WO2025102600A1 - Novel heterocyclic compound - Google Patents

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 type of heterocyclic compound

Cross-references

This application claims priority to Chinese Patent Application No. 202311524928.5 filed on November 16, 2023, with the patent name “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, with the patent name “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, with the patent name “A Novel Heterocyclic Compound”, and all disclosed contents of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to compounds for inhibiting the activity of FGFR proteins, and also relates to preparation methods of the compounds and uses of their pharmaceutical compositions.

Background Art

Fibroblast growth factor receptors (FGFR) are transmembrane polypeptide tyrosine kinases. Five types (FGFR1 to FGFR5) have been discovered so far, of which FGFR2 is mainly distributed in tissues originating from the endoderm, 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, promoting nerve fiber growth and development, wound healing, and promoting cell apoptosis. FGFR2 activates the downstream p38 signaling pathway to trigger endochondral ossification, and activates the downstream MAPK and PKC pathways to regulate the proliferation of mesenchymal stem cells, which has a very important role in promoting direct osteogenesis. FGFR2 also plays a vital role in tooth development.

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 poor prognosis. FGFR2 gene mutations have been found in endometrial cancer, lung cancer, gastric cancer, and urothelial carcinoma. FGFR2 fusion protein exists 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, regulate tumor immune escape, and FGFR2 expression level is closely related to prognosis. Studies have found that FGFR2 gene fusion is found in 10-20% of patients with intrahepatic bile duct carcinoma.

The development of targeted drugs for FGFR2 subtypes is in full swing. In addition to the three drugs already on the market, there are more than 10 FGFR inhibitors in different stages of clinical development. For example, the monoclonal antibody drug Bemarituzumab developed by Amgen and Zai Lab (highest clinical phase II), Alofanib (highest clinical phase I) by Russian Pharmaceutical Technologies, RLY-4008 (highest clinical phase II) developed by Relay Therapeutics, and TAS-120 (Futibatinib) (highest clinical phase II) by Taiho Pharmaceutical.

Summary of the invention

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

In one aspect, the present invention provides 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,

R ₁ is phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl may be optionally substituted by R ₂ ,

R ₂ is selected from halogen, -CN, -NH ₂ , -OH, C _1-6 alkyl, halogenated C _1-6 alkyl, deuterated methyl, or -(CH ₂ ) _0-1 -R ₃ ,

R ₃ 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 by halogen, -CN, -NH ₂ , -OH, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclyl,

L is Or L ₀ ,

L ₀ is -L ₁ -L ₄ -NH-, -L ₄ -L ₅ -L ₆ -, -L ₄ -L ₆ -, -L ₄ -L ₁ -L _6- , -L ₄ -L ₄ -NH-, -L ₄ -L ₅ -NH-, -L ₁ -L ₃ -L ₄ -NH-, -L ₅ -L ₄ -NH-, -L ₄ -L ₂ -L ₆ -, -L ₁ -L ₃ -L ₂ -L ₄ -NH-, -L ₁ -L ₃ -L ₇ -, -L ₁ -L ₃ -L ₄ -L ₅ -NH-, or -L ₈ -L ₄ -NH-,

_L1 is -O-, -S-, or -N(R)-,

_L2 is -(CO)-,

L ₃ is a C _1-6 alkylene group, which may be optionally substituted by a C _1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group,

_L4 is a phenylene group or a 5-7 membered heteroarylene group,

_L5 is a 3-8 membered heterocyclic ring,

L ₆ or

L ₇ or

_L8 is -CH=CH-.

In some embodiments, L ₁ is -O-, -S-, or -N(R)-, and R is H or C _1-6 alkyl, preferably H.

In some embodiments, L ₁ is -O- or -S-.

In some embodiments, _L0 is -L1- _{L4 -} NH-, -L4- _L5 -L6-, _-L4 - _L6- , _-L4 - _L1 -L6-, -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-, and _{L1 , L2} , _L3 , _L4 , _L5 , _L6 , _{L7 ,} and _L8 are _as defined above.

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

in,

X is Cl or -CN,

R ₁ is phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl may be optionally substituted by R ₂ ,

R ₂ is selected from halogen, -CN, -NH ₂ , -OH, C _1-6 alkyl, halogenated C _1-6 alkyl, deuterated methyl, or -(CH ₂ ) _0-1 -R ₃ ,

R ₃ 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 by halogen, -CN, -NH ₂ , -OH, C _1-6 alkyl, or halogenated C _1-6 alkyl,

L is or

In some embodiments, X is -CN.

