Novel heterocyclic compound

Abstract

The present invention relates to a novel heterocyclic compound, which is a compound having FGFR2 protein activity. Specifically, the present invention relates to a compound of formula (III), or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and the use of same in the preparation of a drug used for treating FGFR-related diseases.

Description

A new heterocyclic compound

[0001] Cross-references

[0002] This application claims priority to Chinese Patent Application No. 202311524928.5, filed on November 16, 2023, entitled “A Novel Heterocyclic Compound”, Chinese Patent Application No. 202311845934.0, filed on December 28, 2023, Chinese Patent Application No. 202410121924.0, filed on January 29, 2024, entitled “A Novel Heterocyclic Compound”, Chinese Patent Application No. 202410165964.5, filed on February 5, 2024, and Chinese Patent Application No. 202410288517.9, filed on March 13, 2024, and all disclosed contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to compounds for inhibiting FGFR protein activity, and also relates to preparation methods of these compounds and uses of their pharmaceutical compositions. Background Art

[0004] Fibroblast growth factor receptors (FGFRs) are transmembrane polypeptide tyrosine kinases. Five types (FGFR1 to FGFR5) have been discovered. FGFR2 is primarily distributed in tissues of endodermal origin, such as the stomach, liver, pancreas, esophagus, and bile duct in the digestive system. FGFR2b is distributed in epithelial cells, while FGFR2c is distributed in mesenchymal cells. FGFR2 plays a significant role in promoting cell proliferation and differentiation, nerve fiber growth and development, wound healing, and apoptosis. FGFR2 activates the downstream p38 signaling pathway to trigger endochondral ossification. Activation of the downstream MAPK and PKC pathways regulates the proliferation of mesenchymal stem cells, playing a crucial role in promoting direct osteogenesis. FGFR2 also plays a crucial role in tooth development.

[0005] Previous studies have shown that FGFR2 is associated with a variety of tumors. FGFR2 gene amplification has been reported in triple-negative breast cancer and gastric cancer with a poor prognosis. FGFR2 gene mutations have been found in endometrial cancer, lung cancer, gastric cancer, and urothelial cancer. FGFR2 fusion proteins are present in lung adenocarcinoma, squamous cell carcinoma, thyroid cancer, prostate cancer, and bile duct cancer. In colorectal cancer, FGFR2 can upregulate programmed cell death ligand 1 (PD-L1) expression through the JAK / STAT3 pathway, regulating tumor immune evasion, and FGFR2 expression levels are closely correlated with prognosis. Studies have found that FGFR2 gene fusions are found in 10-20% of patients with intrahepatic bile duct cancer.

[0006] The development of drugs targeting FGFR2 isoforms is underway. In addition to the three marketed drugs, over ten FGFR inhibitors are in various stages of clinical development. Examples include bemarituzumab (currently in Phase II clinical trials), developed by Amgen and Zai Lab; alofanib (currently in Phase I clinical trials), developed by Russian Pharmaceutical Technologies; RLY-4008 (currently in Phase II clinical trials), developed by Relay Therapeutics; and TAS-120 (futibatinib), developed by Taiho Pharmaceuticals (currently in Phase II clinical trials).

[0007] Summary of the Invention

[0008] The present invention provides an FGFR2 inhibitor, which is a compound represented by general formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof. The present invention also provides a series of compounds represented by general formula (I) and pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof, pharmaceutical compositions comprising these compounds, and methods for treating FGFR-related diseases using such compounds.

[0009] In one aspect, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof:

[0010] in,

[0011] X is Cl or -CN,

[0012] Y is H or C 1-6 Alkyl, or

[0013] X and Y together form a 5-7 membered heteroaromatic ring,

[0014] R1 is phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl may be optionally substituted by R2,

[0015] R2 is selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated methyl, or -(CH2) 0-1 -R3,

[0016] R3 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted with halogen, -CN, -NH2, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group,

[0017] L is or L0,

[0018] L0 is -L1-L4-NH-, -L4-L5-L6-, -L4-L6-, -L4-L1-L 6- , -L4-L4-NH-, -L4-L5-NH-, -L1-L3-L4-NH-, -L5-L4-NH-, -L4-L2-L6-, -L1-L3-L2-L4-NH-, -L1-L3-L7-, -L1-L3-L4-L5-NH-, or -L8-L4-NH-,

[0019] L1 is -O-, -S-, or -N(R)-,

[0020] L2 is -(CO)-,

[0021] L3 is C 1-6 Alkylene, which may be optionally replaced by C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl substitution,

[0022] L4 is a phenylene group or a 5-7 membered heteroarylene group,

[0023] L5 is a 3-8 membered heterocyclic ring,

[0024] L6 is or

[0025] L7 is or

[0026] L8 is -CH=CH-.

[0027] In some embodiments, L1 is -O-, -S-, or -N(R)-, and R is H or C 1-6 Alkyl, preferably H.

[0028] In some embodiments, L1 is -O- or -S-.

[0029] In some embodiments, L0 is -L1-L4-NH-, -L4-L5-L6-, -L4-L6-, -L4-L1-L 6- , -L4-L4-NH-, -L4-L5-NH-, -L1-L3-L4-NH-, -L5-L4-NH-, -L4-L2-L6-, -L1-L3-L2-L4-NH-, -L1-L3-L7-, or -L1-L3-L4-L5-NH-, L1, L2, L3, L4, L5, L6, L7 and L8 are as defined above.

[0030] In some embodiments, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof:

[0031] in,

[0032] X is Cl or -CN,

[0033] R1 is phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl may be optionally substituted by R2,

[0034] R2 is selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated methyl, or -(CH2) 0-1 -R3,

[0035] R3 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted with halogen, -CN, -NH2, -OH, C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution,

[0036] L is or

[0037] In some embodiments, X is -CN.

[0038] In some embodiments, R1 is a 5-6 membered heteroaryl, which may be optionally substituted with R2, wherein R2 is as defined above.

[0039] In some embodiments, R1 is pyrazolyl, which may be optionally substituted with R2, wherein R2 is as defined above.

[0040] In some embodiments, L is or Preferably or

[0041] In some embodiments, the present invention provides the following compounds

[0042] or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.

[0043] Another aspect of the present invention relates to a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.

[0044] In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, or a composition thereof, in the preparation of a medicament for treating an FGFR-related disease. Preferably, the FGFR-related disease is a tumor. In some embodiments, the tumor has a mutation in FGFR2 N549, V561, V565, N550, N540, V555, E566, K660, or V550. In some embodiments, the FGFR-related cancer is bile duct cancer, urothelial cancer, lung cancer, bladder cancer, cervical cancer, endometrial cancer, breast cancer, thyroid cancer, intestinal cancer, gastric cancer, liver cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, leukemia, multiple myeloma, Hodgkin's lymphoma, melanoma, and the like.

[0045] The present invention also provides a use for treating diseases related to abnormal expression or mutation of FGFR receptors or abnormal expression and activity of corresponding ligands.

[0046] The present invention also relates to a method for treating tumors resistant to FGFR inhibitors, comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the above-mentioned composition; in some embodiments, the FGFR-related disease is bile duct cancer, urothelial carcinoma, lung cancer, bladder cancer, cervical cancer, endometrial cancer, breast cancer, thyroid cancer, intestinal cancer, gastric cancer, liver cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, leukemia, multiple myeloma, Hodgkin's lymphoma, melanoma, etc., preferably liver cancer and bile duct cancer.

[0047] In some embodiments of the present invention, the subject involved in the present invention is a mammal including humans.

[0048] Detailed Description of the Invention

[0049] Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary of the invention.

[0050] It should be understood that the scope of protection of various aspects of the present invention is determined by the claims, and methods and structures within the scope of these claims and their equivalents are all within the scope of the claims.

[0051] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

[0052] It should be understood that the foregoing brief description and the following detailed description are exemplary and explanatory, rather than limiting, of any subject matter of the present invention. Unless otherwise specifically stated, the use of the singular also includes the plural. Unless otherwise specified, the use of "or" and "alternatively" means "and / or." In addition, the use of the term "include," as well as other forms such as "comprises," "includes," and "comprising" are not limiting.

[0053] Some chemical terms

[0054] The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl." Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any hierarchy between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0055] Unless otherwise indicated, conventional methods within the technical scope of the art, such as mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy and pharmacological methods, are adopted. Unless specifically defined, the relevant terms and experimental procedures and techniques of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the test kit can be utilized, or reactions and purification can be carried out according to methods well known in the art or the description of the present invention. Conventionally, the above-mentioned techniques and methods can be implemented according to conventional methods well known in the art, based on the description in the multiple summaries and more specific documents cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0056] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0057] As used herein, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. A chemical group is often considered to be a chemical entity embedded in or attached to a molecule.

[0058] Some chemical groups named herein may be abbreviated to indicate the total number of carbon atoms. For example, C1-C6 alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated in the abbreviated notation does not include carbon atoms in possible substituents.

[0059] The term "halogen," "halo," or "halide" refers to bromine, chlorine, fluorine, or iodine.

[0060] The compounds of the present invention may contain one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C can be any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O etc.

[0061] As used herein, the terms "aromatic," "aromatic ring," "aromatic," "aromatic," and "aromatic ring" refer to a planar ring or ring moiety having a delocalized electron conjugate system containing 4n+2 electrons, where n is an integer. Aromatic rings can be formed by 5, 6, 7, 8, 9, or more atoms. Aromatic compounds can be optionally substituted and can be monocyclic or polycyclic with fused rings. The term aromatic compound includes all carbon rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).

[0062] As used herein, the term "heteroatom" or "hetero" refers to atoms other than carbon and hydrogen, either alone or as part of another component. Heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different from one another.

[0063]

[0046] The term "fused" or "fused ring," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

[0064]

[00146] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

[0065] The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, connected to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.

[0066] The term "alkylene," as used herein, alone or in combination, refers to a divalent radical derived from a monovalent alkyl radical as defined above.

[0067] The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon radical having one or more C=C double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bonds in these groups can be in cis or trans configurations and are understood to encompass both isomers. Examples include, but are not limited to, ethenyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, and 1,3-butadienyl, among others. Where alkenyl as defined herein appears in a numerical range, for example, "C2-C6 alkenyl" or "C 2-6 The term "alkenyl" refers to an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkenyl group herein also includes the case where no numerical range is specified.

[0068] The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted linear or branched monovalent hydrocarbon radical having one or more C≡C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When a numerical range appears for an alkynyl group as defined herein, for example, "C2-C6 alkynyl" or "C 2-6 The term "alkynyl" refers to an alkynyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkynyl group herein also encompasses the case where no numerical range is specified.

[0069] The term "aryl" refers to an all-carbon monocyclic or fused ring having a completely conjugated π electron system having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. Aryl can be unsubstituted or substituted with one or more substituents, examples of which include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic groups. Non-limiting examples of unsubstituted aryl include but are not limited to phenyl, naphthyl, and anthracenyl.

[0070] The term "arylene" as used herein, alone or in combination, refers to a divalent radical derived from a monovalent aryl radical as defined above.

[0071] The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1, 2, 3 or 4 are selected from N, O, S, with the remaining ring atoms being C, and having a completely conjugated π-electron system. Heteroaryl groups may be unsubstituted or substituted, with substituents including, but not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl and triazinyl.

[0072] The term "heteroarylene," as used herein, alone or in combination, refers to a divalent radical derived from a monovalent heteroaryl radical as defined above.

[0073] The term "cycloalkyl" as used herein, alone or as part of another component, refers to a stable, monovalent, non-aromatic, monocyclic or polycyclic hydrocarbon radical, containing only carbon and hydrogen atoms, which may include fused, spiro or bridged ring systems, containing 3 to 15 ring carbon atoms, preferably 3 to 10 ring carbon atoms, more preferably 3 to 8 ring carbon atoms, which may be saturated or unsaturated, and which is attached to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0074] The terms "heterocycloalkyl," "heterocyclyl," and "heterocycle," as used herein alone or as part of another component, refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur atoms of the heterocyclyl group may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclyl group may be attached to the rest of the molecule via a single bond through a carbon atom or heteroatom in the ring. Heterocyclyl groups containing fused rings may contain one or more aromatic or heteroaromatic rings, as long as the atoms attached to the rest of the molecule are non-aromatic ring atoms. For the purposes of the present application, the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolinyl, dioxolane, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0075] The term "polymorph" or "polymorphism" as used herein refers to compounds of the present invention having multiple crystal lattice morphologies. Some compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

[0076] Intermediate compounds of the compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

[0077] Unless otherwise specified, compounds of the present invention containing olefinic double bonds include both E and Z isomers.

