Novel heterocyclic compound

Abstract

The present invention relates to a novel heterocyclic compound, which is a compound having FGFR2 protein activity. Specifically, the invention relates to a compound as shown in formula (I), or pharmaceutically acceptable salt, solvate, polymorphic substance or isomer thereof, and application of the compound in preparation of medicines for treating diseases related to FGFR (Factor Growth Factor Receptor).

Description

TECHNICAL FIELD

[0001] The present application relates to compounds that inhibit the activity of FGFR proteins, and to methods for the preparation of these compounds and to the use of pharmaceutical compositions thereof. BACKGROUND

[0002] Fibroblast growth factor receptors (FGFRs) belong to the transmembrane polypeptide tyrosine kinases, and there are currently five kinds (FGFR1-FGFR5) found, among which FGFR2 is mainly distributed in tissues derived from endoderm, such as stomach, liver, pancreas, esophagus, bile duct, etc. in the digestive system. Previous studies have shown that FGFR2 is associated with various tumors, FGFR2 gene amplification has been reported in triple-negative breast cancer and poor prognosis gastric cancer, FGFR2 gene mutation is 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 cholangiocarcinoma. In colorectal cancer, FGFR2 can up-regulate programmed cell death ligand 1 (PD-L1) expression through the JAK / STAT3 pathway, regulate tumor immune escape, and the expression level of FGFR2 is closely related to prognosis. Studies have found that FGFR2 gene fusion is found in 10-20% of patients with intrahepatic cholangiocarcinoma. FGFR3 abnormalities, including point mutations, fusions, amplifications and overexpression, can be associated with a variety of tumors, and are found in about 15-20% of advanced urothelial carcinoma, about 15% of uterine carcinosarcoma, about 5% of endometrial carcinoma and other solid tumors. With scientists' in-depth exploration of the mechanism of tumor occurrence, the FGFR (fibroblast growth factor receptor) family has received extensive attention due to its abnormal expression in a variety of tumors. In particular, the two members FGFR2 and FGFR3, which are found to have significant variations in many types of cancer, are closely related to tumor growth, spread, and resistance to traditional treatment methods. Therefore, the development of drugs that can effectively inhibit FGFR2 and FGFR3 has become an urgent problem to be solved in clinical practice. Although the first generation of pan-FGFR inhibitors has shown certain efficacy in clinical practice, their inhibition of FGFR1 has caused side effects (hyperphosphatemia, tissue mineralization) that severely limit their safety window, thereby affecting the clinical application of such drugs. The present application is dedicated to the development of a new generation of oral, high-activity, high-selectivity small molecule FGFR2 / 3 inhibitors. While significantly reducing the inhibition of FGFR1, it maintains high activity against FGFR2 and FGFR3, and is expected to solve various drug resistance problems. SUMMARY

[0003] The present application provides a FGFR inhibitor, which is a compound represented by general formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof. The present application also provides a series of compounds represented by general formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, pharmaceutical compositions comprising these compounds, and methods of using such compounds to treat diseases associated with FGFR.

[0004] In one aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof:

[0005]

[0006] wherein,

[0007] X1 is -Cl or -CN,

[0008] X2 is CH or N,

[0009] R1 is H, C 1-6 alkyl, -L 10- (3-8 membered cycloalkyl), -L 10 -(3-8 membered heterocyclyl), -(CH2) 0-2 -(3-8 membered cycloalkyl), or -(CH2) 0-2 -(3-8 membered heterocyclyl), said alkyl, cycloalkyl and heterocyclyl being optionally substituted with halogen, -CN, -OH, -NH2, C 1-6 alkyl, or R5,

[0010] L 10 is -O-, -S-, or -NR6-,

[0011] R5 is 3-8 membered cycloalkyl or 3-8 membered heterocyclyl, said cycloalkyl and heterocyclyl being optionally substituted with halogen, -CN, -OH, -NH2, or C 1-6 alkyl,

[0012] R6 is H or C 1-6 alkyl,

[0013] L is L1, L2, L3, L4, L5, L6, L7, -L2-L3-, -L2-L4-, -L2-L5-, -L2-L6-, -L2-L3-L7-, -L2-L4-L7-, -L2-L5-L7-, or -L2-L6-L7-,

[0014] L1 is -CH=CH-,

[0015] L2 is -O-CHR2-, wherein R2 is H, methyl, halomethyl, C2-6 alkynyl, or a 3-6 membered cycloalkyl,

[0016] L3is phenylene, which can be optionally substituted with halo or methyl,

[0017] L4is 5-6 membered heteroarylene, which can be optionally substituted with halo or methyl,

[0018] L5is a 3-8 membered heterocycle, which can be optionally substituted with halo, -CN, -OH, NH2, or C 1-6 alkyl,

[0019] L6is a 3-8 membered carbocycle, which can be optionally substituted with halo, -CN, -OH, NH2, or C 1-6 alkyl,

[0020] L7is -O-, -S-, or -NH-,

[0021] L0is or wherein the asterisk bond is attached to the carbonyl group,

[0022] B ring is a 3-8 membered heterocycle, which can be optionally substituted with halo, -CN, -OH, NH2, or C 1-6 alkyl,

[0023] R3is H or methyl,

[0024] R4is H, F, or methyl.

[0025] In some embodiments, R2is H, methyl, halo-methyl, C 2-3 alkynyl, or cyclopropyl, preferably H, methyl, or halo-methyl.

[0026] In some embodiments, R1is H, C 1-6 alkyl, -(CH2) 0-2 -(3-8 membered heterocyclyl), which can be optionally substituted with halo, -CN, -OH, NH2, or C 1-6 alkyl.

[0027] In some embodiments, L is L1, L2, L3, L4, L5, -L2-L3-, -L2-L4-, or -L2-L5-, L2is -O-CHR2-, wherein R2is H or methyl,

[0028] L1, L3, L4, and L5are as defined above.

[0029] In some embodiments, R1is H or C 1-6 alkyl, preferably methyl, more preferably CD3.

[0030] In some embodiments, R4 is H.

[0031] In some embodiments, L is L2, -L2-L3-, -L2-L4-, or -L2-L5-.

[0032] In some embodiments, the present application provides the following compounds

[0033]

[0034]

[0035] or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof.

[0036] Another aspect of the present application also relates to a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and a pharmaceutically acceptable carrier.

[0037] In another aspect, the present application provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, or the above-mentioned composition in the manufacture of a medicament for treating a disease associated with FGFR; as a preferred option, the disease associated with FGFR is a tumor; in some embodiments, the tumor has a mutation in FGFR2 N549, V561, V565, N550, N540, V555, E566, K660, V550. In some embodiments, the disease associated with FGFR is cholangiocarcinoma, 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.

[0038] The present application also provides the use of a compound of the present application or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof in the manufacture of a medicament for treating a disease associated with abnormal expression, mutation, or corresponding ligand abnormal expression and activity of FGFR receptor.

[0039] The present application also relates to a method for treating a tumor with FGFR inhibitor resistance, the method comprising administering to a subject an effective amount of a compound of the present application or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, or the above-mentioned composition; in some embodiments, the disease associated with FGFR is cholangiocarcinoma, 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 cholangiocarcinoma.

[0040] In some embodiments of the application, the subject to which the application is directed is a mammal, including a human. DETAILED DESCRIPTION

[0041] In the following detailed description of the application, illustrative embodiments utilizing principles of the application are described. The features and advantages of the application will be apparent from the following detailed description of the application, taken in conjunction with the accompanying drawings.

[0042] It is to be understood that the scope of the protection is extended to alternate and / or equivalent methods of carrying out the above described invention, and to the materials, compositions, combinations thereof, and use thereof, referred to or described herein. In addition, it is in context to be understood that the scope of the protection encompasses examples of the invention which are not specifically described herein.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents, patent applications, published materials referred to throughout the entire disclosure herein, unless otherwise indicated, are incorporated by reference herein in their entirety.