In some embodiments, R ₁ is a 5-6 membered heteroaryl, which may be optionally substituted by R ₂ , and R ₂ is as defined above.

In some embodiments, R ₁ is pyrazolyl, which may be optionally substituted with R ₂ , R ₂ being as defined above.

In some embodiments, L is or Preferably or

In some embodiments, the present invention provides the following compounds

or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.

Another aspect of the present invention also 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.

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 the above composition in the preparation of a drug for treating a disease associated with FGFR; as a preferred embodiment, the disease associated with FGFR is a tumor; in some embodiments, the tumor has a mutation in FGFR2N549, V561, V565, N550, N540, V555, E566, K660, V550. In some embodiments, the cancer associated with FGFR 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, etc.

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

The present invention also relates to a method for treating a tumor resistant to FGFR inhibitors, the method 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.

In some embodiments of the present invention, the subject involved in the present invention is a mammal including a human.

DETAILED DESCRIPTION OF THE INVENTION

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

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 equivalent methods and structures are all within the scope of the claims.

Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, and public materials cited in the entirety of this article are incorporated herein by reference in their entirety.

It should be understood that the above brief description and the following detailed description are exemplary and explanatory, rather than limiting to any subject matter of the present invention. Unless otherwise specifically stated, the use of singular forms also includes the plural. Unless otherwise stated, the use of "or" and "or" means "and/or". In addition, the use of the term "including" and other forms, such as "including", "containing" and "comprising" are not limiting.

Some chemical terms

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". In addition, the optionally substituted group can be unsubstituted (e.g., -CH ₂ CH ₃ ), fully substituted (e.g., -CF ₂ CF ₃ ), monosubstituted (e.g., -CH ₂ CH ₂ F) or any level between monosubstituted and fully substituted (e.g., -CH ₂ CHF ₂ , -CF ₂ CH ₃ , -CFHCHF ₂ , 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 is sterically impossible to exist and/or cannot be synthesized will be introduced.

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

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

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.

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 the carbon atoms in possible substituents.

The terms "halogen," "halo," or "halide" refer to bromine, chlorine, fluorine, or iodine.

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 may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; O may be in any isotopic form, including ¹⁶ O and ¹⁸ O, etc.

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

The term "heteroatom" or "hetero" as used herein, alone or as part of other ingredients, refers to atoms other than carbon and hydrogen. Heteroatoms are independently selected from 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 each other, or some or all of the two or more heteroatoms may be different from each other.

[0063] 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.

[0063] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure having two or more rings sharing one or more atoms.

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, such as 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.

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

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon group 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 should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH ₂ ), 1-propenyl (CH ₂ CH=CH ₂ ), isopropenyl (C(CH ₃ )=CH ₂ ), butenyl and 1,3-butadienyl, etc. When a numerical range appears for alkenyl as defined herein, for example, "C ₂ -C ₆ alkenyl" or "C _2-6 alkenyl" refers to an alkenyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also encompasses the case where no numerical range is specified.

The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted linear or branched monovalent hydrocarbon group 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, etc. When a numerical range appears in the alkynyl defined herein, for example, "C ₂ -C ₆ alkynyl" or "C _2-6 alkynyl" refers to an alkynyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and the alkynyl herein also encompasses the case where no numerical range is specified.

The term "aryl" refers to a fully conjugated π electron system of all-carbon monocyclic or fused rings 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. Non-limiting examples of unsubstituted aryl include but are not limited to phenyl, naphthyl and anthracenyl.

The term "arylene" as used herein, alone or in combination, refers to a divalent group derived from the monovalent aryl group defined above.

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, wherein 1, 2, 3 or 4 ring atoms are selected from N, O, S, and the remaining ring atoms are C, and have a completely conjugated π-electron system. Heteroaryl can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazinyl.

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

The term "cycloalkyl" used herein alone or as part of other components refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group, containing only carbon atoms and hydrogen atoms, which may include fused rings, spiro rings or bridged ring systems, containing 3-15 ring carbon atoms, preferably 3-10 ring carbon atoms, more preferably 3-8 ring carbon atoms, which may be saturated or unsaturated, and connected 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, etc.

