CN112812105A

CN112812105A - Aminopyridyloxypyrazole derivative and preparation method and application thereof

Info

Publication number: CN112812105A
Application number: CN202110104066.5A
Authority: CN
Inventors: 郑苏欣; 郑明月; 乔刚
Original assignee: Suzhou Almai Biotechnology Co ltd
Current assignee: Suzhou Almai Biotechnology Co ltd
Priority date: 2020-03-24
Filing date: 2021-01-26
Publication date: 2021-05-18

Abstract

The invention relates to an amino pyridyl oxy pyrazole derivative, a preparation method and application thereof, wherein the structure of the amino pyridyl oxy pyrazole derivative is shown as a formula (I). The invention provides a brand-new aminopyridyl oxy pyrazole derivative which has the obvious effects of inhibiting the activity of TGF beta R1(ALK5) kinase and treating cancer or fibrosis related diseases, and the preparation method is simple and easy to operate.

Description

Aminopyridyloxypyrazole derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to an amino pyridyl oxy pyrazole derivative, and a preparation method and application thereof.

Background

TGF-beta (transforming growth factor-beta) is a pleiotropic, pleiotropic cytokine belonging to a group of newly discovered TGF-beta superfamilies that regulate cell growth and differentiation. The family consists of a kind of polypeptide growth factor subfamily related in structure and function, including TGF-beta, activin (activin), Bone Morphogenetic Proteins (BMPs), Growth Differentiation Factors (GDFs) and the like. TGF-beta and its homologous cell membrane receptor (serine/threonine protein kinase) combine to form a compound to participate in cell proliferation, differentiation and apoptosis, and has dynamic balance regulation effects on extracellular matrix synthesis, wound repair, immune function and the like. TGF-beta has at least 5 isomers (TGF-beta 1-5), wherein TGF-beta 1 is most common, almost participates in all pathological and physiological processes, and has close relation with a plurality of clinical diseases. Aberrant TGF β signaling has been elucidated in many diseases, such as cancer and fibrosis. For cancer, TGF β exhibits 2 distinct or opposite effects: in the initial stage of tumorigenesis, the composition plays a role in tumor inhibition by inducing growth inhibition; however, in the later stage of tumorigenesis, TGF β acts to promote Epidermal Mesenchymal Transition (EMT), tumor angiogenesis and immunosuppression, thereby promoting tumor cell infiltration, invasion and metastasis. It has been found that high expression of TGF-beta results in abnormally active TGF-beta/Smads signaling in tumors such as prostate, breast, gastric, colon, bladder, lung, pancreatic, and leukemia. In recent years, more and more researches show that TGF beta plays a remarkable role in the immune regulation of tumor resistance, can inhibit the differentiation of natural immune T cells, negatively regulate the anti-tumor functions of CD8+, dendritic cells and NK cells, and enhance the functions of regulating T cells and myeloid-derived suppressor cells (Nature 2018,554,544 and 548; Nature 2018,554,538 and 543). Therefore, the TGF beta signal pathway plays an important role in regulating the tumor microenvironment, and the inhibitor of the TGF beta signal pathway has the potential to be combined with tumor immune drugs, for example, the combination with the PD1/L1 antibody can enhance the anti-tumor effect.

Known TGF β receptors are divided into three types: type I (TGF-. beta.R 1, also known as ALK5), type II (TGF-. beta.RII), type III (TGF-. beta.RIII); TGF-beta first binds to TGF-beta RII, phosphorylates TGF-beta R1 after complex formation, and then Smad2/3 is also phosphorylated and induces the complex formed with Smad4 to be transferred into the nucleus to participate in the regulation of target genes. At present, the prior art has disclosed that various compounds can be used as inhibitors of TGF- β R1, including WO2016057278, WO2017040448, WO2018017633, WO2016140884, WO2016106266, WO2017215506, WO2018171611, WO2004048382, WO2020088526, WO2020103817, etc., but in order to better meet clinical needs, there is still a need to research and develop new small molecule inhibitors that are safer and more effective against TGF- β R1 target.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide an aminopyridyl radical pyrazole derivative, and a preparation method and application thereof.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides an aminopyridyl radical pyrazole derivative, wherein the structure of the aminopyridyl radical pyrazole derivative is shown in formula (I):

wherein, AR¹Selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-or 6-membered heteroaryl; the substituted phenyl, substituted 5-or 6-membered heteroaryl is independently substituted with at least 1 (e.g., 1,2,3, etc.) R^cSubstituted phenyl, 5-or 6-membered heteroaryl; 2 of said R^cOptionally forming a saturatedAnd or a 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; said cycloalkyl or heterocyclyl is optionally substituted with 1-3 (e.g. 1,2 or 3) R^cSubstitution; the heterocyclyl or heteroaryl independently contains 1-3 (e.g., 1,2, or 3) heteroatoms selected from N, O or S;

