CN109793733B

CN109793733B - 3-amino-5-alkynyl pyrazole compounds as FGFR inhibitors

Info

Publication number: CN109793733B
Application number: CN201910244705.0A
Authority: CN
Inventors: 徐亮; 程航; 程传栩
Original assignee: Sichuan University
Current assignee: Sichuan University
Priority date: 2019-03-28
Filing date: 2019-03-28
Publication date: 2021-11-12
Anticipated expiration: 2039-03-28
Also published as: CN109793733A

Abstract

The present invention provides 3-amino-5-alkynylpyrazoles of the general formula (I) which are useful in the treatment of cell proliferation disorders. The novel compounds of the present invention are potent and broad-spectrum Fibroblast Growth Factor Receptor (FGFRs) inhibitors.

Description

3-amino-5-alkynyl pyrazole compounds as FGFR inhibitors

Technical Field

The invention provides a 3-amino-5-alkynyl pyrazole compound as a Fibroblast Growth Factor Receptor (FGFRs) inhibitor, which has broad-spectrum and strong inhibitory activity on FGFR. The compounds of the present invention are useful for the treatment of cancer.

Background

Cancer is the second leading disease of death worldwide, and global cancer report 2014 issued by the world health organization states that global cancer patients and death cases are all increasing disturbingly, and nearly half of newly added cancer cases appear in asia, most of which are in china. According to global survey data, the following are shown: in 2018, the number of cancer attacks is 1810 thousands, and the number of cancer deaths is 960 thousands, which is predicted to reach 2383 thousands and 1600 thousands respectively in 2050. The most common worldwide by 2018 are lung cancer (176 ten thousand deaths), colorectal cancer (86 ten thousand deaths), gastric cancer (78 ten thousand deaths), liver cancer (78 ten thousand deaths) and breast cancer (62 ten thousand deaths). Among them, the number of cancer deaths in China accounts for 27% of the number of cancer deaths in the world, and with the acceleration of aging of the population in China and the change of life style, the number of cancer deaths caused by invasive cancer will increase year by year.

Fibroblast Growth Factor Receptors (FGFRs) belong to the Receptor tyrosine protein kinase (RPTKs) family, including the four Receptor subtypes FGFR1, FGFR2, FGFR3, and FGFR 4. It plays an important role in the regulation of many physiological processes of tissue development, angiogenesis, wound healing and metabolic regulation (Ornitz, DM.; Itoh N.Wiley Interdiscip Rev Dev biol.2015,4, 215-266). Like other RPTKs, the structure of FGFRs also consists of three regions: an extracellular binding domain (consisting of three extracellular immunoglobulin IgI, IgII and IgIII), a hydrophobic single transmembrane domain and an intracellular tyrosine kinase domain (comprising two tyrosine kinase subdomains (TKI and TKII) (Ullrich, A.; Schlessinger, J.cell 1990,61, 203.; Johnson, Daniel E.; Williams, Lewis T.Adv.cancer Res.,1992,60, 1.) Normal tissue cells, FGFs complex with FGFR under the combined action of Klotho and HSPG, leading to FGFR dimerization and conformational change, FGFR FRs, which are subsequently activated by autophosphorylation of the intracellular tyrosine kinase domain, activate their substrates PLC γ and signaling adaptor protein FRS2 by phosphorylation and activate the downstream signaling pathway PI3K-AKT (mainly associated with cell proliferation and motility), RAF-MAPK (mainly associated with FGFR mediated cell proliferation and γ transfer) and the downstream signaling pathway of the protein kinase (Beken) and lipase (Beken STAT), a.; mohammadi, m.nat Rev Drug discov.2009,8,235-253.) to regulate cell proliferation, differentiation and transfer.

FGFR is widely involved in regulating multiple processes such as cell proliferation, apoptosis, migration, neovascularization, and the like, and plays an important role in regulation of many physiological processes of tissue development, angiogenesis, wound healing, and metabolic regulation. Abnormalities in the FGFR signaling pathway have become an important cause of human disease. Diseases associated with lung tumors such as: such as bone diseases (craniosynostosis syndrome, Kallman syndrome, osteoporotic dysplasia, chondrodysplasia), gonadal dysgenesis (Bagheri-Fam, S.; ONO, M, et al human Molecular Genetics,2015,24,6699-6710.), Blaschko stain reduction in childhood (Kirtsid, D.; Lorente, A.I.; Happle R, et al. British Journal of Dermatology,2015,172,1125-1127.), arthritis (Bono, F.; De Smet, F.; Herbert, C, et al cancer, 2013,23, Cell 477-488); in tumor-related diseases, FGFR signaling pathway abnormalities (including overexpression, amplification, fusion, mutation, or overexpression of FGFs) are involved in the development and progression of tumors, the development of resistance in anticancer therapy, and poor prognosis by promoting tumor angiogenesis, tumor invasion and metastasis, epithelial-mesenchymal transition, and other processes. FGFR is therefore recognized as a potentially important therapeutic target for a variety of tumors (e.g., bladder, breast, cervical, colorectal, endometrial, gastric, head and neck, renal, liver, lung, ovarian, prostate, multiple myeloma, chronic lymphocytic lymphoma, adult T-Cell leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma, etc., particularly some non-target epithelial tumors such as squamous lung carcinoma, cholangiocarcinoma, pancreatic cancer, etc.) (Goetz, R., Mohammadi, M.Nat. Rev. Mol Cell Biol,2013,14, 166-; Helsten T., Elkin, S.; Arthur, E.; Tomson, B.N.; Carter, J., Kurzrock, R.267 therapy in FGFR: analysis of cancer, cancer of 4,853-tumor, 2016.2016.2016). Methods for treating cancer, particularly malignant solid tumors, by blocking FGF/FGFR signaling are expected. The development of FGFR small molecule inhibitors is also receiving increasing attention.

FGFR inhibitors can be broadly classified into four categories according to the target of action: Multi-Target Kinase Inhibitors (TKIs), Pan-FGFR Inhibitors (Pan-FGFR Inhibitors), selective FGFR Inhibitors (including Inhibitors against FGFR1-3 and selective FGFR4 Inhibitors). Due to the high similarity of the FGFR kinase domain and VEGFR, PDGFR and the like, many previous small-molecule TKIs aiming at VEGFR and PDGFR also have FGFR activity, such as dolivitinib (TKI-258), lucitanib (E-3810), nintedanib (BIBF-1120), panatinib (AP-245634), HMPL-012, ARQ-087 and the like. Although performing well in early clinical trials, it is uncertain whether these multi-target TKIs reach effective concentrations to inhibit FGFRs in clinical trials due to dose-limiting side effects (especially hypertension due to VEGFR2 inhibition) (Dieci, m.v.; Arnedos, m.; Andre, f.; Soria, j.c. cancer Discovery 2013,3, 264-; based on these considerations, there is increasing interest in the development of selective FGFR TKIs, and some pan-FGFR inhibitors were first developed: such as PRN1371, PD173074, FIIN-2, FIIN-3, FIIN-4, TAS-120, BAY1163877, ASP5878, LY2874455, etc.; subsequently, some inhibitors that are selective for FGFR 1-3: such as AZD-4547, BGJ398, Debio-1347, INCB054828, etc.; the most common and serious FGFR toxicities targeted by effective doses of FGFR inhibitors are hyperphosphatemia and tissue calcification, since FGF23 binding to FGFR1 plays an important role in regulating the phosphorus and calcium balance of the skeleton and kidney. FGFR1-3 is highly similar to FGFR4 in the spatial structure of the kinase domain, but is much different. Recently, FGFR4 selective inhibitors were developed using a poorly conserved cysteine (Cys552) at position 552 of the hinge region in the ATP binding site of FGFR4 as a potential site (tyrosine (Tyr552) for FGFR 1/2/3): such as H3B-6527, BLU9931, BLU-554, FGF401 and the like show excellent treatment effect in clinical tests of hepatocellular carcinoma, and effectively avoid toxic and side effects of targeted FGFR.

