Aminopyridyloxypyrazole derivatives and preparation method and application thereof

Abstract

The present invention relates to an aminopyridyloxypyrazole derivative and a preparation method and application thereof, wherein the structure of the aminopyridyloxypyrazole derivative is shown in formula (I). The present invention provides a novel aminopyridyloxypyrazole derivative, which has the effects of significantly inhibiting TGFβR1 (ALK5) kinase activity and treating cancer or fibrosis-related diseases, and the preparation method thereof is simple and easy to operate.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to an aminopyridyloxypyrazole derivative and a preparation method and application thereof. Background Art

[0002] TGF-β (transforming growth factor beta) is a multi-directional and multi-effect cytokine that belongs to a group of newly discovered TGF-β superfamily that regulates cell growth and differentiation. The family consists of a class of structurally and functionally related polypeptide growth factor subfamily, including TGF-β, activin, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), etc. TGF-β binds to its homologous cell membrane receptor (serine / threonine protein kinase) to form a complex to participate in cell proliferation, differentiation, and apoptosis, and has a dynamic balance regulating effect on the synthesis of extracellular matrix, wound repair, immune function, etc. TGF-β has at least 5 isoforms (TGF-β1~5), among which TGF-β1 is the most common, involved in almost all pathological and physiological processes, and has a close relationship with a variety of clinical diseases. Abnormal TGFβ signaling has been elucidated in many diseases, such as cancer and fibrosis. For cancer, TGFβ exhibits two different or opposite effects: in the early stage of tumorigenesis, it plays a tumor suppressive role by inducing growth inhibition; however, in the later stage of tumorigenesis, TGFβ promotes epidermal-mesenchymal transition (EMT), tumor angiogenesis and immunosuppression, thereby promoting tumor cell infiltration, invasion and metastasis. At present, it has been found that high expression of TGF-β leads to abnormally active TGF-β / Smads signaling in tumors such as prostate cancer, breast cancer, gastric cancer, colon cancer, bladder cancer, lung cancer, pancreatic cancer and leukemia. In recent years, more and more studies have shown that TGFβ plays a significant role in anti-tumor immunoregulation. It can inhibit the differentiation of natural immune T cells, negatively regulate the anti-tumor function of CD8+, dendritic cells, and NK cells, and enhance the function of regulatory T cells and myeloid-derived suppressor cells (Nature 2018, 554, 544-548; Nature 2018, 554, 538-543). Therefore, the TGFβ signaling pathway plays an important role in regulating the tumor microenvironment. Inhibitors of the TGFβ signaling pathway have the potential to be used in combination with tumor immunotherapy drugs. For example, the combination with PD1 / L1 antibodies can enhance the anti-tumor effect.

[0003] The known TGFβ receptors are divided into three types: type I (TGF-βR1, also known as ALK5), type II (TGF-βRII), and type III (TGF-βRIII); TGF-β first binds to TGF-βRII to form a complex, which then phosphorylates TGF-βR1. Subsequently, Smad 2 / 3 is also phosphorylated and induces the complex formed with Smad4 to move into the cell nucleus to participate in the regulation of target genes. At present, the prior art has disclosed a variety of compounds that can be used as inhibitors of TGF-βR1, including WO2016057278, WO2017040448, WO2018017633, WO2016140884, WO2016106266, WO2017215506, WO2018171611, WO2004048382, WO2020088526, WO2020103817, etc. However, in order to better meet clinical needs, it is still necessary to research and develop new, safer and more effective small molecule inhibitors targeting the TGF-βR1 target. Summary of the invention

[0004] In view of the deficiencies in the prior art, the object of the present invention is to provide an aminopyridyloxypyrazole derivative and a preparation method and application thereof.

[0005] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0006] In a first aspect, the present invention provides an aminopyridyloxypyrazole derivative, the structure of which is shown in formula (I):

[0007]

[0008] Among them, AR 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered or 6-membered heteroaryl; the substituted phenyl, substituted 5-membered or 6-membered heteroaryl are independently substituted by at least 1 (e.g., 1, 2 or 3, etc.) R c substituted phenyl, 5-membered or 6-membered heteroaryl; 2 of said R c Optionally forming a saturated or partially saturated 3-7 membered (e.g., 3, 4, 5, 6 or 7 membered) cycloalkyl or 4-7 membered (e.g., 4, 5, 6 or 7 membered) heterocyclyl; the cycloalkyl or heterocyclyl is optionally substituted by 1-3 (e.g., 1, 2 or 3) R c Substituted; the heterocyclic group or heteroaryl group independently contains 1-3 (eg, 1, 2 or 3) heteroatoms selected from N, O or S;

[0009] R cis independently selected from alkyl, hydroxy, halogen, cyano, alkoxy, cycloalkyl, heterocyclyl, =0, alkenyl or amino, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl or amino is optionally substituted with at least 1 (e.g., 1, 2 or 3) substituents independently selected from alkyl, hydroxy, halogen, cyano, amino or alkoxy;

[0010] R 2 Selected from tetrahydropyran-2-yl, 3,6-dihydro-2H-pyran-4-yl, oxepan-4-yl, cyclohex-1-en-1-yl, 1-3 R c Substituted tetrahydropyran-4-yl; the tetrahydropyran-2-yl, cyclohex-1-en-1-yl is optionally substituted by 1-3 (eg, 1, 2 or 3) R c replaced by;

[0011] R 3 Selected from H or C1-C3 alkyl (e.g., alkyl containing 1, 2 or 3 carbon atoms);

[0012] R 4 is selected from cyclopropyl or C1-C3 alkyl (e.g., alkyl containing 1, 2 or 3 carbon atoms), wherein R 3 and the C atom to which it is attached and R 4 and the N atom to which they are attached are optionally joined to form a 5-7 membered (eg, 5-, 6-, or 7-membered) heterocyclic ring.

[0013] Preferably, the structure of the aminopyridyloxypyrazole derivative is as shown in formula (II),

[0014] Among them, AR 1 and R c It has the same definition as above; n=0-3 (eg, n=0, n=1, n=2, n=3).

[0015] Preferably, the structure of the aminopyridyloxypyrazole derivative is as shown in formula (III),

[0016] Among them, AR 1 The same limitations as above apply.

[0017] Preferably, the structure of the aminopyridyloxypyrazole derivative is as shown in formula (IV):

[0018]

[0019] Among them, AR 1 The same limitations as above apply.

[0020] Preferably, the structure of the aminopyridyloxypyrazole derivative is as shown in formula (V),

[0021] Among them, AR 1 and R c It has the same definition as above; m=1-3 (eg, m=1, m=2, m=3).

[0022] Preferably, the structure of the aminopyridyloxypyrazole derivative is as shown in formula (VI),

[0023] Among them, AR 1 and R c With the same defined range as above; x=0-3 (eg, x=0, x=1, x=2, x=3).

[0024] Preferably, the structure of the aminopyridyloxypyrazole derivative is as shown in formula (VII):

[0025]

[0026] Among them, AR 1 and R 2 The same limitations as above apply.

[0027] Further preferably, the aminopyridyloxypyrazole derivative is selected from any one of the following structures:

[0028]

[0029]

[0030] Typical compounds of the present invention include but are not limited to the compounds in the following table:

[0031]

[0032]

[0033]

[0034]

[0035] In a second aspect, the present invention provides a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof of the aminopyridyloxypyrazole derivative as described in the first aspect.

[0036] In a third aspect, the present invention provides a method for preparing the aminopyridyloxypyrazole derivatives as described in the first aspect, the preparation method comprising: reacting a compound of the general formula (IA) with a compound of the general formula (IB) to obtain the aminopyridyloxypyrazole derivatives, and the reaction process is as follows:

[0037]

[0038] Where X is a halogen, AR 1 , R 2 , R 3 and R 4 The same limitations as above apply.

[0039] As one of the preferred technical solutions of the present invention, the preparation method comprises the following steps:

[0040]

[0041] In a fourth aspect, the present invention provides another method for preparing the aminopyridyloxypyrazole derivative as described in the first aspect, the preparation method comprising: reacting a compound of the general formula (I-Aa) with a compound of the general formula (I-Bb) to obtain the aminopyridyloxypyrazole derivative, and the reaction process is as follows:

[0042]

[0043] Where X is a halogen, AR 1 , R 2 , R 3 and R 4 The same limitations as above apply.

[0044] In a fifth aspect, the present invention provides a pharmaceutical composition comprising the aminopyridyloxypyrazole derivatives as described in the first aspect and / or the stereoisomers, tautomers, and pharmaceutically acceptable salts of the aminopyridyloxypyrazole derivatives as described in the second aspect.

[0045] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0046] In a sixth aspect, the present invention provides an aminopyridyloxypyrazole derivative as described in the first aspect, a stereoisomer, a tautomer, a pharmaceutically acceptable salt of the aminopyridyloxypyrazole derivative as described in the second aspect, and a pharmaceutical composition as described in the fifth aspect for use in the preparation of drugs for treating cancer or fibrosis-related diseases or in the preparation of TGF-βR1 inhibitors.

[0047] Preferably, the cancer comprises colon cancer, hepatocellular carcinoma, pancreatic cancer, renal cancer, breast cancer, myelodysplastic syndrome, glioma, gastric cancer or lung cancer.

[0048] Preferably, the fibrosis-related disease comprises liver fibrosis, chronic kidney disease or acquired lymphedema.

[0049] "Alkyl" refers to a saturated aliphatic hydrocarbon group, comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, a saturated straight chain or branched monovalent hydrocarbon group, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be optionally substituted or unsubstituted.

[0050] "Alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one CC is sp 2 Double bond, wherein the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention, wherein specific examples include but are not limited to vinyl, allyl and butylene, etc. The alkenyl group can be optionally substituted or unsubstituted.

[0051] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably includes 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed and bridged rings. Cycloalkyls can be optionally substituted or unsubstituted.

[0052] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, sulfur atom, etc. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl may be optionally substituted or unsubstituted.

[0053] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, the aryl is a C6-C10 aryl, more preferably phenyl and naphthyl, and most preferably phenyl. The aryl may be substituted or unsubstituted. The "aryl" may be fused with a heteroaryl, a heterocyclic group, or a cycloalkyl group, wherein the aryl ring is linked to the parent structure, and non-limiting examples include, but are not limited to:

[0054]

[0055] "Heteroaryl" refers to an aromatic 5-6-membered monocyclic or 9-10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

[0056]

[0057] "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl is defined in the relevant application. C1-C6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. "Hydroxy" refers to the -OH group. "Halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine. "Amino" refers to -NH2. "Cyano" refers to -CN.

[0058] "Optionally" means that the event it describes may but does not necessarily occur. For example, "AR 1 Optional 1 to multiple R c Replaces" This description contains AR 1 The group can be 1 to multiple R c Replaced or not by R c Replacement situation.

[0059] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1-3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without making too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. "Substituted" or "substituted" as described in this specification, if not otherwise specified, all refer to a group that can be substituted by one or more groups selected from the following.

[0060] The definitions and conventions used in this invention for stereochemistry are generally based on the following references:

[0061] SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms McGraw-Hill Book Company, New York, 1984; Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers, and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute part of the present invention. Diastereomers can be separated into individual diastereomers based on their physical and chemical differences by methods such as chromatography, crystallization, distillation or sublimation. Enantiomers can be separated to convert a chiral isomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers. The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to name the sign of rotation of the plane of polarized light of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. These stereoisomers have the same order of attachment of atoms or groups of atoms to each other, but their stereostructures are different. Specific stereoisomers may be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0062] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons. Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers are all within the scope of the present invention.

[0063] "Pharmaceutically acceptable salts" refer to salts of the compounds of the invention which are safe and effective for use in humans or animals. Salts of the compounds can be prepared by using a sufficient amount of a base or acid in a pure solution or a suitable inert solvent to obtain the corresponding addition salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, and pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and the inorganic and organic acids include hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, butenedioic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, etc. (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).

[0064] Compared with the prior art, the present invention has the following beneficial effects:

[0065] The present invention provides a novel aminopyridyloxypyrazole derivative, which has a significant effect of inhibiting the activity of TGFβR1 (ALK5) kinase and a significant effect of treating cancer or fibrosis-related diseases, and the preparation method thereof is simple and easy to operate. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 This is a graph showing the effects of the aminopyridyloxypyrazole derivatives of the present invention on the Smad signaling pathway of MDA-MB-231 cells. DETAILED DESCRIPTION

[0067] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0068] The present invention is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the invention.

[0069] The examples provide the preparation of representative aminopyridyloxypyrazole derivatives involved in the present invention and the relevant structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0070] The mass spectrum was obtained by LC / MS using ESI as the ionization method.

[0071] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.2mm-0.3mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0072] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0073] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to J&K Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Myrel Chemical Technology Co., Ltd.

