted" or not.

“C_2-6Alkynyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C_2-4Alkynyl groups are preferred. C_2-6Examples of 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 group (C)₅) Hexynyl (C)₆) And so on. The term "C_2-6Alkynyl also includes heteroalkynyl in which one or more (e.g., 1,2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Each of the alkynyl groups is independently optionally substituted, whether or not the alkynyl group is modified by "substituted", for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined below.

“C_1-6Alkoxy "refers to the group-OR, where R is substituted OR unsubstituted C_1-6An alkyl group. In some embodiments, C_1-4Alkoxy groups are particularly preferred. Specific said alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1, 2-dimethylbutoxy. Each of the alkoxy groups, independently, is optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, whether or not the alkoxy group is modified "substituted" before the alkoxy group,suitable substituents are defined below.

“C_1-6Alkylamino "means a radical-NHR or-NR₂Wherein R is substituted or unsubstituted C_1-6An alkyl group. In some embodiments, C_1-4Alkylamino is particularly preferred. Specific said alkylamino groups include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, methylethylamino and diethylamino. Each of the alkylamino groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents being defined below, whether or not the alkylamino group is modified "substituted" before.

"halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (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_1-6Haloalkyl "and" C_1-6Haloalkoxy "means" C "as defined above_1-6Alkyl "and" C_1-6Alkoxy ", which is substituted with one or more halo groups. In some embodiments, C_1-4Haloalkyl is particularly preferred, more preferably C_1-2A haloalkyl group. In some embodiments, C_1-4Haloalkoxy is particularly preferred, more preferably C_1-2A haloalkoxy group. Exemplary said haloalkyl groups include, but are not limited to: -CF₃、-CH₂F、-CHF₂、-CHFCH₂F、-CH₂CHF₂、-CF₂CF₃、-CCl₃、-CH₂Cl、-CHCl₂2,2, 2-trifluoro-1, 1-dimethyl-ethyl, and the like. Exemplary said haloalkoxy groups include, but are not limited to: -OCH₂F、-OCHF₂、-OCF₃And so on.

“C_3-10Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C_3-7Cycloalkyl is preferred, C_3-6Cycloalkyl is particularly preferred, more preferably C_5-6A cycloalkyl group. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C)₃) Cyclopropenyl group (C)₃) Cyclobutyl (C)₄) Cyclobutenyl radical (C)₄) Cyclopentyl (C)₅) Cyclopentenyl group (C)₅) Cyclohexyl (C)₆) Cyclohexenyl (C)₆) Cyclohexyldienyl (C)₆) Cycloheptyl (C)₇) Cycloheptenyl (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 radical (C)₈) Cyclononyl (C)₉) Cyclononenyl (C)₉) Cyclodecyl (C)₁₀) Cyclodecenyl (C)₁₀) octahydro-1H-indenyl (C)₉) Decahydronaphthyl (C)₁₀) Spiro [4.5 ]]Decyl (C)₁₀) And so on. Each of the cycloalkyl groups is independently optionally substituted, whether or not the cycloalkyl group is modified "substituted", for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined below.

"3-to 10-membered heterocyclyl" is or refers to a group having a ring carbon atom and 1 to 4 ring heteroatoms in a 3-to 10-membered non-aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be carbon or a nitrogen atom, as valency permits. In some embodiments, 3 to 7 membered heterocyclic 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 to 6 membered heterocyclic groups are particularly preferred, which are 3 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a5 to 6 membered heterocyclic group which is a5 to 6 membered non aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems wherein 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 number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Each of the heterocyclic groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents being defined below, whether or not the heterocyclic group is pre-modified with "substituted".

Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxacyclopropaneyl, thienylyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulphuryl), and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thiacyclohexyl (thianyl). Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiinyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepane, oxepanyl and thiepane. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azacyclooctyl, oxocyclooctyl and thietanyl. Exemplary with C₆Aryl ring fused 5-membered heterocyclyl (also referred to herein as 5, 6-bicyclic heterocyclyl) includes, but is not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Exemplary ofAnd C₆Aryl ring fused 6-membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) includes, but is not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“C_6-14Aryl "refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) of 6 to 14 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C)₆Aryl "; for example, phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C)₁₀Aryl "; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C)₁₄Aryl "; for example, an anthracene group). In some embodiments, C_6-10Aryl is particularly preferred, more preferably C₆And (4) an aryl group. 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 the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Each of the aryl groups is independently optionally substituted, whether or not the aryl group is modified "substituted", for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined below.

"5-to 10-membered heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) with ring carbon atoms and 1-4 ring heteroatoms, 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 valency permits. Heteroaryl bicyclic ring systems may 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 number of carbon atoms continues to represent 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. Each of the heteroaryl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents being defined below, whether or not the heteroaryl group is modified "substituted" before.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl 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: a tetrazolyl group. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. 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. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxacycloheptyl, and thiacycloheptyl trienyl groups. Exemplary 5, 6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisothiafuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indezinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryls include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.

"carbonyl" means a-C (O) -group.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OR^aa、-ON(R^bb)₂、-N(R^bb)₂、-N(R^bb)₃ ⁺X^-、-N(OR^cc)R^bb、-SH、-SR^aa、-SSR^cc、-C(＝O)R^aa、-CO₂H、-CHO、-C(OR^cc)₂、-CO₂R^aa、-OC(＝O)R^aa、-OCO₂R^aa、-C(＝O)N(R^bb)₂、-OC(＝O)N(R^bb)₂、-NR^bbC(＝O)R^aa、-NR^bbCO₂R^aa、-NR^bbC(＝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^bbC(＝NR^bb)N(R^bb)₂、-C(＝O)NR^bbSO₂R^aa、-NR^bbSO₂R^aa、-SO₂N(R^bb)₂、-SO₂R^aa、-SO₂OR^aa、-OSO₂R^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)₂R^aa、-OP(＝O)₂R^aa、-P(＝O)(R^aa)₂、-OP(＝O)(R^aa)₂、-OP(＝O)(OR^cc)₂、-P(＝O)₂N(R^bb)₂、-OP(＝O)₂N(R^bb)₂、-P(＝O)(NR^bb)₂、-OP(＝O)(NR^bb)₂、-NR^bbP(＝O)(OR^cc)₂、-NR^bbP(＝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 heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2, 3,4 or 5R^ddSubstituted by groups;

or two geminal hydrogens on a carbon atom are replaced by groups ═ O, ═ S, ═ NN (R)^bb)₂、＝NNR^bbC(＝O)R^aa、＝NNR^bbC(＝O)OR^aa、＝NNR^bbS(＝O)₂R^aa、＝NR^bbOr as NOR^ccSubstitution;

R^aaeach is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R^aaThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2, 3,4 or 5R^ddSubstituted by groups;

R^bbeach independently selected from: hydrogen, -OH, -OR^aa、-N(R^cc)₂、-CN、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)₂N(R^cc)₂、-P(＝O)(NR^cc)₂Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R^bbThe groups combining to form a heterocyclyl or heteroaryl ring, wherein eachEach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2, 3,4 or 5R^ddSubstituted by groups;

R^cceach is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R^ccThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2, 3,4 or 5R^ddSubstituted by groups;

R^ddeach independently selected from: halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OR^ee、-ON(R^ff)₂、-N(R^ff)₂,、-N(R^ff)₃ ⁺X^-、-N(OR^ee)R^ff、-SH、-SR^ee、-SSR^ee、-C(＝O)R^ee、-CO₂H、-CO₂R^ee、-OC(＝O)R^ee、-OCO₂R^ee、-C(＝O)N(R^ff)₂、-OC(＝O)N(R^ff)₂、-NR^ffC(＝O)R^ee、-NR^ffCO₂R^ee、-NR^ffC(＝O)N(R^ff)₂、-C(＝NR^ff)OR^ee、-OC(＝NR^ff)R^ee、-OC(＝NR^ff)OR^ee、-C(＝NR^ff)N(R^ff)₂、-OC(＝NR^ff)N(R^ff)₂、-NR^ffC(＝NR^ff)N(R^ff)₂、-NR^ffSO₂R^ee、-SO₂N(R^ff)₂、-SO₂R^ee、-SO₂OR^ee、-OSO₂R^ee、-S(＝O)R^ee、-Si(R^ee)₃、-OSi(R^ee)₃、-C(＝S)N(R^ff)₂、-C(＝O)SR^ee、-C(＝S)SR^ee、-SC(＝S)SR^ee、-P(＝O)₂R^ee、-P(＝O)(R^ee)₂、-OP(＝O)(R^ee)₂、-OP(＝O)(OR^ee)₂Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2, 3,4 or 5R^ggSubstituted by radicals, or two geminal R^ddSubstituents may combine to form ═ O or ═ S;

R^eeis independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2, 3,4 or 5R^ggSubstituted by groups;

R^ffeach is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R^ffThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2, 3,4 or 5R^ggSubstituted by groups;

R^ggis independently from each other: halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OC_1-6Alkyl, -ON (C)_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₃ ⁺X^-、-NH(C_1-6Alkyl radical)₂ ⁺X^-、-NH₂(C_1-6Alkyl radical)⁺X^-、-NH₃ ⁺X^-、-N(OC_1-6Alkyl) (C_1-6Alkyl), -N (OH) (C)_1-6Alkyl), -NH (OH), -SH, -SC_1-6Alkyl, -SS (C)_1-6Alkyl), -C (═ O) (C)_1-6Alkyl), -CO₂H、-CO₂(C_1-6Alkyl), -OC (═ O) (C)_1-6Alkyl), -OCO₂(C_1-6Alkyl), -C (═ O) NH₂、-C(＝O)N(C_1-6Alkyl radical)₂、-OC(＝O)NH(C_1-6Alkyl radicals),-NHC(＝O)(C_1-6Alkyl), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl), -NHCO₂(C_1-6Alkyl), -NHC (═ O) N (C)_1-6Alkyl radical)₂、-NHC(＝O)NH(C_1-6Alkyl), -NHC (═ O) NH₂、-C(＝NH)O(C_1-6Alkyl), -OC (═ NH) (C)_1-6Alkyl), -OC (═ NH) OC_1-6Alkyl, -C (═ NH) N (C)_1-6Alkyl radical)₂、-C(＝NH)NH(C_1-6Alkyl), -C (═ NH) NH₂、-OC(＝NH)N(C_1-6Alkyl radical)₂、-OC(NH)NH(C_1-6Alkyl), -OC (NH) NH₂、-NHC(NH)N(C_1-6Alkyl radical)₂、-NHC(＝NH)NH₂、-NHSO₂(C_1-6Alkyl), -SO₂N(C_1-6Alkyl radical)₂、-SO₂NH(C_1-6Alkyl), -SO₂NH₂、-SO₂C_1-6Alkyl, -SO₂OC_1-6Alkyl, -OSO₂C_1-6Alkyl, -SOC_1-6Alkyl, -Si (C)_1-6Alkyl radical)₃、-OSi(C_1-6Alkyl radical)₃、-C(＝S)N(C_1-6Alkyl radical)₂、C(＝S)NH(C_1-6Alkyl), C (═ S) NH₂、-C(＝O)S(C_1-6Alkyl), -C (═ S) SC_1-6Alkyl, -SC (═ S) SC_1-6Alkyl, -P (═ O)₂(C_1-6Alkyl), -P (═ O) (C)_1-6Alkyl radical)₂、-OP(＝O)(C_1-6Alkyl radical)₂、-OP(＝O)(OC_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Carbocyclyl, C₆-C₁₀Aryl radical, C₃-C₇Heterocyclic group, C₅-C₁₀A heteroaryl group; or two geminal R^ggSubstituents may combine to form ═ O or ═ S; wherein, X^-Are counter ions.

Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR^aa、-N(R^cc)₂、-CN、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^bb)R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)₂N(R^cc)₂、-P(＝O)(NR^cc)₂Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atom^ccThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2, 3,4 or 5R^ddIs substituted by radicals, and wherein R^aa、R^bb、R^ccAnd R^ddAs described above.

"deuterated" or "D" means that one or more hydrogens of the compound or group are replaced with deuterium; deuterium can be mono-, di-, poly-, or fully substituted. The terms "deuterated one or more" and "deuterated one or more" are used interchangeably.

"non-deuterated compound" refers to a compound containing deuterium at an atomic ratio not higher than the natural isotopic content of deuterium (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 salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al in J.pharmaceutical sciencesPharmaceutically acceptable salts of the compounds described in detail in Nos (1977)66: 1-19. 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 with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Salts formed using methods conventional in the art, e.g., ion exchange methods, are also included. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cypionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, picrate, etc, Stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Other pharmaceutically acceptable salts include, if appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed with counterions such as halide, hydroxide, formate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The "subject" to which the drug is administered includes, but is not limited to: a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and/or a dog. 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.

As used herein, unless otherwise specified, the term "treatment" includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also includes the effect that occurs before the subject begins to have the 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 invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form.

Detailed Description

Compound (I)

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

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

wherein the content of the first and second substances,

ring A is an aromatic ring;

ring C is C_6-10Aryl or 5 to 10 membered heteroaryl;

A₁is CR_A1Or N;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

B₁is CR₁Or N;

B₂is CR₂Or N;

B₃is CR₃Or N;

B₄is CR₄Or N;

l is selected from O, S or NR_L；

v is (CR)_V1R_V2)_o；

o ═ 1,2, 3,4, 5, or 6;

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

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

p is 0, 1 or 2;

Ring C

In one embodiment, ring C is C_6-10An aryl group; 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 a5 to 6 membered heteroaryl containing 1-3 heteroatoms of N, O or S; in another embodiment, ring C is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, or thienyl; in another embodiment, ring C is phenyl or pyridyl; in another embodiment, ring C is pyridyl.

A₁、A₂、A₄And A₅

In one embodiment, A is₁Is CR_A1(ii) a In another embodiment, A₁Is CH; in another embodiment, A₁Is N.

In one embodiment, A is₂Is C; in another embodiment, A₂Is N.

In one embodiment, A is₄Is CR_A4(ii) a In another embodiment, A₄Is CH; in another embodiment, A₄Is N.

In one embodiment, A is₅Is C; in another embodiment, A₅Is N.

In one embodiment of the process of the present invention,

selected from the following structures:

preferably, the first and second electrodes are formed of a metal,

selected from the following structures:

preferably, the first and second electrodes are formed of a metal,

selected from the following structures:

B₁、B₂、B₃and B₄

In one embodiment, B₁Is CR₁(ii) a In another embodiment, B₁Is N.