Disclosure of Invention

The invention provides a 3-amino-5-alkynyl pyrazole compound which is used as a fibroblast growth factor receptor inhibitor and has wide and strong inhibitory activity. The compounds of the present invention are useful in the treatment of cell proliferative disorders, such as cancer. The compounds of the invention further improve the pharmacokinetic properties, including metabolic stability and clearance, over existing drugs. In addition, the compounds of the present invention are readily synthesized and can be administered to a patient by a variety of methods.

In one aspect, the present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof:

wherein:

a is selected from CR₄' or N

X, Y are each independently selected from H or halogen;

z is absent or carbonyl;

R₁independently selected from hydrogen or C_1-6An alkyl group;

R₂、R₃each independently selected from H, halogen, -CN, -OR_a、-SR_a、-NR_bR_c、-C(O)R_a、-C(O)OR_a、-C(O)NR_bR_c、C_1-6Alkyl radical, C_1-6Haloalkyl or

Is the point of attachment to the parent nucleus;

R₄selected from H, halogen, -CN, -NO₂、-L-OR_a、-L-SR_a、-L-NR_bR_c、-L-C(O)R_a、-L-C(O)OR_a、-L-C(O)NR_bR_c、-L-S(O)_mR_a、-L-S(O)_mOR_a、-L-S(O)_mNR_bR_c、-O-C_1-6alkylene-R₆、C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl, -L' -C_3-7Cycloalkyl, -L '-3-11 membered heterocyclyl, -L' -C_6-10Aryl or-L' -5-10 membered heteroaryl, said group optionally substituted with 1,2,3, 4 or 5R₅Substituted by groups;

R₄' independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl OR-OR_a；

R₅Selected from H, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Haloalkyl, -C_1-6alkylene-OR_a、-L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl;

or two R on the same carbon atom₅Together form oxo or thioxo;

wherein:

R₅optionally substituted with 1,2 or 3R 'groups, wherein R' is independently selected from H, -OH, halogen, -NO₂Carbonyl, -L-CN, -L-OR_a、-L-SR_a、-L-NR_bR_c、-L-C(O)R_a、-L-C(S)R_a、-L-C(O)OR_a、-L-C(S)OR_a、-L-C(O)-NR_bR_c、-L-C(S)-NR_bR_c、-L-O-C(O)R_a、-L-O-C(S)R_a、-L-N(R_b)-C(O)-R_a、-L-N(R_b)-C(S)-R_a、-L-S(O)_mR_a、-L-S(O)_mOR_a、-L-S(O)_mNR_bR_c、-L-N(R_b)-S(O)_m-R_a、-L-N(R_b)-S(O)_m-NR_bR_c、-L-N(R_b)-C(O)OR_a、-L-N(R_b)-C(S)OR_a、-L-O-C_1-6alkylene-OR_a、-L-C(O)-C_1-6alkylene-NR_bR_c、-L-N(R_b)-C(O)-NR_bR_c、-L-N(R_b)-C(S)-NR_bR_c、-L-O-C(O)-NR_bR_c、-L-O-C(S)-NR_bR_c、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl; wherein said C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl optionally further substituted with one or more of the following groups:

-L-CN、-NO₂carbonyl, -L-OR_a、-L-SR_a、-L-NR_bR_c、-L-C(O)R_a、-L-C(S)R_a、-L-C(O)OR_a、-L-C(S)OR_a、-L-C(O)-NR_bR_c、-L-C(S)-NR_bR_c、-L-O-C(O)R_a、-L-O-C(S)R_a、-L-N(R_b)-C(O)-R_a、-L-N(R_b)-C(S)-R_a、-L-S(O)_mR_a、-L-S(O)_mOR_a、-L-S(O)_mNR_bR_c、-L-N(R_b)-S(O)_m-R_a、-L-N(R_b)-S(O)_m-R_bR_c、-L-N(R_b)-C(O)OR_a、-L-N(R_b)-C(S)OR_a、-L-O-C_1-6alkylene-OR_a、-L-C(O)-C_1-6alkylene-NR_bR_c、-L-N(R_b)-C(O)-NR_bR_c、-L-N(R_b)-C(S)-NR_bR_c、-L-O-C(O)-NR_bR_c、-L-O-C(S)-NR_bR_c；

R_a、R_bAnd R_cIndependently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl;

R_a、R_band R_cOptionally further substituted with one or more of the following groups:

C_1-6alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl;

l is selected from the group consisting of a bond, -C_1-6Alkylene-, -C_2-6alkenylene-or-C_2-6Alkynylene-;

l' is selected from the group consisting of a bond, -O-, -NH-, -C (O) -, -C (O) NH-, -NHC (O) -, -C_1-6Alkylene-, -C_2-6alkenylene-or-C_2-6Alkynylene-;

m represents 0,1 or 2.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient;

in another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient, which further comprises an additional therapeutic agent;

in another aspect, the invention provides kits comprising a compound of the invention, and other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle;

in another aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prevention of an FGFR mediated disease;

in another aspect, the present invention provides a method of treating and/or preventing a FGFR-mediated disease in a subject, comprising administering to the subject a compound of the present invention or a composition of the present invention;

in another aspect, the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of a FGFR mediated disease.

In particular embodiments, the disease includes a cell proliferative disorder, including but not limited to cancer, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders, and other cell proliferative disorders. More specifically, the cancers include, but are not limited to, solid tumors and hematologic malignancies, such as breast cancer, neuroblastoma, malignant rhabdomyoma, well-differentiated and de-differentiated liposarcoma, glioma, lung cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, prostate tumor, sarcoma, ovarian cancer, cervical cancer, pancreatic cancer, melanoma, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, mesothelioma, lymphoma, leukemia, non-hodgkin's lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, Acute Myeloid Leukemia (AML), multiple myeloma. Such as restenosis, atherosclerosis, vascular smooth muscle proliferation and intimal hyperplasia following balloon angioplasty, and other vascular disorders caused by abnormal cell proliferation.

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.

It is to be understood that any of the moieties defined below may be substituted with a number of substituents when described herein, and that the corresponding definitions are within their scope as set forth below, including such substituted moieties. Unless otherwise specified, the term "substituted" is as defined below.

“C_1-6Alkyl "means a straight or branched chain saturated monovalent alk (en) yl group containing 1 to 6 carbon atoms. In some embodiments, C_1-4Alkyl groups are preferred. Typical C_1-6Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl and the like. The term "C_1-6Alkyl "also includes heteroalkyl wherein from 1 to 3 nitrogen atoms selected from O, S, N or substituted may be substituted for carbon atoms. The alkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_2-6Alkenyl "represents a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2-vinylbutyl, 3-hexen-1-yl, and the like. In some embodiments, C_2-4Alkenyl groups are preferred.

“C_2-6Alkynyl "refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms with at least one carbon-carbon triple bond and optionally one or more unsaturated carbon-carbon double bonds. In some embodiments, C2-4 alkynyl is preferred. Typical alkynyl groups include vinyl,Propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and hexenyl. "-C_1-6Alkylene-, -C_2-6alkenylene-or-C_2-6Alkynylene- "means" C "as defined above_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl "is a divalent radical.

“C_1-6Alkylene "means removal of C_1-6One hydrogen of the alkyl group forms a divalent alkylene group and may be a substituted or unsubstituted alkylene group. In some embodiments, C_1-4Alkylene groups are particularly preferred.

“C_2-6Alkenylene "means the removal of C_2-6One hydrogen of an alkenyl group forms a divalent alkenylene group, and may be a substituted or unsubstituted alkenylene group. In some embodiments, C_2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to: vinylidene (-CH-) and propenylene (e.g., -CH-) CHCH₂-、-CH₂-CH＝CH-)。

“C_2-6Alkynylene "means removal of C_2-6One hydrogen of the alkynyl group forms a divalent alkynylene group, and may be a substituted or unsubstituted alkynylene group. In some embodiments, C_2-4Alkynylene groups are particularly preferred. Exemplary such alkynylene groups include, but are not limited to: ethynylene (-C [ identical to ] C-), substituted or unsubstituted propynyl (-C [ identical to ] CCH)₂-) and the like.

"halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

“C_1-6Haloalkyl "represents the above-mentioned" C_1-6Alkyl "substituted with one or more halo groups. Examples include monohalogen substituted, dihalogen substituted and polyhaloalkyl including perhalo.

“C_3-7Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C_3-6Cycloalkyl is particularly preferred, more preferably C_5-6A cycloalkyl group. "3-11 membered heterocyclyl" means a 3 to 11 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatomsWherein 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.

“C_6-10Aryl "refers to a group having a monocyclic or polycyclic (e.g., bicyclic) 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) of 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl).

"5-10 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.

Specific examples of preferred heteroaryl groups include: pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-l,2, 4-triazolyl, 1H-1,2, 3-triazolyl, 2H-l,2, 3-triazolyl, pyranyl, 2-furyl, 3-furan, etc., 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2, 4-oxazolyl, 1,3, 4-oxazolyl, 1,2, 5-oxazolyl, thiazolyl, thiadiazolyl (1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl).

"carbonyl", whether used alone or in combination with other terms (e.g., aminocarbonyl), is designated as-C (O) -.

"oxo" represents ═ O.

"thio" means ═ S.

Other definitions

The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal and pharyngeal (oral), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, hodgkin's disease, hairy cell carcinoma, and leukemia.

The term "pharmaceutically acceptable salts" as used herein refers to those carboxylic acid salts, amino acid addition salts, of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including, where possible, the zwitterionic forms of the compounds of the present invention.

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 a compound of the invention and another therapeutic agent. For example, the compounds of the present invention may be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosage forms, or simultaneously with the other therapeutic agent in a single unit dosage form.

Detailed description of the preferred embodiments

Herein, "compound of the present invention" refers to the following compound of formula (I), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof.

Compounds are generally described herein using standard nomenclature. Compounds having asymmetric centers, it is understood (unless otherwise indicated) that all optical isomers and mixtures thereof are included. Compounds that exist in different tautomeric forms, one such compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms. The general formula used for some compounds includes description, variables. Unless otherwise specified, each variable in such a formula is defined as a plurality of variables that are independent of any other variable and that independently define any one variable in a formula at each occurrence.

In particular embodiments, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof:

wherein:

a is selected from CR₄' or N;

x is selected from H or halogen; preferably, X is selected from F or Cl; preferably, X is selected from Cl;

y is selected from H or halogen; preferably, Y is selected from F or Cl; preferably, Y is selected from Cl;

z is selected from absent or Z is selected from carbonyl;

R₁selected from H, C_1-6An alkyl group; preferably, R₁Selected from H or Me;

R₂selected from H halogen, -CN, -OR_a、-SR_a、-NR_bR_c、-C(O)R_a、-C(O)OR_a、-C(O)NR_bR_c、C_1-6Alkyl radical, C_1-6Haloalkyl or

Preferably, R₂Selected from H, C_1-6Alkyl or

Preferably, R₂Is selected from H or

R₃Selected from H, -OR_a、C_1-6Alkyl or

Preferably, R₃Is selected from H or

Preferably, R₃Is selected from H;

R₄independently selected from H, halogen, -CN, -NO₂、C_1-6Alkyl radical, C_1-6Haloalkyl or optionally substituted with 1,2,3 or 4R₅A group-substituted-L' -3-11 membered heterocyclic group (preferably, a 3-11 membered heterocyclic group); preferably, R₄Independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl or optionally substituted with 1,2,3 or 4R₇A group-substituted-L' -3-11 membered heterocyclic group (preferably, a 3-11 membered heterocyclic group); preferably, R₄Independently selected from H, halogen, -CN, -NO₂、C_1-6Alkyl radical, C_1-6Haloalkyl or optionally substituted with 1,2,3 or 4R₅A group-substituted-L' -5-6 membered heterocyclic group (preferably, a 5-6 membered heterocyclic group); preferably, R₄Independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl or optionally substituted with 1,2,3 or 4R₅A group-substituted-L' -5-6 membered heterocyclic group (preferably, a 5-6 membered heterocyclic group); preferably, R₄Independently selected from H, halogen, -CN, -NO₂、C_1-6Alkyl or C_1-6Haloalkyl or optionally substituted with 1,2,3 or 4R₅The following groups substituted with groups:

preferably, R₄Independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl or optionally substituted with 1,2,3 or 4R₅The following groups substituted with groups:

or, R₄Selected from H, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, -OR_a、-O-C_1-6alkylene-R₆or-L' -3-7 membered heterocyclyl, said group optionally substituted with 1 or 2R₅Substituted by groups; preferably, R₄Is selected from-O-C_1-6alkylene-R₆-L' -3-11 membered heterocyclyl or-C (O) NR_bR_cSaid group being optionally substituted by 1 or 2R₅Substituted by groups;

R₄' independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl or-ORa; preferably, R₄' independently selected from H, C1-6 alkyl OR-OR_a；

R₅Independently selected from H, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Haloalkyl or-C_0-6alkylene-OR_a(ii) a Preferably, R₅Independently selected from H, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₅Independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl or-C_0-6alkylene-OR_a(ii) a Preferably, R₅Independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group;

R_ais selected from H or C_1-6An alkyl group;

R_band R_cIndependently selected from H or 3-7 membered heterocyclyl;

l' is selected from the group consisting of a bond, -O-, -NH-, -C (O) -, -C (O) NH-or-NHC (O) -.

In particular embodiments, the present invention relates to compounds of general formula (II), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof:

wherein:

a is selected from CR₄' or N;

R₂selected from H, -OR_a、C_1-6Alkyl or

Preferably, R₂Selected from H, C_1-6Alkyl or

Preferably, R₂Is selected from H or

R₃Selected from H, -OR_a、C_1-6Alkyl or

Preferably, R₃Is selected from H or C_1-6An alkyl group; preferably, R₃Is selected from H;

R₄selected from the group consisting of optionally substituted by 1,2,3 or 4R₅A 3-11 membered heterocyclyl substituted with a group; r₄Selected from the group consisting of optionally substituted by 1,2,3 or 4R₅A 5-6 membered heterocyclyl substituted with a group;

preferably, R₄Selected from the group consisting of optionally substituted by 1,2,3 or 4R₅The following groups substituted with groups:

preferably, R₄Selected from:

R₄' independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl OR-OR_a(ii) a Preferably, R₄' independently selected from H, C1-6 alkyl OR-OR_a；

R_ais selected from H or C_1-6An alkyl group;

R_band R_cIndependently selected from H or 3-7 membered heterocyclyl;

In a more specific embodiment, the present invention relates to compounds of formula (II), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof, wherein said compounds of formula (II) have the following general structure:

wherein the radicals are as defined above.

In particular embodiments, the present invention relates to compounds of formula (III), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof:

wherein:

a is selected from CR₄' or N; preferably, A is selected from CR₄’；

R₁selected from H, C_1-6An alkyl group; preferably, R₃Selected from H or Me;

R₂selected from H, -OR_a、C_1-6Alkyl or

Preferably, R₂Selected from H, C_1-6Alkyl or

Preferably, R₂Is selected from H or

R₃Selected from H, -OR_a、C_1-6Alkyl or

preferably, R₄Selected from:

R_ais selected from H or C_1-6An alkyl group;

R_band R_cIndependently selected from H or 3-7 membered heterocyclyl;

In a more specific embodiment, the present invention relates to compounds of general formula (III), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof, wherein the compounds of general formula (III) have the following general structure:

wherein the radicals are as defined above.

The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the present invention.

Preferred compounds of the present invention include, but are not limited to, the following listed compounds:

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 a compound of the invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

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.

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.

The present invention provides compounds of the invention useful for treating abnormal cell proliferation, such as cancer. The invention further provides a method of treating abnormal cell proliferation, such as a cancer selected from: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal and pharyngeal (oral), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, hodgkin's disease, hairy cell carcinoma, and leukemia comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention or a composition thereof.

Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are carried out, prepared, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what is claimed herein.

The compounds of formula (I) may be prepared according to the above general reaction scheme. Firstly, methyl esterification is carried out on 3-nitro-1H-pyrazole-5-carboxylic acid (1) under the catalysis of thionyl chloride to obtain a methyl ester intermediate (2). Protecting the intermediate (2) by benzyl or methyl to obtain a corresponding intermediate (3). The intermediate (3) is reduced by diisobutylaluminum hydride to obtain an alcohol intermediate (4), and then oxidized by manganese dioxide to obtain aldehyde (5). And (5) reacting with dimethyl diazomethylphosphonate (DAMP, Bestmann-Ohira reagent) to obtain an alkyne intermediate (6). And (3) carrying out Sonogashira cross-coupling reaction on the intermediate (6) and 1-iodo-3, 5-dimethoxybenzene to obtain 5- ((3, 5-dimethoxyphenyl) ethynyl) -3-nitro-1H-pyrazole (7a), wherein the (7a) can be used for obtaining a corresponding aryl halide intermediate (7b) or (7c) respectively through sulfonyl chloride or a selective fluorine reagent. The nitro group of intermediate (8) is then reduced under iron powder to give amino intermediate (8). Coupling the intermediate amine (8) with the aryl halide (9) affords the compound of formula (II). Wherein the PMB protecting group can be removed in trifluoroacetic acid/anisole by heating; and (3) carrying out esterification reaction on amine (8) and acid (10) to obtain the compound shown in the formula (III).

Preparation of intermediates 7aa, 7ab, 7ba, 7bb, 7ca and 7cb

1) Preparation of 3-nitro-1H-pyrazole-5-carboxylic acid methyl ester 2

3-Nitro-1H-pyrazole-5-carboxylic acid 1(25g) was dissolved in anhydrous methanol (330 mL). Thionyl chloride (34.7mL) was slowly added dropwise to the reaction solution in an ice-water bath. After dropping, the reaction solution is heated to reflux, and the reaction is continued for 16 hours until the silica gel thin layer chromatography shows that the raw material conversion is complete. After the reaction solution was cooled to room temperature, it was concentrated. The resulting pale yellow precipitate was washed twice with acetone (25mL) and recrystallized from petroleum ether/ethyl acetate (1:1) to give the title compound, 2(23.3g, 85%).¹H NMR(400MHz,(CD₃)₂CO)δ14.02(s,1H),7.38(s,1H),3.91(s,3H)。

2) Preparation of 1- (4-methoxybenzyl) -3-nitro-1H-pyrazole-5-carboxylic acid methyl ester 3a

After 2(10g) was dissolved in N, N-dimethylformamide (120mL), potassium carbonate (16.2g) and 4-methoxybenzyl bromide (14.3mL) were added in this order. Heating the reaction solution to 60 ℃, stirring and reacting for 5 hours, cooling to room temperature, carrying out suction filtration, and concentrating the filtrate. The resulting residue was diluted with ethyl acetate (500mL), washed three times with aqueous ammonium chloride (10%, 80mL), washed once with saturated brine (100mL), dried over anhydrous magnesium sulfate, filtered under suction, and concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 4:1) to give the title compound 3a as an off-white solid (16.18g, 95%).¹H NMR(400MHz,CDCl₃)δ7.38(s,1H),7.34(d,J＝8.6Hz,2H),6.84(d,J＝8.6Hz,2H),5.76(s,2H),3.92(s,3H),3.77(s,3H)。

Preparation of 1-methyl-3-nitro-1H-pyrazole-5-carboxylic acid methyl ester 3 b: referring to the preparation of 3a, 3b (8.8g, 81%) was prepared from 2(10g), potassium carbonate (16.1g) and iodomethane (7.3 mL).¹H NMR(400MHz,CDCl₃)δ7.50(s,1H),4.42(s,3H),4.09(s,3H)。

3) Preparation of (1- (4-methoxybenzyl) -3-nitro-1H-pyrazol-5-yl) methanol 4a

Diisobutylaluminum hydride (1.5M in toluene, 32.6mL) was slowly added dropwise to a solution of 3a (6.76g) in dichloromethane (100mL) at 0 ℃. After stirring the reaction at this temperature for 1 hour, the reaction mixture was diluted with diethyl ether (100mL) and water (1.30mL), an aqueous sodium hydroxide solution (15%, 1.30mL) and water (3.26mL) were added dropwise slowly in this order. After dropping, stirring at room temperature for 30 minutes, adding anhydrous magnesium sulfate, continuously stirring and drying for 30 minutes, carrying out suction filtration, and concentrating the filtrate. The residue was purified by flash column chromatography on silica gel (1: 2 petroleum ether/ethyl acetate) to give the title compound 4a as a colorless oil (4.88g, 80%).¹H NMR(600MHz,CDCl₃)δ7.22(d,J＝8.6Hz,2H),6.87(d,J＝8.6Hz,2H),6.85(s,1H),5.42(s,2H),4.58(s,2H),3.79(s,3H)；

Preparation of (1-methyl-3-nitro-1H-pyrazol-5-yl) methanol 4 b: prepared from 3b (8g) according to the procedure for the synthesis of 4a as the title compound 4b (5.8g, 85%) as a colorless oil.¹H NMR(400MHz,CDCl₃)δ6.83(s,1H),4.74(s,1H),4.72(s,1H),4.02(s,3H),2.01(s,1H)。

4)1- (4-methoxybenzyl) -3-nitro-1H-pyrazole-5-carbaldehyde 5a

Manganese dioxide (15.0g) was added to a solution of 4a (4.5g) in methylene chloride at room temperature. The reaction solution was heated to reflux and stirred for further reaction for 12 hours. And cooling the reaction liquid to room temperature, performing suction filtration, and concentrating the filtrate. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 2:1) to give the title compound 5a (4.06g, 91%) as a white solid.¹H NMR(400MHz,CDCl₃)δ9.84(s,1H),7.47(s,1H),7.34(d,J＝8.6Hz,2H),6.85(d,J＝8.6Hz,2H),5.72(s,2H),3.78(s,3H)；

Preparation of 1-methyl-3-nitro-1H-pyrazole-5-carbaldehyde 5 b: referring to the synthesis of 5a, 5b (5.05g, 93%) was prepared as a white solid from 4b (5.5 g).¹H NMR(400MHz,CDCl₃)δ9.89(s,1H),7.48(s,1H),4.27(s,3H)。

5) 5-ethynyl-1- (4-methoxybenzyl) -3-nitro-1H-pyrazole 6a

To a suspension of potassium carbonate (9.1g) and p-toluenesulfonylazide (3.42g) in acetonitrile (150mL) was added dropwise a solution of dimethyl acetonylphosphonate (2.90g) in acetonitrile (20mL) at room temperature. After stirring the reaction for 2 hours, a solution of 5a (3.8g) in methanol (150mL) was slowly added dropwise to the reaction mixture. After the reaction was continued for 8 hours after dropping, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (300mL) and diluted with ether (400 mL). The aqueous phase was separated, extracted with ethyl acetate (2X 300ml), the organic phases combined, dried over anhydrous magnesium sulphate, filtered with suction and the filtrate concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 2:1) to give the title compound 6a (3.03g, 81%) as a white solid.¹H NMR(400MHz,CDCl₃)δ7.33(d,J＝8.6Hz,2H),7.05(s,1H),6.88(d,J＝8.6Hz,2H),5.40(s,2H),3.79(s,3H),3.65(s,1H)；

Preparation of 5-ethynyl-1-methyl-3-nitro-1H-pyrazole 6 b: referring to the synthesis of 6a, 5b (4.2g) was prepared as a white solid, namely 6b (3.15g, 77%).¹H NMR(400MHz,CDCl₃)δ7.04(s,1H),4.03(s,3H),3.63(s,1H)。

6)5- ((3, 5-Dimethoxyphenyl) ethynyl) -1- (4-methoxybenzyl) -3-nitro-1H-pyrazole 7aa