[0078] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. Some compounds of the present invention may also exhibit cis-trans isomerism, which is apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures. These isomers can be separated from their mixtures by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

[0079] As used herein, the term "pharmaceutically acceptable salt" includes both acid-addition salts and base-addition salts.

[0080] "Pharmaceutically acceptable salts" refer to salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, hexanoic acid, carbonic acid, cinnamic acid, and citric acid, which retain the biological efficacy and properties of the free acid and are not biologically or otherwise undesirable. "Pharmaceutically acceptable base-added salts" refer to salts that retain the biological efficacy and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.

[0081] Organic bases for forming salts include, but are not limited to, primary amines, secondary amines, tertiary amines, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0082] Crystallization often produces solvates of the compounds of the invention. The term "solvate" as used herein refers to an association of one or more molecules of the compound of the invention with one or more solvent molecules.

[0083] The solvent may be water, in which case the solvate is a hydrate. Alternatively, it may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may simply accidentally retain water or a mixture of water and some other solvent. The compounds of the present invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also encompassed within the scope of the present invention.

[0084] The term "pharmaceutical composition" as used herein refers to a preparation containing a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans), including all pharmaceutically acceptable carriers.

[0085] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0086] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0087] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by relevant government administrative departments for use in humans and domesticated animals.

[0088] As used herein, the terms "subject," "patient," "subject," or "individual" refer to individuals suffering from a disease, disorder, condition, or the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0089] The term "treatment" as used herein refers to the treatment of a disease or condition in a mammal, especially a human, including

[0090] (i) preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not yet been diagnosed with the disease or condition;

[0091] (ii) inhibiting the disease or condition, i.e., controlling its development;

[0092] (iii) alleviate the disease or condition, i.e., cause the disease or condition to regress;

[0093] (iv) Alleviate symptoms caused by a disease or condition.

[0094] As used herein, the terms "disease" and "disorder" are used interchangeably or may have different meanings because certain diseases or disorders do not yet have a known causative agent (and therefore the cause of the disease is unknown) and therefore cannot be considered diseases but rather are considered to be undesirable conditions or syndromes with more or less specific symptoms that have been confirmed by clinical researchers.

[0095] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0096] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods that enable a compound or composition to be delivered to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0097] Preparation of the compounds of the present invention

[0098] The following reaction schemes show methods for preparing the compounds of the present invention.

[0099] It is understood that in the following description, combinations of substituent groups and / or variables of the described formulas are permissible only if such combinations result in stable compounds.

[0100] Those skilled in the art will also appreciate that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, sulfhydryl, and carboxyl. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butylmethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidino, and guanidine protecting groups include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for sulfhydryl include -C(O)-R" (R" represents alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or arylalkyl esters. Protecting groups can be added or removed by standard techniques known to those skilled in the art. Example

[0101] The following non-limiting examples are illustrative only and are not intended to limit the present invention in any way.

[0102] Unless otherwise stated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing J&K Technology Co., Ltd. and were used directly without further purification unless otherwise stated.

[0103] Unless otherwise noted, the following reactions were performed at room temperature in anhydrous solvents under a positive pressure of nitrogen or argon or using a drying tube; the reaction flasks were fitted with rubber septa to facilitate the addition of substrates and reagents via syringe; and the glassware was oven-dried and / or heat-dried.

[0104] Unless otherwise specified, column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin-layer chromatography silica gel precast plates (HSGF254) produced by Yantai Institute of Chemical Industry were used; MS measurements were performed using a Thermo LCQ Fleet (ESI) liquid chromatography-mass spectrometer; and optical rotation was determined using an SGW-3 automatic polarimeter (Shanghai Shenguang Instrument Co., Ltd.).

[0105] NMR data ( 1 H NMR was performed using a Varian instrument at 400 MHz. Solvents used for NMR data included CDCl₃, CD₃OD, D₂O, and DMSO-d₆, with reference to tetramethylsilane (0.00 ppm) or residual solvent (CDCl₃: 7.26 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; d₆-DMSO: 2.50 ppm). When peak shape multiplicity is indicated, the following abbreviations are used to denote the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double of doublets), and dt (double of triplets). Coupling constants, if given, are in Hertz (Hz).

[0106] Abbreviations:

[0107] Intermediate 1: 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]phenyl trifluoromethylsulfonate

[0108] Step 1: 4-(4-Hydroxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0109] Under nitrogen, 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (371 mg), 4-hydroxyphenylboronic acid pinacol ester (220 mg), and potassium carbonate (278 mg) were dissolved in a 4:1 mixture of dioxane and water (50 mL). Tetrakis(triphenylphosphine)palladium (110 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (275 mg).

[0110] Step 2: 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]phenyl trifluoromethylsulfonate

[0111] At room temperature, the product obtained in step 1 was dissolved in DMF (10 mL), and DIEA (260 mg) was added, followed by N-phenylbis(trifluoromethanesulfonyl)imide (360 mg). The mixture was stirred at room temperature overnight, water (50 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (v:v)) to obtain Intermediate 1 (289 mg).

[0112] Intermediate 2: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0113] Step 1: (R)-tert-Butyl 3-(8-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)azetidine-1-carboxylate

[0114] At room temperature, tert-butyl (R)-8-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (369 mg) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added and the mixture was stirred for 2 hours. The mixture was then concentrated under reduced pressure. Dichloromethane (20 mL) was added to the residue and the mixture was cooled to 0°C. tert-butyl 3-oxoazetidine-1-carboxylate (171 mg) and sodium triacetoxyborohydride (500 mg) were added sequentially. The mixture was then warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 30:1 (v:v)) to obtain the title compound (310 mg).

[0115] Step 2: (R)-tert-Butyl 3-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)azetidine-1-carboxylate

[0116] Tert-butyl (R)-3-(8-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)azetidine-1-carboxylate (310 mg), pinacol bis(boron) (254 mg), and potassium acetate (150 mg) were dissolved in dioxane (20 mL). Pd(dppf)Cl2 (50 mg) was added under nitrogen, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (270 mg).

[0117] Step 3: (R)-tert-Butyl 3-(8-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)azetidine-1-carboxylate

[0118] Under nitrogen, tert-butyl (R)-3-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)azetidine-1-carboxylate (270 mg), 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (220 mg) and potassium carbonate (200 mg) were dissolved in a mixed solvent (50 mL) of dioxane and water (4:1). Tetrakis(triphenylphosphine)palladium (70 mg) was added, and the mixture was heated to 40°C and stirred for 2 hours. Cool to room temperature, add water (100 mL), extract with ethyl acetate, wash the extract with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (285 mg).

[0119] Step 4: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0120] The above product was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (2 mL) was added, and the mixture was stirred for 2 hours. The mixture was then concentrated under reduced pressure. Dichloromethane (20 mL) was added to the residue, and the mixture was cooled to 0°C. Acryloyl chloride (90 mg) and triethylamine (200 mg) were then added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (190 mg).

[0121] Intermediate 3: (S)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0122] Refer to the synthesis method of intermediate 2 to synthesize intermediate 3

[0123] Intermediate 4: (R)-4-(3-acryloyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0124] Refer to the synthesis method of intermediate 2 to synthesize intermediate 4

[0125] Intermediate 5: (S)-4-(3-acryloyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0126] Refer to the synthesis method of intermediate 4 to synthesize intermediate 5

[0127] Intermediate 6: N-(5-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0128] Step 1: 6-Bromo-4-((6-nitropyridin-3-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0129] To a solution of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (238 mg) and 2-nitro-5-fluoropyridine (142 mg) in DMF (10 mL) at 0°C was added solid potassium carbonate (280 mg), heated to 80°C, and stirred for 2 hours. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (310 mg).

[0130] Step 2: N-(5-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0131] At room temperature, 6-bromo-4-((6-nitropyridin-3-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (310 mg) was dissolved in acetic acid (10 mL). Iron powder (300 mg) was added and stirred for 2 hours. The reaction solution was poured into water (50 mL) and extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane (50 mL) was added to the residue, along with acryloyl chloride (100 mg) and triethylamine (200 mg). The mixture was then stirred at room temperature for 1 hour. The reaction solution was poured into saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (developing solvent: dichloromethane:methanol = 30:1 (v:v)) to obtain the title compound (254 mg).

[0132] Intermediate 7: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0133] Refer to the synthesis method of intermediate 2 to synthesize intermediate 7

[0134] Intermediate 8: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0135] Intermediate 8 was synthesized by referring to the synthetic method of Intermediate 2.

[0136] Intermediate 9: 3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0137] Step 1: 4-Hydroxy-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0138] Under nitrogen, 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile 1 (237 mg), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (303 mg), and potassium carbonate (278 mg) were dissolved in a 4:1 mixture of dioxane and water (30 mL). Tetrakis(triphenylphosphine)palladium (110 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (215 mg).

[0139] Step 2: 3-Cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0140] At room temperature, the product obtained in step 1 was dissolved in DMF (10 mL), and DIEA (260 mg) was added, followed by N-phenylbis(trifluoromethanesulfonyl)imide (360 mg). The mixture was stirred at room temperature overnight, water (50 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: eluent: dichloromethane: methanol = 20:1 (v:v)) to obtain Intermediate 9 (249 mg).

[0141] Intermediate 10: 4-(3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate

[0142] Intermediate 10 was synthesized by referring to the synthesis method of intermediate 9.

[0143] Intermediate 11: (E)-6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0144] Step 1: 4-ethynyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0145] Under nitrogen, 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (371 mg), trimethylsilyl acetylene (200 mg), and triethylamine (500 mg) were dissolved in dioxane (50 mL). Bis(triphenylphosphine)palladium(II) dichloride (70 mg) and cuprous iodide (40 mg) were added, and the mixture was heated to 90°C and stirred for 2 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was dissolved in THF (50 mL). TBAF (500 mg) was added, and the mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane:ethyl acetate = 3:1 (v:v)) to give the title product (190 mg).

[0146] Step 2: (E)-6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0147] Under nitrogen, cuprous chloride (2.3 mg) and sodium tert-butoxide (5 mg) were added to a solution of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg) in THF (10 mL). The mixture was stirred at room temperature for 30 minutes, followed by the addition of a solution of pinacol diboron (200 mg) in THF (10 mL). The mixture was stirred at room temperature for 10 minutes, followed by the addition of 4-ethynyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (190 mg). The mixture was stirred overnight and then concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain the title compound (101 mg).

[0148] Example 1: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0149] Under nitrogen, intermediate 2 (52 mg) and potassium carbonate (28 mg) were dissolved in a mixed solvent (10 mL) of dioxane and water (4:1). Tetrakis(triphenylphosphine)palladium (11 mg) was added, and the mixture was heated to 95°C and stirred for 3 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (37 mg).

[0150] MS m / z[LC-MS]:521.25[M+1]. 1H NMR(400MHz, CDCl3),8.60(d,J=1.2Hz,1H),8.24(s,1H),7.78(s,1H),7.66(s,1H),7.41(d,J=1.2Hz,1H),7.11(d ,J=8.0Hz,1H),6.99(d,J=1.6Hz,1H),6.91(dd,J=8.0Hz,1.6Hz,1H),6.35(dd,J=17.2Hz,1.6Hz,1H),6.20(dd,J=1 7.2Hz,10.0Hz,1H),5.69(dd,J=10.0Hz,1.6Hz,1H),4.22-4.30(m,2H),4.05-4.17(m,3H),3.94-4.03(m,4H),3.79 (d,J=12.0Hz,1H),3.21-3.36(m,2H),2.87-2.99(m,2H),2.74-2.84(m,1H),2.16-2.27(m,1H),1.79-1.90(m,1H).

[0151] Example 2: (S)-4-(3-acryloyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0152] The target compound (18 mg) was synthesized by referring to the synthesis method of Example 1.

[0153] MS m / z[LC-MS]:480.23[M+1].

[0154] Example 3: (S)-4-(3-acryloyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(oxetane-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0155] The target compound (10 mg) was synthesized by the method of Reference Example 1.

[0156] MS m / z[LC-MS]:508.22[M+1].