[0074] CD3OD: deuterated methanol; CDCl3: deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; XantPhos: 4,5-bis(diphenylphosphino)ferrocene-9,9-dimethylxanthene; HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate; TLC: thin layer chromatography.

[0075] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L; unless otherwise specified in the embodiments, the solution in the reaction refers to an aqueous solution. Unless otherwise specified in the embodiments, the reaction temperature is room temperature, which is 20°C-30°C.

[0076] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the system of eluent for column chromatography or the developing solvent system for thin layer chromatography used for purifying the compound includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine, can also be added for adjustment.

[0077] Preparation of intermediate 1

[0078] 4-((2-((tert-Butyloxycarbonyl)amino)pyridin-4-yl)oxy)-1-cyclopropyl-1H-pyrazol-3-yl trifluoromethanesulfonate IN-1

[0079]

[0080] Step 1 Methyl 2-((2-chloropyridin-4-yl)oxy)acetate IN-1b

[0081] Compound IN-1a (20.0 g, 154.4 mmol) was dissolved in N,N-dimethylformamide (200 mL), methyl chloroacetate (22.2 g, 204.6 mmol) and cesium carbonate (75.7 g, 232.3 mmol) were added at room temperature, and the mixture was heated to 80°C and stirred for 12 hours. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid. The crude product was slurried with petroleum ether (100 mL), filtered, and the filter cake was washed and dried to obtain the title compound IN-1b (20.1 g, yield 65%) as a white solid.

[0082] Step 2 (E)-2-(((2-chloropyridin-4-yl)oxy)-3-(dimethylamino)acrylate IN-1c

[0083] Compound IN-1b (6.4 g, 31.74 mmol) was dissolved in 1,4-dioxane (20 mL), added to tert-butoxybis(dimethylamino)methane (10.0 mL, 49.75 mmol) at room temperature, heated to 75°C and stirred for 1 hour. TLC showed that the starting material disappeared. The reaction solution was concentrated to obtain the title compound IN-1c (7.1 g, crude product), which was used directly in the next step.

[0084] Step 3 4-((2-chloropyridin-4-yl)oxy)-1H-pyrazol-3-ol IN-1d

[0085] Compound IN-1c (7.1 g, crude product) was dissolved in ethanol (30 mL), hydrazine hydrate (10 mL, 85%) was added at room temperature, and stirred at room temperature for 1 hour. TLC showed that the raw material disappeared. Water (100 mL) was added to the reaction solution, and most of the ethanol was removed by concentration. The mixture was extracted twice with ethyl acetate, and the organic layer was discarded. The aqueous phase was adjusted to weak acidity (pH = 4-5) with acetic acid, and a white solid precipitated. The filter cake was washed with water 3 times and dried to obtain the title compound IN-1d (3.9 g, two-step yield 58%) as a white solid.

[0086] Step 4: 1-acetyl-4-((2-chloropyridin-4-yl)oxy)-1H-pyrazol-3-yl acetate IN-1e

[0087] Compound IN-1d (4.4 g, 20.79 mmol) was dissolved in pyridine (30 mL), heated to 95°C and stirred, acetic anhydride (4.35 g, 42.61 mmol) was dissolved in pyridine (20 mL), slowly added dropwise to the above reaction solution at 95°C, and continued to stir at 95°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated to obtain the title compound IN-1e (crude product), which was directly used in the next step.

[0088] LC-MS: m / z = 296.1 [M+H] +

[0089] Step 5 1-(4-((2-chloropyridinyl-4-yl)oxy)-3-hydroxy-1H-pyrazol-1-yl)ethan-1-one IN-1f

[0090] Compound IN-1e (crude product) was dissolved in ethanol (100 mL), pyridine (2 mL) was added at room temperature, the temperature was raised to 90°C and refluxed for 3 hours, a large amount of white solid precipitated, TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethanol twice, and dried to obtain the title compound IN-1f (2.9 g, two-step yield 55%).

[0091] LC-MS: m / z = 254.1 [M+H] +

[0092] Step 6 1-(3-(Benzyloxy)-4-((2-chloropyridin-4-yl)oxy)-1H-pyrazol-1-yl)ethan-1-one IN-1g

[0093] Compound IN-1f (2.8 g, 11.04 mmol) was dissolved in N,N-dimethylformamide (50 mL), the system was clear, benzyl bromide (2.46 g, 14.38 mmol) and potassium carbonate (3.0 g, 21.71 mmol) were added, stirred at room temperature for 3 hours, TLC showed that the raw material disappeared. Water was added to the reaction solution, solid precipitated, filtered, the filter cake was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a white solid, added petroleum ether (50 mL) to slurry, filtered, the filter cake was washed and dried to obtain the title compound IN-1g (3.1 g, yield 82%) as a white solid.

[0094] LC-MS: m / z=344.1[M+H] +

[0095] Step 7 4-((3-(Benzyloxy)-1H-pyrazol-4-yl)oxy)-2-chloropyridine IN-1h

[0096] Compound IN-1g (3.1g, 9.02mmol) was dissolved in tetrahydrofuran (50mL), and sodium hydroxide aqueous solution (25mL, 5M) was added at room temperature, and the mixture was heated to 70°C and stirred for 60 minutes. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated to remove tetrahydrofuran, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound IN-1h (3.3g, crude product) as an oil, which was directly used in the next step.

[0097] Step 8 4-((3-(Benzyloxy)-1-cyclopropyl-1H-pyrazol-4-yl)oxy)-2-chloropyridine IN-1j

[0098] 2,2-Bipyridine (2.5 g, 16.01 mmol) was dissolved in 1,2-dichloroethane (50 mL), copper acetate (2.9 g, 15.97 mmol) was added at room temperature, and the mixture was heated to 75°C and stirred for 1 hour. The reaction solution was cooled to room temperature, compound IN-1h (3.3 g, crude product), cyclopropylboronic acid IN-1i (1.9 g, 22.12 mmol) and sodium carbonate (2.3 g, 21.70 mmol) were added in sequence, and the mixture was heated to 75°C and stirred for 12 hours. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, extracted with dichloromethane, and the organic phases were combined, washed with water 3 times, washed with dilute hydrochloric acid (1N) 2 times, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound IN-1j (3.7 g, crude product) as a white solid, which was directly used in the next step.

[0099] Step 9: Tert-butyl (4-((3-(benzyloxy)-1-cyclopropyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate IN-1k

[0100] Compound IN-1j (2.48 g, crude product) was dissolved in 1,4-dioxane (20 mL), tert-butyl carbamate (2.12 g, 18.10 mmol), Pd2(dba)3 (660 mg, 0.72 mmol), Xantphos (840 mg, 1.45 mmol) and cesium carbonate (4.72 g, 14.49 mmol) were added at room temperature, and the temperature was raised to 100 ° C for 6 hours under nitrogen protection. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was subjected to silica gel column chromatography to obtain the oily title compound IN-1k (2.5 g, three-step yield 81%).

[0101] Step 10: Tert-butyl (4-((1-cyclopropyl-3-hydroxy-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate IN-11

[0102] Compound IN-1k (2.5 g, 5.92 mmol) was dissolved in methanol (150 mL), palladium carbon (300 mg, 10%) was added at room temperature, and stirred for 1 hour under hydrogen atmosphere. TLC showed that the reaction was complete. A white solid precipitated from the reaction solution, tetrahydrofuran (200 mL) was added, stirred for 30 minutes, and filtered directly (without diatomaceous earth pad). The filtrate was concentrated to obtain the title compound IN-1l (1.8 g, yield 92%) as a white solid.

[0103] Step 11 4-(((2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxy)-1-cyclopropyl-1H-pyrazol-3-yl trifluoromethanesulfonate IN-1

[0104] Compound IN-11 (400 mg, 1.20 mmol) was dissolved in N, N-dimethylformamide (50 mL), and N, N-diisopropylethylamine (0.6 mL) and N-phenylbis(trifluoromethanesulfonyl)imide (516 mg, 1.44 mmol) were added, and stirred at room temperature for 3 hours. TLC showed that the raw material disappeared. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid, which was slurried with petroleum ether (10 mL), filtered, and the filter cake was washed and dried to obtain the title compound IN-1 (420 mg, yield 75%) as a white solid.

[0105] Example 1

[0106] 2-(4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 1

[0107]

[0108] Step 1 2-(4-bromopyridin-2-yl)propan-2-ol 1b

[0109] 4-Bromopicolinic acid methyl ester 1a (13.0 g, 60.18 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL), cooled to 0°C, methylmagnesium bromide (47 mL, 141 mmol, 3 M) was added, and the temperature was slowly raised to room temperature for 12 hours. TLC showed that the reaction was complete. The reaction solution was quenched by adding saturated ammonium chloride solution (200 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 1b (6.1 g, yield 47%) as an oil.

[0110] Step 2 Tert-butyl (4-((1-cyclopropyl-3-(3,4-dihydro-2H-pyran-6-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate 1d

[0111] Intermediate 1IN-1 (500 mg, 1.08 mmol) was dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (1 mL), and 3,4-dihydro-2H-pyran-6-boronic acid pinacol ester 1c (500 mg, 2.36 mmol), Pd2(dba)3 (90 mg, 0.10 mmol) and cesium carbonate (702 mg, 2.0 mmol) were added in sequence. The mixture was stirred at 90°C for 2 hours under nitrogen protection. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with pure water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 1d (450 mg, crude product) as an oily product, which was directly used in the next step.

[0112] Step 3 Tert-butyl (4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate 1e

[0113] Compound 1d (450 mg, crude product) was dissolved in a mixed solvent of dichloromethane (5 mL) and methanol (50 mL), palladium / carbon (200 mg, 10%) was added, and the mixture was stirred at room temperature for 4 hours under hydrogen protection. TLC showed that the raw material disappeared. The reaction solution was filtered through celite pad, and the filtrate was concentrated to obtain the title compound 1e (400 mg, two-step yield 92%).

[0114] Step 4: 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-amine 1f

[0115] Compound 1e (400 mg, 1.00 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated, dichloromethane was added, and saturated sodium bicarbonate aqueous solution (50 mL) was used for separation, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 1f (220 mg, crude product) as a yellow solid, which was used directly in the next step.

[0116] Step 5: 2-(4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 1

[0117] Compound 1f (220 mg, crude product) was dissolved in 1,4-dioxane (50 mL), and compound 1b (237 mg, 1.10 mmol), Pd2(dba)3 (67 mg, 0.07 mmol), Xantphos (84 mg, 0.15 mmol), cesium carbonate (481 mg, 1.48 mmol) were added, and the mixture was reacted at 100°C for 4 hours under nitrogen protection. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified by Prep-TLC to obtain the title compound 1 (150 mg, two-step yield 34%). Chiral column separation (DAICEL AD-H, 30*250mm, 5um, 30mL / min, EtOH:Hexane=20:80) gave compound 1-1 (peak 1, RT: 12.2min) (13.8mg, yield 9%) and compound 1-2 (peak 2, RT: 22.5min) (13.2mg, yield 9%).

[0118] Compound 1:

[0119] LC-MS: m / z=436.3[M+H] +

[0120] 11H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.20 (d, J = 5.6 Hz, 1H), 8.12 (d, J = 6.0 Hz, 1H), 7.88 (s, 1H), 7.70 - 7.67 (m, 2H), 6.56 (dd, J = 6.0, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 5.08 (s, 1H), 4.22 (dd, J = 11.2, 2.8 Hz, 1H), 3.83 - 3.75 (m, 1H), 3.69 (m, 1H), 3.31 (m, 1H), 1.81 - 1.78 (m, 2H), 1.65 - 1.62 (m, 1H), 1.49 - 1.40 (m, 9H), 1.05 - 1.03 (m, 2H), 0.98 - 0.95 (m, 2H).

[0121] Compound 1-1:

[0122] LC-MS: m / z = 436.3 [M+H] +

[0123] 1 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.89 (s, 1H), 7.71 - 7.68 (m, 2H), 6.57 (dd, J = 5.6, 2.0 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 5.12 (s, 1H), 4.21 (dd, J = 9.6, 1.2 Hz, 1H), 3.78 (d, J = 11.2 Hz, 1H), 3.71 - 3.67 (m, 1H), 1.81 - 1.78 (m, 2H), 1.65 - 1.62 (m, 1H), 1.52 - 1.37 (m, 10H), 1.06 - 1.01 (m, 2H), 0.98 - 0.93 (m, 2H).

[0124] Compound 1-2:

[0125] LC-MS: m / z = 436.2 [M+H] +

[0126] 1H NMR(400MHz, DMSO-d6)δ9.51(s,1H),8.21(d,J=5.6Hz,1H),8.13(d,J=5.6Hz,1H),7.90 (s,1H),7.75-7.68(m,2H),6.58(dd,J=5.6,2.0Hz,1H),6.38(d,J=2.0Hz,1H),5.13(s, 1H),4.22(dd,J=10.4,1.6Hz,1H),3.79(d,J=11.6Hz,1H),3.71-3.68(m,1H),1.84-1.7 3(m,2H),1.68-1.59(m,1H),1.51-1.34(m,10H),1.08-1.01(m,2H),0.99-0.92(m,2H).