[0044] It must be noted that, as used herein, the articles "a", "an", and "the" are intended to mean one or more of the items that they are describing. It is also to be understood that the terms "including", "comprising", "having" and variations thereof, when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof.

[0045] Certain Chemical Terms

[0046] The terms "optionally", "optional", or "optionally" mean that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". Also, an optionally substituted group can be unsubstituted (e.g.: -CH2CH3), fully substituted (e.g.: -CF2CF3), singly substituted (e.g.: -CH2CH2F), or any level of substitution intermediate of singly and fully substituted (e.g.: -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). One of skill in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not spatially possible and / or synthetically feasible.

[0047] Unless otherwise indicated, conventional methods of the art are employed in practicing the present application, e.g., in measuring mass spectra, nuclear magnetic, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and pharmacological methods. Unless specific definitions are provided, the nomenclature utilized in connection with the understanding of the application and the experimental procedures and techniques of the application described herein are those known and practiced by those in the art of analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry. Standard techniques can be used, e.g., factory instructions for the use of reagents, or as otherwise known in the art or as described herein. The foregoing techniques and procedures can be readily implemented by the skilled artisan by following the descriptions in the numerous general and more specific references which are cited herein. In the description provided herein, groups and substituents thereof can be selected by one of ordinary skill in the art to provide stable moieties and compounds.

[0048] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent resulting from writing the formula from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0049] As used herein, the terms "group," "chemical group" refer to a specific part or functional group of a molecule. Chemical groups are often recognized as chemical entities that are embedded in or appended to a molecule.

[0050] Some of the chemical groups named herein can be represented by a shorthand notation indicating 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 by the shorthand notation does not include carbon atoms on possible substituents.

[0051] The terms "halogen," "halo," or "halide" mean bromine, chlorine, fluorine, or iodine.

[0052] The compounds of the present application can comprise one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in the compounds, H can be any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C can be any isotopic form, including 12 C, 13 C, and 14 C; O can be any isotopic form, including 16 O, and 18 O, etc.

[0053] The terms "aromatic," "aromatic ring," "aromatics," "aromatics," "aromatic ring" as used herein alone or as part of another term refer to a planar ring or multiple ring moiety having a delocalized electron system with 4n+2 electrons, where n is an integer. The aromatic ring can be formed by 5, 6, 7, 8, 9, or 9 or more atoms. The aromatic compounds can be optionally substituted and can be monocyclic or polycyclic rings that are fused. The term aromatic compounds includes all carbocyclic (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).

[0054] The term "heteroatom" or "hetero" as used herein alone or as part of another term refers to an atom other than carbon and hydrogen. The heteroatom is independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but is not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms can be the same as one another or some or all of the two or more heteroatoms are different from one another.

[0055] The term "fused" or "fused ring" as used herein alone or in combination refers to a ring-like structure in which two or more rings share one or more bonds.

[0056] The term "spiro" or "spiro ring" as used herein alone or in combination refers to a ring-like structure in which two or more rings share one or more atoms.

[0057] The term "alkyl" as used herein alone or in combination refers to an optionally substituted straight-chain or optionally substituted branched-chain monovalent saturated hydrocarbon having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.

[0058] The term "alkynyl" as used herein alone or in combination refers to an optionally substituted straight-chain or branched-chain monovalent hydrocarbon group having one or more C≡C triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, and the like. Where a numerical range, such as "C2-C6alkynyl" or "C2-C6alkynyl" is recited, the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. The alkynyl group is also intended to encompass instances in which no numerical range is specified. 2-6 The term "alkynyl" as used herein alone or in combination refers to an optionally substituted straight-chain or branched-chain monovalent hydrocarbon group having one or more C≡C triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, and the like. Where a numerical range, such as "C2-C6alkynyl" or "C2-C6alkynyl" is recited, the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. The alkynyl group is also intended to encompass instances in which no numerical range is specified.

[0059] The term "heteroaryl" refers to a monocyclic or fused ring having 5 to 12 ring atoms, having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, having 1, 2, 3, or 4 ring atoms selected from N, O, S, with the remaining ring atoms being C, and having a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, with substituents including, but not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, cyano, nitro, carbonyl, and heteroalicyclyl. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.

[0060] The term "heteroarylene," used alone or in combination with other terms, refers to a divalent radical derived from a monovalent heteroaryl group as defined above.

[0061] The term "cycloalkyl," used alone or as part of another term, refers to a stable monovalent non-aromatic monocyclic or polycyclic carbon-hydrogen group comprising only carbon and hydrogen atoms, which can include fused, spiro, or bridged ring systems, containing 3 to 15 ring-forming carbon atoms, preferably containing 3 to 10 ring-forming carbon atoms, more preferably containing 3 to 8 ring-forming carbon atoms, which can or can not be saturated, connected to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and the like.

[0062] The terms "heterocycloalkyl," "heterocyclyl," "heterocycle" used herein alone or as part of another term means 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 can include fused, spiro, or bridged ring systems, the nitrogen, carbon, or sulfur of the heterocyclyl group can optionally be oxidized, the nitrogen atom can optionally be quaternized, and the heterocyclyl group can be partially or fully saturated. The heterocyclyl group can be attached to the remainder of the molecule through a single bond at one of the ring carbon atoms or heteroatoms. The heterocyclyl group containing fused rings can contain one or more aromatic or heteroaromatic rings, provided that the atom which is attached to the remainder of the molecule is on a non-aromatic ring. For purposes of this application, the heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring which contains 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring which contains 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclyl groups include azepinyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0063] The term "carbocycle" used herein alone or as part of another term means a structure covalently closed by carbons, which can be saturated or partially unsaturated. A carbocycle can be formed by 3, 4, 5, 6, 7, 8, 9, or more atoms. The difference between the term carbocycle and heterocycle is that the ring backbone of a heterocycle contains at least one atom other than carbon. A "carbocycle" herein can be monocyclic or polycyclic, and polycyclic carbocycles include spiro, fused, and bridged rings. A carbocycle can be optionally substituted. A "carbocycle" herein preferably contains from about 5 to about 20, or 5 to 10, or 5-8, or 5-6 backbone ring-forming atoms.

[0064] The term "polymorph" or "polymorphism" as used herein means that the compounds of the present application have more than one crystal lattice form. Some of the compounds of the present application can have more than one crystal form, and the present application encompasses all such polymorphic forms or mixtures thereof.

[0065] Intermediate compounds of the compounds of the present application and polymorphs thereof are also within the scope of the present application.

[0066] Unless otherwise specified, the olefinic double bonds contained in the compounds of the present application include both E and Z isomers.

[0067] It is understood that the compounds of the present application can contain asymmetric centers. Such asymmetric centers can independently be of the R or S configuration. Some of the compounds of the present application can also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It is understood that the compounds of the present application include their individual geometric and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers can be separated from their mixtures by known methods of separation techniques, such as chromatographic techniques and recrystallization techniques, or they can be prepared separately from their appropriate intermediates.

[0068] The term "pharmaceutically acceptable salt" as used herein includes both acid and base addition salts.

[0069] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, 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, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, and the like. "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared from a free acid and a base. Salts formed with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and manganese salts.

[0070] Salts of organic bases include, but are not limited to, primary, secondary, and tertiary amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethylarnine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, and caffeine, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0071] Crystallization often produces solvates of the compounds of the present application. The term "solvate" as used herein refers to a combination of one or more molecules of a compound of the present application with one or more molecules of solvent.

[0072] The solvent can be water, in which case the solvate is a hydrate. It also can be an organic solvent. Thus, the compounds of the present application can exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a trihydrate, a tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the present application can be true solvates, but in other cases, the compounds of the present application can be associated with water or mixtures of water and some other solvent only on a stoichiometric basis. The compounds of the present application can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present application are included within the scope of this application.