[0157] Example 4: (S)-4-(3-acryloyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0158] The target compound (12 mg) was synthesized by the synthesis method of Reference Example 1.

[0159] MS m / z[LC-MS]:502.19[M+1].

[0160] Example 5: (S)-4-(3-acryloyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0161] The target compound (6 mg) was synthesized by the synthesis method of Reference Example 1.

[0162] MS m / z[LC-MS]:522.24[M+1]. 1 H NMR(400MHz, CDCl3),8.60(s,1H),8.25(d,J=1.2Hz,1H),7.79(s,1H),7.67(s,1H),7.39(s,1H),7.12(d,J=8.8Hz,1H),7.00(s, 1H),6.90-6.98(m,1H),6.57-6.64(m,1H),6.35(d,J=17.2Hz,1H),5.77(d,J=10.8Hz,1H),4.86(t,J=6.8Hz,2H),4.64-4.82(m, 1H),4.54(t,J=6.0Hz,2H),4.49(d,J=7.2Hz,2H),4.30-4.38(m,1H),4.06-4.17(m,1.5H),3.90-4.00(m,0.5H),3.84(d,J=12.0 Hz,1H),3.53-3.60(m,1H),3.35-3.48(m,0.5H),3.20-3.30(m,1H),2.92-3.12(m,1H),2.82-2.91(m,1H),2.51-2.65(m,0.5H).

[0163] Example 6: (S)-4-(3-acryloyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0164] The target compound (6 mg) was synthesized by the synthesis method of Reference Example 1.

[0165] MS m / z[LC-MS]:469.23[M+1].

[0166] Example 7: N-(5-((3-cyano-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0167] The target compound (16 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0168] MS m / z[LC-MS]:481.22[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.14(s,1H),8.68(s,1H),8.52(d,J=2.0Hz,1H ),8.34(d,J=2.8Hz,1H),8.26(d,J=9.2Hz,1H),7.96(d,J=8.4Hz,1H),7.75(dd,J=9. 2Hz,2.8Hz,1H),7.40(s,1H),6.95(d,J=9.2Hz,1H),6.59(dd,J=16.8Hz,10.0Hz,1H) ,6.30(dd,J=16.8Hz,2.0Hz,1H),5.77(dd,J=10.0Hz,2.0Hz,1H),2.16-3.60(m,11H).

[0169] Example 8: 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0170] The target compound (16 mg) was synthesized by the synthesis method of Reference Example 1.

[0171] MS m / z[LC-MS]:481.22[M+1].

[0172] Example 9: (S)-4-(3-acryloyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0173] The target compound (20 mg) was synthesized by referring to the synthesis method of Example 1.

[0174] MS m / z[LC-MS]:560.29[M+1].

[0175] Example 10: (S)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0176] The target compound (24 mg) was synthesized using Intermediate 3 according to the synthesis method of Reference Example 1.

[0177] MS m / z[LC-MS]:524.27[M+1]. 1 H NMR(400MHz, CDCl3),8.60(s,1H),8.24(s,1H),7.78(s,1H),7.66(s,1H),7.41(s,1H),7.11(d,J=8.4 Hz, 1H), 6.99 (d, J = 2.0Hz, 1H), 6.91 (d, J = 8.4Hz, 1H), 6.35 (dd, J = 16.8Hz, 2.0Hz, 1H), 6.20 (dd, J = 16. 8Hz,10.0Hz,1H),5.68(dd,J=10.0Hz,2.0Hz,1H),4.22-4.29(m,2H),3.94-4.18(m,4H),3.79(d,J=12 .4Hz,1H),3.22-3.36(m,2H),2.86-2.98(m,2H),2.76-2.82(m,1H),2.17-2.26(m,1H),1.81-1.88(m, 1H).

[0178] Example 11: (S)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0179] The target compound (27 mg) was synthesized using Intermediate 3 according to the synthesis method of Reference Example 1.

[0180] MS m / z[LC-MS]:615.33[M+1]. 1H NMR(400MHz, CDCl3),8.64(s,1H),8.25(s,1H),7.55(s,1H),7.50(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,1H),7.01-7 .05(m,3H),6.91(d,J=8.4Hz,1H),6.35(dd,J=17.2Hz,2.0Hz,1H),6.20(dd,J=17.2Hz,10.4Hz,1H),5.68(dd,J=1 0.4Hz,2.0Hz,1H),4.22-4.29(m,2H),4.04-4.17(m,3H),3.96-4.02(m,1H),3.79(d,J=12.4Hz,1H),3.22-3.36(m ,6H),2.87-2.98(m,2H),2.75-2.82(m,1H),2.58-2.61(m,4H),2.36(s,3H),2.17-2.26(m,1H),1.81-1.87(m,1H).

[0181] Example 12: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0182] The target compound (14 mg) was synthesized using Intermediate 2 according to the synthesis method of Reference Example 1.

[0183] MS m / z[LC-MS]:557.23[M+1]. 1H NMR(400MHz, CDCl3),8.67(d,J=1.2Hz,1H),8.28(s,1H),8.12(s,1H),7.95(s,1H),7.42(d,J=1.2Hz,1H),7.24(t ,J=60.4Hz,1H),7.11(d,J=8.0Hz,1H),6.99(d,J=2.0Hz,1H),6.91(d,J=8.0Hz,1H),6.35(dd,J=17.2Hz,2.0Hz,1 H),6.20(dd,J=17.2Hz,10.4Hz,1H),5.69(dd,J=10.4Hz,2.0Hz,1H),4.22-4.30(m,2H),3.95-4.18(m,4H),3.79( d,J=12.0Hz,1H),3.22-3.38(m,2H),2.88-3.00(m,2H),2.75-2.85(m,1H),2.17-2.28(m,1H),1.68-1.76(m,1H).

[0184] Example 13: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0185] The target compound (14 mg) was synthesized using Intermediate 2 according to the synthesis method of Reference Example 1.

[0186] MS m / z[LC-MS]:557.23[M+1]. 1H NMR(400MHz, CDCl3),8.60(d,J=1.2Hz,1H),8.24(s,1H),7.78(s,1H),7.66(s,1H),7.41(d,J=1.2Hz,1H), 7.11(d,J=8.4Hz,1H),6.99(d,J=1.6Hz,1H),6.91(d,J=8.4Hz,1H),6.35(dd,J=16.8Hz,2.0Hz,1H),6.20( dd,J=16.8Hz,10.0Hz,1H),5.69(dd,J=10.0Hz,2.0Hz,1H),4.22-4.30(m,2H),3.96-4.17(m,4H),3.77-3. 80(m,1H),3.22-3.36(m,2H),2.87-2.99(m,2H),2.74-2.83(m,1H),2.16-2.26(m,1H),1.80-1.88(m,1H).

[0187] Example 14: N-(5-((3-cyano-6-(4-hydroxyphenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0188] The target compound (14 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0189] MS m / z[LC-MS]:398.14[M+1].

[0190] Example 16: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0191] The target compound (10 mg) was synthesized using Intermediate 8 according to the synthesis method of Reference Example 1.

[0192] MS m / z[LC-MS]:544.29[M+1]. 1H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 8.63 (s, 1H), 7.74 (d, J = 8.4Hz, 2H), 7.65 (s, 1H) ,7.48(d,J=8.8Hz,2H),7.06(d,J=8.4Hz,2H),6.55(d,J=8.8Hz,2H),6.29(dd,J=17.2 Hz,10.4Hz,1H),6.08(dd,J=17.2Hz,2.0Hz,1H),5.66(dd,J=10.4Hz,2.0Hz,1H),4.42 (s,2H),4.13(s,2H),4.03(s,4H),3.16-3.44(m,4H),2.82-3.02(m,4H),2.56(s,3H).

[0193] Example 17: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0194] The target compound (15 mg) was synthesized using Intermediate 2 according to the synthesis method of Reference Example 1.

[0195] MS m / z[LC-MS]:615.33[M+1]. 1 H NMR(400MHz, CDCl3),8.65(d,J=1.6Hz,1H),8.26(s,1H),7.54(d,J=1.6Hz,1H),7.51(d,J=8.4Hz,2H),7.13(d,J=8.8Hz, 1H),7.01-7.03(m,3H),6.91(dd,J=8.8Hz,2.4Hz,1H),6.34(dd,J=16.8Hz,2.0Hz,1H),6.20(dd,J=16.8Hz,10.0Hz,1H), 5.68(dd,J=10.0Hz,2.0Hz,1H),4.22-4.29(m,2H),4.04-4.17(m,3H),3.96-4.02(m,1H),3.79(d,J=12.0Hz,1H),3.23-3 .36(m,6H),2.87-2.98(m,2H),2.75-2.82(m,1H),2.59-2.69(m,4H),2.40(s,3H),2.16-2.26(m,1H),1.81-1.87(m,1H).

[0196] Example 18: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile

[0197] The target compound (10 mg) was synthesized using 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile according to the synthesis method of intermediate 2.

[0198] MS m / z[LC-MS]:522.25[M+1]. 1 H NMR(400MHz, CDCl3),8.50(s,1H),8.32(s,1H),8.00(s,1H),7.95(s,1H),7.48(dd,J=8.4Hz,2.0Hz,1H),7.4 1(s,1H),6.94(dd,J=8.4Hz,2.0Hz,1H),6.35(dd,J=16.8Hz,1.6Hz,1H),6.20(dd,J=16.8Hz,10.4Hz,1H),5.6 9(dd,J=10.4Hz,1.6Hz,1H),4.22-4.31(m,2H),4.04-4.17(m,3H),3.94-4.03(m,4H),3.80-3.86(m,1H),3.33 -3.42(m,1H),3.22-3.31(m,1H),2.88-3.02(m,2H),2.77-2.84(m,1H),2.17-2.26(m,1H),1.82-1.90(m,1H).

[0199] Example 19: 4-(4-Acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0200] The target compound (21 mg) was synthesized by the method of Reference Example 1.

[0201] MS m / z[LC-MS]:506.24[M+1].

[0202] Example 20: N-(5-((3-cyano-6-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0203] The target compound (8 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0204] MS m / z[LC-MS]:495.23[M+1]. 1 H NMR(400MHz, CDCl3),8.46(d,J=1.2Hz,1H),8.42(d,J=8.8Hz,1H),8.28(d,J=2.8Hz,1H),8.26( s,1H),8.05(s,1H),7.61(dd,J=8.8Hz,2.8Hz,1H),7.36(d,J=8.8Hz,2H),6.96(d,J=8.8Hz,2H) ,6.82(s,1H),6.49(d,J=16.8Hz,1H),6.28(dd,J=16.8Hz,10.0Hz,1H),5.86(d,J=10.0Hz,1H), 4.35-4.46(m,1H),2.68-2.85(m,2H),2.28-2.56(m,5H),2.04-2.18(m,2H),1.84-1.98(m,2H).

[0205] Example 21: N-(5-((3-cyano-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0206] The target compound (11 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0207] MS m / z[LC-MS]:479.23[M+1]. 1 H NMR(400MHz, CDCl3),8.49(s,1H),8.43(d,J=8.8Hz,1H),8.25-8.29(m,2H),8.07(s,1H ),7.61(dd,J=8.8Hz,2.8Hz,1H),7.38(d,J=8.0Hz,2H),7.31(d,J=8.0Hz,2H),6.84(s, 1H),6.49(d,J=16.8Hz,1H),6.28(dd,J=16.8Hz,10.0Hz,1H),5.86(d,J=10.0Hz,1H),3 .02-3.15(m,2H),2.50-2.61(m,1H),2.41(s,3H),2.12-2.26(m,2H),1.82-2.04(m,4H).

[0208] Example 22: N-(5-((3-cyano-6-(4-morpholinophenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0209] The target compound (7 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0210] MS m / z[LC-MS]:467.20[M+1]. 1 H NMR(400MHz, CDCl3),8.47(s,1H),8.43(d,J=8.8Hz,1H),8.28(d,J=2.4Hz,1H) ,8.25(s,1H),8.12(s,1H),77.61(dd,J=8.8Hz,2.4Hz,1H),7.36(d,J=8.8Hz,2 H),6.95(d,J=8.8Hz,2H),6.86(s,1H),6.50(d,J=16.8Hz,1H),6.28(dd,J=16. 8Hz, 10.0Hz, 1H), 5.86 (d, J = 10.0Hz, 1H), 3.85-3.88 (m, 4H), 3.19-3.21 (m, 4H).