[0127] Example 2

[0128]

[0129] 2-(2-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-4-yl)propan-2-ol 2

[0130]

[0131] Step 1 2-Bromo-N-methoxy-N-methylisonicotinamide 2b

[0132] 2-Bromo-4-pyridinecarboxylic acid 2a (4.0 g, 19.80 mmol), HATU (11.28 g, 29.67 mmol) and triethylamine (6.0 g, 59.29 mmol) were dissolved in N, N-dimethylformamide (80 mL), stirred at room temperature for 20 minutes, and dimethylhydroxylamine hydrochloride (2.32 g, 23.78 mmol) was added. The reaction was allowed to proceed overnight at room temperature. TLC monitored the reaction of most of the raw materials. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the light yellow liquid title compound 2b (4.8 g, yield 99%)

[0133] Step 2 1-(2-Bromopyridin-4-yl)ethan-1-one 2c

[0134] Compound 2b (2.0 g, 8.16 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0°C under nitrogen protection, and methylmagnesium bromide (4.1 mL, 12.3 mmol, 3 M) was added dropwise. After the addition was complete, the reaction was continued for 3 hours. TLC detected that the reaction was complete. The reaction solution was quenched by adding saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 2c (1.46 g, crude product), which was directly used in the next step.

[0135] Step 3 2-(2-Bromopyridin-4-yl)propan-2-ol 2d

[0136] Compound 2c (1.46 g, crude product) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0°C under nitrogen protection, and methylmagnesium bromide (9.8 mL, 29.35 mmol, 3 M) was added dropwise. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. TLC monitored the residual raw material. The reaction solution was quenched by adding saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 2d (400 mg, two-step yield 23%) as an oil.

[0137] Step 4: 2-(2-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-4-yl)propan-2-ol 2

[0138] Compound 1f (100 mg, 0.33 mmol), compound 2d (92 mg, 0.43 mmol) and cesium carbonate (216 mg, 0.66 mmol) were dissolved in 1,4-dioxane (5 mL). Pd2(dba)3 (30 mg, 0.03 mmol) and Xantphos (38 mg, 0.06 mmol) were added under nitrogen protection, nitrogen was replaced three times, the temperature was raised to 100 ° C for 4 hours, and TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain white solid compound 2 (30 mg, yield 15%).

[0139] LC-MS: m / z=436.3[M+H] +

[0140] 1H NMR (400MHz, DMSO-d6) δ11.93(br,1H),8.07(d,J=4.4Hz,2H),7.90(s,1H),7.57(br,1H),7.04(br,1H),6.61(br,1H),5.26(br,1H),4.24(d,J=10. 8,2.0Hz,1H),3.79-3.73(m,1H),3.71-3.66(m,1H),1.80-1.78(m,2H),1. 67-1.63(m,1H),1.51-1.40(m,9H),1.08-1.01(m,2H),0.99-0.96(m,2H).

[0141] Example 3

[0142]

[0143] 2-(6-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-4-yl)propan-2-ol 3

[0144]

[0145] Step 1 Methyl 6-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidine-4-carboxylate 3b

[0146] Compound 1f (250 mg, 0.83 mmol) was dissolved in 1,4-dioxane (50 mL), and 6-chloro-pyrimidine-4-carboxylic acid methyl ester 3a (157 mg, 0.91 mmol), Pd2(dba)3 (76 mg, 0.08 mmol), Xantphos (96 mg, 0.17 mmol) and cesium carbonate (540 mg, 1.66 mmol) were added at room temperature. Under nitrogen protection, the temperature was raised to 100 ° C for 2 hours. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 3b (150 mg, yield 41%) as an oil.

[0147] Step 2 2-(6-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-4-yl)propan-2-ol 3

[0148] Compound 3b (150 mg, 0.34 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), methylmagnesium bromide (2 mL, 6 mmol, 3 M) was added, and stirred at room temperature for 12 hours. TLC showed that the raw material disappeared. The reaction solution was added with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the oily title compound 3 (90 mg, yield 60%). Chiral column separation (DAICEL AD-H, 30*250 mm, 5 um, 30 mL / min, IPA: Hexane = 20:80) gave compound 3-1 (peak 1, RT: 22.7 min) (13.3 mg, yield 15%), compound 3-2 (peak 2, RT: 33.9 min) (15.8 mg, yield 18%).

[0149] Compound 3-1:

[0150] LC-MS: m / z=437.2[M+H] +

[0151] 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.59(s,1H),8.16(d,J=6.0Hz,1H),7.94(s,1H), 7.89(s,1H),7.46(s,1H),6.59(dd,J=6.0,2.4Hz,1H),5.28(s,1H),4.23(dd,J=11.2,2. 4Hz,1H),3.82-3.74(m,1H),3.73-3.67(m,1H),3.34-3.27(m,1H),1.84-1.75(m,2H),1 .69-1.61(m,1H),1.48-1.41(m,3H),1.40(s,6H),1.07-1.02(m,2H),0.99-0.93(m,2H).

[0152] Compound 3-2:

[0153] LC-MS: m / z=437.3[M+H] +

[0154] 1H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.59(s,1H),8.16(d,J=6.0Hz,1H),7.93(s,1H), 7.89(s,1H),7.46(s,1H),6.59(dd,J=6.0,2.4Hz,1H),5.28(s,1H),4.23(dd,J=11.2,2. 4Hz,1H),3.80-3.72(m,1H),3.72-3.69(m,1H),3.37-3.27(m,1H),1.85-1.74(m,2H),1 .69-1.60(m,1H),1.47-1.41(m,3H),1.39(s,6H),1.07-1.02(m,2H),0.99-0.93(m,2H).

[0155] Example 4

[0156]

[0157] 2-(2-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-4-yl)propan-2-ol 4

[0158]

[0159] Step 1 2-(2-chloropyrimidin-4-yl)propan-2-ol 4b

[0160] 2-Chloropyrimidine-4-carboxylic acid methyl ester 4a (1.0 g, 5.8 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0°C in an ice bath, and methylmagnesium bromide (14.0 mL, 14.0 mmol, 1 M) was added. The reaction was allowed to react overnight at room temperature. TLC detected that the reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the yellow liquid title compound 4b (1.0 g, crude product), which was used directly in the next step.

[0161] LC-MS: m / z = 173.1 [M+H] +

[0162] Step 2 2-(2-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-4-yl)propan-2-ol 4

[0163] Under nitrogen protection, compound 1f (200 mg, 0.67 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 4b (229 mg, 1.33 mmol), Pd2(dba)3 (61 mg, 0.07 mmol), Xantphos (77 mg, 0.13 mmol) and cesium carbonate (433 mg, 1.33 mmol) were added at room temperature, and the temperature was raised to 100°C for 1 hour. The reaction was complete after TLC detection. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the solid title compound 4 (180 mg, yield 62%). Chiral column separation (DAICEL AD-H, 30*250mm, 5um, 30mL / min, EtOH:Hexane=20:80) gave compound 4-1 (peak 1, RT:19.0min) (22.9mg, yield 13%) and compound 4-2 (peak 2, RT:22.0min) (31.4mg, yield 17%).

[0164] Compound 4-1:

[0165] LC-MS: m / z=437.3[M+H] +

[0166] 1 H NMR (400MHz, DMSO-d6) δ9.84 (s, 1H), 8.51 (d, J = 4.0Hz, 1H), 8.16 (d, J = 5.2Hz, 1H), 7.95(s,1H),7.89(s,1H),7.14(d,J=4.4Hz,1H),6.64(d,J=3.6Hz,1H),5.29(s,1H) ,4.21-4.18(m,1H),3.76-3.74(m,2H),3.34-3.29(m,1H),1.75-1.74(m,2H),1.61- 1.60(m,1H),1.60-1.59(m,3H),1.58(s,6H),1.26-1.04(m,2H),0.96-0.94(m,2H).

[0167] Compound 4-2:

[0168] LC-MS: m / z=437.3[M+H] +

[0169] 1H NMR (400MHz, DMSO-d6) δ9.75(s,1H),8.49(d,J=4.8Hz,1H),8.14(d,J=5.6Hz,1H),7.94(d,J=2 .4Hz,1H),7.89(s,1H),7.14(d,J=4.8Hz,1H),6.64(dd,J=5.6,2.0Hz,1H),5.29(s,1H),4.20( dd,J=10.8,2.0Hz,1H),3.77-3.74(m,1H),3.69-3.65(m,1H),3.33-3.28(m,1H),1.81-1.75(m ,2H),1.64-1.54(m,1H),1.43-1.36(m,3H),1.26(s,6H),1.06-1.01(m,2H),0.98-0.92(m,2H).

[0170] Example 5

[0171]

[0172] 2-(4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)-2-methylpropionitrile 5

[0173]

[0174] Step 1 2-Hydroxymethyl-4-bromopyridine 5b

[0175] Under nitrogen protection, methyl 4-bromopicolinate 5a (5.0 g, 23.14 mmol) was dissolved in anhydrous ethanol (100 mL), sodium borohydride (1.9 g, 50.22 mmol) was added, and the reaction was carried out at room temperature for 1 hour. TLC showed that the reaction was complete. Acetone (25 mL) was added to the reaction solution, concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed twice with water, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 5b (4.08 g, crude product) as a light yellow solid, which was used directly in the next step.

[0176] LC-MS: m / z = 190.0 [M+H] +

[0177] Step 2: Methyl (4-bromopyridin-2-yl) methanesulfonate 5c

[0178] Under nitrogen protection, compound 5b (4.08 g, crude product) was dissolved in dichloromethane (40 mL), cooled to 0°C in an ice-water bath, triethylamine (7.2 mL, 54.25 mmol) was added, and methylsulfonyl chloride (2 mL) was slowly added dropwise. After addition, the temperature was naturally raised to room temperature for 2 hours. TLC showed that the reaction was complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 5c (5.78 g, crude product) (it cannot be concentrated to dryness, otherwise the reaction solution will deteriorate), which was directly used in the next step.

[0179] Step 3 2-(4-bromopyridin-2-yl)acetonitrile 5d

[0180] Under nitrogen protection, compound 5c (5.78 g, crude product) was dissolved in acetonitrile (50 mL), trimethylsilyl cyanide (13.5 mL, 108.5 mmol) and anhydrous potassium carbonate (6.0 g, 43.4 mmol) were added at room temperature, and the temperature was raised to 75°C for 18 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the red liquid title compound 5d (1.61 g, three-step yield 36%).

[0181] LC-MS: m / z = 199.0 [M+H] +

[0182] Step 4: 2-(4-bromopyridin-2-yl)-2-methylpropionitrile 5e

[0183] Sodium hydride (816 mg, 34.0 mmol, 60%) was suspended in N, N-dimethylformamide (10 mL), cooled in an ice-water bath, and a solution of compound 5d (1.61 g, 8.17 mmol) in N, N-dimethylformamide (10 mL) and iodomethane (1.53 mL, 24.51 mmol) were added, and the temperature was slowly raised to room temperature for 40 minutes. TLC showed that the reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5e (1.48 g, yield 80%) as a light yellow solid.

[0184] Step 5 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-amine 1f-1,2

[0185] Compound 1e was separated by chiral column (DAICEL AD-H, 30*250mm, 5um, 30mL / min, EtOH:Hexane=10:90) to obtain compound 1e-1 (peak 1, RT: 28.0min) and compound 1e-2 (peak 2, RT: 35.0min).

[0186] Compound 1e-1 (200 mg, 0.50 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (5 mL) was added, and stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated, diluted with dichloromethane, washed with saturated sodium bicarbonate aqueous solution (50 mL), washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 1f-1 (100 mg, crude product) as a yellow solid, which was directly used in the next step.

[0187] Compound 1e-2 (200 mg, 0.50 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (5 mL) was added, and stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated, diluted with dichloromethane, washed with saturated sodium bicarbonate aqueous solution (50 mL), washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 1f-2 (100 mg, crude product) as a yellow solid, which was directly used in the next step.

[0188] Step 6: 2-(4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)-2-methylpropionitrile 5-1,2

[0189] Under nitrogen protection, compound 1f-1 (100 mg, crude product) was dissolved in 1,4-dioxane (7 mL), and compound 5e (120 mg, 0.53 mmol), cesium carbonate (215 mg, 0.66 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added at room temperature, and the temperature was raised to 100 ° C for 75 minutes. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a solid (116 mg), methyl tert-butyl ether (3 mL) was slurried, filtered (washed with 10 mL methyl tert-butyl ether), and the filter cake was dried to obtain a solid title compound 5-1 (57 mg, two-step yield 26%).