6a (2.5g) was dissolved in toluene (150mL), and 3, 5-dimethoxyiodobenzene (5.05g), bis (triphenylphosphine) palladium dichloride (341mg), cuprous iodide (92.6mg), and diisopropylethylamine (4.8mL) were added in that order at room temperature. The reaction solution was replaced with argon twice, heated to 50 ℃ and stirred to react for 12 hours. The reaction mixture was diluted with ethyl acetate (60mL), and the reaction mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 2:1) to give the title compound 7aa (600mg,1.53mmol, 80%) as an off-white solid.¹H NMR(400MHz,CDCl₃)δ7.34(d,J＝8.7Hz,2H),7.05(s,1H),6.88(d,J＝8.7Hz,2H),6.66(d,J＝2.3Hz,2H),6.55(t,J＝2.3Hz,1H),5.45(s,2H),3.82(s,6H),3.79(s,3H)。

Preparation of 5- ((3, 5-dimethoxyphenyl) ethynyl) -1-methyl-3-nitro-1H-pyrazole 7 ab: referring to the synthesis of 7aa, an off-white solid was prepared from 6b (2.8g) as 7ab (4.1g, 77%).¹H NMR(400MHz,CDCl₃)δ7.46(s,1H),6.89(d,J＝2.4Hz,2H),6.75(d,J＝2.4Hz,1H),4.28(s,3H),4.02(s,6H)。

7) Preparation of 5- ((2, 6-dichloro-3, 5-dimethoxyphenyl) ethynyl) -1- (4-methoxybenzyl) -3-nitro-1H-pyrazole 7ba

Sulfuryl chloride (1.65mL) was added dropwise to a solution of 7aa (800mg) in acetonitrile (12mL) under an ice-water bath. After dropping, the reaction was stirred at this temperature for about 30 minutes until a pale yellow solid precipitated. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (50mL) and diluted with ethyl acetate (100 mL). The aqueous layer was separated, extracted with ethyl acetate (2X 30mL), and the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous magnesium sulfate, filtered with suction, and concentrated. The resulting pale yellow solid was the title compound 7ba (867mg, 80%).¹H NMR(600MHz,CDCl₃)δ7.41(d,J＝8.4Hz,2H),7.16(s,1H),6.85(d,J＝8.4Hz,2H),6.64(s,1H),5.54(s,2H),3.96(s,6H),3.77(s,3H)。

Preparation of 5- ((2, 6-dichloro-3, 5-dimethoxyphenyl) ethynyl) -1-methyl-3-nitro-1H-pyrazole 7 bb: referring to the intermediate 7ba synthesis, 7bb (811mg, 82%) was prepared from 7ab (800mg) as a pale yellow solid. LC-MS (ESI), C₁₄H₁₂Cl₂N₃O₄[M+H]⁺:m/z＝356.1。

8) Preparation of 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -1- (4-methoxybenzyl) -3-nitro-1H-pyrazole 7ca

The selective fluorine reagent (1-chloromethyl-4-fluoro-1, 4-diazabicyclooctane bis (tetrafluoroborate) salt, 1.08g) was added in portions to a solution of 7aa (600mg) in acetonitrile (8mL) under an ice-water bath. After warming to room temperature and stirring the reaction for another 48 hours, the reaction mixture was filtered and the filtrate was concentrated. Ethyl acetate (50mL) and saturated aqueous sodium bicarbonate (40mL) were added to the residue to separate waterThe layers were extracted with ethyl acetate (2X 20mL), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous magnesium sulfate, filtered with suction and the filtrate was concentrated. The crude product was subjected to flash silica gel column chromatography (petroleum ether/ethyl acetate 4:1) to give the title compound 7ca (189.9mg, 29%) as a pale yellow solid. LC-MS (ESI), C₂₁H₁₈F₂N₃O₅[M+H]⁺:m/z＝430.2；

Preparation of 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -1-methyl-3-nitro-1H-pyrazole 7 cb: referring to the procedure for the synthesis of intermediate 7ca, 7cb (168.8mg, 30%) was prepared from 7ab (500 mg). LC-MS (ESI), C₁₄H₁₂F₂N₃O₄[M+H]⁺:m/z＝324.1。

Example 1: preparation of N- (2- ((5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazol-3-yl) amino) -3-methylphenyl) acrylamide

The first step is as follows: a suspension of 7a (120mg), Fe powder (513mg) and ammonium chloride (114mg) in ethanol/water (2:1,3mL) was purged with argon three times. After stirring the reaction for 2 hours while warming to 60 ℃, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (20mL) and diluted with dichloromethane (20 mL). The aqueous layer was separated and extracted with dichloromethane (2X 15ml), the organic phases combined, dried over anhydrous magnesium sulphate, filtered and the filtrate concentrated to give a pale yellow oil, 8a (98mg), which was used in the next reaction without further purification.¹H NMR(400MHz,CDCl₃)δ7.33(d,J＝8.5Hz,2H),6.96(dd,J＝8.8Hz,J＝7.7Hz,1H),6.85(d,J＝8.5Hz,2H),6.64(d,J＝8.8Hz,1H),6.61(d,J＝7.7Hz,1H),6.55(s,1H),5.64(s,1H),5.33(s,2H),3.92(s,6H),3.78(s,3H),2.20(s,3H)。

The second step is that: the crude product obtained in the above step was dissolved in anhydrous tetrahydrofuran (2mL), and sodium hydride (21.6mg) was added under ice-water bath. After stirring the reaction mixture for 10 minutes, 2-fluoro-1-methyl-3-nitrobenzene 9a (62.8mg) was added and the temperature was raised to 65 ℃ for overnight reaction. Adding saturated aqueous sodium bicarbonate solution (10mL) quench the reaction. The aqueous layer was separated, extracted with ethyl acetate (3X 8ml), and the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, suction-filtered, and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 1:1) to give the title compound 11a as a bright yellow solid (110.9mg, two steps 73%).¹H NMR(400MHz,CDCl₃)δ8.51(s,1H),7.96(dd,J＝8.4,1.5Hz,1H),7.36(dd,J＝7.4,1.5Hz,1H),7.25(d,J＝8.6Hz,2H),6.99(dd,J＝8.4,7.4Hz,1H),6.87(d,J＝8.6Hz,2H),6.61(d,J＝2.3Hz,2H),6.49(t,J＝2.3Hz,1H),5.96(s,1H),5.26(s,2H),3.80(s,6H),3.79(s,3H),2.05(s,3H)。

The third step: referring to the reduction of 8a in the first step, a pale yellow solid was prepared from 11a (100mg) as 12a (83.7 mg).

The fourth step: 1-Propylphosphoric anhydride (106. mu.L) was slowly added dropwise to a solution of 12a of crude product (83.7mg) in dichloromethane (2mL) at-50 ℃. After stirring for 30 minutes, acryloyl chloride (29 μ L) was slowly added dropwise to the reaction solution. After 1 hour of further reaction, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (5 mL). The aqueous layer was separated, extracted with dichloromethane (2X 5ml), the organic layers combined, dried over anhydrous magnesium sulfate, filtered with suction and the filtrate concentrated to give 13a (24mg, two steps 23%) as a yellow oil. LC-MS (ESI), C₃₁H₃₁N₄O₄[M+H]⁺:m/z＝523.1。

The fifth step: trifluoroacetic acid (8.5 μ L) was added to a solution of 13a (12mg) in anisole (1mL) at room temperature, warmed to 80 ℃, and the reaction was stirred for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate (3 × 8mL) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered under suction, and the crude product obtained by concentrating the filtrate was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 1:2) to give I-1(6.9mg, 75%) as a white solid.¹H NMR(400MHz,CDCl₃)δ8.32(s,1H),8.21(d,J＝8.2Hz,1H),7.15(dd,J＝8.2Hz,7.6Hz,1H),6.96(d,J＝7.6Hz,1H),6.57(d,J＝2.4Hz,2H),6.44(t,J＝2.4Hz,1H),6.32(d,J＝16.8Hz,1H),6.17(dd,J＝16.8,10.1Hz,1H),5.69(s,1H),5.66(d,J＝10.1Hz,1H),5.61(s,1H),3.73(s,6H),2.21(s,3H)。