[0211] Example 23: N-(5-((3-cyano-6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0212] The target compound (22 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0213] MS m / z[LC-MS]:494.24[M+1]. 1 H NMR(400MHz, CDCl3+CD3OD),8.43(d,J=1.2Hz,1H),8.37(d,J=9.2Hz,1H),8.20-8.21(m, 2H),7.56(dd,J=9.2Hz,2.8Hz,1H),7.31(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),6.83(s, 1H), 6.44 (dd, J=16.8Hz, 1.6Hz, 1H), 6.32 (dd, J=16.8Hz, 10.0Hz, 1H), 5.79 (dd, J=10.0Hz ,1.6Hz,1H),3.16-3.29(m,4H),2.52-2.66(m,4H),2.36-2.50(m,2H),1.02-1.06(m,3H).

[0214] Example 24: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0215] The target compound (9 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylic acid tert-butyl ester.

[0216] MS m / z[LC-MS]:425.18[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.62(s,1H),8.38(s,1H),8.10(s,1H),7.75 (s,1H),7.57(d,J=8.4Hz,2H),7.00(d,J=8.4Hz,2H),6.34(dd,J=17.2Hz,10.4Hz, 1H),6.11(dd,J=17.2Hz,2.0Hz,1H),5.68(dd,J=10.4Hz,2.0Hz,1H),5.11-5.19(m ,1H),4.69-4.72(m,1H),4.40-4.44(m,1H),4.18-4.21(m,1H),3.82-3.90(m,4H).

[0217] Example 25: N-(5-((3-cyano-6-(4-(4-cyclopropylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0218] The target compound (14 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0219] MS m / z[LC-MS]:506.24[M+1]. 1H NMR(400MHz, CDCl3),8.46(d,J=1.2Hz,1H),8.42(d,J=9.2Hz,1H),8.27(d,J=2.8Hz,1H),8 .24(s,1H),8.05(s,1H),7.61(dd,J=9.2Hz,2.8Hz,1H),7.34(d,J=8.8Hz,2H),6.95(d,J=8 .8Hz,2H),6.85(s,1H),6.49(d,J=17.2Hz,1H),6.28(dd,J=17.2Hz,10.4Hz,1H),5.86(d,J =10.4Hz,1H),3.15-3.28(m,4H),2.71-2.84(m,4H),1.60-1.71(m,1H),0.40-0.54(m,4H).

[0220] Example 26: (S)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0221] The target compound (22 mg) was synthesized using Intermediate 3 according to the synthesis method of Reference Example 1.

[0222] MS m / z[LC-MS]:616.33[M+1]. 1 H NMR(400MHz, CDCl3),8.62(s,1H),8.44(d,J=2.4Hz,1H),8.27(s,1H),7.70(dd,J=9.2Hz,2.4Hz,1H),7.48(s,1H),7.12(d ,J=8.4Hz,1H),7.00(d,J=1.2Hz,1H),6.91(d,J=8.4Hz,1H),6.75(d,J=9.2Hz,1H),6.34(d,J=17.2Hz,1H),6.20(dd,J=17. 2Hz,10.0Hz,1H),5.69(d,J=10.0Hz,1H),4.22-4.30(m,2H),3.95-4.18(m,4H),3.76-3.82(m,1H),3.61-3.70(m,4H),3.22 -3.36(m,2H),2.87-2.99(m,2H),2.74-2.83(m,1H),2.48-2.62(m,4H),2.37(s,3H),2.16-2.26(m,1H),1.80-1.88(m,1H).

[0223] Example 27: (S)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(oxirane-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0224] The target compound (14 mg) was synthesized using Intermediate 3 according to the synthesis method of Reference Example 1.

[0225] MS m / z[LC-MS]:563.26[M+1]. 1 H NMR(400MHz, CDCl3),8.63(d,J=1.2Hz,1H),8.26(s,1H),7.89(s,2H),7.42(d,J=1.2Hz,1H),7.12(d,J=8.4Hz,1H),6.9 9(d,J=2.0Hz,1H),6.92(dd,J=8.4Hz,2.0Hz,1H),6.35(dd,J=17.2Hz,2.0Hz,1H),6.20(dd,J=17.2Hz,10.4Hz,1H),5.6 9(dd,J=10.4Hz,2.0Hz,1H),5.47-5.54(m,1H),5.08-5.13(m,4H),4.22-4.30(m,2H),4.04-4.17(m,3H),3.96-4.02(m, 1H),3.76-3.82(m,1H),3.22-3.36(m,2H),2.88-2.98(m,2H),2.76-2.82(m,1H),2.16-2.26(m,1H),1.81-1.87(m,1H).

[0226] Example 28: (S)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(oxetane-3-methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0227] The target compound (4 mg) was synthesized using Intermediate 3 according to the synthesis method of Reference Example 1.

[0228] MS m / z[LC-MS]:577.28[M+1]. 1H NMR(400MHz, CDCl3),8.60(d,J=1.2Hz,1H),8.25(s,1H),7.78(s,1H),7.67(s,1H),7.39(d,J=1.2Hz,1H),7.1 1(d,J=8.4Hz,1H),6.99(d,J=2.0Hz,1H),6.91(dd,J=8.4Hz,2.0Hz,1H),6.35(dd,J=16.8Hz,2.0Hz,1H),6.20 (dd,J=16.8Hz,10.4Hz,1H),5.69(dd,J=10.4Hz,2.0Hz,1H),4.85-4.88(m,2H), 4.54(t,J=6.4Hz,2H),4.49(d,J=7.6Hz,2H),4.23-4.30(m,2H),4.04-4.16(m,3 H),3.96-4.02(m,1H),3.79(d,J=12.0Hz,1H),3.52-3.60(m,1H),3.22-3.36(m, 2H),2.86-2.98(m,2H),2.75-2.82(m,1H),2.17-2.26(m,1H),1.81-1.87(m,1H).

[0229] Example 29: N-(5-((3-cyano-6-(1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0230] The target compound (15 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0231] MS m / z[LC-MS]:511.22[M+1].

[0232] Example 30: N-(5-((3-cyano-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0233] The target compound (17 mg) was synthesized using Intermediate 6 according to the synthesis method of Reference Example 1.

[0234] MS m / z[LC-MS]:522.24[M+1].

[0235] Example 31: N-(6-((3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-3-yl)acrylamide

[0236] The target compound (17 mg) was synthesized by referring to the synthesis method of Example 1.

[0237] MS m / z[LC-MS]:480.23[M+1].

[0238] Example 32: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0239] The target compound (16 mg) was synthesized using Intermediate 2 according to the synthesis method of Reference Example 1.

[0240] MS m / z[LC-MS]:615.33[M+1].

[0241] Example 33: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(oxirane-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0242] The target compound (6 mg) was synthesized using Intermediate 2 according to the synthesis method of Reference Example 1.

[0243] MS m / z[LC-MS]:563.26[M+1].

[0244] Example 34: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(oxetane-3-methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0245] The target compound (5 mg) was synthesized using Intermediate 2 according to the synthesis method of Reference Example 1.

[0246] MS m / z[LC-MS]:577.28[M+1].

[0247] Example 35: N-(5-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)thio)pyridin-2-yl)acrylamide

[0248] The target compound (25 mg) was synthesized by referring to the synthetic method of intermediate 6.

[0249] MS m / z[LC-MS]:402.13[M+1].

[0250] Example 36: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(6-(4-methylpiperazin-1-ylpyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0251] The target compound (5 mg) was synthesized using Intermediate 7 according to the synthesis method of Reference Example 1.

[0252] MS m / z[LC-MS]:588.33[M+1].

[0253] Example 37: 4-(4-((1-acryloylazetidin-3-yl)oxy)phenyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0254] The target compound (16 mg) was synthesized by referring to the synthesis method of intermediate 2 using 4-(4-hydroxyphenyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0255] MS m / z[LC-MS]:519.26[M+1].

[0256] Example 38: N-(4-(4-(3-cyano-6-(4-(-4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)-1H-pyrazol-1-yl)benzene)acrylamide

[0257] The target compound (36 mg) was synthesized using Intermediate 9 by referring to the synthetic methods of Intermediate 2 and Intermediate 6.

[0258] MS m / z[LC-MS]:519.26[M+1].

[0259] Example 39: N-(5-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)(methyl)amino)pyridin-2-yl)acrylamide

[0260] Step 1: 4-(Methyl(6-nitropyridin-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0261] Under nitrogen, 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (37 mg), N-methyl-6-nitropyridin-3-amine (15 mg), RuPhOS Pd G3 (4 mg), and cesium carbonate (66 mg) were added sequentially to DMF (10 mL). The mixture was heated to 90°C and stirred overnight. The mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane. The combined filtrates were concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (19 mg).

[0262] Step 2: N-(5-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)(methyl)amino)pyridin-2-yl)acrylamide

[0263] At room temperature, the product from step 1 was dissolved in acetic acid (5 mL), iron powder (30 mg) was added, and the mixture was stirred for 2 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. At 0°C, the residue was dissolved in dichloromethane (10 mL), triethylamine (50 mg) and acryloyl chloride (10 mg) were added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (7 mg).

[0264] MS m / z[LC-MS]:399.18[M+1].

[0265] Example 40: N-(1-(4-(3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)phenyl]azetidin-3-yl)acrylamide

[0266] The target compound (6 mg) was synthesized using 4-(3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate according to the synthesis method of Reference Example 39.

[0267] MS m / z[LC-MS]:518.28[M+1].

[0268] Example 41: N-(3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)phenyl)acrylamide

[0269] The target compound (14 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0270] MS m / z[LC-MS]:399.17[M+1]. 1 H NMR(400MHz, CDCl3),8.31(s,1H),8.18(s,1H),7.94(s,1H),7.83(d,J=7.6Hz,1H),7.75(s,1H),7.70(s,1H),7.59(s,1H),7.39(t,J=7.6Hz,1H) ,7.21(d,J=7.6Hz,1H),6.85(s,1H),6.43(d,J=16.8Hz,1H),6.26(dd,J=16.8Hz,10.0Hz,1H),5.78(d,J=10.0Hz,1H),5.34(s,2H),5.98(s,3H).

[0271] Example 42: N-(5-(4-(3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-2-yl)acrylamide

[0272] The target compound (4 mg) was synthesized using 3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate according to the synthesis method of Reference Example 39.

[0273] MS m / z[LC-MS]:548.30[M+1]. 1H NMR(400MHz, CDCl3),8.43(d,J=1.2Hz,1H),8.21-8.24(m,2H),8.03(d,J=2.8Hz,1H), 7.92(s,1H),7.50(d,J=8.8Hz,2H),7.38(dd,J=8.8Hz,2.8Hz,1H),7.09(s,1H),7.03( d,J=8.8Hz,2H),6.44(dd,J=16.8Hz,1.2Hz,1H),6.25(dd,J=16.8Hz,10.0Hz,1H),5.7 9(dd,J=10.0Hz,1.2Hz,1H),3.45-3.66(m,8H),3.34-3.42(m,4H),2.48-3.16(m,7H).

[0274] Example 43: N-(6-(4-(3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-3-yl)acrylamide

[0275] The target compound (5 mg) was synthesized using 3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate according to the synthesis method of Reference Example 39.

[0276] MS m / z[LC-MS]:548.30[M+1].

[0277] Example 44: 4-(4-(1-acryloylazetidine-3-carbonyl)phenyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0278] The target compound (39 mg) was synthesized using 3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate with reference to the synthesis method of intermediate 2.

[0279] MS m / z[LC-MS]:531.26[M+1]. 1H NMR(400MHz, CDCl3),8.71(d,J=1.2Hz,1H),8.28(s,1H),8.03(d,J=8.4Hz, 2H),7.81(s,1H),7.71-7.73(m,3H),7.49(d,J=1.2Hz,1H),6.36(dd,J=17.2 Hz,2.0Hz,1H),6.22(dd,J=17.2Hz,10.4Hz,1H),5.71(dd,J=10.0Hz,2.0Hz ,1H),4.65-4.69(m,1H),4.44-4.49(m,2H),4.28-4.35(m,2H),3.99(s,3H).