[0190] LC-MS: m / z=445.3[M+H] +

[0191] 1H NMR (400MHz, DMSO-d6) δ9.63(s,1H),8.27(d,J=6.0Hz,1H),8.11(d,J=6.0Hz,1H),7. 87(s,1H),7.76-7.72(m,2H),6.59(dd,J=6.0,2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.19 (dd,J=10.8,2.4Hz,1H),3.76-3.72(m,1H),3.69-3.63(m,1H),3.29-3.25(m,1H),1.7 7-1.75(m,2H),1.63(s,7H),1.43-1.38(m,3H),1.02-0.99(m,2H),0.95-0.92(m,2H).

[0192] Under nitrogen protection, compound 1f-2 (100 mg, crude product) was dissolved in 1,4-dioxane (7 mL), and compound 5e (120 mg, 0.53 mmol), cesium carbonate (215 mg, 0.66 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added at room temperature, and the temperature was raised to 100 ° C for 75 minutes. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was chromatographed on a silica gel column to obtain a crude product, methyl tert-butyl ether (3 mL) was added for pulping, filtered (washed with 10 mL methyl tert-butyl ether), and the filter cake was dried to obtain a solid title compound 5-2 (73 mg, yield 33%).

[0193] LC-MS: m / z=445.3[M+H] +

[0194] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),8.27(d,J=6.0Hz,1H),8.11(d,J=6.0Hz,1H),7. 88(s,1H),7.76-7.72(m,2H),6.59(dd,J=6.0,2.4Hz,1H),6.33(d,J=2.0Hz,1H),4.18 (dd,J=10.8,2.4Hz,1H),3.77-3.73(m,1H),3.68-3.65(m,1H),3.28-3.26(m,1H),1.7 7-1.75(m,2H),1.63(s,7H),1.40-1.38(m,3H),1.03-1.00(m,2H),0.94-0.91(m,2H).

[0195] Example 6

[0196]

[0197] 4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzonitrile 6

[0198]

[0199] Step 1 4-Bromo-2-methoxybenzonitrile 6b

[0200] 4-Bromo-2-fluorobenzonitrile 6a (1.0 g, 5.0 mmol) was dissolved in tetrahydrofuran (15 mL), sodium methoxide (1.8 g, 10.0 mmol, 30% methanol solution) was added at room temperature, and the temperature was raised to 70°C for half an hour. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 6b (1.1 g, crude product) as a white solid, which was used directly in the next step.

[0201] Step 2 4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzonitrile 6

[0202] Compound 6b (146 mg, 0.688 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 1f (103 mg, 0.343 mmol), cesium carbonate (224 mg, 0.688 mmol), Pd2(dba)3 (31.4 mg, 0.034 mmol), and Xantphos (39.7 mg, 0.069 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100°C for reaction for 1.5 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 6 (248 mg, yield 84%). Chiral column separation (DAICEL AD-H, 30*250mm, 5um, 30mL / min, EtOH:Hexane=10:90) gave compound 6-1 (peak 1, RT: 20.0min) (20mg, yield 8%) and compound 6-2 (peak 2, RT: 24.0min) (18mg, yield 7%).

[0203] Compound 6-1:

[0204] LC-MS: m / z=432.2[M+H]+

[0205] 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.13(d,J=5.6Hz,1H),7.90(s,1H),7.67(s,1H),7 .53(d,J=8.4Hz,1H),7.36(d,J=8.4Hz,1H),6.60(d,J=5.6Hz,1H),6.36(s,1H),4.23-4. 21(m,1H),3.87(s,3H),3.80-3.77(m,1H),3.71-3.68(m,1H),3.36-3.33(m,1H),1.81-1 .76(m,2H),1.66-1.63(m,1H),1.44-1.43(m,3H),1.07-1.04(m,2H),0.98-0.96(m,2H).

[0206] Compound 6-2:

[0207] LC-MS: m / z=432.2[M+H] +

[0208] 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.13(d,J=5.6Hz,1H),7.90(s,1H),7.67(s,1H),7 .52(d,J=8.4Hz,1H),7.36(d,J=8.4Hz,1H),6.61(d,J=5.6Hz,1H),6.36(s,1H),4.25-4. 21(m,1H),3.87(s,3H),3.80-3.77(m,1H),3.71-3.68(m,1H),3.36-3.33(m,1H),1.86-1 .75(m,2H),1.66-1.61(m,1H),1.44-1.43(m,3H),1.06-1.04(m,2H),0.98-0.96(m,2H).

[0209] Example 7

[0210]

[0211] 2-(4-((4-((1-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 7

[0212]

[0213] First step Tert-butyl (4-((1-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate 7b

[0214] Intermediate 1IN-1 (220 mg, 0.47 mmol) was dissolved in 1,4-dioxane (50 mL), and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester 7a (197 mg, 0.94 mmol), cesium carbonate (306 mg, 0.94 mmol), Pd(dppf)Cl2 dichloromethane complex (40 mg, 0.05 mmol) and water (10 mL) were added at room temperature. Under nitrogen protection, the temperature was raised to 80 ° C and stirred for 5 hours. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the oily title compound 7b (80 mg, yield 42%).

[0215] LC-MS: m / z = 399.2 [M+H] +

[0216] Step 2 4-((1-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-amine 7c

[0217] Compound 7b (80 mg, 0.20 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (4 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. TLC showed that the raw material disappeared. The reaction solution was concentrated, saturated sodium bicarbonate aqueous solution (50 mL) was added, and extracted with dichloromethane (50 mL). The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7c (crude product), which was directly used in the next step.

[0218] LC-MS: m / z = 299.2 [M+H] +

[0219] Step 3 2-(4-((4-((1-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 7

[0220] Compound 7c (crude product) was dissolved in 1,4-dioxane (50 mL), and compound 1b (108 mg, 0.5 mmol), Pd2(dba)3 (24 mg, 0.026 mmol), Xantphos (31 mg, 0.054 mmol) and cesium carbonate (174 mg, 0.53 mmol) were added at room temperature. Under nitrogen protection, the temperature was raised to 100 ° C for 4 hours. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 7 (10 mg, two-step yield 11%).

[0221] LC-MS: m / z = 434.2 [M+H] +

[0222] 1 H NMR (400MHz, DMSO-d6) δ9.54(s,1H),8.21(d,J=5.6Hz,1H),8.15(d,J=5.6Hz,1H),7.97(s,1H),7.73-7.66(m,2H),6.60(dd,J=5.6Hz,1H),6.39(d,J =6.0Hz,1H),6.06(s,1H),5.16(s,1H),4.11-4.04(m,2H),3.74-3.71(m,3 H),2.45-2.37(m,2H),1.41(s,6H),1.08-1.05(m,2H),0.99-0.97(m,2H).

[0223] Example 8

[0224]

[0225] 2-(2-((4-((1-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-4-yl)propan-2-ol 8

[0226]

[0227] Compound 4b (98.4 mg, 0.57 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 7c (85 mg, 0.285 mmol), cesium carbonate (187 mg, 0.574 mmol), Pd2(dba)3 (26 mg, 0.028 mmol) and Xantphos (33 mg, 0.057 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 8 (26 mg, yield 21%).

[0228] LC-MS: m / z=435.3[M+H] +

[0229] 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),8.51(d,J=5.2Hz,1H),8.19(d,J=5.6Hz,1H),7.95(s,1H),7.94(d,J=2.0Hz,1H),7.14(d,J=4.8Hz,1H),6.67(dd ,J=6.0,2.4Hz,1H),6.06(s,1H),5.29(s,1H),4.05-4.04(m,2H),3.71-3. 68(m,3H),2.40(s,2H),1.24(s,6H),1.05-1.03(m,2H),0.98-0.95(m,2H).

[0230] Example 9

[0231]

[0232] 2-(4-((4-((1-cyclopropyl-3-(oxepan-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 9

[0233]

[0234] Step 4 - Oxepazine 9b

[0235] Under nitrogen protection, anhydrous ether (200 mL) was added to a 500 mL three-necked flask, and dry ice ethanol was cooled to about -70 °C. n-Butyl lithium (52 ​​mL, 0.13 mol, 2.5 M) was added, and then TMSCHN2 (60 mL, 0.12 mol, 2 M) was slowly added dropwise at low temperature. After the addition was completed, the mixture was stirred at -70 °C for 1 hour. Tetrahydropyran-4-one 9a (10.0 g, 0.10 mol) in anhydrous tetrahydrofuran (3 0mL) solution was added dropwise to the system, and the mixture was stirred at low temperature for 1 hour. Anhydrous methanol (20mL) was added at low temperature to quench the mixture. After slowly warming to room temperature, the reaction solution was diluted with water, extracted twice with methyl tert-butyl ether, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Silica gel (120g) was added to the organic phase, and the mixture was stirred at room temperature for 1 hour. The silica gel was removed by filtration, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 9b (4.3g, yield 37%) as an oil.

[0236] 1 H NMR (400MHz, CDCl3) δ3.77-3.69(m,4H),2.60-2.50(m,4H),1.75-1.70(m,2H).

[0237] Step 2 Mixture of 4-bromo-2,3,6,7-tetrahydrooxepin and 5-bromo-2,3,4,7-tetrahydrooxepin 9c

[0238] Under nitrogen protection, triphenyl phosphite (13.4 g, 43.19 mmol) was added to anhydrous dichloromethane (50 mL), and the temperature was cooled to -60 ° C with dry ice ethanol. Bromine (6.01 g, 37.61 mmol) was added dropwise, and the mixture was stirred at -60 ° C for 30 minutes. Triethylamine (8.1 mL, 58.27 mmol) was added, and the mixture was stirred at -60 ° C for 30 minutes. A dichloromethane (15 mL) solution of compound 9b (3.3 g, 28.91 mmol) was added dropwise, and the mixture was heated to room temperature and stirred for 18 hours. TLC showed that most of the raw materials reacted completely. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 9c (2.1 g, yield 41%) as a colorless oil.

[0239] Step 3 4,4,5,5-tetramethyl-2-(2,3,6,7-tetrahydrooxazol-4-yl)-1,3,2-dioxaborolane and 4,4,5,5-tetramethyl-2-(2,5,6,7-tetrahydrooxazol-4-yl)-1,3,2-dioxaborolane mixture 9d

[0240] Compound 9c (2.1 g, 11.86 mmol) was dissolved in 1,4-dioxane (30 mL), and diboric acid pinacol ester (2.7 g, 10.63 mmol), potassium acetate (3.49 g, 35.56 mmol) and Pd(dppf)Cl2 dichloromethane complex (500 mg, 0.61 mmol) were added. Under nitrogen protection, the temperature was raised to 80 ° C and stirred for 2 hours. TLC showed that the raw materials reacted completely. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 9d (1.01 g, yield 38%) as a colorless oil.

[0241] 1 H NMR (400MHz, CDCl3) δ6.78(t,J=5.6Hz,1H),3.64(t,J=4.8Hz,4H),2.48(t,J=4.8Hz,2H),2.43(q,J=5.2Hz,2H),1.26(s,12H).

[0242] Step 4: Mixture of tert-butyl (4-((1-cyclopropyl-3-(2,3,6,7-tetrahydrooxazol-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate and tert-butyl (4-((1-cyclopropyl-3-(2,5,6,7-tetrahydrooxazol-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate 9e

[0243] Intermediate 1IN-1 (980 mg, 2.11 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1.5 mL), and compound 9d (947 mg, 4.23 mmol), cesium carbonate (1.37 g, 4.20 mmol) and Pd(dppf)Cl2 dichloromethane complex (154 mg, 0.19 mmol) were added at room temperature. Under nitrogen protection, the temperature was raised to 90 ° C and stirred for 16 hours. TLC showed that a small amount of raw materials remained. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 9e (270 mg, yield 31%) as a colorless oil.

[0244] LC-MS: m / z=413.3[M+H] +

[0245] Step 5: Tert-butyl (4-((1-cyclopropyl-3-(oxepan-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate 9f

[0246] Compound 9e (270 mg, 0.655 mmol) was dissolved in anhydrous methanol (40 mL), palladium / carbon (90 mg, 10%) was added, hydrogen was replaced twice, and the mixture was stirred at room temperature for 3 hours. TLC showed that the reaction of the raw material was complete. The reaction solution was filtered through diatomaceous earth, the filter cake was washed twice with dichloromethane, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 9f (230 mg, yield 84%) as an oil.

[0247] LC-MS: m / z=415.3[M+H] +

[0248] Step 6 4-((1-cyclopropyl-3-(oxepan-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-amine 9g

[0249] Compound 9f (230 mg, 0.555 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC showed that the reaction of the raw material was complete. The reaction solution was concentrated to dryness, dissolved in dichloromethane, washed with saturated sodium carbonate aqueous solution, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 9g (180 mg, crude product) as an oil, which was used directly in the next step.