The terms "heterocycloalkyl", "heterocyclyl" and "heterocycle" used herein alone or as part of other components refer to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused rings, spirocyclic or bridged ring systems, the nitrogen, carbon or sulfur on the heterocyclyl can be selectively oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclyl can be partially or fully saturated. The heterocyclyl can be connected to the rest of the molecule through a single bond through a carbon atom or heteroatom on the ring. The heterocyclyl containing fused rings can contain one or more aromatic or heteroaromatic rings, as long as the atoms on the non-aromatic rings are connected to the rest of the molecule. 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, and 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, pyrrolid ... oxazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidine, tetrahydrofuranyl, tetrahydropyranyl and the like.

The term "polymorph" or "polymorphism" used in the present invention refers to a compound of the present invention having multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

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

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

It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers can be independently R or S configurations. 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 techniques and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

The term "pharmaceutically acceptable salt" used herein includes both acid-addition salts and base-addition salts.

"Pharmaceutically acceptable salts of added acids" refer to those salts that retain the biological effectiveness and properties of the free base of the compound, are not biologically or otherwise undesirable, and are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., 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, caproic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base-added salts" refer to those salts that retain the biological effectiveness and properties of the free acid of the compound, are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic base or an organic base. Salts formed by reacting with an inorganic base include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

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, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

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 compounds of the invention with one or more solvent molecules.

The solvent may be water, in which case the solvate is a hydrate. It may also be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and 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 also only accidentally retain water or a mixture of water and some other solvents. The compounds of the present invention may react in a solvent or precipitate or crystallize in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

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). Such a medium includes all pharmaceutically acceptable carriers.

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.

The term "pharmaceutically acceptable" as used herein 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 adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

"Pharmaceutically acceptable carriers" include, but are 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. dose.

As used herein, the terms "subject", "patient", "subject" or "individual" refer to individuals suffering from a disease, disorder or condition, etc., 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, etc. Examples of non-human mammals include, but are not limited to, birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

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

(i) preventing a mammal from developing a disease or condition, particularly a mammal that has been previously exposed to the disease or condition but has not yet been diagnosed with the disease or condition;

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

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

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

As used herein, the terms "disease" and "disorder" may be used interchangeably or may have different meanings because certain specific diseases or disorders do not yet have a known causative agent (so the cause of the disease is still unclear), and therefore cannot be considered a disease but can only be viewed as an unwanted condition or syndrome, the syndrome of which more or less specific symptoms have been confirmed by clinical researchers.

As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

As used herein, the terms "administering", "administering", "administering", etc. refer to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

Preparation of the compounds of the present invention

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

It is to be 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.

Those skilled in the art will also appreciate that in the following described processes, 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 technical methods known to those skilled in the art.

Example

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

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.

Unless otherwise stated, 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.

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

Nuclear magnetic resonance data ( ¹ H NMR) were run at 400 MHz using a Varian instrument. The solvents used for the NMR data were CDCl ₃ , CD ₃ OD, D ₂ O, DMSO-d6, etc., based on tetramethylsilane (0.00 ppm) or residual solvent (CDCl ₃ :7.26ppm; CD ₃ OD:3.31ppm; D ₂ O:4.79ppm; d6-DMSO:2.50ppm). When peak shape diversity is indicated, the following abbreviations are used to represent different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double doublet), dt (double triplet). If coupling constants are given, they are in Hertz (Hz).

Abbreviations:

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

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

Under nitrogen protection, 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 mixed solvent (50 mL) of dioxane and water (4:1), tetrakis(triphenylphosphine)palladium (110 mg) was added, and the temperature was raised 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 a 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 target compound (275 mg).

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

At room temperature, the product obtained in step 1 was dissolved in DMF (10 mL), DIEA (260 mg) was added thereto, and then N-phenylbis(trifluoromethanesulfonyl)imide (360 mg) was added. 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).

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

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

At room temperature, (R)-8-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (369 mg) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2 mL) was added, stirred for 2 hours, and concentrated under reduced pressure. Dichloromethane (20 mL) was added to the residue, cooled to 0°C, tert-butyl 3-oxoazetidine-1-carboxylate (171 mg) and sodium triacetoxyborohydride (500 mg) were added in sequence, and then the mixture was heated to room temperature and stirred for 12 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, 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).

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

Dissolve (R)-3-(8-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)azetidine-1-carboxylic acid tert-butyl ester (310 mg), biboronic acid pinacol ester (254 mg) and potassium acetate (150 mg) in dioxane (20 mL), add Pd(dppf)Cl ₂ (50 mg) under nitrogen protection, raise the temperature to 90°C and stir for 4 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, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (V:V)) to obtain the target compound (270 mg).