[0280] Example 45: 4-(4-((1-acryloylazetidin-3-yl)thio)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0281] The target compound (9 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0282] MS m / z[LC-MS]:441.16[M+1]. 1 H NMR(400MHz, CDCl3),8.66(d,J=1.2Hz,1H),8.26(s,1H),7.80(s,1H),7.70(s,1H),7 .52(d,J=8.4Hz,2H),7.44(d,J=1.6Hz,1H),7.40(d,J=8.4Hz,2H),6.34(dd,J=17.2H z,2.0Hz,1H),6.15(dd,J=17.2Hz,10.4Hz,1H),5.68(dd,J=10.4Hz,1.6Hz,1H),4.62 -4.70(m,1H),4.50-4.55(m,1H),4.15-4.23(m,2H),4.04-4.10(m,1H),3.99(s,3H).

[0283] Example 46: N-(4-(3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)propyl)phenyl)acrylamide

[0284] The target compound (14 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0285] MS m / z[LC-MS]:427.20[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.83(s,1H),8.53(s,1H),8.32(s,1H),8. 05(s,1H),7.55(d,J=8.8Hz,2H),7.22(s,1H),7.19(d,J=8.4Hz,2H),6.40(dd,J =16.8Hz,10.0Hz,1H),6.20(dd,J=16.8Hz,2.0Hz,1H),5.70(dd,J=10.0Hz,2.0H z, 1H), 4.24 (t, J = 6.0Hz, 2H), 3.85 (s, 3H), 2.81-2.85 (m, 2H), 2.05-2.12 (m, 2H).

[0286] Example 47: (R)-N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0287] Step 1: (R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(3-nitrophenyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0288] To a toluene (50 mL) solution of 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (239 mg), (S)-1-(3-nitrophenyl)ethan-1-ol (167 mg), and triphenylphosphine (526 mg) was slowly added dropwise DIAD (310 mg) at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to afford a white solid (305 mg).

[0289] Step 2: (R)-N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0290] (R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(3-nitrophenyl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (39 mg) was dissolved in acetic acid (5 mL) at room temperature. Iron powder (56 mg) was added and stirred for 2 hours. The reaction solution was poured into water (50 mL) and extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane (10 mL) was added to the residue, followed by acryloyl chloride (20 mg) and triethylamine (50 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 30:1 (v:v)) to give the title compound (13 mg).

[0291] MS m / z[LC-MS]:413.18[M+1]. 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.77(s,1H),8.52(s,1H),8.20(s,1H), 7.93(s,1H),7.81(s,1H),7.51-7.53(m,1H),7.29-7.34(m,2H),7.19(s,1H), 6.39(dd,J=17.2Hz,10.0Hz,1H),6.23(dd,J=17.2Hz,2.0Hz,1H),5.90(q,J=6 .0Hz, 1H), 5.72 (dd, J = 10.0Hz, 2.0Hz, 1H), 3.83 (s, 3H), 1.64 (d, J = 6.4Hz, 3H).

[0292] Example 48: (S)-N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0293] The target compound (16 mg) was synthesized using the synthesis method of Reference Example 47 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile and (R)-1-(3-nitrophenyl)ethan-1-ol.

[0294] MS m / z[LC-MS]:413.18[M+1]. 1H NMR(400MHz, CDCl3),8.23(s,1H),8.15(s,1H),7.88(s,1H),7.65(s,2H),7.60(d ,J=8.4Hz,1H),7.48(s,1H),7.35(t,J=8.0Hz,1H),7.21(d,J=8.0Hz,1H),6.73(s ,1H),6.44(dd,J=16.8Hz,1.2Hz,1H),6.26(dd,J=16.8Hz,10.4Hz,1H),5.79(dd, J=10.4Hz, 1.2Hz, 1H), 5.52 (q, J=6.8Hz, 1H), 3.94 (s, 3H), 1.79 (d, J=6.8Hz, 3H).

[0295] Example 49: N-(5-((3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0296] The target compound (7 mg) was synthesized using 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-ol (synthesized according to patent WO2017 / 11776) according to the synthesis method of intermediate 6.

[0297] MS m / z[LC-MS]:395.11[M+1].

[0298] Example 50: N-(3-(((3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)phenyl)acrylamide

[0299] The target compound (3 mg) was synthesized using 4-hydroxy-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0300] MS m / z[LC-MS]:493.25[M+1]. 1H NMR(400MHz, CDCl3),8.28(s,1H),8.13(s,1H),7.71(d,J=7.6Hz,1H),7.67(s,1H),7.41(d,J=8.4Hz,2H),7.30(t,J=7.6Hz,1H),7.18(d ,J=7.6Hz,1H),6.94-6.96(m,3H),6.25-6.35(m,2H),5.67(dd,J=8.4Hz,3.2Hz,1H),5.28(s,2H),3.31-3.50(m,4H),2.50-3.10(m,7H).

[0301] Example 51: N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)prop-2-yn-1-yl)phenyl)acrylamide

[0302] The target compound (12 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0303] MS m / z[LC-MS]:423.17[M+1].

[0304] Example 52: N-(6-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)acrylamide

[0305] The target compound (4 mg) was synthesized by referring to the synthesis method of intermediate 6 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0306] MS m / z[LC-MS]:400.16[M+1]. 1 H NMR(400MHz, CDCl3),8.38-8.50(brs,1H),8.33(s,1H),8.31(d,J=8.4Hz,1H),8.20(s,1H),7.90(t,J=8.0Hz,1H),7.74(s,1H),7.66(s,1H),7 .63(d,J=7.6Hz,1H),6.87(s,1H),6.51(d,J=16.8Hz,1H),6.30(dd,J=16.8Hz,10.8Hz,1H),5.87(d,J=10.4Hz,1H),5.34(s,2H),3.98(s,3H).

[0307] Example 53: N-(2-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)pyridin-4-yl

[0308] The target compound (3 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0309] MS m / z[LC-MS]:400.16[M+1].

[0310] Example 54: N-(4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)acrylamide

[0311] The target compound (13 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0312] MS m / z[LC-MS]:400.16[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),8.90(s,1H),8.57(s,1H),8.37(d,J=5.2Hz,1H),8.34(s,1H),8.31(s,1H),8.08(s,1H),7.45(s,1H),7.4 3(d,J=5.2Hz,1H),6.60(dd,J=16.8Hz,10.0Hz,1H),6.30(dd,J=16.8Hz,2.0Hz,1H),5.77(dd,J=10.0Hz,2.0Hz,1H),5.53(s,2H),3.87(s,3H).

[0313] Example 55: N-(5-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)pyridin-3-yl)acrylamide

[0314] The target compound (5 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0315] MS m / z[LC-MS]:400.16[M+1].

[0316] Example 56: N-(3-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetyl)phenyl)acrylamide

[0317] The target compound (6 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0318] MS m / z[LC-MS]:427.16[M+1].

[0319] Example 57: N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)propyl)phenyl)acrylamide

[0320] The target compound (16 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0321] MS m / z[LC-MS]:427.20[M+1].

[0322] Example 58: 4-((1-acryloylindol-6-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0323] The target compound (10 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0324] MS m / z[LC-MS]:425.18[M+1]. 1H NMR(400MHz,DMSO-d6)δ8.85(d,J=1.2Hz,1H),8.52(s,1H),8.34(s,1H),8.31(s,1H ),8.06(s,1H),7.43(d,J=1.2Hz,1H),7.31(d,J=7.2Hz,1H),7.27(d,J=7.2Hz,1H),6 .73(dd,J=16.4Hz,10.8Hz,1H),6.28(dd,J=16.4Hz,1.6Hz,1H),5.80(dd,J=10.4Hz ,2.4Hz,1H),5.41(s,2H),4.21(t,J=8.0Hz,2H),3.87(s,3H),3.15(t,J=8.0Hz,2H).

[0325] Example 59: N-(6-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyridin-2-yl)acrylamide

[0326] The target compound (9 mg) was synthesized by referring to the synthesis method of intermediate 6 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0327] MS m / z[LC-MS]:414.18[M+1]. 1 H NMR(400MHz, CDCl3),8.22(s,1H),8.20(d,J=8.0Hz,1H),8.16(s,1H),8.08(s,1H ),7.74(t,J=8.0Hz,1H),7.60(s,1H),7.49(s,1H),7.34(d,J=7.2Hz,1H),6.64(s ,1H),6.49(dd,J=16.8Hz,1.2Hz,1H),6.30(dd,J=16.8Hz,10.4Hz,1H),5.84(dd, J=10.4Hz, 1.2Hz, 1H), 5.45 (q, J=6.8Hz, 1H), 3.93 (s, 3H), 1.79 (d, J=6.8Hz, 3H).

[0328] Example 60: N-(1-(4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)azetidin-3-yl)acrylamide

[0329] The target compound (19 mg) was synthesized using the synthesis method of Reference Example 39 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0330] MS m / z[LC-MS]:455.21[M+1].

[0331] Example 61: N-(5-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0332] The target compound (17 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0333] MS m / z[LC-MS]:417.16[M+1]. 1 H NMR(400MHz, CDCl3),8.57(d,J=6.8Hz,1H),8.30(d,J=1.2Hz,1H),8.15(s,1H), 7.75(s,1H),7.74(s,1H),7.48-7.53(m,1H),7.43-7.47(m,1H),7.19(dd,J=10.8 Hz,8.8Hz,1H),6.86(d,J=1.2Hz,1H),6.48(dd,J=17.2Hz,1.2Hz,1H),6.30(dd, J=17.2Hz, 10.4Hz, 1H), 5.85 (d, J=10.4Hz, 2.4Hz, 1H), 5.32 (s, 2H), 3.98 (s, 3H).

[0334] Example 62: N-(5-(((6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3′,4′:3,4]pyrazolo[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acrylamide

[0335] The target compound (2 mg) was synthesized by referring to the synthesis method of intermediate 6 and Example 1 using 6-bromo-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine-4-ol (synthesized by referring to patent WO2023280073) as the starting material.

[0336] MS m / z[LC-MS]:401.16[M+1]. 1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),10.18(s,1H),8.69(s,1H),8.21(s,1H),7.9 3-7.96(m,3H),7.51(d,J=8.0Hz,1H),7.31(t,J=8.0Hz,1H),7.24(d,J=6.8Hz,1H), 7.12(s,1H),6.39(dd,J=16.8Hz,9.6Hz,1H),6.23(dd,J=16.8Hz,2.0Hz,1H),5.89( q, J=6.4Hz, 1H), 5.73 (dd, J=9.6Hz, 2.0Hz, 1H), 3.84 (s, 3H), 1.67 (d, J=6.0Hz, 3H).

[0337] Example 63: (R)-N-(3-(1-((6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3′,4′:3,4]pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0338] The target compound (5 mg) was synthesized by referring to the synthesis method of intermediate 6 and Example 1 using 6-bromo-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine-4-ol (synthesized by referring to patent WO2023280073) as the starting material.

[0339] MS m / z[LC-MS]:428.20[M+1].

[0340] Example 64: (S)-N-(3-(1-((6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3′,4′:3,4]pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0341] The target compound (19 mg) was synthesized using 6-bromo-1H-pyrazolo[3′,4′:3,4]pyrazolo[1,5-a]pyridine-4-ol (synthesized according to patent WO2023280073) as the starting material according to the synthesis method of intermediate 6 and Example 47.

[0342] MS m / z[LC-MS]:428.20[M+1].

[0343] Example 65: (R)-N-(3-(1-((6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0344] The target compound (8 mg) was synthesized using 6-bromo-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine-4-ol (synthesized according to patent WO2023280073) as the starting material according to the synthesis methods of Intermediate 6, Intermediate 2 and Example 47.

[0345] MS m / z[LC-MS]:537.26[M+1].

[0346] Example 66: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(3-cyanopropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0347] The target compound (15 mg) was synthesized using Intermediate 7 according to the synthesis method of Reference Example 1. MS m / z [LC-MS]: 546.29 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ9.21(d,J=1.2Hz,1H),8.62(s,1H),8.47(s,1H),8.16(s,1H),7.72(d,J=1.6Hz,1H),7.48(d, J=8.8Hz,2H),7.07(d,J=8.8Hz,2H),6.30(dd,J=17.2Hz,10.4Hz,1H),6.08(dd,J=17.2Hz,2.0Hz,1H),5.65(dd,J=10 .4Hz,2.0Hz,1H),4.25(t,J=8.0Hz,1H),4.19(t,J=6.4Hz,2H),4.07(dd,J=8.8Hz,4.8Hz,1H),3.96(dd,J=10.4Hz,7. 2Hz,1H),3.77(dd,J=10.4Hz,4.8Hz,1H),3.24-3.27(m,4H),3.15-3.21(m,1H),2.47-2.52(m,6H),2.07-2.14(m,2H).