R^cindependently selected from alkyl, hydroxy, halo, cyano, alkoxy, cycloalkyl, heterocyclyl, ═ O, alkenyl or amino, said alkyl, alkoxy, cycloalkyl, heterocyclyl or amino optionally substituted with at least 1 (e.g. 1,2 or 3) substituents independently selected from alkyl, hydroxy, halo, cyano, amino or alkoxy;

R²selected from tetrahydropyran-2-yl, 3, 6-dihydro-2H-pyran-4-yl, oxepan-4-yl, cyclohex-1-en-1-yl, and 1-3R^cSubstituted tetrahydropyran-4-yl; said tetrahydropyran-2-yl, cyclohex-1-en-1-yl being optionally substituted with 1-3 (e.g. 1,2 or 3) R^cSubstituted;

R³selected from H or C1-C3 alkyl (e.g., alkyl containing 1,2, or 3 carbon atoms);

R⁴selected from cyclopropyl or C1-C3 alkyl (e.g., alkyl containing 1,2, or 3 carbon atoms), wherein R³And C atom and R to which they are attached⁴And the N atom to which they are attached are optionally joined to form a 5-7 membered (e.g., 5-, 6-or 7-membered) heterocyclic ring.

Preferably, the structure of the aminopyridyl radical pyrazole derivative is shown as a formula (II),

wherein, AR¹And R^cHaving the same limitations as described above; n is 0 to 3 (for example, n is 0, n is 1, n is 2, and n is 3).

Preferably, the structure of the aminopyridyl radical pyrazole derivative is shown as a formula (III),

wherein, AR¹Having the same limitations as described above.

Preferably, the structure of the aminopyridyl radical pyrazole derivative is shown as the formula (IV):

wherein, AR¹Having the same limitations as described above.

Preferably, the structure of the aminopyridyl radical pyrazole derivative is shown as a formula (V),

wherein, AR¹And R^cHaving the same limitations as described above; m is 1 to 3 (for example, m is 1, m is 2, m is 3).

Preferably, the structure of the aminopyridyl radical pyrazole derivative is shown as a formula (VI),

wherein, AR¹And R^cHaving the same limitations as described above; x is 0 to 3 (for example, x is 0, x is 1, x is 2, and x is 3).

Preferably, the structure of the aminopyridyl radical pyrazole derivative is shown as the formula (VII):

wherein, AR¹And R²Having the same limitations as described above.

Further preferably, the aminopyridyl radical pyrazole derivatives are selected from any one of the following structures:

typical compounds of the invention include, but are not limited to, the compounds in the following tables:

in a second aspect, the present invention provides a stereoisomer, a tautomer, or a pharmaceutically acceptable salt of an aminopyridinyloxypyrazole derivative according to the first aspect.

In a third aspect, the present invention provides a method for preparing aminopyridyl radical pyrazole derivatives as described in the first aspect, wherein the method comprises: reacting a compound with a general formula (I-A) with a compound with a general formula (I-B) to obtain the aminopyridyl radical pyrazole derivative, wherein the reaction process is as follows:

wherein X is halogen, AR¹、R²、R³And R⁴Having the same limitations as described above.

As one of the preferable technical proposal of the invention, the preparation method comprises the following steps:

in a fourth aspect, the present invention provides another method for preparing aminopyridinyloxypyrazole derivatives according to the first aspect, comprising: reacting a compound with a general formula (I-Aa) and a compound with a general formula (I-Bb) to obtain the aminopyridinyloxy pyrazole derivative, wherein the reaction process is as follows:

In a fifth aspect, the present invention provides a pharmaceutical composition comprising a stereoisomer, a tautomer, a pharmaceutically acceptable salt of an aminopyridinyloxypyrazole derivative according to the first aspect and/or an aminopyridinyloxypyrazole derivative according to the second aspect.

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

In a sixth aspect, the present invention provides an application of the aminopyridinyloxy pyrazole derivatives of the first aspect, stereoisomers, tautomers, pharmaceutically acceptable salts of the aminopyridinyloxy pyrazole derivatives of the second aspect, and the pharmaceutical composition of the fifth aspect in preparing a medicament for treating cancer or fibrosis related diseases, or in preparing a TGF- β R1 inhibitor.

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

Preferably, the fibrosis-associated disease comprises liver fibrosis, chronic kidney disease or acquired lymphedema.

"alkyl" refers to a saturated aliphatic hydrocarbon group comprising a saturated straight or branched chain monovalent hydrocarbon group of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, wherein the alkyl group may independently be 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be optionally substituted or unsubstituted.

"alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical 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 C-C is sp²A double bond, wherein the alkenyl group may independently be optionally substituted with 1 or more substituents described herein, specific examples of which include, but are not limited to, vinyl, allyl, and alkene butyl, and the like. The alkenyl group may be optionally substituted or unsubstituted.

"cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be optionally substituted or unsubstituted.