[0250] LC-MS: m / z=315.2[M+H] +

[0251] Step 7: 2-(4-((4-((1-cyclopropyl-3-(oxepan-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 9

[0252] Compound 9g (180 mg, crude product) was dissolved in 1,4-dioxane (7 mL), and cesium carbonate (373 mg, 1.14 mmol), Pd2(dba)3 (52 mg, 0.06 mmol), Xantphos (66 mg, 0.11 mmol) and compound 1b (185 mg, 0.86 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100 ° C and stirred for 3 hours. TLC showed that the raw materials reacted completely. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography. Prep-TLC purification gave the solid title compound 9 (100 mg, two-step yield 38%).

[0253] LC-MS: m / z = 450.3 [M+H] +

[0254] 1H NMR (400MHz, DMSO-d6) δ9.87(s,1H),8.24(d,J=6.0Hz,1H),8.17(d,J=5.6Hz,1H),7. 86(s,1H),7.80(br,2H),6.66(dd,J=6.0,2.0Hz,1H),6.45(d,J=2.0Hz,1H),5.40(br, 1H),3.69-3.62(m,3H),3.54-3.46(m,2H),2.75-2.70(m,1H),1.89-1.78(m,3H),1.7 5-1.68(m,2H),1.63-1.52(m,1H),1.44(s,6H),1.06-1.02(m,2H),0.97-0.94(m,2H).

[0255] Example 10

[0256]

[0257] 2-(4-((4-((1-cyclopropyl-3-(4,4-dimethylcyclohex-1-en-1-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 10

[0258]

[0259] First step Tert-butyl (4-((1-cyclopropyl-3-(4,4-dimethylcyclohex-1-en-1-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate 10b

[0260] Under nitrogen protection, intermediate 1IN-1 (1.08 g, 2.32 mmol) was dissolved in 1,4-dioxane (20 mL), and 4,4-(dimethylcyclohexene-1-yl)boronic acid pinacol ester 10a (823 mg, 3.48 mmol), water (2 mL), cesium carbonate (1.51 g, 4.63 mmol) and Pd(dppf)Cl2 dichloromethane complex (187 mg, 0.23 mmol) were added in sequence at room temperature, and the temperature was raised to 90°C for 5 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 10b (510 mg, yield 52%).

[0261] Step 2 4-((1-cyclopropyl-3-(4,4-dimethylcyclohex-1-en-1-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-amine 10c

[0262] Compound 10b (330 mg, 0.78 mmol) was dissolved in trifluoroacetic acid (10 mL) and reacted at room temperature for 40 minutes. TLC showed that the reaction was complete. The reaction solution was concentrated to remove trifluoroacetic acid, saturated sodium bicarbonate aqueous solution was added to adjust the pH to neutral, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 10c (250 mg, crude product), which was directly used in the next step.

[0263] Step 3 2-(4-((4-((1-cyclopropyl-3-(4,4-dimethylcyclohex-1-en-1-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 10

[0264] Compound 10c (250 mg, crude product) was dissolved in 1,4-dioxane (10 mL), and compound 1b (251 mg, 1.16 mmol), cesium carbonate (502 mg, 1.54 mmol), Pd2(dba)3 (73 mg, 0.08 mmol) and Xantphos (93 mg, 0.16 mmol) were added. Under nitrogen protection, the temperature was raised to 100°C for 4 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 10 (77 mg, two-step yield 22%).

[0265] LC-MS: m / z = 460.3 [M+H] +

[0266] 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=6.0Hz,1H),8.18(d,J=6.0Hz,1H),7.94(s,1H),7.81(br,2H),6.69-6.23(m,1H),6.43(s,1H),6.02-5.96(m,1 H),3.71-3.68(m,1H),2.36-2.33(m,2H),1.83-1.77(m,2H),1.45(s,6H ),1.36-1.34(m,2H),1.07-1.05(m,2H),0.97-0.94(m,2H),0.83(s,6H).

[0267] Embodiment 11

[0268]

[0269] 1-(4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)cyclopropan-1-ol 11

[0270]

[0271] Step 1 4-Bromopyridine-2-carboxylic acid 11b

[0272] 4-Bromopyridine-2-carboxylic acid methyl ester 11a (10.0 g, 46.29 mmol) was dissolved in ethanol (40 mL), and sodium hydroxide aqueous solution (30.0 g, 187.5 mmol, 25%) was added. The mixture was stirred at room temperature for 20 minutes. TLC showed that the reaction was complete. Glacial acetic acid was added to the reaction solution and the pH was adjusted to 7-8. A large amount of solid precipitated. The filter cake was filtered, washed with petroleum ether, and dried to obtain the title compound 11b (9.7 g, crude product), which was used directly in the next step.

[0273] LC-MS: m / z = 201.9 [MH] -

[0274] Step 2 4-Bromo-N-methoxy-N-methylpicolylamide 11c

[0275] Compound 11b (9.7 g, crude product) was dissolved in dichloromethane (100 mL), and N,N-diisopropylethylamine (26 mL, 157.3 mmol), N,O-dimethylhydroxylamine hydrochloride (6.08 g, 62.33 mmol) and HATU (23.7 g, 62.33 mmol) were added in sequence, and stirred at room temperature overnight. TLC showed that the reaction was complete. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 11c (6.6 g, two-step yield 58%) as a yellow oil.

[0276] LC-MS: m / z = 246.9 [M+H] +

[0277] Step 3 1-(4-bromopyridin-2-yl)ethan-1-one 11d

[0278] Compound 11c (6.1 g, 24.89 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to 0°C under nitrogen protection, and methylmagnesium bromide (12.44 mL, 37.33 mmol, 3 M) was added dropwise. After the addition, the mixture was stirred at low temperature for 10 minutes, and then stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction solution was quenched by adding saturated ammonium chloride, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 11d (4.9 g, yield 98%) as a yellow oil.

[0279] Step 4: 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine 11e

[0280] Compound 11d (1.0 g, 5.00 mmol) was dissolved in dichloromethane (20 mL), cooled to 0°C under nitrogen protection, triethylamine (2.1 mL, 15.1 mmol) was added, tert-butyldimethylsilyl trifluoromethanesulfonate (1.6 g, 6.05 mmol) was added dropwise, and the mixture was heated to room temperature and stirred for 2 hours. TLC showed that the reaction was complete. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 11e (1.46 g, yield 93%) as an oil.

[0281] Step 5: 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine 11f

[0282] Diethylzinc (15mL, 15.00mmol, 1M) was dissolved in dichloromethane (20mL), and the temperature was lowered to 0°C under nitrogen protection. Chloroiodomethane (5.25g, 29.76mmol) was added dropwise, and stirred at 0°C for 20 minutes. A dichloromethane (10mL) solution of compound 11e (1.46g, 4.64mmol) was added dropwise, and stirred at 0°C for 2 hours. TLC showed that the reaction was basically complete. Saturated ammonium chloride was added to the reaction solution to quench, and ethyl acetate was used for extraction. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 11f (1.02g, yield 67%) as an oil.

[0283] Step 6: N-(2-(1-(((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-amine 11g

[0284] Compound 1f (150 mg, 0.50 mmol) was dissolved in 1,4-dioxane (10 mL), and cesium carbonate (325 mg, 1.00 mmol), Pd2(dba)3 (45 mg, 0.05 mmol), Xantphos (57 mg, 0.10 mmol) and compound 11f (211 mg, 0.64 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100°C and stirred for 3 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 11g (270 mg, yield 98%).

[0285] LC-MS: m / z=548.3[M+H] +

[0286] Step 7: 1-(4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)cyclopropan-1-ol 11

[0287] Compound 11g (270mg, 0.49mmol) was dissolved in tetrahydrofuran (10mL), tetrabutylammonium fluoride (515mg, 1.97mmol) was added, and the mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography and Prep-TLC to obtain the title compound 11 as a white solid (100mg, yield 47%). Chiral column separation (DAICEL AD-H, 30*250mm, 5um, 30mL / min, EtOH:Hexane=40:60) gave compound 11-1 (peak 1, RT: 6.1min) (11.8mg, yield 13%), compound 11-2 (peak 2, RT: 10.3min) (13.9mg, yield 15%).

[0288] Compound 11-1:

[0289] LC-MS: m / z = 434.2 [M+H] +

[0290] 1H NMR (400MHz, DMSO-d6) δ9.47(s,1H),8.11(dd,J=6.0,2.8Hz,2H),7.90(s,1H),7.82(d,J=1.6Hz,1H ),7.62(dd,J=5.2,1.6Hz,1H),6.57(dd,J=5.6,2.0Hz,1H),6.38(d,J=2.0Hz,1H),6.02(s,1H),4.2 2(dd,J=10.4,2.4Hz,1H),3.83-3.75(m,1H),3.72-3.66(m,1H),3.35-3.30(m,1H),1.86-1.75(m,2 H),1.68-1.60(m,1H),1.47-1.42(m,3H),1.18-1.15(m,2H),1.07-1.03(m,2H),1.01-0.95(m,4H).

[0291] Compound 11-2:

[0292] LC-MS: m / z = 434.2 [M+H] +

[0293] 1 H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.11(dd,J=6.0,3.2Hz,2H),7.90(s,1H),7.82(d,J=1.6Hz,1H ),7.62(dd,J=5.2,1.6Hz,1H),6.57(dd,J=6.0,2.0Hz,1H),6.38(d,J=1.6Hz,1H),6.02(s,1H),4.2 2(dd,J=10.8,2.0Hz,1H),3.83-3.75(m,1H),3.72-3.66(m,1H),3.31-3.27(m,1H),1.86-1.75(m,2 H),1.68-1.60(m,1H),1.47-1.42(m,3H),1.18-1.15(m,2H),1.07-1.03(m,2H),1.01-0.95(m,4H).

[0294] Example 12

[0295] 2-(4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-2-yl)propan-2-ol 12

[0296]

[0297] Step 1-Cyclopropyl-3-(3,4-dihydro-2H-pyran-6-yl)-1H-pyrazole 12b

[0298] Compound 12a (18 g, 96 mmol) was dissolved in 1,4-dioxane (200 mL) and water (20 mL), and cesium carbonate (47 g, 144 mmol), Pd(dppf)Cl2 dichloromethane complex (1.3 g, 1.6 mmol), and compound 1c (20 g, 95 mmol) were added in sequence at room temperature, and the temperature was raised to 80°C under nitrogen protection to react overnight. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 12b (6.5 g, yield 35%).

[0299] Step 2 1-Cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 12c

[0300] Compound 12b (6.0 g, 31.5 mmol) was dissolved in methanol (50 mL), palladium carbon (420 mg, 10%) was added, and the mixture was reacted at room temperature for 12 hours under a hydrogen atmosphere until the reaction was complete. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the title compound 12c (6.0 g, crude product), which was used directly in the next step.

[0301] Step 3 1-Cyclopropyl-4-iodo-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 12d

[0302] Under nitrogen protection, compound 12c (6.0 g, crude product) was dissolved in N,N-dimethylformamide (100 mL), and NIS (10.5 g, 46.7 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 12d (7.0 g, two-step yield 71%).

[0303] Step 4 (1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)boronic acid 12e

[0304] Compound 12d (7.0 g, 22.0 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to -30°C under nitrogen protection, isopropyl magnesium chloride (16.5 mL, 33 mmol, 3M tetrahydrofuran solution) was added, the temperature was raised to 0°C for half an hour, triisopropyl borate (4.9 g, 26.0 mmol) was added, and the reaction was continued at 0°C for half an hour. The reaction solution was quenched with saturated ammonium chloride to obtain the title compound 12e (crude product) reaction solution, which was directly used in the next step.

[0305] Step 5 1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-ol 12f

[0306] Compound 12e (crude product) was dissolved in anhydrous tetrahydrofuran (30 mL), and urea peroxide (21.56 g, 229 mmol) was added. The reaction was allowed to react at room temperature for 2 hours until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 12f (2.3 g, two-step yield 50%).

[0307] Step 6: 2-Bromo-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridine 12h

[0308] Compound 12f (300 mg, 1.44 mmol) was dissolved in N,N-dimethylformamide (20 mL), 2-bromo-4-fluoropyridine 12g (380 mg, 2.16 mmol) and cesium carbonate (940 mg, 2.88 mmol) were added at room temperature, the temperature was raised to 40°C and stirred for 12 hours, and the reaction was complete. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 12h (255 mg, yield 48%).

[0309] Step 7: 2-Imino-2-isopropoxyethyl acetate hydrochloride 12j

[0310] Ethyl cyanoformate 12i (10.0 g, 101 mmol) was dissolved in ether (100 mL), and isopropanol (6.0 g, 100 mmol) was added, and hydrogen chloride was introduced at 0°C for 2 hours until saturation, and the reaction was continued at 0°C for 5 hours. Solids precipitated from the reaction solution, which was filtered, and the filter cake was washed and dried to obtain the title compound 12j (15 g, crude product), which was used directly in the next step.