[0348] Example 67: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(2-cyano-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0349] The target compound (6 mg) was synthesized using Intermediate 7 according to the synthesis method of Reference Example 1.

[0350] MS m / z[LC-MS]:560.30[M+1].

[0351] Example 68: N-(3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0352] The target compound (13 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0353] MS m / z[LC-MS]:417.16[M+1]. 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.88(s,1H),8.53(s,1H),8.36(s,1 H),8.09(s,1H),8.00(t,J=7.6Hz,1H),7.54(t,J=7.2Hz,1H),7.49(s,1H) ,7.22(t,J=8.0Hz,1H),6.62(dd,J=17.2Hz,10.4Hz,1H),6.27(dd,J=17.2Hz,2.0Hz,1H),5.77(dd,J=10.4Hz,2.0Hz,1H),5.50(s,2H),3.88(s,3H).

[0354] Example 69: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0355] The target compound (5 mg) was synthesized using Intermediate 7 according to the synthesis method of Reference Example 1.

[0356] MS m / z[LC-MS]:601.33[M+1]. 1H NMR (400MHz, DMSO-d6) δ8.87(d,J=1.2Hz,1H),8.64(s,1H),7.86(s,1H),7.48-7.50(m,3H),7.06(d,J=8.8Hz, 2H), 6.30 (dd, J=17.2Hz, 10.4Hz, 1H), 6.08 (dd, J=17.2Hz, 2.0Hz, 1H), 5.65 (dd, J=10.4Hz, 2.0Hz, 1H), 4.41-4. 50(m,1H),4.23-4.27(m,1H),4.07(dd,J=9.2Hz,4.4Hz,1H),3.95(dd,J=10.4Hz,7.6Hz,1H),3.76-3.79(m,1H ),3.47-3.54(m,2H),3.16-3.28(m,7H),2.46-2.50(m,4H),2.45(s,3H),2.02-2.13(m,2H),1.84-1.92(m,2H).

[0357] Example 70: (S)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0358] The target compound (17 mg) was synthesized using Intermediate 3 according to the synthesis method of Reference Example 1.

[0359] MS m / z[LC-MS]:560.26[M+1]. 1H NMR (400MHz, DMSO-d6) δ9.22(d,J=1.2Hz,1H),8.62(s,1H),8.52(s,1H),8.22(s,1H),7.72(d,J=1.2Hz,1H),7.08(dd,J =8.4Hz, 2.0Hz, 1H), 7.00 (d, J = 8.4Hz, 1H), 6.97 (d, J = 1.2Hz, 1H), 6.29 (dd, J = 16.8Hz, 10.4Hz, 1H), 6.08 (dd, J = 16.8Hz, 2.4Hz,1H),5.65(dd,J=10.4Hz,2.0Hz,1H),4.39(t,J=6.0Hz,2H),4.21-4.32(m,2H),4.04-4.11(m,1H),3.92-4.01(m, 2H),3.75-3.90(m,2H),3.07-3.26(m,4H),2.86-3.00(m,2H),2.68-2.73(m,1H),2.04-2.13(m,1H),1.67-1.75(m,1H).

[0360] Example 71: (S)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(3-cyanopropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0361] The target compound (23 mg) was synthesized using Intermediate 3 according to the synthesis method of Reference Example 1.

[0362] MS m / z[LC-MS]:574.28[M+1]. 1H NMR (400MHz, DMSO-d6) δ9.20(d,J=1.6Hz,1H),8.61(s,1H),8.47(s,1H),8.16(s,1H),7.72(d,J=1.6Hz,1H),7.07(dd,J=8.4Hz,2. 4Hz,1H),6.99(d,J=8.4Hz,1H),6.97(d,J=2.4Hz,1H),6.29(dd,J=16.8Hz,10.4Hz,1H),6.08(dd,J=16.8Hz,2.4Hz,1H),5.66(dd,J =10.4Hz,2.4Hz,1H),4.22-4.32(m,2H),4.19(t,J=6.8Hz,2H),4.03-4.11(m,1H),3.92-3.99(m,2H),3.86(d,J=12.0Hz,1H),3.76- 3.81(m,1H),3.09-3.23(m,2H),2.87-2.97(m,2H),2.66-2.75(m,1H),2.50(t,J=7.2Hz,2H),2.04-2.14(m,3H),1.67-1.75(m,1H).

[0363] Example 72: (E)-N-(3-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0364] The target compound (29 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0365] MS m / z[LC-MS]:395.17[M+1]. 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.20(d,J=1.2Hz,1H),8.65(s,1H),8.43(s,1H),8 .26(s,1H),8.16(s,1H),8.00(s,1H),7.73(d,J=16.0Hz,1H),7.64(d,J=16.0Hz,1H),7. 56(d,J=8.0Hz,1H),7.41(t,J=7.6Hz,1H),7.37(d,J=8.0Hz,1H),6.46(dd,J=16.8Hz,10 .0Hz, 1H), 6.27 (dd, J = 16.8Hz, 2.0Hz, 1H), 5.76 (dd, J = 10.0Hz, 2.0Hz, 1H), 3.89 (s, 3H).

[0366] Example 73: N-(2-chloro-5-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)phenyl)acrylamide

[0367] The target compound (28 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0368] MS m / z[LC-MS]:433.13[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.87(s,1H),8.54(s,1H),8.34(s,1H) ,8.07(s,1H),7.98(d,J=1.6Hz,1H),7.56(d,J=8.4Hz,1H),7.44(dd,J=8.4H z,2.0Hz,1H),7.41(s,1H),6.61(dd,J=16.8Hz,10.8Hz,1H),6.27(dd,J=16 .8Hz, 2.0Hz, 1H), 5.78 (dd, J = 10.8Hz, 2.0Hz, 1H), 5.44 (s, 2H), 3.87 (s, 3H).

[0369] Example 74: N-(2-chloro-3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)phenyl)acrylamide

[0370] The target compound (10 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0371] MS m / z[LC-MS]:433.13[M+1]. 1 H NMR (400MHz, CD3OD+CDCl3) δ8.31(s,1H),8.27(d,J=6.8Hz,1H),8.15(s,1H),7.75(s,1H),7.70(s,1H),7.59(d,J=7.6Hz,1H),7.38(t,J=8.0Hz ,1H),6.86(s,1H),6.43(dd,J=16.8Hz,1.2Hz,1H),6.33(dd,J=16.8Hz,10.0Hz,1H),5.80(dd,J=10.0Hz,1.2Hz,1H),5.37(s,2H),3.96(s,3H).

[0372] Example 75: N-(2,6-dichloro-3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)phenyl)acrylamide

[0373] The target compound (8 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0374] MS m / z[LC-MS]:467.09[M+1].

[0375] Example 76: (E)-N-(5-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)-2-fluorophenyl)acrylamide

[0376] The target compound (19 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0377] MS m / z[LC-MS]:413.16[M+1].

[0378] Example 77: (E)-N-(2-chloro-5-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0379] The target compound (15 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0380] MS m / z[LC-MS]:429.14[M+1].

[0381] Example 78: (E)-N-(4-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyridin-2-yl)acrylamide

[0382] The target compound (6 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0383] MS m / z[LC-MS]:396.17[M+1].

[0384] Example 79: (E)-N-(6-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyridin-2-yl)acrylamide

[0385] The target compound (7 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0386] MS m / z[LC-MS]:396.17[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),9.23(d,J=1.2Hz,1H),8.67(s,1H),8.41( s,1H),8.20(s,1H),8.12-8.14(m,2H),8.07(d,J=16.0Hz,1H),7.88(t,J=8.0Hz, 1H),7.53(d,J=16.0Hz,1H),7.37(d,J=7.6Hz,1H),6.68(dd,J=16.8Hz,10.4Hz,1 H), 6.31 (dd, J = 16.8Hz, 2.0Hz, 1H), 5.78 (dd, J = 10.4Hz, 2.0Hz, 1H), 3.88 (s, 3H).

[0387] Example 80: (R)-N-(2-chloro-5-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0388] The target compound (7 mg) was synthesized using the synthesis method of Reference Example 47 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0389] MS m / z[LC-MS]:447.15[M+1]. 1 H NMR (400MHz, CDCl3) δ8.65 (d, J = 2.0Hz, 1H), 8.23 ​​(s, 1H), 8.14 (s, 1H), 7.75-7 .79(m,2H),7.67(s,1H),7.41(d,J=8.4Hz,1H),7.30-7.33(m,1H),6.75(s,1H) ,6.50(dd,J=16.8Hz,1.2Hz,1H),6.34(dd,J=16.8Hz,10.0Hz,1H),5.88(dd,J= 10.0Hz, 1.2Hz, 1H), 5.50 (q, J = 6.4Hz, 1H), 3.95 (s, 3H), 1.81 (d, J = 6.4Hz, 3H).

[0390] Example 81: (E)-4-(2-(1-acryloylindol-6-yl)vinyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0391] The target compound (14 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0392] MS m / z[LC-MS]:421.19[M+1].

[0393] Example 82: (E)-N-(4-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0394] The target compound (4 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0395] MS m / z[LC-MS]:395.17[M+1].

[0396] Example 83: N-(3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-2,6-difluorophenyl)acrylamide

[0397] The target compound (2 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0398] MS m / z[LC-MS]:435.15[M+1].

[0399] Example 84: N-(6-chloro-3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0400] The target compound (12 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0401] MS m / z[LC-MS]:451.13[M+1].

[0402] Example 85: N-(2-chloro-3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-6-fluorophenyl)acrylamide

[0403] The target compound (6 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0404] MS m / z[LC-MS]:451.13[M+1].

[0405] Example 86: (E)-N-(2-chloro-3-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0406] The target compound (5 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0407] MS m / z[LC-MS]:429.14[M+1].

[0408] Example 87: (E)-N-(3-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)-2-fluorophenyl)acrylamide

[0409] The target compound (9 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0410] MS m / z[LC-MS]:413.16[M+1].

[0411] Example 88: N-(5-((((6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3′,4′:3,4]pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0412] The target compound (3 mg) was synthesized by referring to the synthesis method of intermediate 6 and Example 1 using 6-bromo-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine-4-ol (synthesized by referring to patent WO2023280073) as the starting material.

[0413] MS m / z[LC-MS]:471.18[M+1]. 1 H NMR(400MHz,DMSO-d6)δ12.62(s,1H),10.04(s,1H),8.81(s,1H),8.44(s,1 H),8.36(d,J=7.2Hz,1H),8.17(s,1H),7.92(s,1H),7.30-7.35(m,3H),6.64 (dd,J=16.8Hz,10.0Hz,1H),6.29(dd,J=16.8Hz,2.0Hz,1H),5.78(dd,J=10.0Hz,2.0Hz,1H),5.43(s,2H),4.41(t,J=6.4Hz,2H),3.11(t,J=6.4Hz,2H).

[0414] Example 89: N-(5-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-2-fluorophenyl)acrylamide

[0415] The target compound (36 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0416] MS m / z[LC-MS]:431.18[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.80(s,1H),8.52(s,1H),8.25(s,1H), 8.17(d,J=7.6Hz,1H),7.97(s,1H),7.34-7.39(m,1H),7.25-7.30(m,2H),6. 58(dd,J=17.2Hz,10.0Hz,1H),6.26(dd,J=16.8Hz,2.0Hz,1H),5.95(q,J=6. 4Hz, 1H), 5.76 (dd, J = 10.0Hz, 2.0Hz, 1H), 3.84 (s, 3H), 1.63 (d, J = 6.4Hz, 3H).

[0417] Example 90: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-(3-cyanopropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0418] The target compound (13 mg) was synthesized using Intermediate 8 according to the synthesis method of Reference Example 1.