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

Under nitrogen protection, 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]oxazine-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 temperature was raised 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, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to obtain the target compound. (285 mg)

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

At room temperature, the above product was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, stirred for 2 hours, and concentrated under reduced pressure. Dichloromethane (20 mL) was added to the residue, cooled to 0°C, and then acryloyl chloride (90 mg) and triethylamine (200 mg) were added, and then the mixture was heated to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous 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 column chromatography (eluent: dichloromethane: methanol = 20: 1 (V: V)) to obtain the title compound (190 mg).

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

Refer to the synthesis method of intermediate 2 to synthesize intermediate 3

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

Refer to the synthesis method of intermediate 2 to synthesize intermediate 4

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

Refer to the synthesis method of intermediate 4 to synthesize intermediate 5

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

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

At 0°C, solid potassium carbonate (280 mg) was added to a DMF (10 mL) solution of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (238 mg) and 2-nitro-5-fluoropyridine (142 mg), and the mixture was 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 a 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 target compound. (310 mg)

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

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 the mixture was stirred for 2 hours. The reaction solution was poured into water (50 mL), extracted with dichloromethane, and the extract was washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane (50 mL) was added to the residue, and acryloyl chloride (100 mg) and triethylamine (200 mg) were added, and then stirred at room temperature for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane, and the extract was washed with saturated saline, 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).

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

Refer to the synthesis method of intermediate 2 to synthesize intermediate 7

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

Intermediate 8 was synthesized by referring to the synthesis method of Intermediate 2.

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

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

Under nitrogen protection, 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 mixed solvent (30 mL) of dioxane and water (4:1), tetrakis(triphenylphosphine)palladium (110 mg) was added, and the temperature was raised 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 a 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: dichloromethane:methanol=20:1 (V:V)) to obtain the target compound (215 mg).

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

At room temperature, the product obtained in step 1 was dissolved in DMF (10 mL), DIEA (260 mg) was added thereto, 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).

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

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

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

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

Under nitrogen protection, 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) chloride (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 thereto, 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, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:ethyl acetate=3:1 (v:v)) to give the target product (190 mg).

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

Under nitrogen protection, 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), stirred at room temperature for 30 minutes, and then a solution of pinacol diboron (200 mg) in THF (10 mL) was added, stirred at room temperature for 10 minutes, and then 4-ethynyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (190 mg) was added. The mixture was stirred overnight and then concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 1:1) to obtain the target compound (101 mg).

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

Under nitrogen protection, 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 temperature was raised 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 a saturated sodium chloride aqueous 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).

MS m/z[LC-MS]:521.25[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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＝17.2Hz,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).

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

The target compound (18 mg) was synthesized by the synthesis method of Reference Example 1.

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

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

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

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

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

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

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

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-(oxetane-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

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

MS m/z[LC-MS]:522.24[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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),6.90-6.9 8(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＝12.0Hz,1 H),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).

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

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

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

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

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

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).

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

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

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

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

The target compound (20 mg) was synthesized by the synthesis method of Reference Example 1.

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

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

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

MS m/z[LC-MS]:524.27[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),8.60(s,1H),8.24(s,1H),7.78(s,1H),7.66(s,1H),7.41(s,1H),7.11(d,J＝8.4Hz,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,10.0 Hz,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).

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

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

MS m/z[LC-MS]:615.33[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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＝10.4Hz,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).

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

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

MS m/z[LC-MS]:557.23[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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,1H),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).

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

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

MS m/z[LC-MS]:557.23[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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＝8.4 Hz,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).

Example 14: N-(5-((3-cyano-6-(4-hydroxyphenyl)pyrazol[1,5-a]pyridin-4-yl)oxy)pyridin-2-yl)acryloyl amine

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

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

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

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

MS m/z[LC-MS]:544.29[M+1]. ¹ H 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).

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

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

MS m/z[LC-MS]:615.33[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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),7.01-7.0 3(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).

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

The synthesis method of intermediate 2 was based on the use of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile To obtain the title compound (10 mg).

MS m/z[LC-MS]:522.25[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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),7.41(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),5.69(dd,J＝1 0.4Hz,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),3.33-3.4 2(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).

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

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

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

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

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

MS m/z[LC-MS]:495.23[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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).

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

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

MS m/z[LC-MS]:479.23[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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).