"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclyl group containing 3 to 12 ring atoms in which at least one ring atom is a heteroatom, such as oxygen, nitrogen, sulfur, and the like. Preferably having a5 to 7 membered monocyclic ring or a 7 to 10 membered bi-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 to which the parent structure is attached is heterocyclyl. The heterocyclic group may be optionally substituted or unsubstituted.

"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C6-C10 aryl groups, more preferred aryl groups are phenyl and naphthyl groups, and most preferred are phenyl groups. The aryl group may be substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to:

"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 9-to 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, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, 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, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, and benzisoxazolyl. Heteroaryl groups may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples include, but are not limited to:

"alkoxy" means (A), (B), (C), (alkyl-O-). Wherein alkyl is defined in connection with the present application. Alkoxy of C1 to C6 is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like. "hydroxy" refers to an-OH group. "halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine. "amino" means-NH₂. "cyano" means-CN.

"optionally" means that the event it describes may, but need not, occur. For example, "AR¹Optionally substituted by 1 to more R^cSubstituted "the description includes AR¹The radicals may be substituted by 1 to more than one R^cSubstituted or not by R^cAnd (3) the case of substitution.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds. The term "substituted" or "substituted" as used herein means that the group may be substituted with one or more groups selected from the following, unless otherwise specified.

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents:

parker, Ed., McGraw-Hill Dictionary of Chemical termsMcGraw-HillBook Company, New York, 1984; eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but in no way limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Diastereomers may be separated into individual diastereomers on the basis of their physicochemical differences by chromatography, crystallization, distillation, sublimation, or the like. Enantiomers can be separated, such that a chiral isomeric mixture is converted into a diastereomeric mixture by reaction 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 to the corresponding pure enantiomers. The intermediates and compounds of the invention may also exist in different tautomeric forms and all such forms are included within the scope of the invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The atoms or groups of these stereoisomers are attached to each other in the same order, but they differ in their steric structure. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

"tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons. Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are intended to be within the scope of the present invention.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the human or animal body. Salts of the compounds can be obtained by addition of the corresponding salts with a sufficient amount of a base or an acid in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition Salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium Salts and the like, and pharmaceutically acceptable acid addition Salts include Salts of inorganic and organic acids including hydrochloric, hydrobromic, carbonic, bicarbonate, phosphoric, monohydrogen phosphate, dihydrogen phosphate, sulfuric, monohydrogen sulfate, acetic, maleic, malonic, succinic, glutaric, phthalic, benzenesulfonic, p-toluenesulfonic, citric, and methanesulfonic acids and the like (see Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a brand-new aminopyridyl oxy pyrazole derivative which has the obvious effect of inhibiting the activity of TGF beta R1(ALK5) kinase and the obvious effect of treating cancer or fibrosis related diseases, and the preparation method is simple and easy to operate.

Drawings

FIG. 1 is a graph showing the effect of aminopyridyl-oxy-pyrazole derivatives of the present invention on Smad signaling pathway of MDA-MB-231 cells.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.

The examples show the preparation of representative aminopyridyl radical pyrazole derivatives and related methodsStructure identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention.¹The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.¹Method for H NMR expression: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode is ESI.

The thin layer chromatography silica gel plate is HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.2mm-0.3mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm.

The column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius and unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods, and commercially available materials and reagents are used without further purification and unless otherwise indicated, commercially available manufacturers include, but are not limited to, Bailingwei Tech (Shanghai) Kasei Nashiji Tech Co., Ltd, Shanghai Bishi medical Tech Co., Ltd, and Shanghai Mirey chemical Tech Co., Ltd, etc.

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]Palladium dichloride; XantPhos: 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene; HATU: 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate; TLC: thin layer chromatography.

The hydrogen atmosphere refers to that a reaction bottle is connected with a hydrogen balloon with the volume of about 1L; in the examples, the solution in the reaction is an aqueous solution unless otherwise specified. In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing agent used for the reaction, a system of eluents for column chromatography employed for purifying compounds or a developing agent system for thin layer chromatography including: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: n-hexane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.

Preparation of intermediate 1

4- ((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl trifluoromethanesulfonate IN-1

First step methyl 2- ((2-chloropyridin-4-yl) oxy) acetate IN-1b

Compound IN-1a (20.0g,154.4mmol) was dissolved IN N, N-dimethylformamide (200mL), methyl chloroacetate (22.2g,204.6mmol) and cesium carbonate (75.7g,232.3mmol) were added at room temperature, the temperature was raised to 80 ℃ and stirred for 12 hours, TLC showed disappearance of starting material. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid, and the crude product was slurried with petroleum ether (100mL), filtered, and the filter cake was washed and dried to give the title compound IN-1b (20.1g, yield 65%) as a white solid.