[0073] The term "pharmaceutical composition" as used herein refers to a preparation of a compound of the present application in combination with a medium typically accepted in the art for the delivery of biologically active compounds to mammals, such as humans. Such media include all pharmaceutically acceptable carriers.

[0074] The term "acceptable" as used herein in relation to a formulation, composition or ingredient, means having no persistent detrimental effect on the general health of the subject being treated.

[0075] The term "pharmaceutically acceptable" as used herein means a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds of the present application, and is relatively nontoxic, i.e., the material can be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0076] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by a relevant government regulatory body for use in humans and domesticated animals.

[0077] The term "subject," "patient," "object," or "individual" as used herein refers to an individual, including mammals and non-mammals, who has a disease, disorder, or condition, or the like. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (such as chimpanzees and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0078] The term "treatment" as used herein refers to the treatment of a relevant disease or condition in a mammal, particularly in a human, and includes

[0079] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the disease or condition but has not yet been diagnosed as having it;

[0080] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0081] (iii) relieving the disease or condition, i.e., causing regression of the disease or condition;

[0082] (iv) relieving the symptoms resulting from the disease or condition.

[0083] As used herein, the terms "disease" and "condition" can be used interchangeably, or can be different, in that some particular disease or condition has not yet been identified as having a causative agent (so the cause is not yet known), and so it can not yet be recognized as a disease but only as an undesirable state or syndrome, which syndrome has more or less specific symptoms that have been identified by clinical researchers.

[0084] As used herein, the term "effective amount", "therapeutically effective amount", or "pharmaceutically effective amount" means the amount of at least one pharmaceutical agent or compound that, when administered, is sufficient to effect a treatment of a disease or condition for which the treatment is being pursued. The result can be a decrease and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound as disclosed herein that is needed to provide a clinically significant decrease in a symptom of a disease or condition. An effective amount can be determined using techniques such as dose escalation studies.

[0085] As used herein, the terms "administration", "administering", "administer" and the like refer to the methods by which a compound or composition is delivered to the site of biological action for purposes of biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusion), topical administration and transrectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0086] Preparation of compounds of the application

[0087] The following reaction schemes illustrate methods for preparing compounds of the application.

[0088] It will be appreciated that, in the following description, only combinations of substituents and / or variables of the described formulae are permissible where such combinations result in stable compounds.

[0089] Those skilled in the art will also appreciate that in the procedures described below, the functional groups of intermediate compounds can need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxyl. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl groups (e.g. tert-butyimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C(O)-R" (R" represents alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxyl include alkyl, aryl or arylalkyl esters. Protecting groups can be added to and removed from the compounds of the application by standard techniques known to those skilled in the art. Examples

[0090] The following non-limiting examples are merely illustrative and do not in any way limit the application.

[0091] Unless otherwise indicated, temperatures are in degrees Celsius. Reagents were purchased from National Pharmaceutical Group Chemical Reagents Co., Ltd., Beijing, Alfa Aesar, or Beijing Bailingwei Technology Co., Ltd., and were used directly without further purification unless otherwise noted.

[0092] Unless otherwise indicated, the following reactions were carried out at room temperature in anhydrous solvents under a positive pressure of nitrogen or argon or using a dry tube; the reaction vessel was fitted with a rubber septum to allow the addition of substrates and reagents by syringe; glassware was oven dried and / or heat dried.

[0093] Unless otherwise indicated, column chromatography purification used silica gel (200-300 mesh) from Qingdao Haizhuan Chemical Factory; preparative thin layer chromatography used thin layer chromatography silica gel precast plates (HSGF254) produced by Yantai Chemical Industry Research Institute; MS was determined using a Thermo LCQ Fleet (ESI) liquid chromatography-mass spectrometry instrument; optical rotation was determined using an SGW-3 automatic polarimeter, Shanghai Shen Guang Instrument and Apparatus Co., Ltd.

[0094] NMR data 1H NMR) were recorded on a Varian instrument operating at 400 MHz. The solvents used for the NMR data were CDCl3, CD3OD, D2O, DMSO-d6, etc. and the internal reference was tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm). When peak multiplicities are indicated, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If coupling constants are given, they are in Hertz (Hz).

[0095]

[0096]

[0097] Intermediate 1: (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

[0098]

[0099] Step 1: 4-ethynyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0100] Under nitrogen atmosphere, 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4- yltrifluoromethanesulfonate (371 mg), trimethylsilyl acetylene (200 mg) and triethylamine (500 mg) were dissolved in dioxane (50 mL), and bis(triphenylphosphine)palladium(II) dichloride (70 mg) and cuprous iodide (40 mg) were added, and stirred at 90°C for 2 hours. After cooling to room temperature, water (100 mL) was added, and extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was dissolved in THF (50 mL), and TBAF (500 mg) was added thereto, and stirred at room temperature for 1 hour. Water (50 mL) was added, and extracted with ethyl acetate, 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: ethyl acetate = 3:1 (V:V)) to obtain the target compound (190 mg).

[0101] 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

[0102] To a solution of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg) in THF (10 mL) was added cuprous chloride (2.3 mg) and sodium tert-butoxide (5 mg) under nitrogen protection, stirred at room temperature for 30 minutes, then added pinacol diboronic acid (200 mg) in THF (10 mL), stirred at room temperature for 10 minutes, then added 4-ethynyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (190 mg). The mixture was stirred overnight, then concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give the target compound (101 mg). MS m / z [LC-MS]: 376.20 [M+H] +

[0103] Intermediate 2: 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl]phenyl trifluoromethyl sulfonate

[0104]

[0105] Step 1: 4-(4-hydroxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile

[0106] Under nitrogen protection, 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl trifluoromethyl sulfonate (371 mg), 4-hydroxyphenylboronic acid pinacol ester (220 mg) and potassium carbonate (278 mg) were dissolved in a mixed solvent of dioxane and water (4:1) (50 mL), and tetrakis(triphenylphosphine)palladium (110 mg) was added. The mixture was stirred at 90°C for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, 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 give the target compound (275 mg).

[0107] Step 2: 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]phenyl trifluoromethyl sulfonate

[0108] The product from Step 1 was dissolved in DMF (10 mL) at room temperature, DIEA (260 mg) was added to it, followed by N-phenyl bis(trifluoromethanesulfonyl)imide (360 mg). It was stirred at room temperature overnight, water (50 mL) was added, it was extracted with ethyl acetate, 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: petroleum ether: ethyl acetate = 1 : 1 (V:V)) to obtain the intermediate 2 (289 mg).

[0109] MS m / z [LC-MS]: 448.07 [M+H] +

[0110] Example 1: (E)-4-(2-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)vinyl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0111]

[0112] Step 1: (E)-5-(2-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)vinyl)- 3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0113] Intermediate 1 (38 mg), 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)- carboxylic acid tert-butyl ester (33 mg), and potassium carbonate (28 mg) were dissolved in a mixed solvent of dioxane and water (4:1) (30 mL) under nitrogen protection, and tetrakis(triphenylphosphine)palladium (11 mg) was added. It was stirred at 80°C for 2 hours. After cooling to room temperature, water (100 mL) was added, it was extracted with ethyl acetate, 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: petroleum ether: ethyl acetate = 1 : 1 (V:V)) to obtain the target compound (31 mg).

[0114] Step 2: (E)-4-(2-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)vinyl)-6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0115] The above product was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (1 mL) was added, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, dichloromethane (10 mL) was added to the residue, and the mixture was cooled to 0°C, acryloyl chloride (9 mg) and triethylamine (20 mg) were added, and then the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (50 mL), and 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 target compound (19 mg).

[0116] MS m / z [LC-MS]: 385.18 [M+H] + .