In one embodiment, B₂Is CR₂(ii) a In another embodiment, B₂Is N.

In one embodiment, B₃Is CR₃(ii) a In another embodiment, B₃Is N.

In one embodiment, B₄Is CR₄(ii) a In another embodiment, B₄Is N.

R₁、R₂、R₃And R₄

In one embodiment, R₁、R₂、R₃And R₄Independently is H; in anotherIn embodiments, R₁、R₂、R₃And R₄Independently is D; in another embodiment, R₁、R₂、R₃And R₄Independently is halogen; in another embodiment, R₁、R₂、R₃And R₄Independently is-CN; in another embodiment, R₁、R₂、R₃And R₄Independently is C_1-6An alkyl group; in another embodiment, R₁、R₂、R₃And R₄Independently is C_1-6A haloalkyl group; in another embodiment, R₁、R₂、R₃And R₄Independently is C_2-6An alkenyl group; in another embodiment, R₁、R₂、R₃And R₄Independently is C_2-6An alkynyl group; in another embodiment, R₁、R₂、R₃And R₄Independently is-C (O) R_a(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-C (O) OR_a(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-C (O) NR_bR_c(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-NR_bR_c(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-NR_aC(O)R_b(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-NR_aC(O)OR_b(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-NR_aC(O)NR_bR_c(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-OR_a(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-OC (O) R_a(ii) a In another embodimentIn, R₁、R₂、R₃And R₄Independently is-OC (O) OR_a(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is-OC (O) NR_bR_c(ii) a In another embodiment, R₁、R₂、R₃And R₄Independently is C_3-7A cycloalkyl group; in another embodiment, R₁、R₂、R₃And R₄Independently is a 3-to 7-membered heterocyclyl; in another embodiment, R₁、R₂、R₃And R₄Independently is C_6-10An aryl group; in another embodiment, R₁、R₂、R₃And R₄Independently a5 to 10 membered heteroaryl.

In another embodiment, R₁、R₂、R₃And R₄Independently selected from H, D, halogen, -CN, C_1-6Alkyl radical, C_1-6Alkoxy or C_3-7A cycloalkyl group; in another embodiment, R₁、R₂、R₃And R₄Independently selected from H, D, halogen, -CN, C_1-6Alkyl or C_1-6An alkoxy group; in another embodiment, R₁、R₂、R₃And R₄Independently selected from H, D, halogen or C_1-6An alkyl group; in another embodiment, R₁、R₂、R₃And R₄Independently selected from H, D, F, Cl or methyl; in another embodiment, R₁、R₂、R₃And R₄Independently selected from H or Cl. In another embodiment, R₂Is halogen, preferably Cl.

In another embodiment, R₁、R₂、R₃And R₄Independently by one or more R ", for example by 1,2, 3,4, 5,6, 7, 8, 9, 10 or more R".

L

In one embodiment, L is O; in another embodiment, L is S; in another embodiment, L isNR_L(ii) a In another embodiment, L is NH.

V

In one embodiment, V is (CR)_V1R_V2)_o(ii) a In another embodiment, V is (CR)_V1R_V2)₁、(CR_V1R_V2)₂、(CR_V1R_V2)₃、(CR_V1R_V2)₄、(CR_V1R_V2)₅Or (CR)_V1R_V2)₆(ii) a In another embodiment, R_V1And R_V2Each independently H, D, halogen or C_1-6An alkyl group; in another embodiment, R_V1And R_V2Are all H. In another embodiment, V is (CH)₂)_o(ii) a Preferably CH₂。

R₆

In one embodiment, R₆Is H; in another embodiment, R₆Is D; in another embodiment, R₆Is halogen; in another embodiment, R₆is-CN; in another embodiment, R₆Is C_1-6An alkyl group; in another embodiment, R₆Is C_1-6A haloalkyl group; in another embodiment, R₆Is C_3-7A cycloalkyl group; in another embodiment, R₆Is a3 to 7 membered heterocyclyl; in another embodiment, R₆Is C_6-10An aryl group; in another embodiment, R₆Is a5 to 10 membered heteroaryl.

In another embodiment, R₆Substituted with one or more R, for example with 1,2, 3,4, 5,6, 7, 8, 9, 10 or more R.

In another embodiment, R₆Selected from H, halogen, -CN, C_1-6Alkyl radical, C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl; in another embodiment, R₆Selected from H, halogen, -CN or C_1-6An alkyl group; in another embodiment, R₆Is selected fromH. F, Cl, Br, -CN, methyl, ethyl, isopropyl, -CH₂N(CH₃)₂、-CH₂N(CH₃)(CH₂CH₃)、-CH₂N(CH₃)(CH(CH₃)₂)、-CH₂N(CH₂CH₃)₂Or

In another embodiment, R₆Selected from H, F, Cl, methyl or-CH₂N(CH₃)₂(ii) a In another embodiment, R₆Selected from H, methyl or-CH₂N(CH₃)₂(ii) a In another embodiment, R₆Is H.

R₅And R₇

In one embodiment, R₅And R₇Each independently is H; in another embodiment, R₅And R₇Each is independently D; in another embodiment, R₅And R₇Each independently is halogen; in another embodiment, R₅And R₇Each independently is-CN; in another embodiment, R₅And R₇Each independently is C_1-6An alkyl group; in another embodiment, R₅And R₇Each independently is C_1-6A haloalkyl group; in another embodiment, R₅And R₇Together with the double bond to which they are attached, form a triple bond.

In another embodiment, R₅And R₇Each independently selected from H, halogen, -CN or C_1-6An alkyl group; in another embodiment, R₅And R₇Each independently selected from H, halogen or CN; in another embodiment, R₅And R₇Each independently selected from H, F, Cl or CN; in another embodiment, R₅And R₇Each independently selected from H or CN; in another embodiment, R₅And R₇Is H.

R and m

In a fruitIn embodiments, 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_1-6An alkyl group; in another embodiment, R is C_1-6A haloalkyl group; in another embodiment, R is C_2-6An alkenyl group; in another embodiment, R is C_2-6An alkynyl group; in another embodiment, R is-C (O) R_a(ii) a In another embodiment, R is-C (O) OR_a(ii) a In another embodiment, R is-C (O) NR_bR_c(ii) a In another embodiment, R is-NR_bR_c(ii) a In another embodiment, R is-NH₂(ii) a In another embodiment, R is-NR_aC(O)R_b(ii) a In another embodiment, R is-NR_aC(O)OR_b(ii) a In another embodiment, R is-NR_aC(O)NR_bR_c(ii) a In another embodiment, R is-OR_a(ii) a In another embodiment, R is-OH; in another embodiment, R is-OC (O) R_a(ii) a In another embodiment, R is-OC (O) OR_a(ii) a In another embodiment, R is-OC (O) NR_bR_c(ii) a In another embodiment, R is C_3-7A cycloalkyl group; in another embodiment, R is a 3-to 7-membered heterocyclyl; in another embodiment, R is C_6-10An aryl group; in another embodiment, R is 5 to 10 membered heteroaryl; in another embodiment, two R groups on the same atom or on adjacent atoms may together form C_3-7A cycloalkyl group; in another embodiment, two R groups on the same atom or on adjacent atoms may together form a 3-to 7-membered heterocyclyl; in another embodiment, two R groups on the same atom or on adjacent atoms may together form C_6-10An aryl group; in another embodiment, two R groups on the same atom or on adjacent atoms may together form a5 to 10 membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D, up to complete deuteration.

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

p

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

In a further embodiment of the process of the present invention,

selected from the following structures:

preferably:

r' and n

In one embodiment, R' is H; in another embodiment, R' is D; in another embodiment, R' is halogen; in another embodiment, R' is — CN; in another embodiment, R' is C_1-6An alkyl group; in another embodiment, R' is C_1-6A haloalkyl group; in another embodiment, R' is C_2-6An alkenyl group; in another embodiment, R' is C_2-6An alkynyl group; in another embodiment, R' is-C (O) R_a(ii) a In another embodiment, R' is-C (O) OR_a(ii) a In another embodiment, R' is-C (O) NR_bR_c(ii) a In another embodiment, R' is-NR_bR_c(ii) a In another embodiment, R' is-NR_aC(O)R_b(ii) a In another embodimentIn the formula, R' is-NR_aC(O)OR_b(ii) a In another embodiment, R' is-NR_aC(O)NR_bR_c(ii) a In another embodiment, R' is-OR_a(ii) a In another embodiment, R' is-OC (O) R_a(ii) a In another embodiment, R' is-OC (O) OR_a(ii) a In another embodiment, R' is-OC (O) NR_bR_c(ii) a In another embodiment, R' is C_3-7A cycloalkyl group; in another embodiment, R' is a3 to 7 membered heterocyclyl; in another embodiment, R' is C_6-10An aryl group; in another embodiment, R' is a5 to 10 membered heteroaryl.

In another embodiment, R' is substituted with one or more R ", for example with 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 another embodiment, R "is ═ O; in another embodiment, R' is C_1-6An alkyl group; in another embodiment, R' is C_1-6A haloalkyl group; in another embodiment, R' is C_2-6An alkenyl group; in another embodiment, R' is C_2-6An alkynyl group; in another embodiment, R' is-C (O) R_a(ii) a In another embodiment, R' is-C (O) OR_a(ii) a In another embodiment, R' is-C (O) NR_bR_c(ii) a In another embodiment, R' is-NR_bR_c(ii) a In another embodiment, R' is-NH₂(ii) a In another embodiment, R' is-NR_aC(O)R_b(ii) a In another embodiment, R' is-NR_aC(O)OR_b(ii) a In a further embodiment of the process of the present invention,r' is-NR_aC(O)NR_bR_c(ii) a In another embodiment, R' is-OR_a(ii) a In another embodiment, R "is-OH; in another embodiment, R' is-OC (O) R_a(ii) a In another embodiment, R' is-OC (O) OR_a(ii) a In another embodiment, R' is-OC (O) NR_bR_c(ii) a In another embodiment, R' is C_3-7A cycloalkyl group; in another embodiment, R "is a3 to 7 membered heterocyclyl; in another embodiment, R' is C_6-10An aryl group; in another embodiment, R "is a5 to 10 membered heteroaryl; in another embodiment, two R "groups on the same atom or on adjacent atoms may together form C_3-7A cycloalkyl group; in another embodiment, two R "groups on the same atom or on adjacent atoms may together form a 3-to 7-membered heterocyclyl; in another embodiment, two R "groups on the same atom or on adjacent atoms may together form C_6-10An aryl group; in another embodiment, two R "groups on the same atom or on adjacent atoms may together form a5 to 10 membered heteroaryl; wherein each group in the definition of R "is optionally substituted with one or more D, up to complete deuteration.

R*

In one embodiment, R is H; in another embodiment, R is D; in another embodiment, R is halogen; in another embodiment, R is-CN; in another embodiment, R is ═ O; in another embodiment, R is C_1-6An alkyl group; in another embodiment, R is C_1-6A haloalkyl group; in another embodiment, R is C_2-6An alkenyl group; in another embodiment, R is C_2-6An alkynyl group; in another embodiment, R is-C (O) R_a(ii) a In another embodiment, R is-C (O) OR_a(ii) a In another embodiment, R is-C (O) NR_bR_c(ii) a In another embodiment, R is-NR_bR_c(ii) a In another embodiment, R is-NH₂(ii) a In another embodiment, R is-NR_aC(O)R_b(ii) a In another embodiment, R is-NR_aC(O)OR_b(ii) a In another embodiment, R is-NR_aC(O)NR_bR_c(ii) a In another embodiment, R is-OR_a(ii) a In another embodiment, R is-OH; in another embodiment, R is-OC (O) R_a(ii) a In another embodiment, R is-OC (O) OR_a(ii) a In another embodiment, R is-OC (O) NR_bR_c(ii) a In another embodiment, R is C_3-7A cycloalkyl group; in another embodiment, R is a3 to 7 membered heterocyclyl; in another embodiment, R is C_6-10An aryl group; in another embodiment, R is a5 to 10 membered heteroaryl; in another embodiment, two R groups on the same atom or on adjacent atoms may together form C_3-7A cycloalkyl group; in another embodiment, two R groups on the same atom or on adjacent atoms may together form a3 to 7 membered heterocyclyl; in another embodiment, two R groups on the same atom or on adjacent atoms may together form C_6-10An aryl group; in another embodiment, two R groups on the same atom or on adjacent atoms may together form a5 to 10 membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D, up to complete deuteration.

R_a、R_bAnd R_c

In one embodiment, R_a、R_bAnd R_cIndependently is H; in another embodiment, R_a、R_bAnd R_cIndependently is C_1-6An alkyl group; in one embodiment, R_a、R_bAnd R_cIndependently is C_1-6A haloalkyl group; in one embodiment, R_a、R_bAnd R_cIndependently is C_3-7A cycloalkyl group; in one embodiment, R_a、R_bAnd R_cIndependently is a 3-to 7-membered heterocyclyl; in one embodiment, R_a、R_bAnd R_cIndependently is C_6-10An aryl group; in one embodiment, R_a、R_bAnd R_cIndependently is a5 to 10 membered heteroaryl; wherein R is_a、R_bAnd R_cEach group in the definition is optionally substituted with one or more D, up to complete deuteration.

Any of the above embodiments, or any combination thereof, may be combined with any of the other embodiments, or any combination thereof. For example, ring C, A₁、A₂、A₄、A₅、B₁、B₂、B₃、B₄、L、V、R₅、R₆、R₇Any technical scheme of R, m, R', n and p or any combination thereof. The present invention is intended to include all combinations of these solutions, limited to space, not listed one by one.

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 thereof, wherein,

selected from the following structures:

preferably, the first and second electrodes are formed of a metal,

selected from the following structures:

preferably, the first and second electrodes are formed of a metal,

selected 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 solvate thereof, 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.