Example 2: referring to the synthesis of I-1 in example 1, 7ba (100mg) was reacted in five steps to give I-2(7.7mg, 7.6%) as a pale yellow solid.¹H NMR(400MHz,CDCl₃)δ8.49(s,1H),8.22(d,J＝8.3Hz,1H),7.18(dd,J＝8.3Hz,7.6Hz,1H),6.99(d,J＝7.6Hz,1H),6.54(s,1H),6.33(s,1H),6.26(dd,J＝16.7Hz,9.8Hz,1H),6.02(d,J＝16.7Hz,1H),5.69(d,J＝9.8Hz,1H),5.65(s,1H),3.91(s,6H),2.24(s,3H)。

Example 3: referring to the synthesis of 13a in example 1, 7ab (100mg) was reacted in four steps to obtain I-3(13mg, 9.0%) as a pale yellow solid.¹H NMR(600MHz,CDCl₃)δ8.36(s,1H),8.30(d,J＝8.3Hz,1H),7.19(dd,J＝8.3Hz,7.6Hz,1H),6.99(d,J＝7.6Hz,1H),6.61(d,J＝2.4Hz,2H),6.48(t,J＝2.4Hz,1H),6.34(d,J＝16.9Hz,1H),6.20(dd,J＝16.9,10.2Hz,1H),5.70(d,J＝10.2Hz,1H),5.50(s,1H),5.38(s,1H),3.84(s,3H),3.78(s,6H),2.25(s,3H)。

Example 4: referring to the synthesis of 13a in example 1, I-4(15.1mg, 10.4%) was prepared as a pale yellow solid from 7ab (100 mg).¹H NMR(400MHz,CDCl₃)δ8.44(d,J＝8.3Hz,1H),8.39(s,1H),7.42(d,J＝7.9Hz,1H),7.32(t,J＝8.2Hz,1H),6.63(d,J＝2.3Hz,2H),6.49(t,J＝2.3Hz,1H),5.69(s,1H),3.86(s,4H),3.83(d,J＝3.4Hz,2H),3.79(s,9H),2.74(t,J＝6.5Hz,2H)。

Example 5: referring to the synthesis of 13a in example 1, a pale yellow solid was prepared from 7ab (100mg) as I-5(7.3mg, 4.8%).¹H NMR(400MHz,CDCl₃)δ8.56(s,1H),8.06(s,1H),7.15(d,J＝8.7Hz,1H),6.70(dd,J＝8.7,2.9Hz,1H),6.65(d,J＝2.3Hz,2H),6.52–6.50(m,1H),6.44(dd,J＝5.8,1.6Hz,1H),6.39(d,J＝1.3Hz,1H),6.26(dd,J＝17.0,10.2Hz,1H),5.77(dd,J＝10.2,1.3Hz,1H),5.65(d,J＝10.4Hz,1H),3.91(s,3H),3.84(s,3H),3.80(s,6H).

Example 6: referring to the synthesis of 13a in example 1, a pale yellow solid was prepared from 7ab (100mg) as I-6(4.2mg, 2.6%).¹H NMR(400MHz,CDCl₃)δ8.56(d,J＝8.1Hz,1H),8.44(s,1H),7.43–7.40(m,1H),7.34(d,J＝7.8Hz,1H),6.62(d,J＝2.3Hz,2H),6.48(t,J＝2.3Hz,1H),6.34–6.30(m,1H),6.28(d,J＝1.3Hz,1H),6.19–6.12(m,1H),5.72(dd,J＝10.2,1.3Hz,2H),5.68(s,1H),3.85(s,3H),3.79(s,6H)。

Example 7: referring to the synthesis of 13a in example 1, a pale yellow solid was prepared from 7ab (100mg) as I-7(6.1mg, 3.7%).¹H NMR(400MHz,CDCl₃)δ8.54(s,1H),7.82(s,1H),7.57(d,J＝8.6Hz,1H),7.35(d,J＝7.4Hz,1H),7.00(s,1H),6.66(d,J＝2.3Hz,2H),6.50(t,J＝2.4Hz,1H),6.47(d,J＝3.1Hz,2H),6.14(s,1H),5.79–5.76(m,1H),3.88(s,3H),3.80(s,6H)。

Example 8: referring to the synthesis of 13a in example 1, 7bb (100mg) was prepared as a pale yellow solid, i.e., I-8(16mg, 11.7%).¹H NMR(400MHz,CDCl₃)δ8.37(s,1H),8.32(d,J＝8.4Hz,1H),7.19(dd,J＝8.4Hz,7.5Hz,1H),6.98(d,J＝7.5Hz,1H),6.55(s,1H),6.34(d,J＝16.9Hz,1H),6.19(dd,J＝16.9,10.1Hz,1H),5.69(d,J＝10.1Hz,1H),5.57(s,1H),5.34(s,1H),3.92(s,9H),2.24(s,3H)。

Example 9: referring to the synthesis of I-1 in example 1, a pale yellow solid was prepared from 7ca (50mg) as I-9(5.6mg, 11.0%).

Example 10: referring to the synthesis of 13a in example 1, a pale yellow solid was prepared from 7cb (50mg) as I-10(4.2mg, 6.0%).

Example 11: n- (2- ((5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazol-3-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide

1) Reference was made to the synthesis of 11a in example 1, from7aa (100mg) was prepared in a two-step reaction to give 11b (115.8mg, 81% in two steps) as a pale yellow solid. LC-MS (ESI), C₂₇H₂₄BrN₄O₅[M+H]⁺:m/z＝563.3。

2) 11b (112mg) was dissolved in dimethyl sulfoxide (3mL), and N-ethylpiperazine (50.6. mu.L) and diisopropylethylamine (65.8. mu.L) were added. The reaction solution was heated to 85 ℃ and reacted for 10 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (20mL), washed with water (2X 3mL) and saturated brine (3 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (3: 1 petroleum ether/ethyl acetate) to afford 14a as a white solid (103.2mg, 87%).

3) Referring to the synthesis of I-1 in example 1, I-11(16mg, 18.9%) was prepared from 14a (100mg) by three steps of reduction, esterification and deprotection. LC-MS (ESI), C₂₈H₃₃N₆O₃[M+H]⁺:m/z＝501.2。

Example 12: referring to the synthesis of 13b in example 11, I-12(22.3mg, 15.6%) was prepared as a pale yellow solid from 7ab (80 mg).

Example 13: referring to the synthesis of I-11 in example 11, prepared from 7ba (80mg) was I-13(19.1mg, 19.3%) as a pale yellow solid.

Example 14: referring to the synthesis of 13b in example 11, 7bb (80mg) was prepared as a pale yellow solid, i.e., I-14(13.2mg, 10.3%).

Example 15: referring to the synthesis of I-11 in example 11, 7bb (80mg) was prepared as a pale yellow solid, i.e., I-15(16.3mg, 12.4%).

Example 16: referring to the synthesis of 13b in example 11, 7bb (80mg) was prepared as a pale yellow solid, i.e., I-16(16.1mg, 12.5%).

Example 17: referring to the synthesis of 13b in example 11, 7bb (80mg) was prepared as a pale yellow solid, i.e., I-17(17.7mg, 13.5%).

Example 18: referring to the synthesis of 13b in example 11, 7bb (80mg) was prepared as a pale yellow solid, i.e., I-18(11.3mg, 9.0%).