[0117] Example 2: 6-(1-methyl-1H-pyrazol-4-yl)-4-((2-vinylpyridin-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0118]

[0119] Step 1: 4-((2-bromopyridin-4-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0120] To a solution of 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (239 mg) and 2-bromo-4-(bromomethyl)pyridine (251 mg) in acetonitrile (30 mL) was added potassium carbonate (280 mg) at 0°C, and the mixture was stirred at 80°C for 1 hour. The mixture was cooled to room temperature, water (100 mL) was added, and extracted with ethyl acetate, 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: petroleum ether: ethyl acetate = 1:2 (V:V)) to obtain the target compound (321 mg).

[0121] Step 2: 6-(1-methyl-1H-pyrazol-4-yl)-4-((2-vinylpyridin-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0122] To a solution of 4-((2-bromopyridin-4-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (41 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (20 mg) and potassium carbonate (28 mg) in a mixture solvent of dioxane and water (4:1) (20 mL) was added tetrakis(triphenylphosphine)palladium (11 mg) under nitrogen atmosphere. The mixture was stirred at 95°C for 2 hours. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (developing solvent: dichloromethane:methanol = 30:1 (V:V)) to give the target compound (33 mg).

[0123] MS m / z [LC-MS]: 357.15 [M+H] + 1H NMR (400 MHz, CDCl3), 8.63 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.35 (d, J = 5.2 Hz, 1H), 6.87 (dd, J = 17.6 Hz, 10.8 Hz, 1H), 6.81 (s, 1H), 6.34 (dd, J = 17.6 Hz, 1.2 Hz, 1H), 5.54 (dd, J = 10.8 Hz, 1.2 Hz, 1H), 5.34 (s, 2H), 3.98 (s, 3H).

[0124] Example 3: N-((1r,r)-4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)cyclohexyl)acrylamide

[0125]

[0126] Step 1: tert-Butyl (1r,4r)-4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)cyclohexyl)carbamate

[0127] To a solution of 4-hydroxy-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile (239 mg), (lr,4r)-4-(hydroxymethyl)cyclohexyl)carbamic acid tert-butyl ester (229 mg) and triphenylphosphine (526 mg) in toluene (50 mL) was added DIAD (310 mg) slowly dropwise at 0 °C, then stirred at room temperature for 12 hours. The reaction 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 give the target compound (355 mg).

[0128] Step 2: N-((lr,4r)-4-((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)cyclohexyl)acrylamide

[0129] The above product (45 mg) was dissolved in acetic acid (5 mL), and iron powder (56 mg) was added at room temperature, and stirred for 2 hours. The reaction was poured into water (50 mL), extracted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To the residue was added dichloromethane (10 mL), acryloyl chloride (20 mg) and triethylamine (50 mg) were added, and then stirred at room temperature for 1 hour. The reaction was poured into saturated aqueous sodium bicarbonate 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 thin layer chromatography (developing agent: dichloromethane:methanol = 30: 1 (V:V)) to give the target compound (25 mg).

[0130] MS m / z [LC-MS]: 405.21 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.28 (s, 1H), 6.29 (dd, J = 17.2 Hz, 10.4 Hz, 1H), 6.06 (dd, J = 17.2 Hz, 2.4 Hz, 1H), 5.54 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 4.15 (d, J = 6.8 Hz, 2H), 3.90-3.98 (m, 1H), 3.86 (s, 3H), 1.92-2.04 (m, 1H), 1.51-1.75 (m, 8H).

[0131] Example 4: (E)-4-(2-(1-acryloyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)vinyl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0132]

[0133] The target compound (13 mg) was synthesized according to the synthetic method of Example 1. MS m / z [LC-MS]: 399.20 [M+H] + .

[0134] Example 5: 4-((1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0135]

[0136] The target compound (8 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 389.17 [M+H] + .

[0137] Example 6: N-(3-chloro-4-(((3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)acrylamide

[0138]

[0139] The target compound (18 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 470.10 [M+H] + .

[0140] Example 7: N-(3-chloro-4-((3-cyano-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)acrylamide

[0141]

[0142] The target compound (5 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 533.18 [M+H] + .

[0143] Example 8: (R)-N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)-2-fluorophenyl)acrylamide

[0144]

[0145] The target compound (7 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 533.18 [M+H] + .

[0146] Example 9: (R)-N-(2-chloro-5-(1-(3-cyano-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0147]

[0148] The target compound (4 mg) was synthesized according to the synthetic method of Example 3, Reference Intermediate 1. MS m / z [LC-MS]: 449.14 [M+H] + .

[0149] Example 10: (R)-N-(2-chloro-5-(1-(3-cyano-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)ethyl)phenyl)acrylamide

[0150]

[0151] The target compound (14 mg) was synthesized according to the synthetic method of Example 1, Example 3. MS m / z [LC-MS]: 433.12 [M+H] + .

[0152] Example 11: N-(3-bromo-4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)methyl)pyridin-2-yl)acrylamide

[0153]

[0154] The target compound (3 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 478.06 [M+H] + .

[0155] Example 12: N-(3-cyano-4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)acrylamide

[0156]

[0157] The target compound (13 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 425.15 [M+H] + .

[0158] Example 13: N-(3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)methyl)-5-fluorophenyl)acrylamide

[0159]

[0160] The target compound (17 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 417.15 [M+H] + .

[0161] Example 14: 6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(6-vinylpyridin-3-yl)phenyl)pyrazolo[1,5- a]pyridine-3-carbonitrile

[0162]

[0163] The target compound (9 mg) was synthesized according to the synthetic method of Example 1, Example 2. MS m / z [LC-MS]: 403.17 [M+H] + .

[0164] Example 15: N-(2,4-dichloro-3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)methyl)phenyl)acrylamide

[0165]

[0166] The target compound (17 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 467.08 [M+H] + .

[0167] Example 16: (R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(2-vinylpyridin-4-yl)ethoxy)pyrazolo[1,5- a]pyridine-3-carbonitrile

[0168]

[0169] The target compound (12 mg) was synthesized according to the synthetic method of Example 2, Example 3. MS m / z [LC-MS]: 371.16 [M+H] + .

[0170] Example 17: 4-((1-(1-acryloylazetidin-3-yl)piperidin-4-yl)methoxy)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0171]

[0172] Step 1: tert-butyl 4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)methyl)piperidine-1-carboxylate

[0173] To a solution of 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile (239 mg), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (215 mg) and triphenylphosphine (526 mg) in toluene (50 mL) was added DIAD (310 mg) at 0 °C, then warmed to room temperature for 12 hours. The reaction was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 1:1 (V:V)) to give the target compound (321 mg).

[0174] Step 2: tert-butyl 3-(4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)methyl)piperidin-1-yl)azetidine-1-carboxylate

[0175] The above product (218 mg) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2 mL) was added, and stirred for 2 hours at room temperature. The reaction was 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, then warmed to room temperature and stirred for 12 hours. The reaction was poured into saturated aqueous sodium bicarbonate 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 column chromatography (eluent: dichloromethane:methanol = 30:1 (V:V)) to give the target compound (115 mg).

[0176] Step 3: 4-((l-(l-acryloylazetidin-3-yl)piperidin-4-yl)methoxy)-6-(l-methyl-lH- pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile

[0177] The above product (49 mg) was dissolved in dichloromethane (5 mL) at room temperature, trifluoroacetic acid (1 mL) was added, stirred for 2 hours, concentrated under reduced pressure, dichloromethane (20 mL) was added to the residue, cooled to 0°C, then acryloyl chloride (10 mg) and triethylamine (20 mg) were added, then stirred at room temperature for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate 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 target compound (19 mg).

[0178] MS m / z [LC-MS]: 446.23 [M+H] + .