Second step methyl (E) -2- (((2-chloropyridin-4-yl) oxy) -3- (dimethylamino) acrylate IN-1c

Compound IN-1b (6.4g,31.74mmol) was dissolved IN 1, 4-dioxane (20mL), added to tert-butoxybis (dimethylamino) methane (10.0mL,49.75mmol) at room temperature, warmed to 75 deg.C and stirred for 1 hour, TLC indicated disappearance of starting material. The reaction was concentrated to give the title compound IN-1c (7.1g, crude) which was used directly IN the next step.

The third step is 4- ((2-chloropyridin-4-yl) oxy) -1H-pyrazol-3-ol IN-1d

Compound IN-1c (7.1g, crude) was dissolved IN ethanol (30mL), hydrazine hydrate (10mL, 85%) was added at room temperature, stirred at room temperature for 1 hour, and TLC showed disappearance of starting material. The reaction mixture was added with water (100mL), concentrated to remove most of the ethanol, extracted 2 times with ethyl acetate, the organic layer was discarded, the aqueous phase was weakly acidic with acetic acid (pH 4-5), a white solid precipitated, filtered, the cake was washed 3 times with water, and dried to give the title compound IN-1d as a white solid (3.9g, 58% yield over two steps).

The fourth step 1-acetyl-4- ((2-chloropyridin-4-yl) oxy) -1H-pyrazol-3-yl acetate IN-1e

Compound IN-1d (4.4g,20.79mmol) was dissolved IN pyridine (30mL), stirred at 95 ℃ and acetic anhydride (4.35g,42.61mmol) was dissolved IN pyridine (20mL) and added dropwise slowly to the reaction mixture at 95 ℃ and stirred for 1 hour after completion of the addition at 95 ℃ as indicated by TLC. The reaction was cooled to room temperature and concentrated to give the title compound IN-1e (crude) which was used directly IN the next step.

LC-MS:m/z＝296.1[M+H]⁺

The fifth step 1- (4- ((2-chloropyridin-4-yl) oxy) -3-hydroxy-1H-pyrazol-1-yl) ethan-1-one IN-1f

Compound IN-1e (crude) was dissolved IN ethanol (100mL), pyridine (2mL) was added at room temperature, the mixture was heated to 90 ℃ and refluxed for 3 hours, a large amount of white solid precipitated, and TLC showed disappearance of starting material. The reaction was cooled to room temperature, filtered, the filter cake washed 2 times with ethanol and dried to give the title compound IN-1f (2.9g, 55% yield over two steps).

LC-MS:m/z＝254.1[M+H]⁺

Sixth step 1- (3- (benzyloxy) -4- ((2-chloropyridin-4-yl) oxy) -1H-pyrazol-1-yl) ethan-1-one IN-1g

Compound IN-1f (2.8g,11.04mmol) was dissolved IN N, N-dimethylformamide (50mL), the system was clarified, benzyl bromide (2.46g,14.38mmol) and potassium carbonate (3.0g,21.71mmol) were added, the mixture was stirred at room temperature for 3 hours, and TLC showed the disappearance of the starting material. Water was added to the reaction mixture to precipitate a solid, which was then filtered, the filter cake was dissolved IN ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to give a white solid, and then petroleum ether (50mL) was added thereto, slurried, filtered, and the filter cake was washed and dried to give the title compound IN-1g (3.1g, yield 82%) as a white solid.

LC-MS:m/z＝344.1[M+H]⁺

Seventh step 4- ((3- (benzyloxy) -1H-pyrazol-4-yl) oxy) -2-chloropyridine IN-1H

Compound IN-1g (3.1g,9.02mmol) was dissolved IN tetrahydrofuran (50mL), aqueous sodium hydroxide (25mL,5M) was added at room temperature, the temperature was raised to 70 ℃ and the mixture was stirred for 60 minutes, and TLC indicated completion of the reaction. The reaction was cooled to room temperature, concentrated to remove tetrahydrofuran, extracted with ethyl acetate, the combined organic phases washed with water, washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound IN-1h as an oil (3.3g, crude) which was used directly IN the next step.

Eighth step 4- ((3- (benzyloxy) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) -2-chloropyridine IN-1j

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

Ninth step tert-butyl (4- ((3- (benzyloxy) -1-cyclopropyl-1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamate IN-1k

Compound IN-1j (2.48g, crude) was dissolved IN 1, 4-dioxane (20mL) and tert-butyl carbamate (2.12g,18.10mmol), Pd, was added at room temperature₂(dba)₃(660mg,0.72mmol), Xantphos (840mg,1.45mmol) and cesium carbonate (4.72g,14.49mmol), heating to 100 ℃ under nitrogen for 6 hours, and TLC showed disappearance of starting material. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated, and crude silica gel column chromatography was performed to give the title compound IN-1k (2.5g, 81% yield IN three steps) as an oil.