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 thereof, wherein V is (CH)₂)_o(ii) a Preferably CH₂。

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 thereof, 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 thereof, wherein B is₁Is CR₁、B₂Is CR₂、B₃Is CR₃、B₄Is CR₄(ii) a Preferably, R₁、R₂、R₃And R₄Independently selected from H, D, halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl or C_2-6Alkynyl.

selected 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 solvate thereof, which is a compound 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 solvate thereof, which is a compound of formula (II-1), (III-1), or (IV-1):

wherein the content of the first and second substances,

ring A is an aromatic ring;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

wherein R is_A4Is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Alkoxy radical, optionally substituted by oneOr multiple R' substitution;

R₁is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and optionally substituted with one or more R ";

R₂is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and optionally substituted with one or more R ";

R₃is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and optionally substituted with one or more R ";

R₄is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and optionally substituted with one or more R ";

o ═ 1,2, 3, or 4;

each R is independently selected from H, D, halo, -CN, ═ O, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl or C_2-6An alkynyl group; wherein each group in the definition of R is optionally substituted with one or more D, up to complete deuteration;

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

p is 0, 1 or 2;

r' is independently selected from H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and optionally substituted with one or more R ";

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

R₅、R₆and R₇Each independently selected from H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and the aforementioned groups are optionally substituted with one or more R; or, R₅And R₇Together with the double bond to which they are attached form a triple bond;

each R is independently selected from H, D, halogen, -CN, ═ O, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl or C_2-6An alkynyl group; wherein each group in the definition of R is optionally substituted with one or more D, up to complete deuteration;

r' eachIndependently selected from H, D, halogen, -CN, -O, -OR_aor-NR_bR_c；

R_a、R_bAnd R_cEach independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, or R_bAnd R_cTogether with the N atom to which they are attached form a 3-to 7-membered heterocyclyl or 5-to 10-membered heteroaryl; wherein R is_a、R_bAnd R_cEach group in the definition is optionally substituted with one or more D, up to complete deuteration.

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 thereof, which is a compound of formula (II-2), (III-2), or (IV-2):

wherein the content of the first and second substances,

ring A is an aromatic ring;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

wherein R is_A4Is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Alkoxy, optionally substituted with one or more R ";

o ═ 1,2, 3, or 4;

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

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

each R "is independently selected from H, D, halogen, -CN, -O, -OR_aor-NR_bR_c；

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 thereof, which is a compound of formula (V-1) or (VI-1):

wherein the content of the first and second substances,

A₁is CR_A1Or N;

wherein R is_A1Is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Alkoxy, optionally substituted with one or more R ";

o ═ 1,2, 3, or 4;

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

p is 0, 1 or 2;

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

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 thereof, which is a compound of formula (V-2) or (VI-2):

wherein the content of the first and second substances,

A₁is CR_A1Or N;

o ═ 1,2, 3, or 4;

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

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

each R' is independentlySelected from H, D, halogen, -CN, -O, -OR_aor-NR_bR_c；

Each R_a、R_bAnd R_cEach independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, or R_bAnd R_cTogether with the N atom to which they are attached form a 3-to 7-membered heterocyclyl or 5-to 10-membered heteroaryl; wherein R is_a、R_bAnd R_cEach group in the definition is optionally substituted with one or more D, up to complete deuteration.

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 thereof, wherein the compound is selected from the group consisting of:

the compounds of the invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

"tautomer" refers to a compound in which one functional group changes its structure to another functional isomer, and which rapidly interconverts into two isomers in dynamic equilibrium, the two isomers being referred to as tautomers.

One skilled in the art will appreciate that the organic compound may form a complex with a solvent in which it reacts or from which it precipitates or crystallizes. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

The term "solvate" refers to a form of a compound or salt thereof that is combined with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric 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 a 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 associated with an aqueous phase. In general, 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, hydrates of the compounds can be used, for example, of the formula R. x H₂O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrates (x is a number greater than 0 and less than 1), e.g., hemihydrate (R0.5H)₂O)) and polyhydrates (x is a number greater than 1, e.g. dihydrate (R.2H)₂O) and hexahydrate (R.6H)₂O))。

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) in 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, densities, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause a crystalline form to dominate. Various polymorphs of a compound may be prepared by crystallization under different conditions.

The invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the invention, e.g. by incorporation of radioactive isotopes (e.g. by introducing³H and¹⁴C) can be used in drug and/or substrate tissue distribution assays. Tritium, i.e.³H and carbon-14, i.e.¹⁴The C isotopes are particularly preferred because of their ease of preparation and detection. Further, by heavier isotopes, e.g. deuterium, i.e.²H, may be preferred in some cases because of the higher metabolic stability that may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically-labelled compounds of formula (I) and prodrugs thereof according to the invention can generally be prepared by carrying out the procedures described below and/or the examples and preparationsThe disclosed process replaces the non-isotopically labeled reagents with readily available isotopically labeled reagents.

In addition, 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 by hydrolysis, for example in the blood, to its active form with a medicinal effect. 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.bara "Improved oral Delivery: solubility limits overview by the use of drivers, Advanced Drug Delivery Reviews (1996)19(2)115-130, each of which is incorporated herein by reference.

A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a manner such that the modification is effected by routine manipulation or in vivo cleavage to produce the parent compound. Prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, cleaves to form a hydroxy, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of hydroxy, mercapto, and amino functional groups of the compounds of formula (I). In addition, in the case of formic acid (-COOH), esters such as methyl ester, ethyl ester, and the like can be used. The ester itself may be active and/or may hydrolyze under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which readily break down in the human body to release the parent acid or salt thereof.

Treatment of

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

As used herein, "EGFR" refers to the human epidermal growth factor receptor protein, also known as ErbB-1 or HER 1.

Herein, "wild-type EGFR" refers to EGFR without somatic mutations.

Herein, "exon 20 insertion mutation" refers to a mutation in which one or more amino acids (preferably 1 to 7, more preferably 1 to 4) are inserted into the exon 20 region (e.g., amino acid sequence at position 761 to 823) of EGFR; preferably, the mutation is 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 between alanine at position 763 and tyrosine at position 764in the exon 20 region (a763_ Y764 insFQEA); preferably, the mutation is a mutation in which the amino acid sequence ASV (in the order of alanine, serine and valine from the N-terminus) is inserted between valine at position 769 and aspartic acid at position 770in the exon 20 region (V769_ D770 insASV); preferably, the mutation is a mutation in which the amino acid sequence SVD (in the order of serine, valine and aspartic acid from the N-terminus) is inserted between asparagine at position 770 and asparagine at position 771in the exon 20 region (D770-N771 insSVD); preferably, the mutation is a mutation in which the amino acid sequence NPG (asparagine, proline and glycine in this order from the N-terminus) is inserted between aspartic acid at position 770 and asparagine at position 771in the exon 20 region (D770-N771 insNPG); preferably, the mutation is a mutation in which amino acid G (glycine) is inserted between aspartic acid at position 770 and asparagine at position 771 (D770 — N771 insG); preferably, the mutation is a mutation in which aspartic acid at position 770in the exon 20 region is deleted and thereby the amino acid sequence GY (glycine and tyrosine in this order from the N-terminus) is inserted (D770> GY); preferably, the mutation is a mutation in which amino acid N (asparagine) is inserted between asparagine at position 771 and proline at position 772in the exon 20 region (N771_ P772 insN); preferably, the mutation is a mutation in which the amino acid sequence PR (proline and arginine in this order from the N-terminus) is inserted between proline at position 772 and histidine at position 773in the region of exon 20 (P772_ R773 insPR); preferably, the mutation is a mutation in which an amino acid sequence NPH (asparagine, proline and histidine in this order from the N-terminus) is inserted between the 773 rd histidine and the 774 th valine in the exon 20 region (H773_ V774 insNPH); preferably, the mutation is a mutation in which the amino acid sequence PH (proline and histidine in this order from the N-terminus) is inserted between the 773 rd histidine and the 774 th valine in the exon 20 region (H773_ V774 insPH); preferably, the mutation is a mutation in which the amino acid sequence AH (alanine and histidine in this order from the N-terminus) is inserted between the 773 rd histidine and the 774 th valine in the exon 20 region (H773_ V774 insAH); preferably, the mutation is a mutation in which the amino acid H (histidine) is inserted between the 773 rd histidine and the 774 th valine in the exon 20 region (H773_ V774 insH); preferably, the mutation is a mutation in which the amino acid sequence HV (in the order of histidine and valine from the N-terminus) is inserted between valine at position 774 and cysteine at position 775 in the exon 20 region (V774_ C774 insHV); preferably, the mutation is a mutation in which the amino acid sequence EAFQ (in the order of glutamic acid, alanine, phenylalanine and glutamine from the N-terminus) is inserted between alanine at position 761 and glutamic acid at position 762in the exon 20 region (A761_ E762 insEAFQ). More preferably, the mutation is a mutation in which the amino acid sequence ASV (in the order of alanine, serine and valine from the N-terminus) is inserted between valine at position 769 and aspartic acid at position 770in the exon 20 region (V769_ D770 insASV); more preferably, the mutation is a mutation in which the amino acid sequence SVD (in the order of serine, valine and aspartic acid from the N-terminus) is inserted between asparagine at position 770 and asparagine at position 771in the exon 20 region (D770-N771 insSVD); more preferably, the mutation is a mutation in which the amino acid sequence NPG (asparagine, proline and glycine in this order from the N-terminus) is inserted between aspartic acid at position 770 and asparagine at position 771in the exon 20 region (D770-N771 insNPG); more preferably, the mutation is a mutation in which amino acid G (glycine) is inserted between aspartic acid at position 770 and asparagine at position 771in the exon 20 region (D770-N771 insG); more preferably, the mutation is a mutation in which an amino acid sequence NPH (asparagine, proline and histidine in this order from the N-terminus) is inserted between the 773 rd histidine and the 774 th valine in the exon 20 region (H773_ V774 insNPH); more preferably, the mutation is a mutation in which the amino acid sequence PH (proline and histidine in this order from the N-terminus) is inserted between the 773 rd histidine and the 774 th valine in the exon 20 region (H773_ V774 insPH); more preferably, the mutation is a mutation in which the amino acid sequence SVD (in the order of serine, valine and aspartic acid from the N-terminus) is inserted between aspartic acid at position 770 and aspartic acid at position 771in the exon 20 region (D770-N771 insSVD); more preferably, the mutation is a mutation in which amino acid G (glycine) is inserted between aspartic acid at position 770 and asparagine at position 771in the exon 20 region (D770-N771 insG).

Herein, "cancer patient expressing EGFR having exon 20 insertion mutation" refers to a cancer patient expressing EGFR having exon 20 insertion mutation in at least a part of exon 20 region of EGFR. EGFR may have exon 20 insertion mutations in two or more different portions, but preferably one of them. Furthermore, EGFR may also have other mutations in addition to the exon 20 insertion mutation (e.g., exon 19 deletion mutation, L858R mutation, or T790M mutation).

In the present invention, the method for detecting an insertion mutation expressing EGFR exon 20in a cancer patient 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 may be any one of the gene sequence of the EGFR gene, the transcription product of the EGFR gene, and the EGFR protein.

The sample for detecting the 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 (e.g., blood, urine, etc.), tissues, extracts thereof, and cultures from which tissues are obtained. The method of isolating the biological sample may be appropriately selected depending on the type of the biological sample.

The biological sample is prepared by appropriate treatment according to the detection method. In addition, a reagent for detection (for example, a reagent containing a primer or a probe) can be prepared by a conventional method 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 a malignant tumor may be performed prior to administering an anti-tumor agent to the cancer patient.

Herein, "exon 18 point mutation" means a point mutation in an amino acid in the exon 18 region of wild-type EGFR. Preferably, the mutation is a point mutation or a deletion mutation in which 1 amino acid in the exon 18 region is substituted; more preferably, the mutation is a point mutation wherein the glutamic acid encoded by codon 709 in exon 18 is substituted with an arbitrary amino acid (i.e., E790X), and a point mutation wherein the glycine encoded by codon 719 in exon 18 is substituted with an arbitrary amino acid (i.e., G719X). Specifically, E790X may, for example: a point mutation in which the glutamic acid encoded by codon 709 in the region of exon 18 is substituted with lysine (i.e., E709K), and a point mutation in which the glutamic acid encoded by codon 709 in the region of exon 18 is substituted with alanine (i.e., E709A). G719X may for example: a point mutation wherein the glycine encoded by codon 719 in the region of exon 18 is replaced with alanine (i.e., G719A), a point mutation wherein the glycine encoded by codon 719 in the region of exon 18 is replaced with serine (i.e., G719S), and a point mutation wherein the glycine encoded by codon 719 in the region of exon 18 is replaced with cysteine (i.e., G719C), with G719A being most common.

Herein, "exon 18 point mutant EGFR" means EGFR having at least 1 exon 18 point mutation; preferably the EGFR has more than 2 relevant exon 18 point mutations; more preferably, the EGFR has 1 exon 18 point mutation. Furthermore, the EGFR may have other mutations (e.g., exon 19 deletion mutation, L858R mutation, T790M mutation, etc.) other than the exon 18 point mutation.

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

Herein, "exon 21 point mutation" means a point mutation in the amino acids of the exon 21 region of wild-type EGFR. Preferably, the exon 21 point mutation is a point mutation wherein 1 amino acid in the exon 21 region is replaced; more preferably, the exon 21 point mutation is a point mutation wherein the leucine encoded by codon 861 in the region of exon 21 is substituted with any amino acid (i.e.L861X), for example a point mutation wherein the leucine encoded by codon 861 in the region of exon 21 is substituted with glutamine (i.e.L861Q).

Herein, "exon 21 point mutant EGFR" means EGFR having at least 1 exon 21 point mutation; preferably the EGFR has more than 2 relevant exon 21 point mutations; more preferably, the EGFR has 1 exon 21 point mutation. Furthermore, the EGFR may have other mutations (e.g., exon 19 deletion mutation, L858R mutation, T790M mutation, etc.) other than the exon 21 point mutation.

In a specific embodiment, the mutant EGFR is a mutant EGFR having a T790M mutation and having at least one mutation selected from an exon 20 insertion mutation, an exon 18 point mutation, an exon 21 point mutation, an exon 19 deletion mutation or a L858R mutation.

Specifically, the mutant EGFR having the T790M mutation and having a point selected from the group consisting of exon 18 point mutant EGFR and exon 21 point mutant EGFR in the present invention is any one of the following: mutant EGFR having the T790M mutation and having exon 18 region E709X and/or G719X; mutant EGFR with the T790M mutation and with exon 21 region L861X. Specifically any of the following: mutant EGFR having the T790M mutation and having E709K or E709A; EGFR with the T790M mutation and with G719A, G719S, or G719C mutation; (ii) EGFR with the T790M mutation and with L861Q mutation; among these, mutant EGFR with the T790M mutation and with G719A and with T790M mutation and with L861Q are more common.