[0179] Example 18: N-(3-chloro-4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)methylacrylamide

[0180]

[0181] The target compound (11 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0182] Example 19: 4-((2-cyanopyridin-4-yl)methoxy)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile

[0183]

[0184] The target compound (14 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0185] Example 20: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)-N-methylacrylamide

[0186]

[0187] The target compound (11 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0182] Example 19: 4-((2-cyanopyridin-4-yl)methoxy)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile

[0183]

[0184] The target compound (14 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0185] Example 20: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)-N-methylacrylamide

[0186]

[0187] The target compound (11 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0182] Example 19: 4-((2-cyanopyridin-4-yl)methoxy)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile

[0183]

[0184] The target compound (14 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0185] Example 20: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)-N-methylacrylamide

[0186]

[0187] The target compound (11 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0182] Example 19: 4-((2-cyanopyridin-4-yl)methoxy)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile

[0183]

[0184] The target compound (14 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0185] Example 20: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)-N-methylacrylamide

[0186]

[0187] The target compound (11 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0182] Example 19: 4-((2-cyanopyridin-4-yl)methoxy)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile

[0183]

[0184] The target compound (14 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0185] Example 20: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)-N-methylacrylamide

[0186]

[0187] The target compound (11 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0182] Example 19: 4-((2-cyanopyridin-4-yl)methoxy)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile

[0183]

[0184] The target compound (14 mg) was synthesized according to the synthesis method of Example 3. MS m / z [LC-MS]: 448.13 [M+H] + .

[0185] Example 20: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyrid

[0188] The target compound (7 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 533.18 [M+H] + .

[0189] Example 21: N-(2-chloro-3-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)-4-fluorophenyl)acrylamide

[0190]

[0191] The target compound (6 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 451.11 [M+H] + .

[0192] Example 22: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)-2-fluoropropenamide

[0193]

[0194] To a solution of tert-butyl (4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)-3-fluoropyridin-2-yl)carbamate (46 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at room temperature, and stirred for 30 minutes. Concentrated under reduced pressure, the residue was dissolved in pyridine (10 mL), then HATU (76 mg) and fluoropropenoic acid (20 mg) were added. The mixture was heated to 60 °C and stirred overnight, then concentrated under reduced pressure, the residue was purified by thin layer chromatography (eluent: methanol / ethyl acetate = 1:30) to give the target compound (5 mg). MS m / z [LC-MS]: 436.14 [M+H] + .

[0195] Example 23: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)piperidin-l-yl)acrylamide

[0196]

[0197] The target compound (16 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 406.20 [M+H] + .

[0198] Example 24: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)-3-fluoropyridin-2-yl)methylacrylamide

[0199]

[0200] To a solution of tert-butyl (4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)-3-fluoropyridin-2-yl)carbamate (46 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at room temperature and stirred for 30 minutes. The mixture was concentrated under reduced pressure, then the residue was dissolved in dichloromethane (10 mL), and then triethylamine (100 mg) and acryloyl chloride (20 mg) were added. The mixture was stirred at room temperature overnight, then concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: methanol / ethyl acetate = 1:20) to give the target compound (7 mg). MS m / z [LC-MS]: 432.16 [M+H] + .

[0201] Example 25: N-(3-chloro-4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)pyridin-2-yl)-2-fluoropropenamide

[0202]

[0203] The target compound (4 mg) was synthesized according to the synthetic method of Example 22. MS m / z [LC-MS]: 452.11 [M+H] + .

[0204] Example 26: (R)-N-(3-(l-(3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)ethyl)phenyl)-2-fluoropropenamide

[0205]

[0206] The target compound (17 mg) was synthesized according to the synthetic methods of Example 3 and Example 22. MS m / z [LC-MS]: 431.18 [M+H] + .

[0207] Example 27: N-(3-(((3-cyano-6-(l-(methyl-d3)-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)propenamide

[0208]

[0209] The target compound (22 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 420.18 [M+H] + .

[0210] Example 28: N-(4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)methyl)bicyclo[2.2.2]oct-1-yl)acrylamide

[0211]

[0212] The target compound (32 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 431.23 [M+H] + .

[0213] Example 29: N-(4-(((3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)acrylamide

[0214]

[0215] The target compound (17 mg) was synthesized according to the synthetic method of Example 2. MS m / z [LC-MS]: 427.12 [M+H] + .

[0216] Example 30: (R)-N-(3-(1-(3-cyano-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin- 4-yl)oxy)ethyl)phenyl)acrylamide

[0217]

[0218] The target compound (22 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 416.20 [M+H] + .

[0219] Example 31: N-(3-(((3-cyano-6-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrazolo[1,5-a]pyridin- 4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0220]

[0221] The target compound (11 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 526.24 [M+H] + .

[0222] Example 32: (R)-N-(3-(1-(3-cyano-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0223]

[0224] The target compound (10 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 469.21 [M+H] + .

[0225] Example 33: (R)-N-(3-(1-(3-cyano-6-(1-(-3-cyanopropyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0226]

[0227] The target compound (13 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 466.21 [M+H] + .

[0228] Example 34: N-(3-(((3-cyano-6-(1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0229]

[0230] The target compound (15 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 542.24 [M+H] + .

[0231] Example 35: 4-((3-((1-acryloylazetidin-3-yl)thio)benzyl)oxy)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0232]

[0233] The target compound (15 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 471.17 [M+H] + .

[0234] Example 36: (R)-N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)phenyl)-2-fluoropropenamide

[0235]

[0236] The target compound (7 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 435.15 [M+H] + .

[0237] Example 37: N-(3-(((3-cyano-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5- a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)propenamide

[0238]

[0239] The target compound (14 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 511.24 [M+H] + .

[0240] Example 38: N-(3-(((3-cyano-6-(1-(3-cyanopropyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)propenamide

[0241]

[0242] The target compound (23 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 470.19 [M+H] + .

[0243] Example 39: (S)-N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-2-fluoroethyl)phenyl)propenamide

[0244]

[0245] Step 1: (S)-4-(2-fluoro-1-(3-nitrophenyl)ethoxy)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0246] To a solution of 4-hydroxy-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile (239 mg) and (R)-2-fluoro-l-(3-nitrophenyl)ethan-l-ol (185 mg, reference: Journal of Organic Chemistry, 2013, vol. 78, #14, p. 7312-7317 synthesis) and triphenylphosphine (526 mg) in toluene (50 mL) at 0 °C, DIAD (310 mg) was added slowly, then the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1: 1 (V:V)) to give the target compound (221 mg).

[0247] Step 2: ((S)-N-(3-(l-(3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-fluoroethyl)phenyl)acrylamide

[0248] To a solution of (S)-4-(2-fluoro-l-(3-nitrophenyl)ethoxy)-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (221 mg) in acetic acid (10 mL) at room temperature, iron powder (300 mg) was added, and the mixture was stirred for 2 hours. The reaction mixture was poured into water (50 mL), extracted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), cooled to 0 °C, and acryloyl chloride (90 mg) and triethylamine (200 mg) were added successively, then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate 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 thin layer chromatography (developing agent: dichloromethane:methanol = 30: 1 (V:V)) to give the target compound (43 mg). MS m / z [LC-MS]: 431.18 [M+H] + .

[0249] Example 40: N-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)-2-fluoropropenamide

[0250]

[0251] The target compound (7 mg) was synthesized according to the synthetic method of Example 22. MS m / z [LC-MS]: 411.17 [M+H] + .

[0252] Example 41: (R)-N-(3-(1-(3-cyano-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0253]

[0254] The target compound (16 mg) was synthesized according to the synthetic method of Example 1, 3. MS m / z [LC-MS]: 512.25 [M+H] + .

[0255] Example 42: (R)-N-(3-(1-(3-cyano-6-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0256]

[0257] The target compound (17 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 538.27 [M+H] + .

[0258] Example 43: (R)-N-(3-(1-(3-cyano-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrazolo[1,5-a]pyridin-4- yl)oxy)ethyl)phenyl)acrylamide

[0259]

[0260] The target compound (13 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 506.27 [M+H] + .