Tenth step tert-butyl (4- ((1-cyclopropyl-3-hydroxy-1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamate IN-1l

Compound IN-1k (2.5g,5.92mmol) was dissolved IN methanol (150mL), palladium on carbon (300mg, 10%) was added at room temperature, and the mixture was stirred under hydrogen atmosphere for 1 hour, TLC showed completion of the reaction. The reaction mixture was precipitated as a white solid, tetrahydrofuran (200mL) was added, the mixture was stirred for 30 minutes, direct filtration was performed (celite was not used), and the filtrate was concentrated to give the title compound IN-1l as a white solid (1.8g, yield 92%).

Eleventh step 4- (((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -1-cyclopropyl-1H-pyrazol-3-yl trifluoromethanesulfonate IN-1

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

Example 1

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

First step 2- (4-Bromopyridin-2-yl) propan-2-ol 1b

Methyl 4-bromopicolinate 1a (13.0g,60.18mmol) was dissolved in anhydrous tetrahydrofuran (250mL), cooled to 0 deg.C, methylmagnesium bromide (47mL,141mmol,3M) was added and the reaction was allowed to warm slowly to room temperature for 12h, and TLC indicated completion. The reaction mixture was quenched with saturated ammonium chloride solution (200mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to give the title compound 1b as an oil (6.1g, 47% yield).

Second step tert-butyl (4- ((1-cyclopropyl-3- (3, 4-dihydro-2H-pyran-6-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamate 1d

Intermediate 1IN-1(500mg,1.08mmol) was dissolved IN a mixed solvent of 1, 4-dioxane (15mL) and water (1mL), and 3, 4-dihydro-2H-pyran-6-boronic acid pinacol ester 1c (500mg,2.36mmol), Pd were added IN this order₂(dba)₃(90mg,0.10mmol) and cesium carbonate (702mg,2.0mmol), stirring at 90 ℃ for 2 hours under nitrogen, TLC showed disappearance of starting material. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with pure water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to give the title compound 1d (450mg, crude) as an oil, which was used in the next step.

The third step (4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamic acid tert-butyl ester 1e

Compound 1d (450mg, crude) was dissolved in a mixed solvent of dichloromethane (5mL) and methanol (50mL), palladium on carbon (200mg, 10%) was added, and the mixture was stirred at room temperature for 4 hours under hydrogen protection, and TLC showed disappearance of the starting material. The reaction mixture was filtered through celite, and the filtrate was concentrated to give the title compound 1e (400mg, 92% yield over two steps).

The fourth step 4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine 1f

Compound 1e (400mg,1.00mmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (5mL) was added, and the mixture was stirred at room temperature for 1 hour, TLC showed completion of the reaction. The reaction mixture was concentrated, followed by addition of dichloromethane and saturated aqueous sodium bicarbonate (50mL) for liquid separation, water washing, brine washing, drying over anhydrous sodium sulfate, and concentration to give the title compound 1f (220mg, crude product) as a yellow solid, which was used in the next step.

The fifth step is 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

Compound 1f (220mg, crude) was dissolved in 1, 4-dioxane (50mL), and compound 1b (237mg,1.10mmol), Pd, was added₂(dba)₃(67mg,0.07mmol), Xantphos (84mg,0.15mmol), cesium carbonate (481mg,1.48mmol), reacted at 100 ℃ for 4h under nitrogen, and TLC showed disappearance of starting material. Inverse directionThe reaction solution was cooled to room temperature, water was added, extraction was performed with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC separation to give the title compound 1(150mg, 34% yield over two steps). Chiral column resolution (DAICEL AD-H,30 × 250mm,5um,30mL/min, EtOH: Hexane ═ 20:80) yielded 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%).

Compound 1:

LC-MS:m/z＝436.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ9.45(s,1H),8.20(d,J＝5.6Hz,1H),8.12(d,J＝6.0Hz,1H),7.88(s,1H),7.70-7.67(m,2H),6.56(dd,J＝6.0,2.4Hz,1H),6.38(d,J＝2.4Hz,1H),5.08(s,1H),4.22(dd,J＝11.2,2.8Hz,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).

compound 1-1:

LC-MS:m/z＝436.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ9.48(s,1H),8.20(d,J＝5.2Hz,1H),8.12(d,J＝5.6Hz,1H),7.89(s,1H),7.71-7.68(m,2H),6.57(dd,J＝5.6,2.0Hz,1H),6.37(d,J＝2.0Hz,1H),5.12(s,1H),4.21(dd,J＝9.6,1.2Hz,1H),3.78(d,J＝11.2Hz,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).

compounds 1-2:

LC-MS:m/z＝436.2[M+H]⁺

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),1.84-1.73(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).

example 2

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

First step 2-bromo-N-methoxy-N-methylisonicotinamide 2b

2-bromo-4-pyridinecarboxylic acid 2a (4.0g,19.80mmol), HATU (11.28g,29.67mmol) and triethylamine (6.0g,59.29mmol) were dissolved in N, N-dimethylformamide (80mL), stirred at room temperature for 20 minutes, dimethylhydroxylamine hydrochloride (2.32g,23.78mmol) was added, the reaction was allowed to proceed overnight at room temperature, and the starting material was monitored by TLC for the majority of the reaction. Diluting the reaction solution with water, extracting with ethyl acetate, mixing organic phases, washing with water, washing with saturated salt solution, drying with anhydrous sodium sulfate, concentrating, and purifying by silica gel column chromatography to obtain title compound 2b (4.8g, yield 99%) as light yellow liquid