[0311] Step 8 Ethyl 2-amino-2-iminoacetate hydrochloride 12k

[0312] Compound 12j (15 g, crude product) was suspended in ether (300 mL), triethylamine (17 g, 168 mmol) was slowly added dropwise at 0°C, and the temperature was raised to room temperature for 5 hours after the addition was completed. The reaction solution was filtered, the filter cake was washed with ether, the filtrate was concentrated, dissolved in ethanol (200 mL), ammonium chloride (5.3 g, 99 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was filtered to remove insoluble matter, and the filtrate was the title compound 12k (200 mL, ethanol solution), which was used directly in the next step.

[0313] Step 9: 4-aminopyrimidine-2-carboxylic acid ethyl ester 12m

[0314] Add 2-chloroacrylonitrile 12l (1.0 g, 11.4 mmol) to the ethanol solution of compound 12k in the previous step (20 mL, theoretically 10 mmol), cool to 0°C, add triethylamine (3.0 g, 29.6 mmol) dropwise, slowly warm to room temperature and react overnight. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography to obtain the title compound 12m (0.5 g, three-step yield 60%) as an oil.

[0315] LC-MS: m / z = 168.1 [M+H] +

[0316] Step 10 2-(4-aminopyrimidin-2-yl)propan-2-ol 12n

[0317] Compound 12m (0.5 g, 3.0 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to -20°C under nitrogen protection, and methylmagnesium bromide (5 mL, 5 mmol, 1 M) was added dropwise. After addition, the mixture was warmed to room temperature and reacted overnight. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 12n (150 mg, yield 33%) as an oil.

[0318] LC-MS: m / z=154.1[M+H] +

[0319] Step 11 2-(4-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-2-yl)propan-2-ol 12

[0320] Compound 12h (88.5 mg, 0.24 mmol) was dissolved in 1,4-dioxane (10 mL), and cesium carbonate (160 mg, 0.49 mmol), Pd2(dba)3 (22 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol) and compound 12n (150 mg, 0.98 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100 ° C for 3 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 12 (50 mg, yield 48%).

[0321] LC-MS: m / z=437.2[M+H] +

[0322] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),8.39(d,J=5.6Hz,1H),8.17(d,J=5.6Hz,1H),7.90 (s,1H),7.56(br,1H),7.40-7.37(m,1H),6.70(dd,J=6.0,2.4Hz,1H),4.89(s,1H),4.22- 4.19(m,1H),3.77-3.74(m,1H),3.70-3.67(m,1H),3.34-3.27(m,1H),1.79-1.76(m,2H), 1.64-1.60(m,1H),1.50-1.41(m,3H),1.34(s,6H),1.06-1.04(m,2H),0.97-0.93(m,2H).

[0323] Example 13

[0324] N-(4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine 13

[0325]

[0326]

[0327] Step 1: 3-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 13b

[0328] 3-Nitropyrazole 13a (10.0 g, 88.43 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to 0°C under nitrogen protection, sodium hydride (7.07 g, 176.8 mmol, 60%) was added, stirred at 0°C for 30 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (29.5 g, 176.9 mmol) was added dropwise, and the mixture was heated to room temperature and stirred for 2 hours. TLC showed that the reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 13b (27.0 g, crude product) as an oil, which was directly used in the next step.

[0329] Step 2 5-Iodo-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 13c

[0330] Diisopropylamine (11.14 g, 110.0 mmol) was dissolved in tetrahydrofuran (100 mL), and the temperature was lowered to -60 °C under nitrogen protection. A solution of n-butyl lithium (44.0 mL, 110.0 mmol, 2.5 M n-hexane solution) was added dropwise. After addition, the temperature was raised to -20 °C and stirred for 1 hour. The temperature was lowered to -60 °C, and a solution of compound 13b (13.5 g, crude product) in tetrahydrofuran (20 mL) was added dropwise. After addition, the temperature was raised to -60 °C and stirred for 5 hours. A solution of iodine (16.8 g, 66.19 mmol) in tetrahydrofuran (20 mL) was added dropwise. After addition, the temperature was raised slowly to room temperature and reacted overnight. TLC showed that the raw material remained. The reaction solution was quenched with a saturated sodium sulfite solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 13c (6.5 g, two-step yield 40%) as an oil.

[0331] Step 3 3-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-pyrazole 13d

[0332] Compound 13c (6.5 g, 17.60 mmol) was dissolved in 1,4-dioxane (80 mL) and water (10 mL), and potassium trifluoroborate (4.72 g, 35.24 mmol), potassium phosphate (7.47 g, 35.20 mmol) and Pd(dppf)Cl2 dichloromethane complex (645 mg, 0.88 mmol) were added in sequence at room temperature, and the mixture was heated to 100°C and stirred for 15 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 13d (4.4 g, yield 93%) as an oil.

[0333] Step 4: 3-Nitro-5-vinyl-1H-pyrazole 13e

[0334] Compound 13d (4.3 g, 15.96 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (10 mL) was added, and stirred at room temperature for 15 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the solid title compound 13e (3.7 g, crude product), which was used directly in the next step.

[0335] LC-MS: m / z = 138.0 [MH] -

[0336] Step 5 1-allyl-3-nitro-5-vinyl-1H-pyrazole 13f

[0337] Compound 13e (3.7 g, crude product) was dissolved in N,N-dimethylformamide (50 mL), 3-bromopropylene (6.4 g, 52.90 mmol) and cesium carbonate (17.3 g, 53.10 mmol) were added, and stirred at room temperature for 2 hours. TLC showed that the raw material was completely reacted. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 13f (1.8 g, two-step yield 63%) as an oil.

[0338] LC-MS: m / z = 180.1 [M+H] +

[0339] 1 H NMR (400MHz, CDCl3) δ7.00(s,1H),6.55(dd,J=16.0,12.0Hz,1H),5.97(s,1H),5.85(d,J=16.0Hz, 1H), 5.56 (d, J = 12.0Hz, 1H), 5.31 (d, J = 8.0Hz, 1H), 5.13 (d, J = 16.0Hz, 1H), 4.86 (d, J = 4.0Hz, 2H).

[0340] Step 6: 2-Nitro-6H-pyrrolo[1,2-b]pyrazole 13g

[0341] Compound 13f (730 mg, 4.07 mmol) was dissolved in toluene (50 mL), Grubbs second-generation catalyst (346 mg, 0.41 mmol) was added, and the mixture was heated to 100°C and stirred for 3 hours under nitrogen protection. TLC showed that the raw material was not completely reacted. The reaction solution was cooled to room temperature and concentrated. The crude product was separated and purified by silica gel column chromatography to obtain the title compound 13g (270 mg, yield 44%) as a gray solid.

[0342] LC-MS: m / z = 152.1 [M+H] +

[0343] 1 H NMR (400MHz, CDCl3) δ6.74-6.70 (m, 3H), 4.78 (s, 2H).

[0344] Step 7: 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine 13h

[0345] Compound 13g (130 mg, 0.86 mmol) was dissolved in a mixed solvent of anhydrous ethanol (20 mL) and dichloromethane (2 mL), and Pd / C (27 mg, 10%) was added. The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. TLC showed that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated to obtain the solid title compound 13h (180 mg, crude product), which was directly used in the next step.

[0346] LC-MS: m / z = 124.2 [M+H] +

[0347] Step 8 N-(4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine 13

[0348] Compound 12h (88 mg, 0.24 mmol) was dissolved in 1,4-dioxane (10 mL), and cesium carbonate (160 mg, 0.49 mmol), Pd2(dba)3 (22 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol) and compound 13h (60 mg, 0.49 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100°C and stirred for reaction. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 13 (50 mg, yield 51%).

[0349] LC-MS: m / z=407.2[M+H] +

[0350] 1 H NMR(400MHz,DMSO-d6)δ10.27(br,1H),7.95-7.94(m,2H),6.80-6.51(m,2H),5.86( s,1H),4.24(dd,J=11.2,2.0Hz,1H),4.05(t,J=7.2Hz,2H),3.79-3.76(m,1H),3.72- 3.69(m,1H),3.30-3.35(m,1H),2.88(t,J=6.8Hz,2H),2.59-2.52(m,2H),1.80-1.77 (m,2H),1.70-1.64(m,1H),1.54-1.33(m,3H),1.06-1.04(m,2H),0.99-0.95(m,2H).

[0351] Embodiment 14

[0352] 2-(4-((4-((1-cyclopropyl-3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)-2-methylpropionitrile 14

[0353]

[0354] Compound 7c (85 mg, 0.28 mmol) and compound 5e (127 mg, 0.56 mmol) were dissolved in 1,4-dioxane (5 mL), and cesium carbonate (185 mg, 0.57 mmol), Pd2(dba)3 (26 mg, 0.03 mmol) and Xantphos (33 mg, 0.06 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100°C for 2 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with water, washed with saturated laboratory water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 14 (26 mg, yield 21%) as a white solid.

[0355] LC-MS: m / z=443.2[M+H] +

[0356] 1 H NMR (400MHz, DMSO-d6) δ9.67(s,1H),8.30(d,J=5.6Hz,1H),8.16(d,J=5.6Hz,1H),7.99(s,1H),7.76-7.74(m,2H),6.64(dd,J=5.6,2.0Hz,1H) ,6.36(d,J=2.0Hz,1H),6.06(s,1H),4.07(d,J=2.4Hz,2H),3.73-3.70( m,3H),2.41(s,2H),1.66(s,6H),1.09-1.05(m,2H),1.01-0.95(m,2H).

[0357] Embodiment 15

[0358] 2-(6-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 15

[0359]

[0360] Step 1 2-(6-bromopyridin-2-yl)propan-2-ol 15b

[0361] 2-Acetyl-6-bromopyridine 15a (1.0 g, 5.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0°C, and methylmagnesium bromide (2.5 mL, 7.5 mmol, 3 M tetrahydrofuran solution) was added, stirred at room temperature for 1 hour, and the reaction was complete after TLC detection. The reaction solution was quenched with saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 15b (600 mg, yield 64%) as an oil.

[0362] Step 2 2-(6-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 15

[0363] Compound 1f (200 mg, 0.67 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 15b (285 mg, 1.32 mmol), Pd2(dba)3 (61 mg, 0.07 mmol), Xantphos (77 mg, 0.13 mmol) and cesium carbonate (433 mg, 1.33 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100°C for 1 hour. TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 15 (180 mg, yield 62%) as a white solid.

[0364] LC-MS: m / z = 436.2 [M+H] +

[0365] 1 H NMR(400MHz,DMSO-d6)δ9.56(br,1H),8.09(d,J=5.2Hz,1H),7.86(s,1H),7.69-7.51(m,2 H),7.23(d,J=8.0Hz,1H),7.11(d,J=7.2Hz,1H),6.59(s,1H),5.04(s,1H),4.22(d,J=10. 4Hz,1H),3.78(d,J=10.8Hz,1H),3.69-3.65(m,1H),3.33-3.25(m,1H),1.80-1.77(m,2H) ,1.63-1.60(m,1H),1.50-1.41(m,3H),1.30(s,6H),1.07-1.02(m,2H),0.98-0.93(m,2H).

[0366] Example 16

[0367] 2-(2-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylpropionitrile 16

[0368]

[0369] Step 1: tert-Butyl 2-(2-chloropyrimidin-4-yl)-2-cyanoacetate 16c

[0370] 2,4-Dichloropyrimidine 16a (2.0 g, 13.4 mmol) and tert-butyl cyanoacetate 16b (4.8 mL, 33.6 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0°C, sodium hydride (1.3 g, 32.5 mmol, 60%) was added in batches, and the mixture was heated to room temperature for 2 hours. TLC showed that the reaction was complete. Ice water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 16c (2.2 g, yield 64%) as a yellow solid.

[0371] Step 2 2-(2-chloropyrimidin-4-yl)acetonitrile 16d

[0372] Compound 16c (2.2 g, 8.67 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added, and the mixture was reacted at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 16d (370 mg, yield 27%) as a yellow solid.

[0373] Step 3 2-(2-chloropyrimidin-4-yl)-2-methylpropionitrile 16e

[0374] Sodium hydride (65 mg, 1.63 mmol, 60%) was dispersed in N, N-dimethylformamide (5 mL), cooled to 0°C, compound 16d (100 mg, 0.65 mmol) was added in batches, iodomethane (274 mg, 1.93 mmol) was added, and the mixture was heated to room temperature for 1 hour. TLC showed that the reaction was complete. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 16e (110 mg, crude product), which was used directly in the next step.

[0375] Step 4: 2-(2-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylpropionitrile 16-1,2

[0376] Under nitrogen protection, compound 1e-1 (100 mg, 0.33 mmol) was dissolved in 1,4-dioxane (8 mL), and compound 16e (91 mg, 0.50 mmol), cesium carbonate (215 mg, 0.66 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added at room temperature, and the temperature was raised to 100 ° C for 2 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography, methyl tert-butyl ether was added for pulping, filtered, and the filter cake was washed and dried to obtain the solid title compound 16-1 (47 mg, yield 33%).