In this context, the EGFR expressed by a cancer patient is detected as having a point mutation of exon 18 and/or exon 21 as long as the mutation can be detected, and a known detection method can be used.

The sample for detecting the 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, particularly a sample obtained from a cancer patient and containing malignant tumor cells. Examples of biological samples include body fluids (e.g., blood, urine, etc.), tissues, extracts thereof, and cultures from which tissues are obtained. The method of isolating the biological sample may be appropriately selected depending on the type of the biological sample.

In one embodiment of the invention, the step of detecting the presence of exon 18 and/or exon 21 point mutations expressed in a patient with a malignant tumor may be performed prior to administering an anti-neoplastic agent to the cancer patient.

Specific examples of mutated EGFR kinase-mediated tumors of the present invention include, but are not limited to: head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, bile duct cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer and rectal cancer), and the like), lung cancer (e.g., non-small cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer, and endometrial cancer), and the like), urinary tract cancer (e.g., renal cancer, bladder cancer, prostate cancer, and testicular cancer), hematopoietic tumors (e.g., leukemia, malignant lymphoma, and multiple myeloma), osteosarcoma, soft tissue sarcoma, skin cancer, brain tumor, and the like. Preferred examples include lung cancer, breast cancer, head and neck cancer, brain cancer, uterine cancer, hematopoietic cancer or skin cancer.

In particular embodiments, the mutant EGFR has the T790M mutation and has a mutation selected from the group consisting of exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, and L858R mutant EGFR.

The present invention also provides a method for treating a patient having a tumor comprising the step of administering an effective amount of an antitumor agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient expressing a tumor having an exon 20 insertion mutant EGFR, an exon 18 point mutant EGFR, an exon 21 point mutant EGFR, an exon 19 deletion mutant EGFR or an L858R mutant EGFR.

The invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in treating a patient expressing a tumor having an expression 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.

The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a patient having a tumor 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.

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

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

(2) a step of predicting that chemotherapy is most likely to exhibit a sufficient therapeutic effect on a patient when the result of the detection in step (1) reveals that the EGFR gene has a mutation selected from the group consisting of an exon 20 insertion mutation, an exon 18 point mutation, an exon 21 point mutation, an exon 19 deletion mutation and an L858R mutation.

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

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

(2) a step of treating the patient with the compound of the present invention or a pharmaceutically acceptable salt thereof when the EGFR gene is found to have a mutation selected from the group consisting of an exon 20 insertion mutation, an exon 18 point mutation, an exon 21 point mutation, an exon 19 deletion mutation and an L858R mutation as a result of the examination in step (1).

Herein, "HER 2" includes HER2 of a human or non-human mammal. Also, the term "HER 2" includes the subtype.

In the present invention, the HER2 kinase-mediated tumor is preferably a tumor having HER2 overexpression, HER2 gene amplification or HER2 mutation. The "tumor" is not particularly limited, and examples thereof include head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder-bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone-soft tissue sarcoma, hematological cancer, multiple myeloma, skin cancer, brain tumor, and mesothelial cancer. Preferred are breast cancer, gastric cancer, esophageal cancer, ovarian cancer, lung cancer, esophageal cancer, gallbladder-bile duct cancer, biliary tract cancer, bladder cancer, and colon cancer, more preferred are breast cancer, gastric cancer, esophageal cancer, biliary tract cancer, ovarian cancer, lung cancer, and esophageal cancer, and further preferred are breast cancer, gastric cancer, and lung cancer.

In the methods of treatment 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 dose of a compound of the invention can be determined by conventional methods (e.g., modeling, dose escalation, or clinical trials) and by conventional factors (e.g., the mode or route of drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the health and weight of the individual, and the judgment of the treating physician). Exemplary doses are in the range of about 0.1mg to 1g per day, or about 1mg to 50mg per day, or about 50mg to 250mg per day, or about 250mg to 1g per day. The total dose can be administered as a single dose or as separate dosage units (e.g., BID, TID, QID).

After the patient has developed an improvement in the disease, the dosage can be adjusted for prophylactic or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced to an amount that maintains the desired therapeutic or prophylactic effect, depending on the symptoms. Of course, if the symptoms have been alleviated to an appropriate degree, treatment may be discontinued. However, when either symptom recurs, the patient may require long-term intermittent treatment. Patients may also require chronic treatment for extended periods of time.

Pharmaceutical compositions, formulations and kits

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

Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may 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, partial glyceride mixtures 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

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

The pharmaceutical compositions provided by the present invention may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implant or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intracerebrospinal 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 a physician, as the case may be, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

When used to prevent a condition according to the invention, a subject at risk of developing the condition is administered a compound provided herein, typically based on physician's advice and under the supervision of a physician, at a dosage level as described above. Subjects at risk of developing a particular disorder, typically include subjects with a family history of the disorder, or those determined to be particularly susceptible to developing the disorder by genetic testing or screening.

The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). By long-term administration is meant administration of the compound or pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue for an indefinite period of time, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within the therapeutic window.

Various methods of administration may 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, e.g., in order to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the targeted systemic level of the active ingredient, e.g., an intramuscular or subcutaneous bolus dose results in a slow release of the active ingredient, while a bolus delivered directly to the vein (e.g., by IV intravenous drip) can be delivered more rapidly, allowing the concentration of the active ingredient in the blood to rise rapidly to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV intravenous drip, 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 continuous infusion.

Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the compositions are provided in unit dosage form for convenient administration of the precise dosage. 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 the purpose of producing the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful in forming the desired form of administration.

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

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

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

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, as well as buffers, suspending and dispersing agents, coloring and flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds with similar properties: a binder, for example, microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example, starch or lactose, disintegrants, for example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, e.g., colloidal silicon dioxide; sweetening agents, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.

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

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 as a cream with a cream base, for example of the oil-in-water type. 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 means. Thus, transdermal administration can be achieved using a reservoir (reservoir) or porous membrane type, or a patch of various solid matrices.

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

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

The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation 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 one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, e.g., U.S.5,376,645. In some embodiments, the formulation includes hexapropyl- β -cyclodextrin (e.g., 10-50% in water).

Pharmaceutical 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 conditions described herein. Other additional active ingredients include other therapeutic agents or agents that mitigate the adverse effects of treatment against the intended disease target. The combinations can be used to increase efficacy, ameliorate other disease symptoms, reduce one or more side effects, or reduce the required dose of the compounds of the invention. The additional active ingredients may be formulated as separate pharmaceutical compositions from the compounds of the present invention or may be included in a single pharmaceutical composition with the compounds of the present invention. The additional active ingredient may be administered simultaneously with, before or after the administration of the compound of the invention.

Combination agents include those active ingredients known or observed to be effective in treating the diseases and conditions described herein, including those effective against another target associated with the disease. For example, the compositions and formulations of the invention, as well as methods of treatment, may further comprise other drugs, such as other agents useful for treating or ameliorating a target disease or associated symptoms or conditions. For cancer indications, the other agents include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib); raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib); standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormonal therapy, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory agents, such as NSAIDs. The pharmaceutical compositions of the invention may additionally comprise one or more of said active agents, and the method of treatment may additionally comprise administering an effective amount of one or more of said active agents.

Examples

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not specified, in the following examples are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Parts and percentages are parts and percentages by weight unless otherwise indicated.

In general, in the preparative schemes, each reaction is carried out in an inert solvent at temperatures ranging from room temperature to reflux temperature (e.g., 0 ℃ to 100 ℃, preferably 0 ℃ to 80 ℃). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 24 hours.

Abbreviations used herein have the following meanings:

Pd(PPh₃)₄: tetrakis (triphenylphosphine) palladium

Na₂CO₃: sodium carbonate

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

HOBT: 1-hydroxybenzotriazoles

NIS: n-iodosuccinimide

DMF: n, N-dimethylformamide

Pd(dppf)Cl₂: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

MTBE: methyl tert-butyl ether

DME: ethylene glycol dimethyl ether

NBS: n-bromosuccinimide

Cbz: benzyloxycarbonyl group

TEA: triethylamine

DCM: methylene dichloride

ACN: acetonitrile

POCl₃: phosphorus oxychloride

tert-Butyl nitrate: nitrous acid tert-butyl ester

TPP: triphenylphosphine

The DIAD: diisopropyl azodicarboxylate

NH₄OAc: ammonium acetate

DMSO, DMSO: dimethyl sulfoxide

B₂pin₂: biboronic acid pinacol ester

KOAc (Koac): potassium acetate

A Dioxane: dioxane (dioxane)

NaNO₂: sodium nitrite

EtOH: ethanol

NaOH: sodium hydroxide

DIPEA: n, N-diisopropylethylamine

TFAA: trifluoroacetic anhydride

H₂O₂: hydrogen peroxide solution

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

NaH: sodium hydride

THF: tetrahydrofuran (THF)

i-PrOH: isopropanol (I-propanol)

PtO₂: platinum dioxide

EA: ethyl acetate

EtOH: ethanol

Tosmic: p-methylbenzenesulfonylmethylisonitrile

PdCl₂: palladium dichloride

TESiH: triethylsilane

NaIO₄: sodium periodate

Intermediate A13- (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:

adding 3-iodine-1H-pyrazolo [4,3-d ] into a reaction bottle]Pyrimidin-7-amine (1.2g, 4.6mmol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.1g, 6.9mmol), tetrakis (triphenylphosphine) palladium (53mg, 0.05mmol) and sodium carbonate (975mg, 9.2mmol) were added, 20ml dioxane and 2ml water were added and dissolved, the reaction was stirred for 6 hours with heating to 90 ℃ under nitrogen protection, TLC monitored for completion, the solvent was concentrated off and purified by silica gel column chromatography to give 1.17g of product, yield: 80.7 percent. LC-MS (APCI): M/z 317.2(M +1)⁺。

Intermediate A23- (7-amino-1H-pyrazolo [4, 3-d)]Preparation of pyrimidin-3-yl) piperidine-1-carboxylic acid tert-butyl ester

The following synthetic route was used:

adding 3- (7-amino-1H-pyrazolo [4, 3-d) into a reaction bottle]Pyrimidin-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (1.17g, 3.7mmol), catalytic amount of palladium on carbon, adding 20ml of methanol to dissolve, charging hydrogen balloon, stirring at room temperature for 5 hours, detecting by TLC after reaction is completed, filtering to remove the catalyst, concentrating, and purifying by silica gel column chromatography to obtain 1.05g of product with yield: 89 percent. LC-MS (APCI): M/z 319.5(M +1)⁺。

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

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

Adding 2-aminomethyl-3-chloropyrazine hydrochloride (1.0g, 4.62mmol), (R) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (1.11g, 4.85mmol) and HOBT (0.94g, 6.93mmol) into a reaction flask, dissolving with 20ml anhydrous DMF, adding triethylamine (2.34g, 23.1mmol), cooling to 0 ℃ under nitrogen protection, adding EDCI (1.33g, 6.93mmol) in portions, heating to room temperature, stirring for reaction overnight, adding excessive water after TLC monitoring reaction, quenching reaction, extracting with ethyl acetate for 3-4 times, combining organic phases, washing with saturated common salt solution column chromatography, concentrating, purifying, and drying in vacuum to obtain 1.11g of colorless oily product, wherein the yield is as follows: 67.8 percent. LC-MS (APCI): M/z 355.3(M +1)⁺。

Step 2 Synthesis of (R) -3- (8-chloroimidazo [1, 5-alpha ] pyrazin-3-yl) piperidine-1-carboxylic acid tert-butyl ester

Adding (R) -3- (((3-chloropyrazin-2-yl) methyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester (1.0g, 2.82mmol) into a reaction bottle, adding 25ml of anhydrous ethyl acetate under the protection of nitrogen for dissolving, adding 3.7ml of anhydrous DMF, slowly dropwise adding phosphorus oxychloride (2.6g, 17.0mmol) under an ice salt bath, heating to room temperature and stirring for reaction for 1h after the addition is finished, monitoring the reaction by TLC, dropwise adding 20ml of saturated sodium carbonate aqueous solution under an ice bath for quenching reaction, separating out an organic phase, extracting an aqueous phase for 3-4 times by using ethyl acetate, combining the organic phase, washing by using saturated saline solution, concentrating, and purifying by using column chromatography silica gel (petroleum ether: ethyl acetate 2:1) to obtain 0.89g of oily product, wherein the yield is as follows: 93.8 percent. 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

Adding (R) -3- (8-chloroimidazo [1, 5-alpha ] into a reaction bottle]Pyrazin-3-yl) piperidine-1-carboxylic acid tert-butyl ester (0.89g, 2.64mmol) was addedDissolving 10ml DMF, adding NIS (0.62g, 2.77mmol) at room temperature, heating to 50 ℃, stirring for reaction overnight, after TLC monitoring reaction, slowly adding saturated sodium bicarbonate solution to quench the reaction, extracting with ethyl acetate for 3-4 times, combining organic phases, washing with saturated saline, concentrating, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate 2:1) to obtain 1.06g beige solid with yield: 86.9 percent. 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

Adding (R) -3- (8-chloro-1-iodoimidazo [1, 5-alpha ] into a reaction bottle]Pyrazine-3-yl) piperidine-1-carboxylic acid tert-butyl ester (1.06g, 2.29mmol), 8ml 2-butanol was added, ammonia (6.7ml, 176mmol) was added, the reaction was heated to 90 ℃ under closed conditions overnight, cooled to room temperature, TLC monitored the completion of the reaction, diluted with excess water, extracted 3-4 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to remove the solvent, added MTBE, slurried and purified to give 0.89g product, yield: 87.6 percent. LC-MS (APCI) M/z 444.3(M +1)⁺。

Intermediate A43- (4-amino-5-bromopyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester Preparation of esters

The following synthetic route was used:

step 13 Synthesis of tert-butyl 4- (aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Reacting 4-amino-7-bromopyrrolo [2,1-f ]][1,2,4]Triazine (4.69g, 13.6mmol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester(5.04g，16.3mmol)，Pd(dppf)Cl₂(0.5g, 0.68mmol) and Na₂CO₃(4.35g, 41mmol) was added to 70mL DME and 15mL water, purged with nitrogen three times, and allowed to warm to 90 deg.C for overnight reaction. The reaction mixture was cooled to room temperature, 100mL of water was added, extraction was performed with ethyl acetate (60mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 3.21g of a pale yellow solid with a yield of 75%. ESI-MS:316[ M ]⁺+1].