[0261] Example 44: 4-((3-acryloyl-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0262]

[0263] The target compound (22 mg) was synthesized according to the synthetic method of Example 3. MS m / z [LC-MS]: 389.18 [M+H] + .

[0264] Example 45: (R)-N-(4-(l-(3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)ethyl)bicyclo[2.2.2]octan-l-yl)acrylamide

[0265]

[0266] Step 1: (S)-(4-(l-hydroxyethyl)bicyclo[2.2.2]octan-l-yl)carbamic acid tert-butyl ester

[0267] To a solution of (R)-methyl-CBS catalyst (28 mg, CAS: 112022-83-0) in THF (20 mL) was added BH3-Me2S (2 M in THF, 1 mL) at 0 °C and stirred for 30 min. The mixture was cooled to -20 °C and a solution of tert-butyl (4-acetylbicyclo[2.2.2]octan-l-yl)carbamate (267 mg, 0.12 mmol) in THF (5 mL) was added slowly dropwise. It was stirred at 0 °C for 12 h. MeOH (1 mL) was added slowly. It was diluted with saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3 x 25 mL). The extract was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5: 1 (V:V)) to give the target compound (190 mg).

[0268] Step 2, 3 The target compound (22 mg) was synthesized by following the synthetic procedure of Example 3 with the selection of appropriate alternative starting materials. MS m / z [LC-MS]: 445.25 [M+H] + .

[0269] Example 46: N-(4-(((3-cyano-7-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridin-5- yl)oxy)methyl)-3-fluoropyridin-2-yl)acrylamide

[0270]

[0271] Step 1: tert-Butyl (4-(((3-cyano-7-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridin-5- yl)oxy)methyl)-3-fluoropyridin-2-yl)carbamate

[0272] To a solution of 5-chloro-7-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2- a]pyridine-3-carbonitrile (257 mg) and tert-butyl (3-fluoro-4- (hydroxymethyl)pyridin-2-yl)carbamate (242 mg) in THF (20 mL) was added sodium tert-butoxide (192 mg) at 0 °C, then stirred at room temperature for 2 hours. Water (100 mL) was added, extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1: 1 (V:V)) to give the target compound. (190 mg)

[0273] Step 2: N-(4-(((3-cyano-7-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2- a]pyridin-5-yl)oxy)methyl)-3-fluoropyridin-2-yl)acrylamide

[0274] Step 3: N-(4-(((3-cyano-7-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2- a]pyridin-5-yl)oxy)methyl)-3-fluoropyridin-2-yl)acrylamide + .

[0275] Example 47: (R)-N-(3-(l-(5-cyano-2-(l-methyl-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0276]

[0277] Step 1: (R)-2-(l-methyl-lH-pyrazol-4-yl)-4-(l-(3-nitrophenyl)ethoxy)-l-((2- (trimethylsilyl)ethoxymethyl)-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile

[0278] To a solution of 4-chloro-2-(l-methyl-lH-pyrazol-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (387 mg, synthesized according to patent CN117964643) and ((R)-l-(3-nitrophenyl)ethan-l-ol (242 mg) in THF (50 mL) was added solid sodium tert-butoxide (192 mg) at 0 °C, and the reaction was stirred at room temperature for 2 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1: 1 (V:V)) to give the target compound.

[0279] (350 mg)

[0280] Step 2: (R)-N-(3-(l-(5-cyano-2-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0281] (R)-2-(l-methyl-lH-pyrazol-4-yl)-4-(l-(3-nitrophenyl)ethoxy)-l-((2- (trimethylsilyl)ethoxymethyl)-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (350 mg) was dissolved in acetic acid (10 mL) at room temperature, and iron powder (300 mg) was added. The reaction was stirred for 2 h, and the reaction mixture was poured into water (50 mL). The mixture was extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (10 mL). The reaction was cooled to 0 °C, and acryloyl chloride (45 mg) and triethylamine (200 mg) were added sequentially. The reaction was stirred at room temperature for 1 h. The reaction was poured into saturated aqueous sodium bicarbonate solution (50 mL), and the mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (developing agent: dichloromethane:methanol = 30: 1 (V:V)) to give the target compound (33 mg). MS m / z [LC-MS]: 413.18 [M+H] + .

[0282] Example 48: N-(l-(4-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)methyl)cyclohexyl)azetidin-3-yl)acrylamide

[0283]

[0284] The target compound (11 mg) was synthesized according to the synthetic method of Example 17 by selecting appropriate alternative starting materials. MS m / z [LC-MS]: 460.26 [M+H] + .

[0285] Example 49: N-(4-chloro-3-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)methyl)-2-fluorophenyl)acrylamide

[0286]

[0287] The target compound (38 mg) was synthesized according to the synthetic method of Example 3 by using tert-butyl (4-chloro-2-fluoro-3-(hydroxymethyl)phenyl)carbamate as an alternative starting material. MS m / z [LC-MS]: 451.12 [M+H] + .

[0288] Example 50: (R)-N-(3-(1-(3-cyano-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0289]

[0290] Step 1: 4-hydroxy-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile

[0291] Under nitrogen protection, 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (238 mg), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (238 mg) and potassium carbonate (280 mg) were dissolved in a mixed solvent of dioxane and water (4:1) (30 mL), and tetrakis(triphenylphosphine)palladium (112 mg) was added, and stirred at 90°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (100 mL) was added, extracted with ethyl acetate, 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: petroleum ether: ethyl acetate = 1:2 (V:V)) to obtain the target compound (181 mg).

[0292] Step 2: (R)-4-(1-(3-nitrophenyl)ethoxy)-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile

[0293] To a solution of 4-hydroxy-6-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile (140 mg), (S)-l-(3-nitrophenyl)ethan-l-ol (167 mg) and triphenylphosphine (263 mg) in toluene (30 mL) was added DIAD (204 mg) slowly at 0 °C, then warmed to room temperature for 12 h. The reaction was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1: 1 (V:V)) to give the target compound (111 mg).

[0294] Step 3: (R)-4-(l-(3-nitrophenyl)ethoxy)-6-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridine-3-carbonitrile

[0295] To a solution of (R)-4-(l-(3-nitrophenyl)ethoxy)-6-(l-(oxetan-3-yl)-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (111 mg) in acetic acid (5 mL) was added iron powder (200 mg) at room temperature, stirred for 2 h, poured into water (50 mL), extracted with dichloromethane, the extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), cooled to 0 °C, acryloyl chloride (50 mg) and triethylamine (100 mg) were added successively, then warmed to room temperature and stirred for 1 h. The reaction was poured into saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by thin layer chromatography (developing agent: dichloromethane:methanol = 30: 1 (V:V)) to give the target compound (47 mg). MS m / z [LC-MS]: 455.20 [M+H] + .

[0296] Example 51: (R)-N-(3-(l-(3-cyano-6-(l-isopropyl-lH-pyrazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0297]

[0298] The target compound (7 mg) was synthesized according to the synthetic method of Example 50 using l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as a replacement starting material. MS m / z [LC-MS]: 441.22 [M+H] + .

[0299] Example 52: N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)but-2-yn-1-yl)phenyl)acrylamide

[0300]

[0301] The target compound (13 mg) was synthesized according to the synthetic method of Example 50 using 1-(3-nitrophenyl)but-2-yn-1-ol as a replacement starting material. MS m / z [LC-MS]: 437.18 [M+H] + .

[0302] Example 53: (R)-N-(3-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)(cyclopropyl)methyl)phenyl)acrylamide

[0303]

[0304] The target compound (23 mg) was synthesized according to the synthetic procedure of Reference Example 45, Step 1, Step 2; Example 50, Step 3 using cyclopropyl(3-nitrophenyl)methanone as a replacement starting material. MS m / z [LC-MS]: 439.20 [M+H] + .