[0377] LC-MS: m / z=446.3[M+H] +

[0378] 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.61(d,J=4.8Hz,1H),8.17(d,J=5.6Hz,1H),7. 91(d,J=2.0Hz,1H),7.89(s,1H),7.13(d,J=4.8Hz,1H),6.65(dd,J=6.0,2.4Hz,1H),4. 21(dd,J=10.8,2.0Hz,1H),3.76-3.67(m,2H),3.31-3.28(m,1H),1.84-1.72(m,2H),1. 66-1.59(m,1H),1.57(s,6H),1.48-1.37(m,3H),1.08-1.02(m,2H),1.00-0.92(m,2H).

[0379] Under nitrogen protection, compound 1e-2 (100 mg, 0.33 mmol) was dissolved in 1,4-dioxane (7 mL), and compound 16e (91 mg, 0.50 mmol), cesium carbonate (215 mg, 0.66 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) were added at room temperature, and the temperature was raised to 100 ° C for 2 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography, methyl tert-butyl ether was added for pulping, filtered, and the filter cake was washed and dried to obtain the solid title compound 16-2 (63 mg, yield 42%).

[0380] LC-MS: m / z=446.3[M+H] +

[0381] 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),8.58(d,J=5.2Hz,1H),8.13(d,J=5.6Hz,1H),7. 87(d,J=2.4Hz,1H),7.85(s,1H),7.10(d,J=5.2Hz,1H),6.62(dd,J=6.0,2.4Hz,1H),4. 19(dd,J=10.8,2.4Hz,1H),3.73-3.64(m,2H),3.31-3.18(m,1H),1.80-1.68(m,2H),1. 59-1.56(m,1H),1.53(s,6H),1.46-1.33(m,3H),1.04-0.97(m,2H),0.95-0.86(m,2H).

[0382] Embodiment 17

[0383] 2-(4-((4-((1-cyclopropyl-3-(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 17

[0384]

[0385]

[0386] Step 1: 3-Methyltetrahydropyran-4-one 17b

[0387] Diisopropylamine (14.2 g, 0.14 mol) was dissolved in anhydrous tetrahydrofuran (150 mL). The temperature was lowered to -60 °C under nitrogen protection. n-Butyl lithium (52 ​​mL, 0.13 mol, 2.5 M tetrahydrofuran solution) was added dropwise. After the addition, the mixture was stirred at -20 °C for 2 hours. The temperature was lowered to -60 °C. A solution of tetrahydropyran-4-one 17a (10.0 g, 0.10 mol) in tetrahydrofuran (50 mL) was added dropwise. Then, hexamethylphosphoric triamide (17.9 g, 0.10 mol) was added dropwise. After the addition, the mixture was stirred at -60 °C for 30 minutes. Methyl iodide (31 mL, 0.50 mol) was added dropwise. After the addition, the mixture was heated to room temperature and stirred for 2 hours. TLC showed that a small amount of raw material remained. The reaction solution was quenched with water and concentrated to remove tetrahydrofuran. The crude product was dissolved in ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 17b (1.6 g, yield 14%) as an oil.

[0388] Step 2 3-Methyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate 17c

[0389] Compound 17b (1.6 g, 14.0 mmol) was dissolved in anhydrous tetrahydrofuran (80 mL), cooled to -60 ° C under nitrogen protection, and lithium bis(trimethylsilyl)amide (18.0 mL, 18.0 mmol, 1M tetrahydrofuran solution) was added dropwise, and stirred at -60 ° C for 3 hours. A solution of N-phenylbis(trifluoromethane)sulfonyl imide (6.0 g, 16.8 mmol) in tetrahydrofuran (40 mL) was added dropwise, and stirred at low temperature for 20 minutes after the addition, and stirred at room temperature for 3 hours. TLC showed that the reaction was complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 17c (1.55 g, yield 45%) as an oil.

[0390] Step 3 4,4,5,5-Tetramethyl-2-(3-methyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolane 17d

[0391] Compound 17c (1.5 g, 6.09 mmol) was dissolved in 1,4-dioxane (30 mL), and diboronic acid pinacol ester (1.7 g, 6.69 mmol), potassium acetate (1.3 g, 13.25 mmol) and Pd(dppf)Cl2 (490 mg, 0.67 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 80°C and stirred for 3 hours. TLC showed that the reaction was basically complete. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 17d (724 mg, yield 48%).

[0392] Step 4: Tert-butyl (4-((1-cyclopropyl-3-(3-methyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate 17e-1,2

[0393] Intermediate 1IN-1 (1.0 g, 2.15 mmol) was dissolved in 1,4-dioxane (15 mL) and water (1.3 mL), and cesium carbonate (1.4 g, 4.30 mmol), Pd(dppf)Cl2 (157 mg, 0.21 mmol) and compound 17d (724 mg, 3.23 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 90°C and stirred for 16 hours. TLC showed that the reaction was basically complete. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain solid compound 17e (160 mg, yield 18%). Chiral separation (DAICEL AD-H, 30*250mm, 5um, 30mL / min, IPA:Hexane=20:80) gave the title compound 17e-1 (peak 1, RT: 9.8min) (60mg, yield 38%) and the title compound 17e-2 (peak 2, RT: 12.5min) (65mg, yield 41%).

[0394] LC-MS: m / z=413.2[M+H] +

[0395] Step 5: Tert-butyl (4-((1-cyclopropyl-3-(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)carbamate 17f-1,2

[0396] Compound 17e-1 (200 mg, 0.48 mmol) was dissolved in methanol (10 mL), palladium / carbon (100 mg, 10%) was added, and the mixture was stirred at room temperature for 3 hours until the starting material disappeared. The reaction solution was filtered through celite pad, and the filtrate was concentrated to obtain the oily title compound 17f-1 (190 mg, crude product), which was used directly in the next step.

[0397] Compound 17e-2 (230 mg, 0.56 mmol) was dissolved in methanol (10 mL), palladium / carbon (100 mg, 10%) was added, and stirred at room temperature for 3 hours until the starting material disappeared. The reaction solution was filtered through celite pad, and the filtrate was concentrated to obtain the oily title compound 17f-2 (200 mg, crude product), which was directly used in the next step.

[0398] Step 6 4-((1-cyclopropyl-3-(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-amine 17g-1,2

[0399] Compound 17f-1 (190 mg, crude product) was dissolved in trifluoroacetic acid (10 mL) and stirred at room temperature for 3 hours. TLC showed that the starting material disappeared. The reaction solution was concentrated, saturated sodium bicarbonate aqueous solution was added to adjust the pH to alkaline, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the oily title compound 17g-1 (140 mg, crude product), which was directly used in the next step.

[0400] Compound 17f-2 (200 mg, crude product) was dissolved in trifluoroacetic acid (10 mL) and stirred at room temperature for 3 hours. TLC showed that the starting material disappeared. The reaction solution was concentrated, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to alkaline, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the oily title compound 17g-2 (150 mg, crude product), which was directly used in the next step.

[0401] Step 7 2-(4-((4-((1-cyclopropyl-3-(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 17-1,2

[0402] Compound 17g-1 (140 mg, crude product) was dissolved in 1,4-dioxane (15 mL), and cesium carbonate (400 mg, 1.23 mmol), Pd2(dba)3 (50 mg, 0.05 mmol), Xantphos (72 mg, 0.12 mmol) and compound 1b (264 mg, 1.22 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100 ° C and stirred for 2 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 17-1 (70 mg, three-step yield 32%) as a light yellow solid.

[0403] LC-MS: m / z = 450.3 [M+H] +

[0404] 1H NMR (400MHz, DMSO-d6) δ10.21(br,1H),8.27(d,J=6.4Hz,1H),8.21-8.19(m,1H),7.91(d,J=6.4Hz,1H),7. 90(br,2H),6.69-6.68(m,1H),6.52-6.50(m,1H),5.63(br,1H),3.92-3.57(m,3H),3.45-3.39(m,1H),3.3 0-3.27(m,1H),2.94-2.91(m,1H),2.34-2.30(m,0.5H),1.95-1.85(m,0.5H),1.85-1.77(m,1H),1.57-1.5 4(m,1H),1.46(s,6H),1.05-1.03(m,2H),0.97-0.95(m,2H),0.76(d,J=7.2Hz,2H),0.59(d,J=7.2Hz,1H).

[0405] Compound 17g-2 (150 mg, crude product) was dissolved in 1,4-dioxane (15 mL), and cesium carbonate (400 mg, 1.23 mmol), Pd2(dba)3 (50 mg, 0.05 mmol), Xantphos (72 mg, 0.12 mmol) and compound 1b (264 mg, 1.22 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100 ° C and stirred for 2 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 17-2 (100 mg, three-step yield 40%) as a light yellow solid.

[0406] LC-MS: m / z = 450.3 [M+H] +

[0407] 1H NMR (400MHz, DMSO-d6) δ10.22(br,1H),8.27(d,J=6.4Hz,1H),8.22-8.20(m,1H),7.92(d,J=6.4Hz,1H),7. 90(br,2H),6.73-6.65(m,1H),6.52-6.50(m,1H),5.63(br,1H),3.91-3.57(m,3H),3.45-3.39(m,1H),3.3 0-3.27(m,1H),2.94-2.88(m,1H),2.33-2.27(m,0.5H),1.96-1.93(m,0.5H),1.84-1.82(s,1H),1.58-1.5 4(m,1H),1.47(s,6H),1.05-1.03(m,2H),0.97-0.95(m,2H),0.76(d,J=7.2Hz,2H),0.59(d,J=7.2Hz,1H).

[0408] Embodiment 18

[0409] 2-(4-((4-((2-(tetrahydro-2H-pyran-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 18

[0410]

[0411]

[0412] Step 1 5-(4-chlorobutyryl)-2,2-dimethyl-1,3-dioxane-4,6-dione 18c

[0413] Cycloisopropyl malonate 18a (30.0 g, 208.1 mmol) was dissolved in dichloromethane (500 mL), pyridine (32.93 g, 416.3 mmol) was added at room temperature, cooled to 0°C, 4-chlorobutyryl chloride 18b (33.75 g, 239.4 mmol) was slowly added dropwise, stirred overnight at 0°C, TLC showed that the reaction was complete. The reaction solution was poured into ice water, extracted with dichloromethane, the organic phases were combined, washed with water, washed with dilute hydrochloric acid (1N) until pyridine was completely removed, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 18c (30.0 g, crude product), which was directly used in the next step.

[0414] Step 2 6-Chloro-3-oxohexanoic acid ethyl ester 18d

[0415] Compound 18c (30.0 g, crude product) was dissolved in ethanol (200 mL), heated to 95°C and stirred for 24 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18d (21.2 g, two-step yield 53%).

[0416] Step 3 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-ol 18e

[0417] Compound 18d (21.2 g, 110.0 mmol) was dissolved in ethanol (200 mL), hydrazine hydrate (10.3 g, 164.6 mmol, 80%) was added at room temperature, the temperature was raised to 90°C and stirred for 12 hours, TLC showed that the reaction was complete; the reaction solution was cooled to room temperature, potassium carbonate (30.42 g, 220.1 mmol) was added, the temperature was raised to 90°C and reacted for 12 hours, TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated to remove ethanol, the crude product was slurried with a mixed solution of dichloromethane / methanol (10:1), filtered, the filter cake was washed, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18e (6.88 g, yield 50%).

[0418] Step 4: 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl trifluoromethanesulfonate 18f

[0419] Compound 18e (5.5 g, 44.30 mmol) was dissolved in dichloromethane (200 mL), triethylamine (8.97 g, 88.64 mmol) was added at room temperature, cooled to 0°C, trifluoromethanesulfonic anhydride (18.75 g, 66.45 mmol) was slowly added dropwise, stirred at 0°C for 1 hour, and the reaction was complete. The reaction solution was poured into ice water, extracted and separated, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18f (9.5 g, yield 84%).

[0420] Step 5: 2-(3,4-dihydro-2H-pyran-6-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 18g

[0421] Compound 18f (1.5 g, 5.85 mmol) was dissolved in 1,4-dioxane (50 mL), and 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxin 1c (2.48 g, 11.80 mmol), Pd(dppf)Cl2 (489 mg, 0.67 mmol), cesium carbonate (4.8 g, 14.76 mmol) and water (5 mL) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100 ° C and stirred overnight. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, poured into ice water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18g (1.1 g, yield 99%).

[0422] Step 6: 2-(Tetrahydro-2H-pyran-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 18h

[0423] Compound 18g (1.28 g, 6.73 mmol) was dissolved in methanol (50 mL), palladium / carbon (70 mg, 10%) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. TLC showed that the reaction was complete. The reaction solution was filtered through celite pad, the filter cake was washed with methanol, and the filtrate was concentrated to obtain the title compound 18h ​​(1.26 g, crude product), which was used directly in the next step.