[0419] MS m / z[LC-MS]:503.24[M+1]. 1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.61(s,1H),8.47(s,1H),8.15(s,1H),7.68(s ,1H),7.45(d,J=8.4Hz,2H),6.55(d,J=8.4Hz,2H),6.29(dd,J=16.8Hz,10.4Hz,1H), 6.08(dd,J=16.8Hz,2.4Hz,1H),5.66(dd,J=10.4Hz,2.4Hz,1H),4.42(s,2H),4.19( t,J=6.4Hz,2H),4.13(s,2H),4.02(s,4H),2.50(t,J=6.4Hz,2H),2.06-2.14(m,2H).

[0420] Example 91: N-(3-((3-cyano-6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0421] The target compound (6 mg) was synthesized by referring to the synthesis method of intermediate 6 using 6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile.

[0422] MS m / z[LC-MS]:456.17[M+1].

[0423] Example 92: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0424] The target compound (3 mg) was synthesized using Intermediate 8 by referring to the synthesis method of Intermediate 2 and Example 1.

[0425] MS m / z[LC-MS]:559.28[M+1].

[0426] Example 93: N-((5-((3-cyano-6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0427] The target compound (13 mg) was synthesized by referring to the synthesis method of intermediate 6 using 6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile.

[0428] MS m / z[LC-MS]:456.17[M+1].

[0429] Example 94: N-(3'-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-[1,1'-biphenyl]-3-yl)acrylamide

[0430] The target compound (18 mg) was synthesized using the synthesis method of Reference Example 1 using 6-(1-methyl-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0431] MS m / z[LC-MS]:495.23[M+1]. 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.28(d,J=1.6Hz,1H),8.65(s,1H),8.40(s,1H),8.1 3(s,1H),8.05(s,1H),7.90(d,J=1.6Hz,1H),7.82(s,1H),7.73-7.77(m,1H),7.68(d,J=8.8 Hz,1H),7.61-7.65(m,2H),7.52(d,J=8.0Hz,1H),7.42(t,J=8.0Hz,1H),6.44(dd,J=17.2Hz ,10.0Hz,1H),6.25(dd,J=17.2Hz,2.0Hz,1H),5.75(dd,J=10.0Hz,2.0Hz,1H),3.86(s,3H).

[0432] Example 95: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0433] The target compound (6 mg) was synthesized using Intermediate 8 by referring to the synthesis method of Intermediate 2 and Example 1.

[0434] MS m / z[LC-MS]:558.29[M+1].

[0435] Example 96: N-((4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-3-fluoropyridin-2-yl)acrylamide

[0436] The target compound (4 mg) was synthesized by referring to the synthesis method of intermediate 6 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0437] MS m / z[LC-MS]:418.15[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.92(s,1H),8.58(s,1H),8.38(s,1H),8.31(d,J=5.2Hz,1H),8.10(s,1H),7.74(t,J=5.2Hz,1H), 7.52(s,1H),6.50(dd,J=17.2Hz,10.0Hz,1H),6.29(dd,J=17.2Hz,2.0Hz,1H),5.81(dd,J=10.0Hz,2.0Hz,1H),5.61(s,2H),3.88(s,3H).

[0438] Example 97: N-((6-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)pyrazin-2-yl)acrylamide

[0439] The target compound (17 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0440] MS m / z[LC-MS]:401.16[M+1]. 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.42(s,1H),8.92(s,1H),8.76(s,1H),8.57(s,1H),8.35(s,1H),8.09(s,1H),7.47(s,1 H), 6.63 (dd, J = 16.8Hz, 10.4Hz, 1H), 6.36 (dd, J = 16.8Hz, 1.6Hz, 1H), 5.85 (dd, J = 10.4Hz, 1.6Hz, 1H), 5.50 (s, 2H), 3.87 (s, 3H).

[0441] Example 98: (S)-N-(2-chloro-5-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0442] The target compound (9 mg) was synthesized using the synthesis method of Reference Example 47 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0443] MS m / z[LC-MS]:447.15[M+1].

[0444] Example 99: (E)-N-(5-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyridin-3-yl)acrylamide

[0445] The target compound (10 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0446] MS m / z[LC-MS]:396.17[M+1].

[0447] Example 100: (E)-N-(5-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyridin-2-yl)acrylamide

[0448] The target compound (8 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0449] MS m / z[LC-MS]:396.17[M+1].

[0450] Example 101: (E)-N-(4-(2-(3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0451] The target compound (4 mg) was synthesized using Intermediate 9 by referring to the synthesis method of Intermediate 2.

[0452] MS m / z[LC-MS]:395.17[M+1].

[0453] Example 102: (E)-N-(4-(2-(3-cyano-6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0454] The target compound (13 mg) was synthesized using 3-cyano-6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as described in the synthesis method of intermediate 2.

[0455] MS m / z[LC-MS]:434.19[M+1].

[0456] Example 103: (E)-N-(6-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyridin-3-yl)acrylamide

[0457] The target compound (9 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0458] MS m / z[LC-MS]:396.17[M+1].

[0459] Example 104: (E)-N-(4-(2-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0460] The target compound (14 mg) was synthesized using 3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as described in Intermediate 2.

[0461] MS m / z[LC-MS]:431.16[M+1].

[0462] Example 105: (E)-N-(4-(2-(3-cyano-6-(1-(difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0463] The target compound (6 mg) was synthesized using 3-cyano-6-(1-(difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as described in Intermediate 2.

[0464] MS m / z[LC-MS]:445.17[M+1].

[0465] Example 106: (R)-4-(3-(1-acryloylazetidin-3-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0466] The target compound (17 mg) was synthesized using Intermediate 4 by referring to the synthesis method of Intermediate 2 and Example 1.

[0467] MS m / z[LC-MS]:629.32[M+1].

[0468] Example 107: N-(3-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethyl)phenyl)acrylamide

[0469] The target compound (9 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

[0470] MS m / z[LC-MS]:397.19[M+1].

[0471] Example 108: (E)-4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenylvinyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0472] The target compound (4 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0473] MS m / z[LC-MS]:476.23[M+1].

[0474] Example 109: (R)-N-(2-chloro-5-(1-((6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3′,4′:3,4]pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0475] The target compound (8 mg) was synthesized by referring to the synthesis methods of Intermediate 6, Intermediate 2 and Example 47 using 6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3',4':3,4]pyrazolo[1,5-a]pyridine-4-ol as the starting material.

[0476] MS m / z[LC-MS]:462.16[M+1].

[0477] Example 110: (E)-N-(3-(2-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0478] The target compound (7 mg) was synthesized by referring to the synthetic method of intermediate 2.

[0479] MS m / z[LC-MS]:410.19[M+1].

[0480] Example 111: (E)-N-(4-(2-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0481] The target compound (17 mg) was synthesized by referring to the synthetic method of intermediate 2.

[0482] MS m / z[LC-MS]:410.19[M+1].

[0483] Example 112: N-(3-(((3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)phenyl)acrylamide

[0484] The target compound (3 mg) was synthesized using 4-hydroxy-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0485] MS m / z[LC-MS]:434.13[M+1].

[0486] Example 113: N-(3-chloro-4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)acrylamide

[0487] The target compound (13 mg) was synthesized using 4-hydroxy-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0488] MS m / z[LC-MS]:434.13[M+1].

[0489] Example 114: (R)-N-(2,6-dichloro-3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0490] The target compound (2 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of Reference Example 47.

[0491] MS m / z[LC-MS]:481.11[M+1].

[0492] Example 115: (E)-N-(2-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyridin-4-yl)acrylamide

[0493] The target compound (19 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0494] MS m / z[LC-MS]:396.17[M+1].

[0495] Example 116: (R)-N-(4-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-3-fluoropyridin-2-yl)acrylamide

[0496] The target compound (12 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of Reference Example 47.

[0497] MS m / z[LC-MS]:432.17[M+1].

[0498] Example 117: (R)-N-(3-chloro-6-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyridin-2-yl)acrylamide

[0499] The target compound (9 mg) was synthesized using the synthesis method of Reference Example 47 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0500] MS m / z[LC-MS]:448.14[M+1].

[0501] Example 118: N-(6-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-3-fluoropyridin-2-yl)acrylamide

[0502] The target compound (6 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0503] MS m / z[LC-MS]:418.15[M+1].

[0504] Example 119: (E)-N-(6-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyridazin-3-yl)acrylamide

[0505] The target compound (19 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0506] MS m / z[LC-MS]:397.16[M+1].

[0507] Example 120: (E)-N-(2-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyrimidin-5-yl)acrylamide

[0508] The target compound (4 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0509] MS m / z[LC-MS]:397.16[M+1].

[0510] Example 121: (E)-N-(5-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyrazin-2-yl)acrylamide

[0511] The target compound (10 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0512] MS m / z[LC-MS]:397.16[M+1].

[0513] Example 122: (E)-N-(5-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)pyrimidin-2-yl)acrylamide

[0514] The target compound (1 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0515] MS m / z[LC-MS]:397.16[M+1].

[0516] Example 123: (R)-N-(6-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrazin-2-yl)acrylamide

[0517] The target compound (3 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of Reference Example 47.

[0518] MS m / z[LC-MS]:415.18[M+1].

[0519] Example 124: (E)-N-(4-(2-(3-cyano-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0520] The target compound (6 mg) was synthesized using Intermediate 8 by referring to the synthesis method of Intermediate 2 and Example 1.

[0521] MS m / z[LC-MS]:504.24[M+1].

[0522] Example 125: (E)-4-(2-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)vinyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0523] The target compound (11 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0524] MS m / z[LC-MS]:385.19[M+1].

[0525] Example 126: (E)-4-(2-(1-acryloylpiperidin-4-yl)vinyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0526] The target compound (12 mg) was synthesized using 3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as described in Intermediate 2.

[0527] MS m / z[LC-MS]:387.21[M+1].

[0528] Example 127: (E)-N-(4-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)-2-fluorophenyl)acrylamide

[0529] The target compound (32 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0530] MS m / z[LC-MS]:413.16[M+1].

[0531] Example 128: (E)-N-(4-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)-3-fluorophenyl)acrylamide

[0532] The target compound (22 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0533] MS m / z[LC-MS]:413.16[M+1].

[0534] Example 129: (E)-N-(3-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)-2-fluorophenyl)acrylamide

[0535] The target compound (17 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0536] MS m / z[LC-MS]:413.16[M+1].

[0537] Example 130: N-(2-cyano-3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)phenyl)acrylamide

[0538] The target compound (13 mg) was synthesized using 4-hydroxy-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of intermediate 6.

[0539] MS m / z[LC-MS]:424.16[M+1].

[0540] Example 131: (E)-N-(2-chloro-4-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0541] The target compound (8 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0542] MS m / z[LC-MS]:429.14[M+1].

[0543] Example 132: (E)-4-(2-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)vinyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0544] The target compound (15 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0545] MS m / z[LC-MS]:437.18[M+1].

[0546] Example 133: N-(4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-5-fluoropyridin-2-yl)acrylamide

[0547] The target compound (17 mg) was synthesized using the synthesis method of Reference Example 47 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0548] MS m / z[LC-MS]:418.15[M+1].

[0549] Example 134: N-(6-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)pyrimidin-4-yl)acrylamide

[0550] The target compound (6 mg) was synthesized using the synthesis method of Reference Example 47 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0551] MS m / z[LC-MS]:401.16[M+1].

[0552] Example 135: (E)-N-(4-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)-3-methoxyphenyl)acrylamide

[0553] The target compound (9 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0554] MS m / z[LC-MS]:425.18[M+1].

[0555] Example 136: (R)-N-(2-chloro-5-(1-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0556] The target compound (12 mg) was synthesized using 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of Reference Example 80 and Example 1.

[0557] MS m / z[LC-MS]:483.13[M+1].

[0558] Example 137: (R)-4-((1-acryloylpiperidin-3-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0559] The target compound (6 mg) was synthesized using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile according to the synthesis method of Reference Example 47.

[0560] MS m / z[LC-MS]:391.20[M+1].

[0561] Example 138: (R)-N-(2-chloro-5-(1-(3-cyano-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0562] The target compound (5 mg) was synthesized using (R)-N-(5-(1-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-2-chlorophenyl)acrylamide according to the synthesis method of Reference Example 1.

[0563] MS m / z[LC-MS]:503.17[M+1].

[0564] Example 139: (R)-N-(2-chloro-5-(1-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0565] The target compound (13 mg) was synthesized using (R)-N-(5-(1-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-2-chlorophenyl)acrylamide according to the synthesis method of Reference Example 1.

[0566] MS m / z[LC-MS]:461.16[M+1].