[0305] Example 54: N-(3-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-2,2-difluoroethyl)phenyl)acrylamide

[0306]

[0307] The target compound (13 mg) was synthesized according to the synthetic method of Example 50 using 2,2-difluoro-1-(3-nitrophenyl)ethan-1-ol as a replacement starting material. MS m / z [LC-MS]: 449.17 [M+H] + .

[0308] Example 55: 4-((1'-acryloyl-[1,4'-bipiperidin]-4-yl)methoxy)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0309]

[0310] The target compound (21 mg) was synthesized according to the synthetic method of Example 17 by selecting tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate as a replacement starting material. MS m / z [LC-MS]: 474.27 [M+H] + .

[0311] Example 56: (R)-N-(3-(l-(3-cyano-6-(l-methyl-lH-imidazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0312]

[0313] The target compound (4 mg) was synthesized according to the synthetic method of Example 50 by using l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- imidazole as a replacement starting material. MS m / z [LC-MS]: 413.18 [M+H] + .

[0314] Example 57: N-(4-(((5-cyano-2-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-4- yl)oxy)methyl)-3-fluoropyridin-2-yl)acrylamide

[0315]

[0316] The target compound (2 mg) was synthesized according to the synthetic method of Example 47 by using tert-butyl (3-fluoro-4-(hydroxymethyl)pyridin-2-yl)carbamate as a replacement starting material. MS m / z [LC-MS]: 418.15 [M+H] + .

[0317] Example 58: (S)-N-(4-(l-(3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)ethyl)bicyclo[2.2.2]octan-l-yl)acrylamide

[0318]

[0319] The target compound (8 mg) was synthesized according to the synthetic method of Example 45 by using (S)-methyl-CBS as a replacement catalyst. MS m / z [LC-MS]: 445.25 [M+H] + .

[0320] Example 59: N-(5-(((3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)methyl)naphthalen-l-yl)acrylamide

[0321]

[0322] The target compound (10 mg) was synthesized according to the synthetic method of Example 50 using (5-nitronaphthalen-1-yl)methanol as a replacement starting material. MS m / z [LC-MS]: 449.18 [M+H] + .

[0323] Example 60: ((R)-N-(3-(1-(3-cyano-6-(1-cyclobutyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0324]

[0325] The target compound (14 mg) was synthesized according to the synthetic method of Example 50 using 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole as a replacement starting material. MS m / z [LC-MS]: 453.22 [M+H] + .

[0326] Example 61: N-((1R,1r)-4-((R)-1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)ethyl)cyclohexyl)acrylamide

[0327]

[0328] The target compound (9 mg) was synthesized according to the synthetic procedure of Reference Example 45 using tert-butyl (1r,4r)-4-acetylcyclohexyl)carbamate as a replacement starting material. MS m / z [LC-MS]: 419.23 [M+H] + .

[0329] Example 62: 4-((1R)-1-[(1R,5S)-3-acryloyl-3-azabicyclo[3.1.0]hexan-6-yl)ethoxy)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0330]

[0331] The target compound (19 mg) was synthesized according to the synthetic procedure of Reference Example 45 using tert-butyl (1R,5S)-6-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate as a replacement starting material. MS m / z [LC-MS]: 388.18 [M+H] + .

[0332] Example 63: (R)-N-(3-(l-(3-cyano-6-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[0333]

[0334] The target compound (16 mg) was synthesized according to the synthetic method of Example 50 using l-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole as a substitute starting material. MS m / z [LC-MS]: 483.23 [M+H] + .

[0335] Example 64: (R)-N-(3-(l-(3-cyano-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)ethyl-2,2,2-d3)phenyl)acrylamide

[0336]

[0337] Step 1: l-(3-nitrophenyl)ethanone-2,2,2-d3

[0338] The m-nitroacetophenone (165 mg) was dissolved in a mixed solvent of dioxane (10 mL) and heavy water (30 mL) at room temperature, and tetrahydro-pyrrolidine (14 mg) was added, and stirred for 12 hours. Saturated aqueous ammonium chloride solution (100 mL) was added, extracted with ethyl acetate, 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: petroleum ether: ethyl acetate = 20: 1 (V:V)) to obtain the target compound (150 mg).

[0339] Step 2: The synthesis of Step 3 refers to Example 45; the synthesis of Step 4 refers to Example 50 to obtain the target compound (27 mg). MS m / z [LC-MS]: 416.20 [M+H] + .

[0340] Biological activity experiment

[0341] 1. In vitro enzymatic activity assay of the compound on FGFR2 WT

[0342] The IC of the compound in the patent for the enzymatic activity of FGFR2 WT 50 ​​The assay was performed using homogeneous time-resolved fluorescence (HTRF) method. The compound was diluted in 100% DMSO with 5-fold gradient starting from 0.2 mM (7 concentrations in total), 2 μL of each concentration was added to 48 μL of reaction buffer (50 mM HEPES pH 7.5, 0.1 mM Na3VO4, 5 mM MnCl2, 1 mM DTT, 0.001% Tween 20 and 0.01% BSA) for dilution and mixing. 2.5 μL of the diluted compound was added to 384-well plate (OptiPlate-384, purchased from PerkinElmer), followed by 5 μL of GST-FGFR2 WT (399-821 aa, final concentration 0.3 nM), centrifuged and mixed, and then incubated in an incubator at 23 °C for 1 hour. Then 2.5 μL of ATP (final concentration 1 μM) and TK Peptide Substrate mix (final concentration 1 μM, purchased from Cisbio) were added to start the reaction, and the total reaction volume was 10 μL. The 384-well plate was incubated in an incubator at 23 °C for 1 hour, 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 an incubator for another 1 hour, the fluorescence value (320 nm excitation, detection of 665 nm and 620 nm emission, and the ratio of the two was the signal of enzyme activity) was read on Envision (purchased from PerkinElmer). The signal of enzyme activity of FGFR2 WT was measured at 7 concentrations for each compound, and the IC 50 value of the compound was calculated using GraphPad Prism software.

[0343] 2. The compound for the in vitro enzyme activity assay of FGFR2 N549K

[0344] The compound for the in vitro enzyme activity assay of FGFR2 N549K in the present patent 5o ​The assay was performed using homogeneous time-resolved fluorescence (HTRF) method. The compound was diluted in 100% DMSO with 5-fold gradient starting from 0.2 mM (7 concentrations in total), 2 μL of each concentration was added to 48 μL of reaction buffer (50 mM HEPES pH 7.5, 0.1 mM Na3VO4, 5 mM MnCl2, 1 mM DTT, 0.001% Tween 20 and 0.01% BSA) for dilution and mixing. 2.5 μL of the diluted compound was added to 384-well plate (OptiPlate-384, purchased from PerkinElmer), followed by 5 μL of GST-FGFR2 N549KK (399-821 aa, final concentration 0.5 nM), centrifuged and mixed, and then incubated in an incubator at 23 °C for 1 hour. Then 2.5 μL of ATP (final concentration 30 nM) and TK Peptide Substrate mix (final concentration 1 μM, purchased from Cisbio) were added to start the reaction, and the total reaction volume was 10 μL. The 384-well plate was incubated in an incubator at 23 °C 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 an incubator for another 1 hour, the fluorescence value (320 nm excitation, detection of 665 nm and 620 nm emission, and the ratio of the two is the signal of enzyme activity) was read on Envision (purchased from PerkinElmer). The signal of enzyme activity of FGFR2 N549K was measured at 7 concentrations for each compound, and the IC 50 value of the compound was calculated using GraphPad Prism software.