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

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

MS m/z[LC-MS]:467.20[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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,2H),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).

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

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

MS m/z[LC-MS]:494.24[M+1]. ¹ H NMR (400MHz, CDCl ₃ +CD ₃ OD),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(d d,J＝16.8Hz,1.6Hz,1H),6.32(dd,J＝16.8Hz,10.0Hz,1H),5.79(dd,J＝10.0Hz,1.6H z,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).

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

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.

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).

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

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

MS m/z[LC-MS]:506.24[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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).

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

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

MS m/z[LC-MS]:616.33[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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,10.0 Hz,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),3.22-3.3 6(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).

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

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

MS m/z[LC-MS]:563.26[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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),6.99(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), 5.69 (dd, J＝1 0.4Hz,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).

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

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

MS m/z[LC-MS]:577.28[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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),7.11(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).

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

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

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

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

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

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

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

The target compound (17 mg) was synthesized by the synthesis method of Reference Example 1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

At room temperature, the product obtained in step 1 was dissolved in acetic acid (5 mL), iron powder (30 mg) was added, stirred for 2 hours, water (100 mL) was added, extracted with ethyl acetate, the extract was washed with saturated sodium bicarbonate aqueous 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) was added, acryloyl chloride (10 mg) was added, and then the mixture was heated to room temperature and stirred for 1 hour. The reaction solution was poured into saturated sodium bicarbonate aqueous solution (50 mL), 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 thin layer chromatography (developing solvent: dichloromethane: methanol = 20:1 (V:V)) to obtain the title compound (7 mg).

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

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

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.

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

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

The target compound (14 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.

MS m/z[LC-MS]:399.17[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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).

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

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.

MS m/z[LC-MS]:548.30[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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＝8.8H z,2H),6.44(dd,J＝16.8Hz,1.2Hz,1H),6.25(dd,J＝16.8Hz,10.0Hz,1H),5.79(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).

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

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.

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

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

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

MS m/z[LC-MS]:531.26[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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＝17.2Hz,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).

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

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.

MS m/z[LC-MS]:441.16[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),8.66(d,J＝1.2Hz,1H),8.26(s,1H),7.80(s,1H),7.70(s,1H),7.52(d,J＝8.4H z,2H),7.44(d,J＝1.6Hz,1H),7.40(d,J＝8.4Hz,2H),6.34(dd,J＝17.2Hz,2.0Hz, 1H),6.15(dd,J＝17.2Hz,10.4Hz,1H),5.68(dd,J＝10.4Hz,1.6Hz,1H),4.62-4.7 0(m,1H),4.50-4.55(m,1H),4.15-4.23(m,2H),4.04-4.10(m,1H),3.99(s,3H).

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

The target compound (14 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.

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).

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

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

At 0°C, DIAD (310 mg) was slowly added dropwise 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)ethane-1-ol (167 mg) and triphenylphosphine (526 mg). After the addition was complete, the mixture was warmed to room temperature and stirred for 12 hours. The reaction solution 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 obtain a white solid (305 mg).

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

At room temperature, (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), iron powder (56 mg) was added, and the mixture was stirred for 2 hours. The reaction solution was poured into water (50 mL), extracted with dichloromethane, and the extract was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane (10 mL) was added to the residue, and acryloyl chloride (20 mg) and triethylamine (50 mg) were added, and then stirred at room temperature for 1 hour. The reaction solution was poured into a 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 obtain the title compound (13 mg).

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).

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

The target compound (16 mg) was synthesized using the synthetic 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)ethane-1-ol.

MS m/z[LC-MS]:413.18[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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),6.4 4(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).

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

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

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

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

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

MS m/z[LC-MS]:493.25[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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).

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

The target compound (12 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.

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

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

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.

MS m/z[LC-MS]:400.16[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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).

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

The target compound (3 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.

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

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

The target compound (13 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.

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).

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

The target compound (5 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.

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

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

The target compound (6 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.

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

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

The target compound (16 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.

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

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

The target compound (10 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.

MS m/z[LC-MS]:425.18[M+1]. ¹ H 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).

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

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.

MS m/z[LC-MS]:414.18[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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),6.4 9(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).

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

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.

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

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

The target compound (17 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.

MS m/z[LC-MS]:417.16[M+1]. ¹ H NMR (400MHz, CDCl ₃ ),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＝10.8Hz,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).

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

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.

MS m/z[LC-MS]:401.16[M+1]. ¹ H 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).

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

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.