Second step 1- (2-bromopyridin-4-yl) ethan-1-one 2c

Dissolving the compound 2b (2.0g,8.16mmol) in anhydrous tetrahydrofuran (20mL), cooling to 0 ℃ under the protection of nitrogen, dropwise adding methyl magnesium bromide (4.1mL,12.3mmol,3M), continuing to react for 3 hours after dropwise adding, and detecting the reaction completion by TLC. The reaction was quenched with saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound 2c (1.46g, crude) which was used directly in the next step.

The third step is 2- (2-bromopyridin-4-yl) propan-2-ol 2d

Compound 2c (1.46g, crude) was dissolved in anhydrous tetrahydrofuran (20mL), cooled to 0 ℃ under nitrogen, and methyl magnesium bromide (9.8mL,29.35mmol,3M) was added dropwise, after which the reaction was allowed to proceed overnight at room temperature, and the starting material was left over by TLC. The reaction mixture was quenched with 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 purified by crude silica gel column chromatography to give the title compound 2d as an oil (400mg, 23% yield over two steps).

The fourth step 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

Compound 1f (100mg,0.33mmol), compound 2d (92mg,0.43mmol) and cesium carbonate (216mg,0.66mmol) were dissolved in 1, 4-dioxane (5mL) and Pd was added under nitrogen protection₂(dba)₃(30mg,0.03mmol) and Xantphos (38mg,0.06mmol), displaced with nitrogen three times, warmed to 100 ℃ for 4h and TLC indicated completion of the reaction. 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 purified by crude silica gel column chromatography to give compound 2 as a white solid (30mg, yield 15%).

LC-MS:m/z＝436.3[M+H]⁺

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).

Example 3

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

First step methyl 6- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyrimidine-4-carboxylate 3b

Compound 1f (250mg,0.83mmol) was dissolved in 1, 4-dioxane (50mL) and 6-chloro-pyrimidine-4-carboxylic acid methyl ester 3a (157mg,0.91mmol), Pd was added at room temperature₂(dba)₃(76mg,0.08mmol), Xantphos (96mg,0.17mmol) and carbonic acidCesium (540mg,1.66mmol), under nitrogen, was warmed to 100 ℃ for 2 hours and TLC showed the disappearance of starting material. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentration and purification by crude silica gel column chromatography to give the title compound 3b as an oil (150mg, yield 41%).

Second step 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

Compound 3b (150mg,0.34mmol) was dissolved in anhydrous tetrahydrofuran (10mL), methylmagnesium bromide (2mL,6mmol,3M) was added, stirred at room temperature for 12h, and TLC showed disappearance of starting material. The reaction mixture 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 purified by crude silica gel column chromatography to give the title compound 3 as an oil (90mg, yield 60%). Chiral column resolution (DAICEL AD-H,30 × 250mm,5um,30mL/min, IPA: Hexane ═ 20:80) gave compound 3-1 (Peak 1, RT:22.7min) (13.3mg, yield 15%), compound 3-2 (Peak 2, RT:33.9min) (15.8mg, yield 18%).

Compound 3-1:

LC-MS:m/z＝437.2[M+H]⁺

¹H 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).

compound 3-2:

LC-MS:m/z＝437.3[M+H]⁺

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).

example 4

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

First step 2- (2-Chloropyrimidin-4-yl) propan-2-ol 4b

Methyl 2-chloropyrimidine-4-carboxylate 4a (1.0g,5.8mmol) was dissolved in anhydrous tetrahydrofuran (20mL), cooled to 0 ℃ in an ice bath, methylmagnesium bromide (14.0mL,14.0mmol,1M) was added, and the reaction was completed by TLC overnight at room temperature. The reaction was quenched with water, extracted with ethyl acetate, the combined organic phases washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound 4b (1.0g, crude) as a yellow liquid which was used directly in the next step.

LC-MS:m/z＝173.1[M+H]⁺

Second step 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

Compound 1f (200mg,0.67mmol) was dissolved in 1, 4-dioxane (10mL) under nitrogen, and compound 4b (229mg,1.33mmol), Pd, was added at room temperature₂(dba)₃(61mg,0.07mmol), Xantphos (77mg,0.13mmol) and cesium carbonate (433mg,1.33mmol), and the reaction was warmed to 100 ℃ for 1 hour and checked by TLC for completion. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentration and crude product column chromatography on silica gel to give the title compound 4(180mg, yield 62%) as a solid. Chiral column resolution (DAICEL AD-H,30 × 250mm,5um,30mL/min, EtOH: Hexane ═ 20:80) yielded 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%).