Step 23 Synthesis of tert-butyl 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) piperidine-1-carboxylate

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

Step 33 Synthesis of tert-butyl (4-amino-5-bromopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) piperidine-1-carboxylate

Reacting 3- (4-aminopyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester (2.9g, 9.16mmol) was dissolved in 30mL DMF, NBS (1.78g, 10mmol) was added in portions under ice-bath, and the mixture was allowed to naturally warm to room temperature overnight. After completion of the reaction, 100mL of water was added to the reaction mixture, and extraction was performed with ethyl acetate (40mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 2.54g of a pale yellow solid with a yield of 70%. ESI-MS 398[ M ]⁺+2].

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

The following synthetic route was used:

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

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

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

(R) -piperidine-1, 3-dicarboxylic acid (1-benzyl) (3-succinimidyl) ester (10.15g, 28.2mmol) and 3-amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one acetate (5.67g, 28.2mmol) were dissolved in 100mL acetonitrile, triethylamine (8.54g, 84.6mmol) was added, and the reaction was allowed to warm to 50 ℃ overnight. After the reaction was cooled, 150mL of water was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (80mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 8.07g of a pale yellow solid with a yield of 74%. ESI-MS 387[ M ]⁺+1].

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

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

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

Mixing (R) -3- (2-amino-4-oxo-3, 4-dihydroimidazo [5, 1-f)][1,2,4]Benzyl triazin-7-yl) piperidine-1-carboxylate (5.78g, 15.7mmol) was dissolved in 40mL DMF and NBS (2.94g, 16.5mmol) was added portionwise under ice-bath and allowed to warm to room temperature naturally overnight. After completion of the reaction, 100mL of water was added to the reaction mixture, and extraction was performed with ethyl acetate (50mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 5.77g of a pale yellow solid with a yield of 82%. ESI-MS 449[ M ]⁺+2].

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

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

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

Mixing (R) -3- (5-bromo-4-oxo-3, 4-dihydroimidazo [5, 1-f)][1,2,4]Benzyl triazin-7-yl) piperidine-1-carboxylate (4.79g, 11.1mmol) and 1,2, 4-triazole (2.3g, 33.3mmol) were dissolved in 40mL pyridine, phosphorus oxychloride (5.1g, 33.3mmol) was slowly added dropwise under ice bath, and after the addition was completed, the mixture was allowed to shift to room temperature for reaction for 2 hours. An ammonia-ethanol solution (15mL, 7mol/L) was slowly added dropwise to the reaction mixture in an ice bath, and the mixture was stirred at room temperature for 2 hours after completion of the dropwise addition. The reaction was completed by TLC, the reaction solution was quenched with water, extracted with ethyl acetate (80mL × 3), and the organic phase was washed with 2N hydrochloric acid to pH 5-6, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and isolated with silica gel column to give 3.6g of pale yellow solid with a yield of 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 of

The following synthetic route was used:

4-chloro-5-iodo-7H-pyrrolo [2,3-d ] was added to a 50mL three-necked flask equipped with magnetic stirring in sequence]Pyrimidine (2.50g, 8.95mmol) and anhydrous tetrahydrofuran (40mL), stirred to dissolve, added tert-butyl (S) -3-hydroxypiperidine-1-carboxylate (1.80g, 8.95mmol), cooled to 0 ℃ under nitrogen, added triphenylphosphine (3.05g, 11.63mmol), stirred for 5 minutes, slowly added DIAD (2.35g, 11.63mmol) dropwise, after addition, removed the ice bath and stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100mL), washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was passed through a silica gel column to give 500mg of a white solid with a yield of 12.08%. LC-MS (APCI): M/z 463.1(M +1)⁺.¹H NMR(400MHz,CDCl₃)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 B13- (1-cyano-2-methoxy-2-oxoethyl) piperidine-1-carboxylic acid tert-butyl ester

The following synthetic route was used:

step Synthesis of tert-butyl 13- (1-cyano-2-methoxy-2-oxoethylidene) piperidine-1-carboxylate

To a reaction flask were added tert-butyl 3-oxopiperidine-1-carboxylate (5.0g, 25mmol), methyl 2-cyanoacetate (2.5g, 25mmol) and ammonium acetate (0.25g, 3.25mmol), 25ml toluene and 0.5ml glacial acetic acid were added, the mixture was heated to reflux (water diversion) and stirred for 7 hours, after TLC monitoring the reaction was complete, the solvent was removed by concentration and purified by silica gel column chromatography to give 6.75g colorless oily liquid, yield: 96.4 percent. LC-MS (APCI) M/z 281.1(M +1)⁺。

Step 23 Synthesis of tert-butyl 1- (1-cyano-2-methoxy-2-oxoethyl) piperidine-1-carboxylate (intermediate B1)

Adding 3- (1-cyano-2-methoxy-2-oxoethylene) piperidine-1-carboxylic acid tert-butyl ester (6.75g, 24mmol) and a catalytic amount of palladium-carbon into a reaction bottle, adding 100ml ethanol for dissolving, filling a hydrogen balloon, heating to 50 ℃, stirring for reacting overnight, filtering to remove the catalyst after TLC monitoring reaction, concentrating the filtrate, and purifying by silica gel column chromatography to obtain 6.51g pale yellow oily liquid, wherein the yield is as follows: 96.3 percent. LC-MS (APCI) M/z 283.4(M +1)⁺。

Preparation of intermediate B23-chloro-4- (pyridin-2-ylmethoxy) aniline

The following synthetic route was used:

step 12 Synthesis of- ((2-chloro-4-nitrophenoxy) methyl) pyridine

To a reaction flask were added 2-chloro-4-nitrophenol (5.2g, 30mmol), 2-chloromethylpyridine hydrochloride (5.42g, 33mmol) and anhydrous sodium carbonate (7.95g,75mmol), adding 20ml of anhydrous DMF for dissolution, heating to 80 ℃, stirring for reaction for 4 hours, monitoring by TLC, cooling to room temperature after the reaction is finished, adding excessive water for dilution, extracting for 3-4 times by ethyl acetate, combining organic phases, washing by saturated saline solution, concentrating, and purifying by silica gel column chromatography to obtain 4.5g of a product, wherein the yield is as follows: 56.8 percent. LC-MS (APCI) M/z 265.7(M +1)⁺。

Step Synthesis of 23-chloro-4- (pyridin-2-ylmethoxy) aniline (intermediate B2)

Adding 2- ((2-chloro-4-nitrophenoxy) methyl) pyridine (4.5g, 17mmol) and a catalytic amount of palladium-carbon into a reaction bottle, adding 50ml of ethanol for dissolving, filling a hydrogen balloon, stirring at room temperature for reaction overnight, after the reaction is monitored by TLC, filtering to remove the catalyst, concentrating the filtrate, and purifying by silica gel column chromatography to obtain 3.76g of light yellow oily liquid, wherein the yield is as follows: 94.1 percent. LC-MS (APCI) M/z 235.4(M +1)⁺。

Preparation of intermediate B32- ((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 of DMSO, triethylamine (5.05g, 50mmol) was added, and the reaction was heated at 80 ℃ for 3 hours. The reaction mixture was diluted with 100mL of water, extracted with ethyl acetate (50mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to give 4g of pale yellow solid with a yield of 82%. ESI-MS 300[ M ]⁺+2].

Intermediate B42- ((2-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) Preparation of Yl) methyl) pyridine

The following synthetic route was used:

2- ((4-bromo-2-chlorophenoxy) methyl) pyridine (3.98g, 13.3mmol), pinacol ester diboron (4.06g, 16mmol), Pd (dppf) Cl₂(0.49g, 0.67mmol) and potassium acetate (3.92g, 40mmol) were added to 60mL dioxane, replaced with nitrogen three times, and the temperature was raised to 90 ℃ for reaction for 3 hours. The reaction mixture was cooled to room temperature, 100mL of water was added, extraction was performed with ethyl acetate (60mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 3.45g of a pale yellow solid with a yield of 75%. ESI-MS 346[ M ]⁺+1].

Example 13- (1-Acrylopiperidin-3-yl) -4-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) benzene Preparation of 1H-pyrazole-5-carbonitrile

The following synthetic route was used:

step 13 Synthesis of tert-butyl 1- (2- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) hydrazono) -2-methoxy-2-oxoethyl) piperidine-1-carboxylate

Adding the intermediate B2(468mg, 2mmol) into a reaction bottle, adding 1N hydrochloric acid aqueous solution (5ml, 5mmol) for dissolving, adding sodium nitrite (230mg, 3.33mmol), and stirring at room temperature for half an hour to obtain a solution A; in another reaction flaskAdding intermediate B1(470mg, 1.67mmol), adding 10ml ethanol for dissolving, adding 5ml saturated ammonium chloride aqueous solution under ice bath, then slowly dropwise adding the solution A, stirring at room temperature for reacting overnight, after TLC monitoring reaction, adding a small amount of water for diluting, extracting with ethyl acetate for 3-4 times, combining organic phases, washing with saturated ammonium chloride and saturated saline water once, concentrating, and purifying by silica gel column chromatography to obtain 340mg oily liquid, yield: 40.6 percent. LC-MS (APCI): M/z 503.1(M +1)⁺。

Step 22- (1- (tert-Butoxycarbonyl) piperidin-3-yl) -2- (2- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) hydrazono) acetic acid Synthesis

Adding 3- (1- (2- (3-chloro-4- (pyridine-2-ylmethoxy) phenyl) hydrazono) -2-methoxy-2-oxoethyl) piperidine-1-carboxylic acid tert-butyl ester (340mg, 0.68mmol) into a reaction bottle, adding 15ml tetrahydrofuran for dissolution, adding 3ml aqueous solution of sodium hydroxide (1.2g, 30mmol), stirring at room temperature for reaction overnight, after TLC monitoring reaction is finished, adding 1N diluted hydrochloric acid to adjust pH to acidity, extracting with ethyl acetate for 3-4 times, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating to obtain 310mg of product, and directly putting into the next reaction without purification.

Step 33 Synthesis of tert-butyl 2-amino-1- (2- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) hydrazono) -2-oxoethyl) piperidine-1-carboxylate

2- (1- (tert-butoxycarbonyl) piperidin-3-yl) -2- (2- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) hydrazono) acetic acid (310mg, 0.63mmol), EDCI (243mg, 1.26mmol) and HOBT (171mg, 1.26mmol) were charged into a reaction flask, dissolved with 10ml of dichloromethane, added with ammonia (0.05ml, 1.26mmol) and DIPEA (0.31ml, 1.89mmol) under nitrogen protection, stirred at room temperature for 2 hours, TLC monitored after completion of the reaction, diluted with a small amount of dichloromethane, washed with 1N diluted hydrochloric acid, saturated sodium bicarbonate solution and saturated brine in order, and concentrated and purified by silica gel column chromatography to give 301mg of product in yield: 98 percent. LC-MS (APCI) M/z 488.5(M +1)⁺。

Step 43 Synthesis of tert-butyl 1- (1-cyano-1- (2- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) hydrazono) methyl) piperidine-1-carboxylate

Adding 3- (2-amino-1- (2- (3-chloro-4- (pyridine-2-ylmethoxy) phenyl) hydrazono) -2-oxoethyl) piperidine-1-carboxylic acid tert-butyl ester (392mg, 0.8mmol) and pyridine (0.5ml, 5.6mmol) into a reaction bottle, adding 10ml dichloromethane for dissolving, cooling to 0 ℃ under the protection of nitrogen, slowly dropwise adding trifluoroacetic anhydride (0.6ml, 4.0mmol), stirring at room temperature after the addition is finished for 1 hour, monitoring the reaction by TLC, adding a small amount of dichloromethane for dilution, washing with 1N diluted hydrochloric acid, saturated sodium bicarbonate solution and saturated saline solution in turn, drying anhydrous sodium sulfate, concentrating to dryness, and directly putting into the next reaction without purification.

Step 53- (4-amino-5-cyano-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester Synthesis

Directly dissolving the intermediate obtained in the previous step in 15ml of tert-butyl alcohol, adding bromoacetonitrile (0.11ml, 1.61mmol), adding potassium tert-butoxide (270mg, 2.41mmol) in batches under the protection of nitrogen, stirring at room temperature for 2 hours for reaction, adding a small amount of water after TLC monitoring reaction is finished, quenching the reaction, extracting with ethyl acetate for 3-4 times, combining organic phases, washing with saturated saline, concentrating, and purifying by silica gel column chromatography to obtain 250mg of light yellow solid, wherein the yield is as follows: 61.1 percent. LC-MS (APCI): M/z 509.7(M +1)⁺。

Step 63 Synthesis of (1-acryloylpiperidin-3-yl) -4-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazole-5-carbonitrile

To a reaction flask was added tert-butyl 3- (4-amino-5-cyano-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazol-3-yl) piperidine-1-carboxylate (120mg, 0.24mmol), 4N ethyl hydrogen chloride acetate solution (2.5ml, 10mmol) was added under nitrogen protection, the reaction was stirred at room temperature for 1H, and after completion of the TLC monitoring, the reaction was concentrated to dryness and directly charged to the next step.

Adding 5ml of anhydrous dichloromethane and triethylamine (0.07ml, 0.47mmol) into the intermediate, dropwise adding acryloyl chloride (22.4mg, 0.25mmol) under ice bath, stirring after the addition is finished, reacting for 10 minutes, then monitoring the reaction by TLC, adding dichloromethane for dilution, washing by water and saturated saline in turn, concentrating, and purifying by silica gel column chromatography to obtain 80mg of off-white solid, wherein the yield is as follows: 73.4％。LC-MS(APCI):m/z＝463.5(M+1)⁺。¹H NMR(400MHz,DMSO-d₆)δ8.53(d,J＝2.3Hz,1H),8.13(t,J＝4.6Hz,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 23- (1-Acrylopiperidin-3-yl) -4-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) benzene Preparation of 1H-pyrrole-5-carboxamides

The following synthetic route was used:

step Synthesis of tert-butyl 13- (4-amino-5-carbamoyl-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazol-3-yl) piperidine-1-carboxylate

Adding 3- (4-amino-5-cyano-1- (3-chloro-4- (pyridine-2-ylmethoxy) phenyl) -1H-pyrazole-3-yl) piperidine-1-carboxylic acid tert-butyl ester (150mg, 0.29mmol) into a reaction bottle, adding 5ml of methanol for dissolving, adding 3ml of aqueous solution of sodium hydroxide (240mg, 6mmol), dropwise adding 30% hydrogen peroxide (1ml) under ice bath, heating to room temperature, stirring for reaction for 3 hours, adding ethyl acetate for extraction for 3-4 times after TLC monitoring reaction, combining organic phases, washing with saturated saline, concentrating, and purifying by silica gel column chromatography to obtain 113mg of target product, wherein the yield is as follows: 74.1 percent. LC-MS (APCI) M/z 527.9(M +1)⁺。

Step synthesis of 23- (1-acryloylpiperidin-3-yl) -4-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazole-5-carboxamide

To a reaction flask was added tert-butyl 3- (4-amino-5-carbamoyl-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazol-3-yl) piperidine-1-carboxylate (113mg, 0.22mmol), 4N ethyl hydrogen chloride acetate solution (2.5ml, 10mmol) was added under nitrogen protection, the reaction was stirred at room temperature for 1H, and after completion of the TLC monitoring, the reaction was concentrated to dryness and directly charged to the next step.