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

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

The synthetic method of reference intermediate 6 and Example 47 uses 6-bromo-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine-4-ol (synthesized by reference patent WO2023280073) as the starting material to synthesize the target compound (19 mg).

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

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

The synthetic method of reference intermediate 6, intermediate 2 and Example 47 uses 6-bromo-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine-4-ol (synthesized by reference patent WO2023280073) as the starting material to synthesize the target compound (8 mg).

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

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

The target compound (15 mg) was synthesized using the intermediate 7 according to the synthesis method of Reference Example 1. MS m/z [LC-MS]: 546.29 [M+1]. ¹ H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J = 1.2 Hz, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.30 (dd, J = 17.2 Hz, 10.4 Hz, 1H), 6.08 (dd, J = 17.2 Hz, 2.0 Hz, 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).

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

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

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

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

The target compound (13 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.

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).

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

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

MS m/z[LC-MS]:601.33[M+1]. ¹ H 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).

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

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

MS m/z[LC-MS]:560.26[M+1]. ¹ H 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).

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

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

MS m/z[LC-MS]:574.28[M+1]. ¹ H 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).

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

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.

MS m/z[LC-MS]:395.17[M+1]. ¹ H 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).

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

The target compound (28 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.

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).

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

The target compound (10 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.

MS m/z[LC-MS]:433.13[M+1]. ¹ H NMR (400MHz, CD ₃ OD+CDCl ₃ )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).

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

The target compound (8 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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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).

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

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

MS m/z[LC-MS]:447.15[M+1]. ¹ H NMR (400MHz, CDCl ₃ )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)

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

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.

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

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

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.

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

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

The target compound (2 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.

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

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

The target compound (12 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.

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

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

The target compound (6 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.

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

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

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.

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

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

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.

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

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

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.

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).

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

The target compound (36 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.

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).

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

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

MS m/z[LC-MS]:503.24[M+1]. ¹ H 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).

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

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.

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

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

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

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

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

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.

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

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

The target compound (18 mg) was synthesized using the synthetic 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.

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).

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

The target compound (6 mg) was synthesized using Intermediate 8 according to the synthesis method of Intermediate 2 and Example 1.

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

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

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.

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).

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

The target compound (17 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.

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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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.

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

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

The target compound (7 mg) was synthesized by referring to the synthesis method of intermediate 2.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The target compound (12 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.

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

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

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.

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

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

The target compound (6 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The target compound (6 mg) was synthesized using Intermediate 8 according to the synthesis method of Intermediate 2 and Example 1.

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

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

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

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

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

The target compound (12 mg) was synthesized by referring to the synthesis method of intermediate 2 using 3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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

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

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

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.

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

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

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.

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

Biological activity test

1. In vitro enzymatic activity assay of compounds against FGFR2 ^WT

The IC ₅₀ value of the compound's inhibition of FGFR2 ^WT enzyme activity in this patent is determined by homogeneous time-resolved fluorescence (HTRF) method. The compound is diluted 5 times with 100% DMSO starting from 0.2mM (7 concentrations in total), and 2μL of the compound at each concentration is added to 48μL of reaction buffer (50mM HEPES pH7.5, 0.1mM Na ₃ VO ₄ , 5mM MnCl ₂ , 1mM DTT, 0.001% Tween 20 and 0.01% BSA) for dilution and mixing. Take 2.5 μL of the diluted compound and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 5 μL of GST-FGFR2 ^WT (399-821aa, final concentration of 0.3 nM), centrifuge and mix, place in an incubator at 23°C for 1 hour, then add 2.5 μL of ATP (final concentration 1 μM) and TK Peptide Substrate mixture (final concentration 1 μM, purchased from Cisbio) to start the reaction, the total reaction volume is 10 μL. Place the 384-well plate in an incubator at 23°C for 1 hour, then add 5 μL of TK Antibody (purchased from Cisbio) and 5 μL of StreptavidiN-XL665 (purchased from Cisbio) to stop the reaction. After incubation in the incubator for another 1 hour, the fluorescence value was read on Envision (purchased from PerkinElmer) (excitation at 320 nm, detection of emission light at 665 nm and 620 nm, the ratio of the two being the activity signal of the enzyme). The enzymatic activity signal of FGFR2 ^WT was measured at 7 concentrations for each compound, and the data were calculated using GraphPad Prism software to obtain the IC ₅₀ value of the compound.