[0567] Example 140: (R)-N-(2-chloro-5-(1-(3-cyano-6-(1-(-3-cyanopropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0568] The target compound (11 mg) was synthesized using (R)-N-(5-(1-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-2-chlorophenyl)acrylamide according to the synthesis method of Reference Example 1.

[0569] MS m / z[LC-MS]:500.17[M+1].

[0570] Example 141: (R)-N-(2-chloro-5-(1-(3-cyano-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0571] The target compound (11 mg) was synthesized using (R)-N-(5-(1-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-2-chlorophenyl)acrylamide according to the synthesis method of Reference Example 1.

[0572] MS m / z[LC-MS]:546.21[M+1].

[0573] Example 142: (E)-4-(2-(2-acryloyl-2-azaspiro[3.5]non-6-en-7-yl)vinyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0574] The target compound (16 mg) was synthesized using Intermediate 11 by referring to the synthesis method of Intermediate 2.

[0575] MS m / z[LC-MS]:425.22[M+1].

[0576] Example 143: (R)-N-(2-chloro-5-(1-(3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0577] The target compound (24 mg) was synthesized using (R)-N-(5-(1-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-2-chlorophenyl)acrylamide according to the synthesis method of Reference Example 1.

[0578] MS m / z[LC-MS]:541.22[M+1].

[0579] Example 144: (R)-N-(4-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-3-fluoropyridin-2-yl)acrylamide

[0580] The target compound (22 mg) was synthesized using the synthesis method of Reference Example 47 using 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0581] MS m / z[LC-MS]:448.14[M+1].

[0582] Biological activity experiments

[0583] 1. Compounds for FGFR2 WTIn vitro enzymatic activity assay

[0584] The compounds in this patent have an effect on FGFR2 WT IC of enzyme activity inhibition 50 The value was determined using homogeneous time-resolved fluorescence (HTRF) method. The compound was diluted 5-fold with 100% DMSO starting from 0.2mM (7 concentrations in total). 2μL of the compound at each concentration was added to 48μL of reaction buffer (50mM HEPES pH7.5, 0.1mM Na3VO4, 5mM MnCl2, 1mM DTT, 0.001% Tween 20 and 0.01% BSA) and diluted and mixed. 2.5μL of the diluted compound was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), and then 5μL of GST-FGFR2 was added. WT (399-821aa, final concentration of 0.3nM), centrifuge and mix, place in an incubator at 23°C for 1 hour, then add 2.5μL of ATP (final concentration 1μM) and TK Peptide Substrate mixture (final concentration 1μM, purchased from Cisbio) to start the reaction, and the total reaction volume is 10μL. Place the 384-well plate in an incubator at 23°C for 1 hour, then add 5μL of TK Antibody (purchased from Cisbio) and 5μL of StreptavidiN-XL665 (purchased from Cisbio) to stop the reaction. After incubating in the incubator for another 1 hour, read the fluorescence value on Envision (purchased from PerkinElmer) (320nm excitation, detection of 665nm and 620nm emission light, the ratio of the two is the enzyme activity signal). Each compound was measured at 7 concentrations of FGFR2 WT The enzymatic activity signal was calculated using GraphPad Prism software to obtain the IC 50 value.

[0585] 2. Effects of Compounds on FGFR2 N549K In vitro enzymatic activity assay

[0586] The compounds in this patent have an effect on FGFR2 N549K IC of enzyme activity inhibition 50The value was determined using homogeneous time-resolved fluorescence (HTRF) method. The compound was diluted 5-fold with 100% DMSO starting from 0.2mM (7 concentrations in total). 2μL of the compound at each concentration was added to 48μL of reaction buffer (50mM HEPES pH7.5, 0.1mM Na3VO4, 5mM MnCl2, 1mM DTT, 0.001% Tween 20 and 0.01% BSA) and diluted and mixed. 2.5μL of the diluted compound was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), and then 5μL of GST-FGFR2 was added. N549K (399-821aa, final concentration of 0.5nM), centrifuge and mix, place in an incubator at 23°C for 1 hour, then add 2.5μL of ATP (final concentration 30nM) and TK Peptide Substrate mixture (final concentration 1μM, purchased from Cisbio) to start the reaction, and the total reaction volume is 10μL. Place the 384-well plate in an incubator at 23°C for 2 hours, then add 5μL of TK Antibody (purchased from Cisbio) and 5μL of StreptavidiN-XL665 (purchased from Cisbio) to stop the reaction. After incubating in the incubator for another 1 hour, read the fluorescence value on Envision (purchased from PerkinElmer) (320nm excitation, detection of 665nm and 620nm emission light, the ratio of the two is the enzyme activity signal). Each compound was measured at 7 concentrations of FGFR2 N549K The enzymatic activity signal was calculated using GraphPad Prism software to obtain the IC 50 value.

[0587] 3. Effects of Compounds on FGFR3 V555M In vitro enzymatic activity assay

[0588] The compounds in this patent have an effect on FGFR3 V555M IC of enzyme activity inhibition 50 The value was determined by homogeneous time-resolved fluorescence (HTRF) method. The compound was diluted 5-fold with 100% DMSO starting from 0.2mM (7 concentrations in total). 2μL of the compound was added to 48μL of reaction buffer (50mM HEPES pH7.5, 0.1mM Na3VO4, 5mM MnCl2, 1mM DTT, 0.001% Tween 20 and 0.01% BSA) for dilution and mixing. 2.5μL was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), and then 5μL of GST-RET was added.V555M (436-806aa, final concentration of 0.25nM), centrifuge and mix, place the 384-well plate in an incubator at 23°C for 1 hour, then add 2.5μL of ATP (final concentration 0.4μM) and TK Peptide Substrate mixture (final concentration 1μM, purchased from Cisbio) to start the reaction, and the total reaction volume is 10μL. Place the 384-well plate in an incubator at 23°C for 1 hour, then add 5μL of TK Antibody (purchased from Cisbio) and 5μL of StreptavidiN-XL665 (purchased from Cisbio) to stop the reaction. After incubating in the incubator for another 1 hour, read the fluorescence value on Envision (purchased from PerkinElmer) (320nm excitation, detection of 665nm and 620nm emission light, the ratio of the two is the enzyme activity signal). Each compound was measured at 7 concentrations of FGFR3 V555M The enzymatic activity signal was calculated using GraphPad Prism software to obtain the IC 50 value.

[0589] 4. Determination of the inhibitory activity of FGFR2 compounds on AN3-CA cell proliferation

[0590] Human endometrial adenocarcinoma cells, AN3-CA (FGFR2 N549K mutation), were cultured in MEM medium supplemented with 10% fetal bovine serum (FBS, Gibico) and 1% penicillin / streptomycin (P / S, Life Technologies) at 37°C and 5% CO2. The day before compound testing, AN3-CA cells were plated in a 96-well plate (#3917, Corning) at a density of 2000 cells / 195 μL / well. After 24 hours, compounds were serially diluted three-fold starting at 10 mM in 100% DMSO (10 concentrations total). At each concentration, 2 μL of compound was added to 48 μL of MEM medium for dilution. 5 μL of each diluted compound concentration was added to the plated cell suspension. The compound and cells were incubated in a cell culture incubator for 72 hours (3 days). After aspirating the culture medium, 25 μL of Cell-Titer Glo (G7570, purchased from Promega) was added and incubated again for 5-10 minutes. Fluorescence was then read on an Envision microscope, and the data were used to calculate the IC50 value for the compound's inhibition of cell proliferation using GraphPad Prism software.

[0591] 5. Compounds for FGFR2 N549K -PHGDH / 3T3 cell proliferation activity assay

[0592] FGFR2 fusion cell line constructed by lentiviral infection N549K -PHGDH / 3T3 cells were cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS, purchased from Gibco) and 1% penicillin / streptomycin (P / S, purchased from Life Technologies) at 37°C and 5% CO2. N549K -PHGDH / 3T3 cells were plated in a 96-well plate (#3917, purchased from Corning) at a concentration of 1000 cells / 195 μL / well. After 24 hours, the compound was diluted 3-fold with 100% DMSO starting from 10 mM (a total of 10 concentrations), and then 2 μL of the compound was added to 48 μL of DMEM culture medium for dilution. 5 μL of each concentration of the diluted compound was added to the plated cell suspension, and the compound and cells were co-incubated in a cell culture incubator for 72 hours (3 days). After the culture medium was aspirated, 25 μL of Cell-Titer Glo (G7570, purchased from Promega) reagent was added and incubated again for 5-10 minutes. Afterwards, the cells were cultured in a CLARIO star Plus The fluorescence value was read on a multifunctional microplate reader, and the data were calculated using GraphPad Prism software to obtain the IC value of the compound for inhibition of cell proliferation. 50 value.

[0593] Table 1. Activity and cell inhibitory activity data of some examples

[0594] The result "A" indicates IC 50 <5nM; "B" indicates IC 50 <20nM; “-” means not tested

[0595] 7. Pharmacokinetic testing:

[0596] Male Sprague-Dawley rats were obtained from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Rats were divided into groups of three and orally administered with a suspension of the test sample (5 mg / kg, in a suspension containing 0.5% CMC and 0.1% Tween 80). Animals were fasted overnight and from 10 hours before dosing until 4 hours after dosing. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. After isoflurane anesthesia using a small animal anesthesia machine, 0.3 mL of whole blood was collected from the retinal venous plexus into a heparinized tube. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C. Plasma was transferred to a centrifuge tube and stored at -80°C until analysis. Plasma samples were extracted using protein precipitation, and the extracts were analyzed by LC / MS.

[0597] Table 2. Pharmacokinetic data of some compounds

Claims

1. A compound of formula (III) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof: in, X is Cl or -CN, Y is H or C 1-6 Alkyl, or X and Y together form a 5-7 membered heteroaromatic ring, R1 is phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl may be optionally substituted by R2, R2 is selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated methyl, or -(CH2) 0-1 -R3, R3 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with halogen, -CN, -NH2, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, L is or L0, L0 is -L1-L4-NH-, -L4-L5-L6-, -L4-L6-, -L4-L1-L 6- , -L4-L4-NH-, -L4-L5-NH-, -L1-L3-L4-NH-, -L5-L4-NH-, -L4-L2-L6-, -L1-L3-L2-L4-NH-, -L1-L3-L7-, -L1-L3-L4-L5-NH-, or -L8-L4-NH-, L1 is -O-, -S-, or -N(R)-, L2 is -(CO)-, L3 is C 1-6 Alkylene, which may be optionally replaced by C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl substitution, L4 is a phenylene group or a 5-7 membered heteroarylene group, L5 is a 3-8 membered heterocyclic ring, L6 L7 L8 is -CH=CH-.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein L1 is -O-, -S-, or -N(R)-, and R is H or C 1-6 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein L0 is -L1-L4-NH-, -L4-L5-L6-, -L4-L6-, -L4-L1-L 6- , -L4-L4-NH-, -L4-L5-NH-, -L1-L3-L4-NH-, -L5-L4-NH-, -L4-L2-L6-, -L1-L3-L2-L4-NH-, -L1-L3-L7-, or -L1-L3-L4-L5-NH-, L1, L2, L3, L4, L5, L6, L7 and L8 are as defined in claim 2.

4. The compound according to claim 3 or its pharmaceutically acceptable salt, solvate, polymorph or isomer, which has a structure shown in formula (II) in X is Cl or -CN, R1 is phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl may be optionally substituted by R2, R2 is selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated methyl, or -(CH2) 0-1 -R3, R3 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with halogen, -CN, -NH2, -OH, C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution, L is 5. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein X is -CN.

6. The compound according to claim 4 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R1 is a 5-6 membered heteroaryl group, which may be optionally substituted by R2, and R2 is as defined in claim 4.

7. The compound according to claim 4 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein L is 8. The following compounds or their pharmaceutically acceptable salts, solvates, polymorphs or isomers 9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating a disease associated with FGFR. The use according to claim 10 , wherein the disease associated with FGFR is a tumor.

12. The use according to claim 10, wherein the disease associated with FGFR is bile duct cancer, urothelial carcinoma, lung cancer, bladder cancer, cervical cancer, endometrial cancer, breast cancer, thyroid cancer, intestinal cancer, gastric cancer, liver cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, leukemia, multiple myeloma, Hodgkin's lymphoma, or melanoma.

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