Adding 5ml of anhydrous dichloromethane and triethylamine (0.06ml, 0.43mmol) into the intermediate, dropwise adding acryloyl chloride (20.4mg, 0.23mmol) under ice bath, stirring after the addition is finished, reacting for 10 minutes, then monitoring the reaction by TLC, adding dichloromethane for dilution, washing by water and saturated saline in turn, concentrating, and purifying by silica gel column chromatography to obtain 82mg of off-white solid, wherein the yield is as follows: 79.5 percent. LC-MS (APCI) M/z 481.3(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ10.47(s,2H),8.33(d,J＝2.4Hz,1H),8.10(t,J＝4.6Hz,1H),7.75(s,1H),7.70(d,J＝4.6Hz,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 31- (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 Synthesis of tert-butyl 13- (7-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazolo [4,3-d ] pyrimidin-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Intermediate A1(60mg, 0.2mmol), intermediate B3(120mg, 0.4mmol), N-dimethylglycine (13mg, 0.12mmol) and cuprous iodide (8mg, 0.04mmol) were added to a reaction flask, and nitrogen was maintained under vacuumAdding 3ml of anhydrous DMF under the protection, adding DBU (92mg, 0.6mmol), heating to 110 ℃ after the addition is finished, stirring and reacting for 20 hours, adding saturated ammonium chloride to quench the reaction after the TLC monitoring reaction is finished, extracting for 3-4 times by using ethyl acetate, combining organic phases, washing by using saturated saline solution, concentrating, and purifying by using silica gel column chromatography to obtain 74mg of product, wherein the yield is as follows: 69.4 percent. LC-MS (APCI) M/z 534.7(M +1)⁺。

Step Synthesis of 21- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -3- (1,2,5, 6-tetrahydropyridin-3-yl) -1H-pyrazolo [4,3-d ] pyrimidin-7-amine

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

Synthesis of step 31- (3- (7-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazolo [4,3-d ] pyrimidin-3-yl) -5, 6-dihydropyridin-1 (2H) -yl) prop-2-en-1-one

Adding 5ml of anhydrous dichloromethane and triethylamine (42.5mg, 0.42mmol) into the intermediate, dropwise adding acryloyl chloride (12.7mg, 0.14mmol) under ice bath, stirring after the addition is finished, reacting for 10 minutes, then monitoring the reaction by TLC, adding dichloromethane for dilution, washing with water and saturated saline in turn, concentrating, and purifying by silica gel column chromatography to obtain 41mg of light yellow solid, wherein the yield is as follows: 60.1 percent. LC-MS (APCI) M/z 488.1(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ8.77(s,1H),8.64(d,J＝3.6Hz,1H),8.23(t,J＝4.2Hz,1H),8.05(s,1H),7.72(d,J＝4.2Hz,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 41- (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:

synthesis of step 13- (7-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazolo [4,3-d ] pyrimidin-3-yl) piperidine-1-carboxylic acid tert-butyl ester

Adding intermediate A2(432mg, 1.36mmol), intermediate B3(807mg, 2.72mmol), N-dimethylglycine (84mg, 0.82mmol) and cuprous iodide (52mg, 0.27mmol) into a reaction bottle, adding 5ml of anhydrous DMF under the protection of nitrogen, adding DBU (620mg, 4.08mmol), after the addition is finished, heating to 110 ℃, stirring for reaction for 15 hours, after the TLC monitoring reaction is finished, adding saturated ammonium chloride to quench the reaction, extracting with ethyl acetate for 3-4 times, combining organic phases, washing with saturated common salt water, concentrating, and purifying by silica gel column chromatography to obtain 290mg of product, wherein the yield is as follows: 39.9 percent. LC-MS (APCI): M/z 536.7(M +1)⁺。

Step Synthesis of 21- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -3- (piperidin-3-yl) -1H-pyrazolo [4,3-d ] pyrimidin-7-amine

To a reaction flask was added tert-butyl 3- (7-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazolo [4,3-d ] pyrimidin-3-yl) piperidine-1-carboxylate (290mg, 0.54mmol), 4N hydrogen chloride dioxane solution (5ml, 20mmol) was added under nitrogen protection, the reaction was stirred at room temperature for 1H, and after completion of the TLC monitoring, the reaction was concentrated to dryness and directly fed to the next step.

Synthesis of step 31- (3- (7-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -1H-pyrazolo [4,3-d ] pyrimidin-3-yl) piperidin-1-yl) prop-2-en-1-one

10ml of anhydrous dichloromethane and triethylamine (189mg, 1.87mmol) were added to the intermediate, acryloyl chloride (49mg, 0.54mmol) was added dropwise in an ice bath, the reaction was stirred for 10 minutes after the end of the addition, TLC was used to monitor the completion of the reaction, and dichloromethane was added to dilute the mixtureWashed with water and saturated brine in this order, concentrated and purified by silica gel column chromatography to give 120mg of a yellow solid in yield: 45.5 percent. LC-MS (APCI): M/z ═ 490.6(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ8.71(s,1H),8.68(d,J＝4.8Hz,1H),8.15(t,J＝4.4Hz,1H),7.92(s,1H),7.72(d,J＝4.4Hz,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, 3-d]preparation of pyrimidin-3-yl) piperidin-1-yl) prop-2-en-1-one

120mg of the racemic compound of example 4 was dissolved in a methanol solution, and separation was carried out under the following chiral preparative column and chiral resolution conditions to obtain 43mg of the objective product (retention time: 27.79min, defined as R configuration). LC-MS (APCI): M/z ═ 490.6(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ8.69(s,1H),8.52(d,J＝4.8Hz,1H),8.13(t,J＝4.4Hz,1H),7.92(s,1H),7.72(d,J＝4.4Hz,1H),7.41(d,J＝4.8Hz,1H),7.32(t,J＝4.4Hz,1H),6.82(d,J＝5.5Hz,1H),6.51(m,1H),6.01(d,J＝8.4Hz,1H),5.52(d,J＝8.4Hz,1H),5.37(s,2H),3.82(m,1H),3.79(m,3H),3.11(m,1H),2.07(m,1H),1.88(m,3H).

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

Column temperature: 30 deg.C

Flow rate: 4.0mL/min

Ultraviolet detection wavelength: 254nm

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

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

120mg of the racemic compound of example 4 was dissolved in a methanol solution, and separation was carried out under the following chiral preparative column and chiral resolution conditions to obtain 45mg of the objective product (retention time: 22.48min, defined as S configuration). LC-MS (APCI): M/z ═ 490.6(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ8.71(s,1H),8.69(d,J＝4.8Hz,1H),8.16(t,J＝4.4Hz,1H),7.94(s,1H),7.72(d,J＝4.4Hz,1H),7.45(d,J＝4.8Hz,1H),7.31(t,J＝4.4Hz,1H),6.82(d,J＝5.5Hz,1H),6.51(m,1H),6.00(d,J＝8.4Hz,1H),5.52(d,J＝8.4Hz,1H),5.37(s,2H),3.82(m,1H),3.79(m,3H),2.86(m,1H),2.17(m,1H),1.89(m,3H)

Column temperature: 30 deg.C

Flow rate: 4.0mL/min

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

Adding intermediate A3(220mg, 0.5mmol), intermediate B4(207mg, 0.6mmol), tetrakis (triphenylphosphine) palladium (30mg, 0.025mmol) and anhydrous sodium carbonate (106mg, 1.0mmol) into a reaction flask, adding 20ml ethylene glycol dimethyl ether and 5ml water under the protection of nitrogen, reacting at 90 ℃ overnight, cooling to room temperature, after TLC monitoring reaction is finished, adding excessive water to quench the reaction, extracting with ethyl acetate for 3-4 times, combining organic phases, washing with saturated brine, and purifying by silica gel column chromatography after concentration to obtain 170mg of yellow solid, wherein the yield is as follows: and (3.7). LC-MS (APCI): M/z 535.7(M +1)⁺。

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

Adding (R) -3- (8-amino-1- (3-chloro-4- (pyridine-2-ylmethoxy) phenyl) imidazo [1, 5-alpha ] pyrazine-3-yl) piperidine-1-carboxylic acid tert-butyl ester (132mg, 0.25mmol) into a reaction bottle, adding 4N ethyl hydrogen chloride acetate solution (5ml, 20mmol), stirring at room temperature for 1h, monitoring by TLC to complete the reaction, concentrating to dryness, and directly putting into the next reaction.

Adding 8ml of anhydrous dichloromethane into a reaction bottle in the previous step, adding triethylamine (0.1ml, 0.5mmol), cooling to 0 ℃ under the protection of nitrogen, dropwise adding acryloyl chloride (24.5mg, 0.27mmol), stirring for reaction for 0.5h after the addition is finished, adding a saturated ammonium chloride aqueous solution to quench the reaction after TLC monitoring reaction is finished, extracting the aqueous phase for 2-3 times by dichloromethane, combining organic phases, washing by saturated saline solution, and purifying by silica gel column chromatography after concentration to obtain 66mg of white-like solid, wherein the yield is as follows: 54.8 percent. LC-MS (APCI) M/z 489.5(M +1)⁺。¹H NMR(400MHz,DMSO-d₆)δ8.71(d,J＝2.3Hz,1H),8.13(m,3H),7.82(m,2H),7.57(d,J＝4.6Hz,1H),7.34(t,J＝2.3Hz,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 81- (3- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) pyrrolo [2, 1-f)][1, 2,4]Triazine-7-Preparation of yl) piperidin-1-yl) prop-2-en-1-one

The following synthetic route was used:

step 13 Synthesis of tert-butyl 4- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) piperidine-1-carboxylate

Intermediate A4(645mg, 1.63mmol), intermediate B4(677mg, 1.96mmol), Pd (dppf) Cl₂(58mg, 0.08mmol) and Na₂CO₃(520mg, 4.9mmol) was added to 12mL DME and 4mL water, purged with nitrogen three times, and allowed to warm to 90 ℃ for reaction overnight. The reaction mixture was cooled to room temperature, 30mL of water was added, extraction was performed with ethyl acetate (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 540mg of a pale yellow solid with a yield of 62%. ESI-MS:536[ M +1 ]]⁺.

Step 25 Synthesis of- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7- (piperidin-3-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-amine

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

Step 31 Synthesis of 3- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) piperidin-1-yl) prop-2-en-1-one

Reacting 5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7- (piperidin-3-yl) pyrrolo [2,1-f][1,2,4]Triazine-4-amine (322mg, 0.74mmol) and triethylamine (0.15g, 1.48mmol) were dissolved in 10mL of dichloromethane, cooled to-20 ℃ in an ice bath, acryloyl chloride (67mg, 0.74mmol) was added slowly, the ice bath was removed after the addition, and the mixture was stirred at room temperature for 1 hour. Diluting with 20mL of water, extracting with dichloromethane (15 mL. times.3), washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating, and separating with silica gel column to obtain 240mg of light yellow solid with a yield of 65%. ESI-MS 500[ M +1 ]]⁺.¹H NMR(400MHz,CDCl₃)δ8.61(dt,J＝4.8,1.5Hz,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)] [1,2,4]Preparation of triazin-7-yl) piperidin-1-yl) prop-2-en-1-one

100mg of the racemic compound of example 8 was dissolved in methanol solution and separated under chiral preparative chromatography and chiral resolution conditions described below to give the desired product (retention time: 61.925min, relative content: 50.04%, named R configuration). ESI-MS 500[ M +1 ]]⁺.¹H NMR(400MHz,CDCl₃)δ8.61(dt,J＝4.8,1.5Hz,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).

Column temperature: 30 deg.C

Flow rate: 1.0mL/min

Ultraviolet detection wavelength: 254nm

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

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

100mg of the racemic compound of example 8 was dissolved in a methanol solution and separated under chiral preparative chromatography column and chiral resolution conditions described below to give 43mg of the objective product (retention time: 65.193min, relative content: 49.96%, named S configuration). ESI-MS 500[ M +1 ]]⁺.¹H NMR(400MHz,CDCl₃)δ8.61(dt,J＝4.8,1.5Hz,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).

Column temperature: 30 deg.C

Flow rate: 1.0mL/min

Ultraviolet detection wavelength: 254nm

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

The following synthetic route was used:

step 1 Synthesis of benzyl 3- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) imidazo [5,1-f ] [1,2,4] triazin-7-yl) piperidine-1-carboxylate

Intermediate A5(330mg, 0.76mmol), intermediate B4(342mg, 0.99mmol), Pd (dppf) Cl₂(30mg, 0.04mmol) and Na₂CO₃(244mg, 2.3mmol) was added to 12mL DME and 4mL water, purged with nitrogen three times, and allowed to warm to 90 deg.C for reaction overnight. The reaction mixture was cooled to room temperature, 30mL of water was added, extraction was performed with ethyl acetate (20mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column to obtain 285mg of a pale yellow solid with a yield of 66%. ESI-MS 571[ M +1 ]]⁺.

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

Reacting (R) -3- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) imidazo [5, 1-f)][1,2,4]Triazin-7-yl) piperidine-1-carboxylic acid benzyl ester (285mg, 0.5mmol) was dissolved in 15mL of anhydrous ethanol, 30mg of 10% palladium on carbon was added, hydrogen was substituted three times, and stirring was carried out under a hydrogen atmosphere of one atmosphereOvernight. After the reaction is completed, palladium-carbon is filtered, the filtrate is concentrated, and the light yellow oily substance of 180mg is obtained by silica gel column separation, with the yield of 82%. ESI-MS 437[ M ]⁺+1].