[0424] Step 7: 3-iodo-2-(tetrahydro-2H-pyran-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 18i

[0425] Compound 18h ​​(1.26 g, crude product) was dissolved in N,N-dimethylformamide (20 mL), N-iodosuccinimide (2.21 g, 9.82 mmol) was added, and stirred at room temperature for 12 hours. TLC showed that the reaction was complete. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium sulfite, water, and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18i (1.38 g, two-step yield 64%).

[0426] Step 8 (2-(tetrahydro-2H-pyran-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)boronic acid 18j

[0427] Compound 18i (1.5 g, 4.72 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), trimethyl borate (1.96 g, 18.84 mmol) was added at room temperature, and the mixture was cooled to -70 °C under nitrogen protection, and n-butyl lithium (6.9 mL, 17.36 mmol, 2.5 M tetrahydrofuran solution) was slowly added dropwise until the reaction was complete. The reaction solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 18j (600 mg, crude product), which was directly used in the next step.

[0428] Step 9 2-(Tetrahydro-2H-pyran-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ol 18k

[0429] Compound 18j (200 mg, crude product) was dissolved in acetonitrile (20 mL), urea peroxide (400 mg, 4.25 mmol) was added, and stirred at room temperature for 1 hour. TLC showed that the reaction was complete. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 18k (150 mg, crude product), which was directly used in the next step.

[0430] Step 10: 3-((2-bromopyridin-4-yl)oxy)-2-(tetrahydro-2H-pyran-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 18l

[0431] Compound 18k (2.0 g, crude product) was dissolved in N,N-dimethylformamide (30 mL), 2-bromo-4-fluoropyridine 12 g (1.69 g, 9.60 mmol) and cesium carbonate (6.26 g, 19.20 mmol) were added at room temperature, the temperature was raised to 50°C and stirred for 2 hours, TLC showed that the raw materials were completely reacted. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18l (870 mg, three-step yield 11%).

[0432] Step 11: 4-((4-((2-(tetrahydro-2H-pyran-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)pyridin-2-yl)amino)picolinic acid methyl ester 18n

[0433] Compound 18l (250 mg, 0.69 mmol) was dissolved in 1,4-dioxane (20 mL), and cesium carbonate (270 mg, 0.83 mmol), Pd2(dba)3 (80 mg, 0.08 mmol), methyl 4-aminopicolinate 18m (158 mg, 1.04 mmol) and Xantphos (90 mg, 0.16 mmol) were added in sequence at room temperature. Under nitrogen protection, the temperature was raised to 100°C and stirred for 3 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18n (300 mg, yield 84%).

[0434] Step 12 2-(4-((4-((2-(tetrahydro-2H-pyran-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)propan-2-ol 18

[0435] Compound 18n (300 mg, 0.69 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0°C under nitrogen protection, and methylmagnesium bromide (0.46 mL, 1.38 mmol, 3M tetrahydrofuran solution) was slowly added dropwise. After addition, the mixture was stirred at 0°C for 1 hour until the reaction was complete. The reaction solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18 (65 mg, yield 22%).

[0436] LC-MS: m / z = 436.2 [M+H] +

[0437] 1 H NMR (400MHz, DMSO-d6) δ10.25(br,1H),8.27(d,J=6.4Hz,1H),8.20(d,J=5.6Hz,1H),7 .89(br,2H),6.71(d,J=4.0Hz,1H),6.50(s,1H),5.76(s,1H),4.23(dd,J=11.2,2.4Hz, 1H),4.08(t,J=7.2Hz,2H),3.80-3.76(m,1H),3.38-3.37(m,1H),2.74-2.70(m,2H),2. 58-2.53(m,2H),1.82-1.77(m,2H),1.66-1.63(m,1H),1.47(s,6H),1.47-1.39(m,3H).

[0438] Test Example 1 Test of the inhibitory effect of compounds on TGFβR1 (ALK5) kinase activity

[0439] The inhibitory effect of the compounds of the present invention on the in vitro TGFβR1 (ALK5) kinase activity was determined by the following method:

[0440] (1) Compound preparation: dilute the compound to 5 times the required highest concentration with DMSO (Sigma, D2650), 4-fold dilution to a total of 6 concentration gradients. Take 1 ul and transfer to a 384-well plate (Corning, 4512).

[0441] (2) Kinase reaction: 2uL ALK5 kinase (SignalChem, T07-11G-10) solution, 2uL ATP (Promega, V9102) and ALK5 substrate peptide (SignalChem, T36-58) solution were added to a 384-well plate (Corning, 4512) containing the compound. After standing at room temperature for 2 hours, 5uL ADP-Glo ​​(Promega, V9102) solution was added to each well. After standing at room temperature for 30 minutes, 10uL Detection Reagent (Promega, V9102) was added to each well and the plate was allowed to stand for 30 minutes.

[0442] (3) Detection: The chemiluminescent signal value was detected using Synergy H1 (BioTek) multifunctional microplate reader.

[0443] (4) Calculation: Graphpad prism 5.0 software was used to calculate the IC50 value based on the compound concentration and the corresponding signal value. Test results: See Table 1.

[0444] Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on the kinase activity of TGFβR1 (ALK5), and most of the compounds have higher inhibitory activity than LY3200882.

[0445] Test Example 2 Effect of Compounds on the Inhibition of NIH3T3 Cell Proliferation

[0446] The inhibitory effect of the compounds of the present invention on the proliferation of NIH3T3 cells (Chinese Academy of Sciences Cell Bank: GNM 6) in vitro was determined by the following method:

[0447] (1) Cell seeding: NIH3T3 cells in good logarithmic growth state were seeded into a 96-well plate at 3000 cells / well and cultured overnight at 37°C and 5% CO2.

[0448] (2) Administration: The cells cultured overnight were replaced with 90uL of DMEM medium containing 10% FBS, 1% PS, and 5ng / mL TGFβR1 (novoprotein, CK33) recombinant protein. The compound was diluted 4-fold with the above medium and cultured in a cell culture incubator at 37°C and 5% CO2 for 72 hours.

[0449] (3) Detection: 10 uL CCK8 (CK04, Japan Tongren) solution was added to each well, and the cells were incubated in a cell culture incubator at 37°C and 5% CO2 for 1 hour. The OD450 value was read using a Synergy H1 (BioTek) multi-function microplate reader.

[0450] (4) Calculation: Graphpad prism 5.0 software was used to calculate the IC50 value based on the compound concentration and the corresponding signal value. Test results: See Table 1.

[0451] Conclusion: The compounds of the examples of the present invention have an inhibitory effect on cell proliferation, and most of the compounds have an inhibitory activity comparable to or even higher than that of LY3200882.

[0452] Table 1

[0453]

[0454] Test Example 3 Determination of the inhibitory activity of compounds on the Smad signaling pathway of MDA-MB-231 cells

[0455] The inhibitory effect of the compounds of the present invention on the Smad signaling pathway of MDA-MB-231 cells (ATCC: 70015968) in vitro was determined by the following method:

[0456] (1) Cell inoculation: Take MDA-MB-231 cells with good logarithmic growth status and inoculate them at 2*10 5 Each well was inoculated into a six-well plate and cultured overnight at 37°C and 5% CO2.

[0457] (2) Administration: The cells cultured overnight were replaced with 2 mL of DMEM medium containing the compound, 10% FBS, 1% PS, and 5 ng / mL TGFβR1 recombinant protein (novoprotein, CA59), and cultured in a cell culture incubator at 37°C and 5% CO2 for 1 hour.

[0458] (3) Protein extraction and quantification: discard the cell culture medium, rinse with PBS three times, aspirate the residual liquid, add 80uL of cell lysis buffer to each well and place on ice, shake on a shaker for 10 minutes, collect the cell suspension into a 1.5mL centrifuge tube, centrifuge at 12000g for 5 minutes, collect the supernatant, which is the total protein solution; measure the protein concentration by BCA method.

[0459] (4) WB detection and imaging, the results are as follows Figure 1 shown.

[0460] Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on Smad2 / 3 phosphorylation, and most of the compounds have a stronger inhibitory effect on Smad phosphorylation than LY3200882.

[0461] The applicant declares that the present invention uses the above-mentioned embodiments to illustrate an aminopyridyloxypyrazole derivative and its preparation method and application, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0462] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0463] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. An aminopyridyloxypyrazole derivative, characterized in that: The structure of the aminopyridyloxypyrazole derivative is shown in formula (I): Among them, AR 1 is selected from substituted or unsubstituted phenyl, pyridyl, pyrimidyl; the substituted phenyl, pyridyl, pyrimidyl is independently substituted by at least one R c replace; When the substituted phenyl, pyridyl, pyrimidyl group is independently substituted with at least one R c When replaced, R c Independently selected from C1-C20 alkyl, cyano, methoxy or cyclopropyl, wherein the alkyl or cyclopropyl is optionally substituted by at least one independently selected from C1-C20 alkyl, hydroxyl or cyano; R 2 is selected from tetrahydropyran-2-yl, 3,6-dihydro-2H-pyran-4-yl, oxepan-4-yl, cyclohex-1-en-1-yl; the tetrahydropyran-2-yl, cyclohex-1-en-1-yl is optionally substituted by 1-3 R c replaced by; When the tetrahydropyran-2-yl, cyclohex-1-en-1-yl is optionally substituted with 1 to 3 R c When replaced by c Independently selected from C1-C20 alkyl, cyano, methoxy or cyclopropyl; R 3 Selected from H or C1-C3 alkyl; R 4 is selected from cyclopropyl or C1-C3 alkyl, when R 4 When selected from C1-C3 alkyl, R 3 and the C atom to which it is attached and R 4 and the N atom to which it is attached are connected to form a 5-membered heterocyclic ring.

2. The aminopyridyloxypyrazole derivative according to claim 1, characterized in that: The structure of the aminopyridyloxypyrazole derivative is shown in formula (II): Among them, AR 1 and R c Having the same definition as claim 1; n=0-3.

3. The aminopyridyloxypyrazole derivative according to claim 1, characterized in that: The structure of the aminopyridyloxypyrazole derivative is shown in formula (III): Among them, AR 1 It has the same definition as claim 1.

4. The aminopyridyloxypyrazole derivative according to claim 1, characterized in that: The structure of the aminopyridyloxypyrazole derivative is shown in formula (IV): Among them, AR 1 It has the same definition as claim 1.

5. The aminopyridyloxypyrazole derivative according to claim 1, characterized in that: The structure of the aminopyridyloxypyrazole derivative is shown in formula (VI): Among them, AR 1 and R c Having the same definition as claim 1; x=0-3.

6. The aminopyridyloxypyrazole derivative according to claim 1, characterized in that: The structure of the aminopyridyloxypyrazole derivative is shown in formula (VII): Among them, AR 1 and R 2 It has the same definition as claim 1.

7. The aminopyridyloxypyrazole derivative according to claim 1, characterized in that: The aminopyridyloxypyrazole derivative is selected from any one of the following structures:

8. A stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof of the aminopyridyloxypyrazole derivative according to any one of claims 1 to 7.

9. The method for preparing the aminopyridyloxypyrazole derivatives according to any one of claims 1 to 7, characterized in that: The preparation method comprises: reacting a compound of the general formula (IA) with a compound of the general formula (IB) to obtain the aminopyridyloxypyrazole derivative, and the reaction process is as follows: Where X is a halogen, AR 1 , R 2 , R 3 and R 4 It has the same definition as claim 1.

10. The method for preparing the aminopyridyloxypyrazole derivative according to any one of claims 1 to 7, characterized in that: The preparation method comprises: reacting a compound of the general formula (I-Aa) with a compound of the general formula (I-Bb) to obtain the aminopyridyloxypyrazole derivative, and the reaction process is as follows: Where X is a halogen, AR 1 , R 2 , R 3 and R 4 It has the same definition as claim 1.

11. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the stereoisomers, tautomers and pharmaceutically acceptable salts of the aminopyridyloxypyrazole derivatives according to any one of claims 1 to 7 and / or the aminopyridyloxypyrazole derivatives according to claim 8.

12. The pharmaceutical composition according to claim 11, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

13. Use of the aminopyridyloxypyrazole derivatives according to any one of claims 1 to 7, the stereoisomers, tautomers, and pharmaceutically acceptable salts of the aminopyridyloxypyrazole derivatives according to claim 8, and the pharmaceutical composition according to claim 11 in the preparation of drugs for treating cancer or fibrosis-related diseases associated with TGF-βR1 activity or in the preparation of TGF-βR1 inhibitors.

14. The use according to claim 13, characterized in that The cancer includes colon cancer, hepatocellular carcinoma, pancreatic cancer, kidney cancer, breast cancer, brain glioma, gastric cancer or lung cancer.

15. The use according to claim 13, characterized in that The fibrosis-related diseases include liver fibrosis, chronic kidney disease or acquired lymphedema.

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