2. In vitro enzymatic activity assay of compounds against FGFR2 ^N549K

The IC ₅₀ value of the compound's inhibitory effect on the enzymatic activity of FGFR2 ^N549K in this patent is determined by homogeneous time-resolved fluorescence (HTRF) method. The compound is diluted 5 times with 100% DMSO starting from 0.2mM (7 concentrations in total), and 2μL of the compound at each concentration is added to 48μL of reaction buffer (50mM HEPES pH7.5, 0.1mM Na ₃ VO ₄ , 5mM MnCl ₂ , 1mM DTT, 0.001% Tween 20 and 0.01% BSA) for dilution and mixing. Take 2.5 μL of the diluted compound and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 5 μL of GST-FGFR2 ^N549K (399-821aa, final concentration of 0.5 nM), centrifuge and mix, place in an incubator at 23°C for 1 hour, then add 2.5 μL of ATP (final concentration 30 nM) and TK Peptide Substrate mixture (final concentration 1 μM, purchased from Cisbio) to start the reaction, the total reaction volume is 10 μL. Place the 384-well plate in the incubator The reaction was carried out at 23°C in an incubator for 2 hours, and then 5 μL of TK Antibody (purchased from Cisbio) and 5 μL of StreptavidiN-XL665 (purchased from Cisbio) were added to stop the reaction. After incubation in the incubator for another hour, the fluorescence value was read on Envision (purchased from PerkinElmer) (320nm excitation, detection of 665nm and 620nm emission light, the ratio of the two is the enzyme activity signal). The enzymatic activity signal of FGFR2 ^N549K was measured at 7 concentrations for each compound, and the data were calculated using GraphPad Prism software to obtain the IC ₅₀ value of the compound.

3. In vitro enzymatic activity assay of compounds against FGFR3 ^V555M

The IC ₅₀ value of the compound's inhibitory effect on the enzymatic activity of FGFR3 ^V555M in this patent was determined by homogeneous time-resolved fluorescence (HTRF) method. The compound was diluted 5 times with 100% DMSO starting from 0.2mM (7 concentrations in total), and 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) for dilution and mixing. Take 2.5 μL and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 5 μL of GST-RET ^V555M (436-806aa, final concentration of 0.25 nM), centrifuge and mix, place the 384-well plate in an incubator at 23°C for 1 hour, then add 2.5 μL of ATP (final concentration 0.4 μM) and TK Peptide Substrate mixture (final concentration 1 μM, purchased from Cisbio) to start the reaction, and the total reaction volume is 10 μL. Place the 384-well plate in an incubator at 23°C for 1 hour, then add 5 μL of TK Antibody (purchased from Cisbio) and 5 μL of StreptavidiN-XL665 (purchased from Cisbio) to stop the reaction. After incubation in the incubator for another 1 hour, the fluorescence value was read on Envision (purchased from PerkinElmer) (excitation at 320 nm, detection of emission at 665 nm and 620 nm, the ratio of the two being the activity signal of the enzyme). The enzymatic activity signal of FGFR3 ^V555M was measured at 7 concentrations for each compound, and the data were calculated using GraphPad Prism software to obtain the IC ₅₀ value of the compound.

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

Human endometrial adenocarcinoma cells AN3-CA (FGFR2N549K mutation) were cultured in MEM medium supplemented with 10% fetal bovine serum (FBS, purchased from Gibico) and 1% penicillin/streptomycin (P/S, purchased from Life Techonology) at 37°C and 5% CO2. One day before compound detection, AN3-CA cells were plated in a 96-well plate (#3917, purchased from Corning) at a concentration of 2000 cells/195 μL/well. After 24 hours, the compound was diluted 3-fold from 10 mM with 100% DMSO (a total of 10 concentrations), and then 2 μL of the compound was added to 48 μL of MEM medium for dilution at each concentration. After dilution, 5 μL of each concentration of the compound was added to the cell suspension. The compound and cells were incubated in a cell culture incubator for 72 hours (3 days). After the culture medium was completely drained, 25 μL of Cell-Titer Glo (G7570, purchased from Promega) reagent was added and incubated again for 5-10 minutes. The fluorescence value was then read on Envision, and the data was calculated using GraphPad Prism software to obtain the IC50 value of the compound's inhibition of cell proliferation.