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

Reacting (R) -5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7- (piperidin-3-yl) imidazo [5,1-f][1,2,4]Triazine-4-amine (180mg, 0.41mmol) and triethylamine (83mg, 0.82mmol) were dissolved in 10mL of dichloromethane, cooled to-20 ℃ in an ice bath, acryloyl chloride (37mg, 0.41mmol) was added slowly, the ice bath was removed after the addition, and the mixture was stirred at room temperature for 1 hour. Diluting with 20mL of water, extracting with dichloromethane (10 mL. times.3), washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating, and separating with silica gel column to obtain light yellow solid 120mg with yield 60%. ESI-MS 491[ M ]⁺+1]⁺.¹H NMR(400MHz,CDCl₃)δ8.59(ddd,J＝4.9,1.8,1.0Hz,1H),7.87(d,J＝12.4Hz,1H),7.80–7.70(m,2H),7.63(dt,J＝7.9,1.1Hz,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 121- (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 Synthesis of tert-butyl (R) -3- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) piperidine-1-carboxylate

To a 50mL single neck flask equipped with magnetic stirring and a condenser was added in order intermediate A6(350mg, 0.79mmol), intermediate B4(300mg, 0.87mmol), sodium carbonate (251mg, 2.37mmol), ethylene glycol dimethyl ether (5mL), and water (5mL), and under nitrogen, tetrakis (triphenylphosphine) palladium (91mg, 0.079mmol) was added, the temperature was raised to 100 ℃ under nitrogen, and the reaction was stirred at constant temperature overnight. After cooling to room temperature, water (20mL) and ethyl acetate (30mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was passed through a silica gel column to give 310mg of a yellow solid with 73.38% yield. LC-MS (APCI): M/z 535.2(M +1)⁺.¹H NMR(500MHz,CDCl₃)δ(ppm):8.62(d,J＝5.0Hz,1H),8.33(s,1H),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 Synthesis of (R) -5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7- (piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amino

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

Step Synthesis of 31- (3- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7H-pyrrolo [2,3-d ] pyrimidin-7-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 deg.C, a solution of acryloyl chloride (78mg, 0.86mmol) in acetonitrile (1mL) was slowly added dropwise under nitrogen, and after dropwise addition, the reaction was stirred at 0 deg.C for 1 hour. Saturated aqueous sodium bicarbonate (10mL) and ethyl acetate (20mL) were added and stirred for 5 minutes, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (15mL x2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 120mg of a pale yellow solid with a yield of 42.69%. LC-MS (APCI) M/z 489.2(M +1)⁺.¹H NMR(400MHz,CDCl₃)δ(ppm):8.63(d,J＝5.2Hz,1H),8.34(s,1H),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 131- (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

To a 250mL single neck flask equipped with magnetic stirring was added in order intermediate B4(3.0g, 8.7mmol), acetone (60mL) and water (60mL), the solution was stirred and dissolved, and ammonium acetate (3) was added in order.36g, 43.5mmol) and sodium periodate (7.92g, 34.77mmol), the reaction mixture was stirred at room temperature under nitrogen for 3 hours. Acetone was evaporated under reduced pressure, extracted with ethyl acetate (50mL x3), the organic phases were combined, washed with saturated brine (60mL), dried over colorless sodium sulfate, filtered, concentrated and passed through a silica gel column to give 2.1g of a white solid with a yield of 91.8%. LC-MS (APCI): M/z ═ 264.1(M +1)⁺.

Step Synthesis of tert-butyl 23- (1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -5-cyano-4- (1, 3-dioxoisoindol-2-yl) -1H-pyrrol-3-yl) piperidine-1-carboxylate

To a 50mL three-necked flask equipped with magnetic stirring were added tert-butyl 3- (5-cyano-4- (1, 3-dioxoisoindol-2-yl) -1H-pyrrol-3-yl) piperidine-1-carboxylate (1.26g, 3.0mmol), (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) boronic acid (1.58g, 6.0mmol) and copper acetate (546mg, 3.0mmol), evacuated and replaced with an oxygen atmosphere three times, and anhydrous dichloromethane (40mL) and triethylamine (909mg, 9.0mmol) were added dropwise, and after completion, the reaction was stirred at room temperature under an oxygen atmosphere overnight. Water (40mL) and methylene chloride (40mL) were added, stirred for 10 minutes, the organic phase was separated, the aqueous phase was extracted with methylene chloride (20mLx2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 1.0g of a white solid in 52.3% yield. LC-MS (APCI): M/z 638.2(M +1)⁺.¹H NMR(300MHz,CDCl₃)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 33 Synthesis of tert-butyl 4- (4-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -5-cyano-1H-pyrrol-3-yl) piperidine-1-carboxylate

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

Step 43 Synthesis of tert-butyl 4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) piperidine-1-carboxylate

To a 50mL single neck flask equipped with a magnetic stirrer and condenser was added tert-butyl 3- (4-amino-1- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -5-cyano-1H-pyrrol-3-yl) piperidine-1-carboxylate (350mg, 0.6mmol) and absolute ethanol, the mixture was stirred to dissolve, and formamidine acetate (620mg, 6.0mmol) was added, and the mixture was refluxed overnight under nitrogen. Cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was passed through a silica gel column to give 290mg of a white solid in a yield of 90.1%. LC-MS (APCI): M/z 535.2(M +1)⁺.

Step 55- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7- (piperidin-3-yl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine Synthesis

To a 50mL single-necked flask equipped with magnetic stirring was added 3- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -5H-pyrrolo [3,2-d]Pyrimidin-7-yl) piperidine-1-carboxylic acid tert-butyl ester (290mg, 0.54mmol) and dichloromethane (20mL), trifluoroacetic acid (4mL) was added and the reaction stirred at room temperature under nitrogen for 2 hours. Concentrated to dryness under reduced pressure, dichloromethane (30mL) and saturated aqueous sodium bicarbonate (20mL) were added, the organic phase separated, the aqueous phase extracted with dichloromethane (30mL x2), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 225mg of a brown solid in 96.9% yield. LC-MS (APCI) M/z 435.2(M +1)⁺.

Step Synthesis of 61- (3- (4-amino-5- (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -5H-pyrrolo [3,2-d ] pyrimidin-7-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 (225mg, 0.52mmol) was dissolved in acetonitrile (8mL) and water (4mL), triethylamine (78mg, 0.78mmol) was added, cooled to 0 deg.C, a solution of acryloyl chloride (60mg, 0.67mmol) in acetonitrile (2mL) was slowly added dropwise under nitrogen, and the reaction was stirred at 0 deg.C for 1 hour after dropwise addition. Saturated aqueous sodium bicarbonate (30mL) and ethyl acetate (60mL) were added, the mixture was stirred for 5 minutes, and the organic phase was separatedThe aqueous phase was extracted with ethyl acetate (15mLx2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 140mg of a pale yellow solid in 55.2% yield. LC-MS (APCI) M/z 489.2(M +1)⁺.¹H NMR(500MHz,CDCl₃)δ(ppm):8.62(d,J＝5.0Hz,1H),8.32(s,1H),7.81-7.7.77(m,1H),7.71(d,J＝2.5Hz,1H),7.67(d,J＝8.0Hz,1H),7.54(dd,J＝8.5Hz,J＝2.5Hz,1H),7.28-7.25(m,1H),7.11(d,J＝9.0Hz,1H),6.92(s,1H),6.69-6.64(m,1H),6.45-6.41(m,1H),6.34(br s,2H),5.83-5.80(m,1H),5.35(s,2H),4.81-4.77(m,1H),4.12-4.10(m,1H),3.28-3.22(m,1H),2.55-2.50(m,1H),2.32-2.29(m,1H),2.01-1.98(m,1H),1.94-1.91(m,1H),1.70-1.65(m,1H).

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

140mg of the racemic compound of example 13 was dissolved in a dichloromethane (10mL) solution and separated under chiral preparative chromatography and chiral resolution conditions described below to give 51mg of the desired product (retention time: 25.955min, named S configuration). LC-MS (APCI) M/z 489.2(M +1)⁺.¹H NMR(500MHz,CDCl₃)δ(ppm):8.62(d,J＝5.0Hz,1H),8.32(s,1H),7.81-7.7.77(m,1H),7.71(d,J＝2.5Hz,1H),7.67(d,J＝8.0Hz,1H),7.54(dd,J＝8.5Hz,J＝2.5Hz,1H),7.28-7.25(m,1H),7.11(d,J＝9.0Hz,1H),6.92(s,1H),6.69-6.64(m,1H),6.45-6.41(m,1H),6.34(br s,2H),5.83-5.80(m,1H),5.35(s,2H),4.81-4.77(m,1H),4.12-4.10(m,1H),3.28-3.22(m,1H),2.55-2.50(m,1H),2.32-2.29(m,1H),2.01-1.98(m,1H),1.94-1.91(m,1H),1.70-1.65(m,1H).

Column temperature: 25 deg.C

Flow rate: 1.0mL/min

Ultraviolet detection wavelength: 254nm

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

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

140mg of the racemic compound of example 13 was dissolved in a dichloromethane (10mL) solution and separated under chiral preparative chromatography and chiral resolution conditions described below to give 48mg of the desired product (retention time: 21.520min, named R configuration). LC-MS (APCI) M/z 489.2(M +1)⁺.¹H NMR(500MHz,CDCl₃)δ(ppm):8.62(d,J＝5.0Hz,1H),8.32(s,1H),7.81-7.7.77(m,1H),7.71(d,J＝2.5Hz,1H),7.67(d,J＝8.0Hz,1H),7.54(dd,J＝8.5Hz,J＝2.5Hz,1H),7.28-7.25(m,1H),7.11(d,J＝9.0Hz,1H),6.92(s,1H),6.69-6.64(m,1H),6.45-6.41(m,1H),6.34(br s,2H),5.83-5.80(m,1H),5.35(s,2H),4.81-4.77(m,1H),4.12-4.10(m,1H),3.28-3.22(m,1H),2.55-2.50(m,1H),2.32-2.29(m,1H),2.01-1.98(m,1H),1.94-1.91(m,1H),1.70-1.65(m,1H).

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

Column temperature: 25 deg.C

Flow rate: 1.0mL/min

Ultraviolet detection wavelength: 254nm

Biological activity assay

Biological example 1: kinase inhibition assay

1) EGFR (WT) and EGFR (D770_ N771insNPG) kinase Activity inhibition assay

The inhibitory activity of the test drug on EGFR (WT) and EGFR (D770-N771 insNPG) (SignalChem, E-10-132GG) was determined using ADP-GloTM Kinase Assay kit (Promega, V9102).

The highest concentration of the drug to be detected is 1 mu M, and the drug is diluted by 3 times of gradient and has 12 concentrations. A384 well plate (Perkin Elmer, 6007290) was prepared by adding 0.1. mu.L of each concentration of drug solution to each well, mixing with 5. mu.L of EGFR (WT) or 5. mu.L of EGFR (D770_ N771insNPG), and double-plating wells. After incubation at 25 ℃ for 15min, 5. mu.L of substrate was added to start the reaction and incubation at 25 ℃ for 60 min. The final reaction concentrations in the system were: 0.5nM EGFR, 10. mu.M ATP,0.03mg/mL Poly (4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl₂10mM, Brij350.01%. Then 10. mu.L ADP Glo reagent was added and incubation continued for 40min at 25 ℃. After 20. mu.L of the detection reagent was added and incubated at 25 ℃ for 40min, the enzyme inhibition rate of the compound at different concentrations was calculated by reading on an Envision microplate reader (Perkin Elmer, 2104). Data were analyzed using GraphPad Prism 6.0 software, and dose-response curves were derived by fitting the data using non-linear curve regression, and IC was calculated therefrom₅₀The value is obtained.

2) HER2(WT) and HER2(A775_ G776insYVMA) kinase activity inhibition assay

The inhibitory activity of the test drugs on HER2(WT) and HER2(A775_ G776insYVMA) (SignalChem, E27-13BG) was determined using an ADP-GloTM Kinase Assay kit (Promega, V9102).

The highest concentration of the drug to be detected is 1 mu M, and the drug is diluted by 3 times of gradient and has 12 concentrations. A384 well plate (Perkin Elmer, 6007290) was double-plated with 0.1. mu.L of each concentration of drug solution mixed with 5. mu.L of HER2(WT) or 5. mu.L of HER2 (A775-G776 insYVMA). After incubation at 25 ℃ for 15min, 5. mu.L of substrate was added to start the reaction and incubation at 25 ℃ for 60 min. The final reaction concentrations in the system were: 20nM HER2, 5. mu.M ATP,0.03mg/mL Poly (4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl₂10mM, Brij350.01%. Then 10. mu.L ADP Glo reagent was added and incubation continued for 40min at 25 ℃. After 20. mu.L of the detection reagent was added and incubated at 25 ℃ for 40min, the enzyme inhibition rate of the compound at different concentrations was calculated by reading on an Envision microplate reader (Perkin Elmer, 2104). Data were analyzed using GraphPad Prism 6.0 software, and dose-response curves were derived by fitting the data using non-linear curve regression, and IC was calculated therefrom₅₀The value is obtained.

The compounds of the present invention were tested in the above kinase inhibition assay and found to have potent activity against EGFR (WT), EGFR (D770_ N771insNPG) and HER2(WT), HER2(a775_ G776insYVMA) kinases. The results for representative example compounds are summarized in table 1 below.

TABLE 1

*: the control compound was 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 for 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

The a431 cells and the a549 cells are wild-type EGFR cells; h1975 cells are EGFR cells with L858R point mutation and with T790M point mutation; HCC827 cells are mutant EGFR cells with exon 19 deletion.

Adjusting the concentration of A431(WT EGFR) cells, A549 cells (WT EGFR), H1975 cells (L858R/T790M EGFR) and HCC827 cells (Ex19del), adding 50. mu.L of the cell suspension to 384-well plates, respectively, at 37 ℃ and 5% CO₂The culture was carried out overnight. The Tecan D300E program was set up. Adding the medicine by using a Tecan D300E instrument, wherein the highest concentration of the medicine to be detected is 10 mu M, diluting by 3 times of gradient, carrying out 10 concentrations, carrying out double-hole dilution, and continuously culturing for 72 h. The 384 well plates were removed and equilibrated at room temperature for 30min, 30. mu.L of CTG (Promega, G7573) reagent was added to each well, and after 10min at room temperature, the Luminescence values were read on an EnVision (Perkin Elmer 2104) after the signal had stabilized. Inhibition ratio (%) - (1-Lum)_{Drug to be tested}/Lum_{Negative control}) x100, negative control 0.667% DMSO. IC (integrated circuit)₅₀XL-fit software was used for the calculation of (1).