Compound 4-1:

LC-MS:m/z＝437.3[M+H]⁺

¹H 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).

compound 4-2:

LC-MS:m/z＝437.3[M+H]⁺

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).

example 5

2- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2-methylpropanenitrile 5

First step 2-hydroxymethyl-4-bromopyridine 5b

Methyl 4-bromopicolinate 5a (5.0g,23.14mmol) was dissolved in anhydrous ethanol (100mL) under nitrogen, sodium borohydride (1.9g,50.22mmol) was added and the reaction was allowed to react at room temperature for 1 hour and TLC indicated completion. The reaction was added to acetone (25mL), concentrated, diluted with water, extracted with ethyl acetate, the organic phases combined, washed twice with water, twice with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound 5b as a pale yellow solid (4.08g, crude) which was used directly in the next step.

LC-MS:m/z＝190.0[M+H]⁺

Second step (4-bromopyridin-2-yl) methanesulfonic acid methyl ester 5c

Under the protection of nitrogen, the compound 5b (4.08g, crude product) is dissolved in dichloromethane (40mL), cooled to 0 ℃ in an ice-water bath, added with triethylamine (7.2mL,54.25mmol), slowly added with methanesulfonyl chloride (2mL) dropwise, naturally warmed to room temperature for 2 hours, and TLC shows that the reaction is complete. The reaction solution was diluted with water, extracted with dichloromethane, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 5c (5.78g, crude product) (which could not be concentrated to dryness, and the reaction solution deteriorated upon drying of concentration) which was used directly in the next step.

The third step is 2- (4-bromopyridin-2-yl) acetonitrile 5d

Compound 5c (5.78g, crude) was dissolved in acetonitrile (50mL) under nitrogen, trimethylsilyl cyanide (13.5mL,108.5mmol) and anhydrous potassium carbonate (6.0g,43.4mmol) were added at room temperature, the temperature was raised to 75 ℃ and the reaction was complete by TLC. The reaction mixture was cooled to room temperature, 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 purified by crude silica gel column chromatography to give the title compound 5d as a red liquid (1.61g, 36% yield over three steps).

LC-MS:m/z＝199.0[M+H]⁺

Fourth step 2- (4-Bromopyridin-2-yl) -2-methylpropanenitrile 5e

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

The fifth step 4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine 1f-1,2

Compound 1e was resolved by chiral column (DAICEL AD-H, 30X 250mm,5um,30mL/min, EtOH: Hexane ═ 10:90) to give compound 1e-1 (Peak 1, RT:28.0min), compound 1e-2 (Peak 2, RT:35.0 min).

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

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

Sixth step 2- (4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyridin-2-yl) -2-methylpropanenitrile 5-1,2

Compound 1f-1(100mg, crude) was dissolved in 1, 4-dioxane (7mL) under nitrogen, and compound 5e (120mg,0.53mmol), cesium carbonate (215mg,0.66mmol), Pd were added at room temperature₂(dba)₃(27mg,0.03mmol) and Xantphos (35mg,0.06mmol), and the reaction was warmed to 100 ℃ for 75 minutes and complete by TLC. The reaction mixture 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 purified by column chromatography on crude silica gel to give a solid (116mg), slurried with methyl tert-butyl ether (3mL), filtered (10mL of methyl tert-butyl ether), and the filter cake was dried to give the title compound 5-1 as a solid (57mg, 26% yield over two steps).

LC-MS:m/z＝445.3[M+H]⁺

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),1.77-1.75(m,2H),1.63(s,7H),1.43-1.38(m,3H),1.02-0.99(m,2H),0.95-0.92(m,2H).

Compound 1f-2(100mg, crude) was dissolved in 1, 4-dioxane (7mL) under nitrogen, and compound 5e (120mg,0.53mmol), cesium carbonate (215mg,0.66mmol), Pd were added at room temperature₂(dba)₃(27mg,0.03mmol) and Xantphos (35mg,0.06mmol), and the reaction was warmed to 100 ℃ for 75 minutes and complete by TLC. 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, subjected to silica gel column chromatography to give a crude product, slurried with methyl tert-butyl ether (3mL), filtered (10mL of methyl tert-butyl ether), and the filter cake was dried to give the title compound 5-2 as a solid (73mg, yield 33%).

LC-MS:m/z＝445.3[M+H]⁺

¹H 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),1.77-1.75(m,2H),1.63(s,7H),1.40-1.38(m,3H),1.03-1.00(m,2H),0.94-0.91(m,2H).