[0345] 3. In vitro enzyme activity assay of the compound on FGFR1 WT

[0346] In this patent, the compound on FGFR1 WT ​The IC50 value of enzyme activity inhibition was determined using homogeneous time-resolved fluorescence (HTRF). The compound was serially diluted 5-fold with 100% DMSO starting at 0.2 mM (totaling 7 concentrations). 2 μL of each concentration was added to 48 μL of reaction buffer (50 mM HEPES pH 7.5, 0.1 mM Na3VO4, 5 mM MnCl2, 1 mM DTT, 0.001% Tween 20, and 0.01% BSA) and mixed thoroughly. Add 2.5 μL of the diluted compound to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 5 μL of GST-FGFR1WT (398-822 aa, final concentration 1.0 nM), centrifuge to mix, and incubate at 23°C for 1 hour. Then add 2.5 μL of a mixture of ATP (final concentration 2 μM) and TK Peptide Substrate (final concentration 1 μM, purchased from Cisbio) to start the reaction, with a total reaction volume of 10 μL. Incubate the 384-well plate at 23°C for 2 hours, then add 5 μL of TK Antibody (purchased from Cisbio) and 5 μL of Streptavidin-XL665 (purchased from Cisbio) to stop the reaction. After a second 1-hour incubation in an incubator, fluorescence values ​​were read on an Envision (PerkinElmer) microscope (excitation at 320 nm, detection of emission at 665 nm and 620 nm, the ratio of which represents the enzyme activity signal). FGFR1 was measured at seven concentrations for each compound. WT The enzymatic activity signal was obtained, and the IC50 of the compound was calculated using GraphPad Prism software. 50 value.

[0347] 4. Compounds on FGFR3 V555M In vitro enzyme activity assay

[0348] The compound in this patent affects FGFR3. V555M Enzymatic activity inhibits IC 50 Value determination was performed using homogeneous time-resolved fluorescence.

[0349] The procedure was performed using a light-to-light (HTRF) method. The compound was introduced at a 5-fold gradient with 100% DMSO, starting at 0.2 mM.

[0350] Dilution (7 concentrations in total), 2 μL of compound was added to 48 μL of reaction buffer (50 mM HEPES pH 7.5, 0.1 mM Na3VO4, 5 mM MnCl2, 1 mM DTT, 0.001% Tween 20 and 0.01% BSA) for dilution and mixing. 2.5 μL was added to 384-well plate (OptiPlate-384, purchased from PerkinElmer), then 5 μL of GST-RET V555M (436-806aa, final concentration 0.25 nM) was added and mixed by centrifugation. The 384-well plate was pre-incubated in the incubator at 23 °C for 1 hour, then 2.5 μL of ATP (final concentration 0.4 μM) and TK Peptide Substrate mix (final concentration 1 μM, purchased from Cisbio) were added to start the reaction, with a total reaction volume of 10 μL. The 384-well plate was incubated at 23 °C for 1 hour, 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 another 1 hour incubation in the incubator, the fluorescence value (320 nm excitation, detection of 665 nm and 620 nm emission, ratio of the two as the enzyme activity signal) was read on Envision (purchased from PerkinElmer). The enzyme activity signal of FGFR3 V555M was measured at 7 concentrations for each compound, and the IC 50 value of the compound was calculated using GraphPad Prism software.

[0351] 5. Compound FGFR2 N549K -PHGDH / 3T3 cell proliferation activity assay

[0352] FGFR2 N549K -PHGDH / 3T3 cell line was constructed using lentivirus infection. FGFR2 N549K-PHGDH / 3T3 cells were plated in 96-well plates (#3917, purchased from Coming) at a concentration of 1000 cells / 195 μL / well. After 24 hours, compounds were diluted in 100% DMSO in a 3-fold gradient starting from 10 mM (a total of 10 concentrations), then 2 μL of each concentration of compound was added to 48 μL of DMEM medium for dilution. After dilution, 5 μL of each concentration of compound was added to the cell suspension, and the compound and cells were incubated together in a cell incubator for 72 h (3 days). After the medium was aspirated, 25 μL of Cell-Titer Glo (G7570, purchased from Promega) reagent was added and incubated for 5-10 min. Then the fluorescence value was read on a CLARIOstar microplate reader, and the IC50 value of the compound for cell proliferation inhibition was calculated using GraphPad Prism software. Plus Multifunctional Enzyme Labeling Instrument, and the IC50 value of the compound for cell proliferation inhibition was calculated using GraphPad Prism software. 50

[0353] Table 1. Partial Example Protein Activity and Cell Inhibition Activity Data

[0354]

[0355]

[0356] Result "A" indicates IC 50 <2nM; "B" indicates IC 50 <10nM; "C" indicates IC 50 >50nM; "-" indicates not tested

[0357] 7. Pharmacokinetic Test:

[0358] Male SD rats were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. The rats were divided into groups, with 3 rats in each group, and were orally administered with the suspension of the test sample (5 mg / kg, the suspension agent was CMC 0.5%, 0.1% Tween80). The animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. After anesthesia with isoflurane using a small animal anesthetic machine, 0.3 mL of whole blood was collected through the orbital plexus, and was 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 a protein precipitation method, and the extract was analyzed by LC / MS. It was detected that the pharmacokinetic test of the compound achieved excellent results.

[0359] ​

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof: in, X1 is either -Cl or -CN. X2 is CH or N. R1 represents H and C. 1-6 Alkyl, -L 10 -(3-8 membered cycloalkyl), -L 10 -(3-8 membered heterocyclic group), -(CH2) 0-2 -(3-8 membered cycloalkyl), or -(CH2) 0-2 -(3-8 membered heterocyclic group), wherein the alkyl, cycloalkyl, and heterocyclic group may optionally be replaced by halogen, -CN, -OH, -NH2, C 1-6 Alkyl or R5 substituted, L 10 For -O-, -S-, or -NR6-, R5 is a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group, wherein the cycloalkyl group or heterocyclic group may optionally be converted by a halogen, -CN, -OH, -NH2, or C. 1-6 Alkyl substitution, R6 is either H or C. 1-6 alkyl, L is L1, L2, L3, L4, L5, L6, L7, -L2-L3-, -L2-L4-, -L2-L5-, -L2-L6-, -L2-L3-L7-, -L2-L4-L7-, -L2-L5-L7-, or -L2-L6-L7-, L1 is -CH=CH-, L2 is -O-CHR2-, where R2 is H, methyl, halomethyl, C 2-6 Alkyne group, or 3-6 membered cycloalkyl group, L3 is a phenylene group, which may optionally be substituted with a halogen or a methyl group. L4 is a 5-6 membered heteroaryl group, which may be optionally substituted with a halogen or a methyl group. L5 is a 3-8 membered heterocycle, which can be optionally replaced by halogen, -CN, -OH, NH2, or C. 1-6 Alkyl substitution, L6 is a 3- to 8-membered carbon ring, which can be optionally replaced by halogens, -CN, -OH, NH2, or C. 1-6 Alkyl substitution, L7 can be -O-, -S-, or -NH-. L0 is or The asterisk bond connects to the carbonyl group. The B ring is a 3-8 membered heterocycle, which can be optionally replaced by a halogen, -CN, -OH, NH2, or C. 1-6 Alkyl substitution, R3 is H or methyl. R4 can be H, F, or methyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R2 is H, methyl, or halomethyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R1 is H or C. 1-6 Alkyl group, -(CH2) 0-2 -(3-8 membered heterocyclic group), wherein the heterocyclic group may optionally be replaced by a halogen, -CN, -OH, NH2, or C. 1-6 Alkyl substitution, L can be L1, L2, L3, L4, L5, -L2-L3-, -L2-L4-, or -L2-L5-. L2 is -O-CHR2-, where R2 is H or methyl. L1, L3, L4, and L5 are as defined in claim 1.

4. The compound of claim 3 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R1 is methyl.

5. The compound of claim 3 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R1 is CD3.

6. The compound of claim 3 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R4 is H.

7. The compound of claim 3 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein L is L2, -L2-L3-, -L2-L4-, or -L2-L5-.

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

10. Use of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating diseases associated with FGFR.

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

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