Example 19: n- (5- ((2, 6-dichloro-3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazol-3-yl) -5- (4-ethylpiperazin-1-yl) pyridin-2-amine

1) Referring to the synthesis of 8a in example 1, a yellow solid, crude reduction product (85mg) was prepared from 7ba (100 mg). To a solution of 1- (6-chloropyridin-3-yl) -4-ethylpiperazine (133mg) in tetrahydrofuran (2mL) was added LiHMDS (1M in THF,0.39mL) dropwise under an ice-water bath. The reaction was allowed to warm to room temperature and stirred for 30 minutes, the crude product from the previous step (85mg) was added and the reaction was continued for about 3 hours until TLC indicated complete conversion of the starting material. The reaction was quenched by the addition of half-saturated aqueous sodium bicarbonate (10mL), the aqueous layer was separated, extracted with ethyl acetate (3X 8mL), the organic phases were combined, washed with saturated aqueous sodium chloride (5mL), dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (dichloromethane/methanol 40:1) to yield 11b as a yellow solid (104.9mg, 78% over two steps). LC-MS (ESI), C₃₂H₃₅Cl₂N₆O₃[M+H]⁺:m/z＝621.2。

2) Referring to the synthesis of I-1 in example 1, I-19(63.3mg, 77%) was prepared as a bright yellow solid by deprotecting the PMB from 11b (102 mg). LC-MS (ESI), C₂₄H₂₇Cl₂N₆O₂[M+H]⁺:m/z＝501.1。

Example 20: referring to the synthesis of 11b in example 19, 7bb (50mg) was reacted in two steps to produce I-20 as a pale yellow solid (23.0mg, 31.8%).

Example 21: referring to the synthesis of 11b in example 19, 7bb (50mg) was reacted in two steps to produce I-21 as a pale yellow solid (20.6mg, 30.0%).

Example 22: n- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxyphenyl) ethynyl) -1-methyl-1H-pyrazol-3-yl) amino) -5- (4-ethylpiperazin-1-yl) pyridin-3-yl) acrylamide

1) Referring to the synthesis of 11b in example 19, crude reduction product (85mg) was prepared from 7bb (100mg) and further reacted with 1- (6-chloro-5-nitropyridin-3-yl) -4-ethylpiperazine (141.5mg) to prepare 11c (118.1mg, 75% over two steps) as a pale yellow solid. LC-MS (ESI), C₂₅H₂₈Cl₂N₇O₄[M+H]⁺:m/z＝560.1。

2) Referring to the synthesis of 13a in example 1, a yellow solid, I-22(34.6mg, 28.9% over two steps) was prepared from 11c (115mg) by a two step reaction of reduction followed by esterification. LC-MS (ESI), C₂₈H₃₂Cl₂N₇O₃[M+H]⁺:m/z＝584.2。

Example 23: n- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazol-3-yl) amino) -5- (4-ethylpiperazin-1-yl) pyridin-3-yl) acrylamide

Referring to the synthesis of I-22 in example 22, 7ba (60mg) was reacted in five steps to give I-23 as a pale yellow solid (13.3mg, 18.0%). LC-MS (ESI), C₂₇H₃₀Cl₂N₇O₃[M+H]⁺:m/z＝570.2。

Example 24: 3-acrylamido-N- (5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazol-3-yl) benzamide

1) Referring to the preparation of intermediate 8a, a reduced crude product (65mg) was prepared from 7aa (80 mg).

2) The crude product from the above step (65mg) was dissolved in methylene chloride (3mL), and 3-nitrobenzoic acid (59.8mg), dicyclohexylcarbodiimide (59.0. mu.L) and 1-hydroxybenzotriazole (12mg) were added successively. After 4 hours of reaction at room temperature, the reaction mixture was diluted with dichloromethane (20mL), washed with saturated brine (5mL), dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (1:1 petroleum ether/ethyl acetate) to give 15a as a yellow solid (74mg, 71% over two steps). LC-MS (ESI), C₂₈H₂₅N₄O₆[M+H]⁺:m/z＝513.1。

3) Referring to the synthesis of I-1 in example 1, a light yellow solid, I-24(13.0mg, 22.9%) was prepared from 15a (70mg) in three steps. LC-MS (ESI), C₂₃H₂₁N₄O₄[M+H]⁺:m/z＝417.2。

Example 25: referring to the synthesis of I-24 in example 24, a pale yellow solid was prepared as I-25(9.9mg, 18.1%) from 7ab (50mg) by a four-step reaction.¹H NMR(400MHz,Acetone-d₆)δ9.97(s,1H),9.56(s,1H),8.32(d,J＝2.0Hz,1H),8.03–8.00(m,1H),7.82–7.79(m,1H),7.47(d,J＝7.9Hz,1H),7.01(s,1H),6.78(d,J＝2.3Hz,2H),6.58(t,J＝2.3Hz,1H),6.49(dd,J＝16.9,9.8Hz,2H),6.38(dd,J＝16.8,2.2Hz,2H),5.74(d,J＝2.3Hz,1H),3.90(s,3H),3.83(s,6H).

Example 26: referring to the synthesis of I-24 in example 24, 7bb (50mg) and o-nitrobenzene were usedFormic acid (42.8mg) was reacted in four steps to give a pale yellow solid, i.e., I-26(7.3mg, 10.4%).¹H NMR(400MHz,CDCl₃)δ11.29(s,1H),8.80–8.69(m,2H),7.62(d,J＝7.8Hz,1H),7.54(t,J＝7.9Hz,1H),7.13(t,J＝7.6Hz,1H),7.01(s,1H),6.52(s,1H),6.43(d,J＝17.0Hz,1H),6.31(dd,J＝17.0,10.1Hz,1H),5.78(d,J＝10.1Hz,1H),3.88(s,3H),3.82(s,6H).

Example 27: referring to the synthesis of I-24 in example 24, 7ba (50mg) and o-nitrobenzoic acid (32.6mg) were reacted in four steps to give I-27(6.1mg, 11.6%) as a pale yellow solid.

Example 28: referring to the synthesis of I-24 in example 24, 7ba (50mg) and 4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -2-nitrobenzoic acid (68.5mg, for the synthesis of this side chain we refer to wo 200807474749) were reacted in five steps to give I-28 as a pale yellow solid (5.6mg, 9.1%).

Example 29: referring to the procedure for the synthesis of I-24 in example 24, 7ba (50mg) and 4- (4- (tert-butoxycarbonyl) -3, 5-dimethylpiperazin-1-yl) -2-nitrobenzoic acid (74.1mg) were reacted in five steps to give I-29(4.2mg, 6.5%) as a pale yellow solid.

Example 30: referring to the synthesis of I-24 in example 24, 7ba (50mg) and 4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-nitrobenzoic acid (52.1mg) were reacted in five steps to give I-30 as a pale yellow solid (8.6mg, 13.6%).

Example 31: referring to the synthesis of I-24 in example 24, 7ba (50mg) and 4- (4-ethylpiperazin-1-yl) -2-nitrobenzoic acid (54.5mg) were reacted in five steps to give I-31 as a pale yellow solid (7.2mg, 11.1%).

Example 32: referring to the synthesis of I-24 in example 24, 7ba (50mg) and 4-morpholino-2-nitrobenzoic acid (49.2mg) were reacted in five steps to give I-32(3.3mg, 5.3%) as a pale yellow solid.

Example 33: referring to the synthesis of I-24 in example 24, 7bb (30mg) and 4- (4-ethylpiperazin-1-yl) -2-nitrobenzoic acid (42.4mg) were reacted in four steps to give I-33 as a pale yellow solid (7.7mg, 14.9%).

Example 34: n- (5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazol-3-yl) -4- (4-ethylpiperazin-1-yl) benzamide

Referring to the synthesis of 15a in example 24, 7aa (50mg) and 4- (4-ethylpiperazin-1-yl) benzoic acid (53.6mg) were reacted in three steps to give I-34 as a pale yellow solid (11.2mg, 19.1%). LC-MS (ESI), C₂₆H₃₀N₅O₃[M+H]⁺:m/z＝460.4。

Example 35: referring to the synthesis of I-24 in example 24, 7ba (30mg) and 4- (4- (tert-butoxycarbonyl) piperazin-1-yl) benzoic acid (35.9mg) were reacted in five steps to give I-35(6.8mg, 20.9%) as a pale yellow solid.

Example 36: referring to the synthesis of I-24 in example 24, 7bb (30mg) and 4- (4-ethylpiperazin-1-yl) benzoic acid (35.6mg) were reacted in five steps to give I-36 as a pale yellow solid (7.5mg, 16.8%).