The compounds of the present invention were tested in the cytotoxicity experiments described above, and found to have no inhibitory activity on a431 cells and a549 cells of wild-type EGFR and have potent activity and high selectivity on H1975 cells and HCC827 cells of mutant EGFR, and thus it was found that the compounds of the present invention can inhibit mutant EGFR with exon 19 deletion and mutant EGFR of L858R/T790M with high specificity. The results for representative example compounds are summarized in table 2 below.

2) Test of growth inhibitory Activity of Ba/F3 parental, Ba/F3 EGFR-D770-N771ins _ SVD, Ba/F3EGFR-L858R, Ba/F3EGFR-L858R/T790M, Ba/F3 EGFR-Del19/T790M and Ba/F3 EGFR-V769_ D770insASV cells

And taking cells in logarithmic growth phase, and detecting the cell viability by using a trypan blue exclusion method to ensure that the cell viability is over 90 percent. Adjusting the concentration of Ba/F3 parental, Ba/F3 EGFR-D770-N771ins _ SVD, Ba/F3EGFR-L858R, Ba/F3EGFR-L858R/T790M, Ba/F3 EGFR-Del19/T790M and Ba/F3 EGFR-V769_ D770insASV cells, adding 90 μ L cell suspension to 96-well plate, 37 ℃ and 5% CO₂The culture was carried out overnight. The highest concentration of the drug to be detected is 1 mu M, and the drug is diluted by 3.16 times of gradient and has 9 concentrations. 10 μ L of each drug solution with various concentrations was added to each well of a 96-well plate, and the culture was continued for 72 hours in triplicate. The 96-well plate is taken out and placed at room temperature for 30min in balance, equal volume of CTG reagent is added into each well, cells are cracked by vibrating on an orbital shaker for 5min, and after a stable luminescence signal is placed at room temperature for 20min, the luminescence value is read on a SpectraMax multi-label microplate detector (MD, 2104-0010A). Cell survival (%) — (luminescence of test drug-luminescence of culture control)/(luminescence of cell control-luminescence of culture control) × 100%. Data were analyzed using GraphPad Prism 7.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom₅₀The value is obtained.

The compound also has strong activity and high selectivity on Ba/F3 EGFR-D770-N771ins _ SVD, Ba/F3EGFR-L858R, Ba/F3EGFR-L858R/T790M, Ba/F3 EGFR-Del19/T790M and Ba/F3 EGFR-V769_ D770insASV cells, so that the compound can inhibit the mutant EGFR with exon 20 insertion, the mutant EGFR with L858R, the mutant EGFR with L858R/T790M and the mutant EGFR with Del19/T790M with high specificity. The results for representative example compounds are summarized in tables 2 and 3 below.

Table 2:

Table 3:

Biological example 3: testing for 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. Adjusting the concentrations of SK-BR-3 cells and NCI-N87 cells, adding 50. mu.L of cell suspension to 384-well plate, respectively, at 37 deg.C and 5% CO₂The culture was carried out overnight. The Tecan D300E program was set up. Adding the medicine by using a Tecan D300E instrument, wherein the highest concentration of the medicine to be detected is 10 mu M, diluting by 3 times of gradient, carrying out 10 concentrations, carrying out double-hole dilution, and continuously culturing for 72 h. The 384 well plates were removed and equilibrated at room temperature for 30min, 30. mu.L of CTG (Promega, G7573) reagent was added to each well, and after 10min at room temperature, the Luminescence values were read on an EnVision (Perkin Elmer 2104) after the signal had stabilized. Inhibition ratio (%) - (1-Lum)_{Drug to be tested}/Lum_{Negative control}) x100, negative control 0.667% DMSO. IC (integrated circuit)₅₀XL-fit software was used for the calculation of (1).

The compounds of the present invention were tested in the above cytotoxicity experiments and found to have potent activity against SK-BR-3 cells and NCI-N87 cells of wild-type HER2, and thus it was found that the compounds of the present invention can inhibit wild-type HER2 with high specificity. The results for representative example compounds are summarized in table 4 below.

2)Ba/F₃Parent and Ba/F₃Test of growth inhibitory Activity of HER2-A775_ G776insYVMA cells

And taking cells in logarithmic growth phase, and detecting the cell viability by using a trypan blue exclusion method to ensure that the cell viability is over 90 percent. The concentrations of Ba/F3 parental and Ba/F3 HER2-A775_ G776insYVMA cells were adjusted by adding 90. mu.L of the cell suspension to a 96-well plate at 37 ℃ with 5% CO₂The culture was carried out overnight. The highest concentration of the drug to be detected is 1 mu M, and the drug is diluted by 3.16 times of gradient and has 9 concentrations. 10 μ L of the drug solution was added to each well of the 96-well plate, and the culture was continued for 72 hours in triplicate. The 96-well plate is taken out and placed at room temperature for 30min in balance, equal volume of CTG reagent is added into each well, cells are cracked by vibrating on an orbital shaker for 5min, and after a stable luminescence signal is placed at room temperature for 20min, the luminescence value is read on a SpectraMax multi-label microplate detector (MD, 2104-0010A). Cell survival (%) — (luminescence of test drug-luminescence of culture control)/(luminescence of cell control-luminescence of culture control) × 100%. Data were analyzed using GraphPad Prism 7.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom₅₀The value is obtained.

The compounds of the invention also have potent activity and high selectivity against Ba/F3 HER2-A775_ G776insYVMA cells, and the results for representative example compounds are summarized in Table 4 below.

Table 4:

Biological example 4: pharmacokinetic experiment of rat

6 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups of 3 per group and compared for pharmacokinetic differences by intravenous or oral administration of a single dose of compound (10 mg/kg oral).

Rats were fed with standard feed and given water. Fasting began 16 hours prior to the experiment. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit at 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr post-dose.

The rats were briefly anesthetized after ether inhalation and 300 μ L of blood was collected from the orbit into a test tube. The tube contains 30. mu.L of 1% heparin sodium solution. Before use, the tubes were dried overnight at 60 ℃. After completion of blood collection at the last time point, rats were sacrificed after ether anesthesia.

Immediately after blood collection, the tubes were gently inverted at least 5 times to ensure mixing and then placed on ice. The blood samples were centrifuged at 5000rpm for 5 minutes at 4 ℃ to separate the plasma from the erythrocytes. Pipette 100 μ L of plasma into a clean plastic centrifuge tube, designating the name of the compound and the time point. Plasma was stored at-80 ℃ before analysis. The concentration of the compounds of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

Experiments show that the compound has better pharmacokinetic property in animals, thereby having better pharmacodynamics and treatment effect.

The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the 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:

wherein the content of the first and second substances,

ring A is an aromatic ring;

ring C is C_6-10Aryl or 5 to 10 membered heteroaryl;

A₁is CR_A1Or N;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

B₁is CR₁Or N;

B₂is CR₂Or N;

B₃is CR₃Or N;

B₄is CR₄Or N;

l is selected from O,S or NR_L；

v is (CR)_V1R_V2)_o；

o ═ 1,2, 3,4, 5, or 6;

R₆is H, D, halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl, and optionally substituted with one or more R;

R₅and R₇Each independently selected from H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and optionally substituted with one or more R; or, R₅And R₇Together with the double bond to which they are attached form a triple bond;

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

r' is independently selected from H, D,Halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) R_a、-C(O)OR_a、-C(O)NR_bR_c、-NR_bR_c、-NR_aC(O)R_b、-NR_aC(O)OR_b、-NR_aC(O)NR_bR_c、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_bR_c、C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl, and optionally substituted with one or more R ";

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

p is 0, 1 or 2;

2. A compound according to claim 1, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,

selected from the following structures:

preferably, the first and second electrodes are formed of a metal,

selected from the following structures:

preferably, the first and second electrodes are formed of a metal,

selected from the following structures:

3. a compound according to claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, 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. A compound according to any one of claims 1-3, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein V is (CH)₂)_o(ii) a Preferably CH₂。

5. A compound according to any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L is O.

6. A compound according to any one of claims 1-5, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein B is₁Is CR₁、B₂Is CR₂、B₃Is CR₃、B₄Is CR₄(ii) a Preferably, R₁、R₂、R₃And R₄Independently selected from H, D, halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl or C_2-6Alkynyl.

7. A compound according to any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,

selected from the following structures:

preferably:

8. a compound according to any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate 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 according to claim 8, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (II-1), (III-1), or (IV-1):

wherein the content of the first and second substances,

ring A is an aromatic ring;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

wherein R is_A4Is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Alkoxy, and optionally is substitutedOne or more R' substitutions;

o ═ 1,2, 3, or 4;

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

p is 0, 1 or 2;

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

R₅、R₆and R₇Each independently selected from H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and optionally substituted with one or more R; or, R₅And R₇Together with the double bond to which they are attached form a triple bond;

r' are each independentlyIs selected from H, D, halogen, -CN, -O, -OR_aor-NR_bR_c；

10. A compound according to claim 9, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (II-2), (III-2), or (IV-2):

wherein the content of the first and second substances,

ring A is an aromatic ring;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

wherein R is_A4Is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Alkoxy, and optionally substituted with one or more R ";

o ═ 1,2, 3, or 4;

each R is independently selected from H, D, halo, -CN, ═ O, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl or C_2-6An alkynyl group; wherein R isEach group in the meaning is optionally substituted with one or more D up to complete deuteration;

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

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

11. The compound according to claim 8, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (V-1) or (VI-1):

wherein the content of the first and second substances,

A₁is CR_A1Or N;

o ═ 1,2, 3, or 4;

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

p is 0, 1 or 2;

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

R_a、R_bAnd R_cEach independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, or R_bAnd R_cTogether with the N atom to which they are attached form 3To 7-membered heterocyclyl or 5-to 10-membered heteroaryl; wherein R is_a、R_bAnd R_cEach group in the definition is optionally substituted with one or more D, up to complete deuteration.

12. A compound according to claim 11, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (V-2) or (VI-2):

wherein the content of the first and second substances,

A₁is CR_A1Or N;

wherein R is_A1Is H, D, halogen, -CN, C_1-6Alkyl or C_1-6Alkoxy, and optionally substituted with one or more R ";

o ═ 1,2, 3, or 4;

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

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

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 a compound of any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.

15. Use of a compound of any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 14, in the manufacture of a medicament for the treatment and/or prevention of a wild-type and/or mutant EGFR kinase-mediated tumor;

preferably, 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;

preferably, wherein the exon 20 insertion mutation is selected from the group consisting of V769_ D770insASV, D770_ N771insSVD, D770_ N771insNPG, D770_ N771insG, H773_ V774insNPH, and H773_ V774 insPH;

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

preferably, wherein said exon 21 point mutation is selected from the group consisting of the L861Q mutation;

preferably, wherein the mutant EGFR also simultaneously has the T790M mutation.

16. Use of a compound of any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 14, in the manufacture 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.

17. Use of a compound of any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 14, in the manufacture of a medicament for the treatment and/or prevention of a tumor mediated by wild-type and/or mutant HER2 kinase;

preferably, wherein the mutated HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_ T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R86 869C mutant HER2, L755S mutant HER2, or ex20 insymva mutant HER 2;

preferably, wherein the ex20insYVMA mutant HER2 is selected from a775_ G776insYVMA mutant HER2 mutation.

18. Use of a compound of any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 14, in the manufacture of a medicament for the treatment and/or prevention of: lung cancer, gastric cancer or breast cancer.

Claims

wherein the content of the first and second substances,

ring A is an aromatic ring;

ring C is C_6-10Aryl or 5 to 10 membered heteroaryl;

A₁is CR_A1Or N;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

B₁is CR₁Or N;

B₂is CR₂Or N;

B₃is CR₃Or N;

B₄is CR₄Or N;

l is selected from O, S or NR_L；

v is (CR)_V1R_V2)_o；

o ═ 1,2, 3,4, 5, or 6;

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

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

p is 0, 1 or 2;

each R is independently selected from H, D, halogen, -CN, ═ O, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) R_a、-C(O)OR_a、-C(O)NR_bR_c、-NR_bR_c、-NR_aC(O)R_b、-NR_aC(O)OR_b、-NR_aC(O)NR_bR_c、-OR_a、-OC(O)R_a、-OC(O)OR_a、-OC(O)NR_bR_c、C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl; alternatively, two R groups on the same atom or on adjacent atoms may be oneForm C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl, C_6-10Aryl or 5 to 10 membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D, up to complete deuteration;

2. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of the general formula:

wherein each group is as defined in claim 1.

3. The compound of claim 2, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (II-1), (III-1), or (IV-1):

wherein the content of the first and second substances,

ring A is an aromatic ring;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

o ═ 1,2, 3, or 4;

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

p is 0, 1 or 2;

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

4. The compound of claim 3, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (II-2), (III-2), or (IV-2):

wherein the content of the first and second substances,

ring A is an aromatic ring;

A₂is C or N;

A₄is CR_A4Or N;

A₅is C or N;

o ═ 1,2, 3, or 4;

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

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

5. The compound of claim 2, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (V-1) or (VI-1):

wherein the content of the first and second substances,

A₁is CR_A1Or N;

o ═ 1,2, 3, or 4;

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

p is 0, 1 or 2;

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

6. The compound of claim 5, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of formula (V-2) or (VI-2):

wherein the content of the first and second substances,

A₁is CR_A1Or N;

o ═ 1,2, 3, or 4;

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

r' is independently selected from H, D, halogen, -CN, C_1-6Alkyl or C_1-6Haloalkyl, and optionallySubstituted with one or more R';

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

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

8. a pharmaceutical composition comprising a compound of any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.

9. Use of a compound of any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 8, for the manufacture of a medicament for the treatment and/or prevention of a wild-type and/or mutant EGFR kinase-mediated tumor;

preferably, wherein the mutant EGFR also simultaneously has the T790M mutation.

10. Use of a compound of any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 8, for the manufacture of a medicament for the treatment and/or prevention of a tumor mediated by wild type and/or mutant HER2 kinase;