5. Determination of the proliferation activity of compounds on FGFR2 ^N549K -PHGDH/3T3 cells

The FGFR2 fusion cell line FGFR2 ^N549K -PHGDH/3T3 cells constructed by lentiviral infection were cultured in DMEM medium with 10% fetal bovine serum (FBS, purchased from Gibco) and 1% penicillin/streptomycin double antibody (P/S, purchased from Life Techonology), and the culture conditions were 37°C, 5% CO2. The day before the compound detection, FGFR2 ^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 times from 10mM with 100% DMSO (a total of 10 concentrations), and then 2 μL of the compound was added to 48 μL of DMEM medium for dilution at each concentration. 5 μL of each diluted compound concentration was added to the cell suspension, and the compound and cells were co-incubated in a cell culture incubator for 72 h (3 days). After the culture medium was completely aspirated, 25 μL of Cell-Titer Glo (G7570, purchased from Promega) reagent was added and incubated again for 5-10 minutes. The fluorescence value was then read on a CLARIO star ^Plus multifunctional microplate reader, and the data were calculated using GraphPad Prism software to obtain the IC ₅₀ value of the compound's inhibition of cell proliferation.

Table 1. Activity and cell inhibitory activity data of some examples of proteins

The result "A" means IC ₅₀ <5nM;"B" means IC ₅₀ <20nM;"-" means not tested

7. Pharmacokinetic testing:

Male SD rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The rats were divided into groups, with 3 rats in each group, and the suspension of the sample to be tested (5 mg/kg, suspension was CMC 0.5%, 0.1% Tween80) was orally administered. The animals fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. After isoflurane anesthesia using a small animal anesthesia machine, 0.3 mL of whole blood was collected through the fundus venous plexus and placed in a heparin anticoagulant tube. The sample was centrifuged at 4°C and 4000 rpm for 5 minutes, and the plasma was transferred to a centrifuge tube and stored at -80°C until analysis. The sample in the plasma was extracted using protein precipitation, and the extract was analyzed by LC/MS.

Table 2. Pharmacokinetic data of some compounds

Claims (12)

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, R ₁ is phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl may be optionally substituted by R ₂ , R ₂ is selected from halogen, -CN, -NH ₂ , -OH, C _1-6 alkyl, halogenated C _1-6 alkyl, deuterated methyl, or -(CH ₂ ) _0-1 -R ₃ , R ₃ 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 by halogen, -CN, -NH ₂ , -OH, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclyl, L is Or L ₀ , L ₀ is -L ₁ -L ₄ -NH-, -L ₄ -L ₅ -L ₆ -, -L ₄ -L ₆ -, -L ₄ -L ₁ -L _6- , -L ₄ -L ₄ -NH-, -L ₄ -L ₅ -NH-, -L ₁ -L ₃ -L ₄ -NH-, -L ₅ -L ₄ -NH-, -L ₄ -L ₂ -L ₆ -, -L ₁ -L ₃ -L ₂ -L ₄ -NH-, -L ₁ -L ₃ -L ₇ -, -L ₁ -L ₃ -L ₄ -L ₅ -NH-, or -L ₈ -L ₄ -NH-, _L1 is -O-, -S-, or -N(R)-, _L2 is -(CO)-, L ₃ is C _1-6 alkylene, which may be optionally substituted by C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, _L4 is a phenylene group or a 5-7 membered heteroarylene group, _L5 is a 3-8 membered heterocyclic ring, L ₆ L _{7 L8} is -CH=CH-. 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 _C1-6 alkyl. 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} - _L6- , -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-} , and _L1 , L2, _L3 , _L4 , _L5 , _L6 , _{L7 and L8} are as defined in claim 2. 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, R ₁ is phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl may be optionally substituted by R ₂ , R ₂ is selected from halogen, -CN, -NH ₂ , -OH, C _1-6 alkyl, halogenated C _1-6 alkyl, deuterated methyl, or -(CH ₂ ) _0-1 -R ₃ , R ₃ 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 by halogen, -CN, -NH ₂ , -OH, C _1-6 alkyl, or halogenated C _1-6 alkyl, L is The compound according to claim 4 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein X is -CN. The compound according to claim 4 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R ₁ is a 5-6 membered heteroaryl group, which may be optionally substituted by R ₂ , and R ₂ is as defined in claim 4. The compound according to claim 4 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein L is The following compound or its pharmaceutically acceptable salt, solvate, polymorph or isomer



A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, and pharmaceutically acceptable carriers. 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 related to FGFR. The use according to claim 10, wherein the disease associated with FGFR is a tumor. The use according to claim 10, wherein the disease related to 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.