Example 37: referring to the synthesis of I-24 in example 24, 7bb (30mg) and 4-morpholinobenzoic acid (31.5mg) were reacted in four steps to give I-37 as a pale yellow solid (4.5mg, 10.6%).

Kinase activity assay

1) And (3) kinase reaction process:

1. a1 XKinase buffer was prepared.

2. Preparation of compound concentration gradient: test compounds were tested at 1000nM, diluted to 100-fold final concentration in 100% DMSO solutions in 384source plates, and compounds were diluted 3-fold with Precision, 10 concentrations. Using a dispenser Echo 550 to the target plate OptiPlate-384F transfer 250nL 100 times the final concentration of compounds.

3. A2.5 fold final concentration of Kinase solution was prepared using a 1 XKinase buffer.

4. Add 10. mu.L of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; mu.L of 1 XKinase buffer was added to the negative control wells.

5.1000 rpm for 30 seconds, the reaction plate was shaken and mixed well and incubated at room temperature for 60 minutes.

6. A mixture of ATP and Kinase substrate22 was made up at 5/3 fold final concentration using 1 XKinase buffer.

7. The reaction was initiated by adding 15. mu.L of a mixed solution of ATP and substrate at 5/3-fold final concentration.

8. The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken and mixed and incubated at room temperature for the appropriate time.

9. Add 30. mu.L of termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix.

10. The conversion was read using a Caliper EZ Reader.

2) Data analysis

Wherein: conversion% _ sample is the Conversion reading for the sample; conversion% _ min: negative control well mean, representing conversion readings without enzyme live wells; conversion% _ max: positive control wells are averaged for conversion readings in wells without compound inhibition. The dose-response curves were fitted using the log values of the concentrations as the X-axis and the percent inhibition as the Y-axis, using the analysis software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope, to obtain the IC50 values of each compound for enzyme activity. The formula is Y ═ Bottom + (Top-Bottom)/(1+10^ ((LogicC 50-X) } HillSlope))

3) Reagent and consumable

4) Test results

The results of the enzyme inhibitory activity of the most representative compounds of the present invention are shown in the following table, wherein A represents IC₅₀<2 nM; b represents IC₅₀Is 2-20 nM; c represents IC₅₀Is 20-50 nM; d represents IC₅₀Is 50-200 nM; e represents IC₅₀200 and 500 nM.

The foregoing is a more detailed description of the invention, taken in conjunction with specific preferred embodiments thereof, and it is not intended that the invention be limited to the specific embodiments described. 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.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, and mixtures thereof:

wherein:

a is selected from CR₄' or N;

x, Y are each independently selected from H or halogen;

z is absent or is

R₁Independently selected from hydrogen, C_1-6An alkyl group;

R₂、R₃independently selected from H, -OR_a、-C_1-6Alkyl radical, C_1-6Haloalkyl or

R₄Selected from H, -L-NR_bR_c、C_1-6Alkyl radical, C_1-6Haloalkyl, 3-to 11-membered heterocyclyl, said group being substituted with 1,2 or 3R₅Substituted by groups; the 3-11 membered heterocyclyl is selected from:

R₅Selected from H, -NH₂、-NHC_1-6Alkyl, N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Haloalkyl, -C_1-6alkylene-OR_a；

R_a、R_bAnd R_cIndependently selected from H, C_1-6An alkyl group;

l is selected from the group consisting of a bond, -C_1-6Alkylene-;

and the compound of the formula (I) is not

2. A compound of formula (II-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, and mixtures thereof:

x, Y are each independently selected from H, F or Cl;

R₁independently selected from H or Me;

R₂、R₃independently selected from H, -OR_a、C_1-6Alkyl radical, C_1-6Haloalkyl or

R₄Selected from the group consisting of 1,2 or 3R₅The following groups substituted with groups:

R₄' independently selected from H, -OR_a、C_1-6Haloalkyl or C_1-6An alkyl group;

R₅independently selected from H, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Haloalkyl or-C_0-6alkylene-OR_a；

R_a、R_bOr R_cIs selected from H or C_1-6An alkyl group.

3. The compound according to claim 2, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof, wherein:

x, Y are each independently selected from H, F or Cl;

R₁independently selected from H or Me;

R₂、R₃independently selected from H or

R₄Selected from:

R₄' independently selected from H, -OR_a、C_1-6Alkyl or C_1-6A haloalkyl group;

R₅independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group.

4. A compound of formula (II-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, and mixtures thereof:

wherein the content of the first and second substances,

R₁independently selected from H or Me;

R₂independently selected from H, -OR_a、C_1-6Alkyl radical, C_1-6Haloalkyl or

R_a、R_bOr R_cIs selected from H or C_1-6An alkyl group.

5. The compound according to claim 4, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof, wherein:

R₁independently selected from H or Me;

R₂is selected from

R₄Selected from:

R₅independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group.

6. A compound of formula (II-3), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, and mixtures thereof:

wherein the content of the first and second substances,

R_a、R_bOr R_cIs selected from H or C_1-6An alkyl group.

7. The compound according to claim 6, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof, wherein:

R₂is selected from

R₄Selected from:

R₅independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group.

8. A compound of formula (II-4), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, and mixtures thereof:

wherein the content of the first and second substances,

x, Y are each independently selected from H, F or Cl;

R₁independently selected from H or Me;

R_a、R_bOr R_cIs selected from H or C_1-6An alkyl group.

9. The compound according to claim 8, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof, wherein:

x, Y are each independently selected from F or Cl;

R₁independently selected from H or Me;

R₂is selected from

R₄Selected from:

R₅independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group.

10. A compound of formula (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, and mixtures thereof:

x, Y are each independently selected from H, F or Cl;

R₁independently selected from H or Me;

R_a、R_bOr R_cIs selected from H or C_1-6An alkyl group.

11. The compound according to claim 10, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof, wherein:

x, Y are each independently selected from H, F or Cl;

R₁independently selected from H or Me;

R₂、R₃independently selected from H or

R₄Selected from:

R₅independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group.

12. A compound of formula (III-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, and mixtures thereof:

wherein

R_a、R_bOr R_cIs selected from H or C_1-6An alkyl group.

13. The compound according to claim 12, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof, and mixtures thereof, wherein:

R₂is selected from

R₄Selected from:

R₅independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group.

14. The following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof:

15. a pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof, and a pharmaceutically acceptable excipient.

16. Use of a compound according to any one of claims 1 to 14 in the manufacture of a medicament for the treatment and/or prophylaxis of FGFR mediated diseases.

17. Use according to claim 16, characterized in that: the FGFR-mediated disease is a cell proliferative disease.

18. Use according to claim 16, characterized in that: the FGFR-mediated disease is cancer, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders, and other cell proliferation disorders; the cancer is solid tumor and blood malignant tumor.

19. Use according to claim 18, characterized in that: the cancer is breast cancer, neuroblastoma, malignant rhabdomyoma, glioma, lung cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumor, hepatocellular carcinoma, prostate cancer, sarcoma, ovarian cancer, cervical cancer, pancreatic cancer, melanoma, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, mesothelioma, lymphoma, leukemia, multiple myeloma.

20. Use according to claim 19, characterized in that: the sarcoma is high-differentiation and dedifferentiation liposarcoma, the leukemia is acute myelocytic leukemia, and the lymphoma is non-Hodgkin lymphoma, mantle cell lymphoma or anaplastic large cell lymphoma.

21. The following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof:

22. use of a compound of claim 21 in the manufacture of a medicament for the treatment and/or prevention of an FGFR-mediated disease, said FGFR being FGFR1, FGFR2 or FGFR 3.

23. The following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof:

24. use of a compound of claim 23 in the manufacture of a medicament for the treatment and/or prevention of an FGFR-mediated disease, said FGFR being FGFR1 or FGFR 3.

25. The following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates thereof:

26. use of a compound of claim 25 for the manufacture of a medicament for the treatment and/or prevention of an FGFR-mediated disease, said FGFR being FGFR 1.