Example 6

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

First step 4-bromo-2-methoxybenzonitrile 6b

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

Second step 4- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) -2-methoxybenzonitrile 6

Compound 6b (146mg,0.688mmol) was dissolved in 1, 4-dioxane (10mL), and compound 1f (103mg,0.343mmol), cesium carbonate (224mg,0.688mmol), Pd were added sequentially at room temperature₂(dba)₃(31.4mg,0.034mmol), Xantphos (39.7mg,0.069mmol), under nitrogen, the temperature was raised to 100 ℃ for 1.5 hours, and TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on a crude silica gel to give title compound 6(248mg, yield 84%). Chiral column resolution (DAICEL AD-H,30 × 250mm,5um,30mL/min, EtOH: Hexane ═ 10:90) gave compound 6-1 (Peak 1, RT:20.0min) (20mg, yield 8%), compound 6-2 (Peak 2, RT:24.0min) (18mg, yield 7%).

Compound 6-1:

LC-MS:m/z＝432.2[M+H]⁺

¹H 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).

compound 6-2:

LC-MS:m/z＝432.2[M+H]⁺

¹H 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).

example 7

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

The 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

Intermediate 1IN-1(220mg,0.47mmol) was dissolved IN 1, 4-dioxane (50mL), and 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester 7a (197mg,0.94mmol), cesium carbonate (306mg,0.94mmol), Pd (dppf) Cl, was added at room temperature₂Dichloromethane complex (40mg,0.05mmol) and water (10mL) were heated to 80 ℃ under nitrogen and stirred for 5 hours, TLC showed disappearance of starting material. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 7b as an oil (80mg, yield 42%).

LC-MS:m/z＝399.2[M+H]⁺

Second step 4- ((1-cyclopropyl-3- (3, 6-dihydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine 7c

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

LC-MS:m/z＝299.2[M+H]⁺

The third step is 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

Compound 7c (crude) was dissolved in 1, 4-dioxane (50mL), and compound 1b (108mg,0.5mmol), Pd, was added at room temperature₂(dba)₃(24mg,0.026mmol), Xantphos (31mg,0.054mmol) and cesium carbonate (174mg,0.53mmol), heating to 100 ℃ under nitrogen for 4 hours, and TLC showed disappearance of the starting material. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude Prep-TLC to give the title compound 7(10mg, 11% yield in two steps).

LC-MS:m/z＝434.2[M+H]⁺

¹H 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,3H),2.45-2.37(m,2H),1.41(s,6H),1.08-1.05(m,2H),0.99-0.97(m,2H).

Example 8

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

Compound 4b (98.4mg,0.57mmol) was dissolved in 1, 4-dioxane (10mL), and compound 7c (85mg,0.285mmol), cesium carbonate (187mg,0.574mmol), Pd were added sequentially at room temperature₂(dba)₃(26mg,0.028mmol) and Xantphos (33mg,0.057mmol), under nitrogen, warm to 100 ℃ for 1 hour and TLC shows completion of the reaction. The reaction mixture was cooled to room temperature, water was added thereto, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on a crude silica gel to give the title compound 8(26mg, yield 21%).

LC-MS:m/z＝435.3[M+H]⁺

¹H 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).

Example 9

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

First step 4-Oxapazone 9b

Under the protection of nitrogen, anhydrous ether (200mL) is added into a 500mL three-necked flask, dry ice ethanol is cooled to about-70 ℃, n-butyl lithium (52mL,0.13mol,2.5M) is added, and then TMSCHN is slowly dropped at low temperature₂(60mL,0.12mol,2M), stirring for 1 hour at-70 ℃, dropwise adding a solution of tetrahydropyran-4-one 9a (10.0g,0.10mol) in anhydrous tetrahydrofuran (30mL) to the system at low temperature, stirring for 1 hour at low temperature after dropwise adding, adding anhydrous methanol (20mL) at low temperature to quench, slowly raising the temperature to room temperature, adding water to dilute the reaction solution, extracting twice with methyl tert-butyl ether, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, adding silica gel (120g) to the organic phase, stirring for 1 hour at room temperature, filtering to remove the silica gel, concentrating the filtrate, and purifying by crude silica gel column chromatography to obtain the title compound 9b (4.3g, yield 37%) as an oily substance.

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

The second step 9c mixture of 4-bromo-2, 3,6, 7-tetrahydrooxazepine and 5-bromo-2, 3,4, 7-tetrahydrooxazepine

Triphenyl phosphite (13.4g,43.19mmol) is added to anhydrous dichloromethane (50mL) under nitrogen protection, dry ice ethanol is cooled to-60 ℃, bromine (6.01g,37.61mmol) is added dropwise, stirring is carried out for 30 minutes at-60 ℃ after dropping, triethylamine (8.1mL,58.27mmol) is added again, stirring is carried out for 30 minutes at-60 ℃, a solution of compound 9b (3.3g,28.91mmol) in dichloromethane (15mL) is added dropwise, stirring is carried out for 18 hours after dropping to room temperature, and TLC shows that most of the raw materials are reacted completely. The reaction mixture was diluted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by crude silica gel column chromatography to give the title compound 9c as a colorless oil (2.1g, yield 41%).

The third step is a mixture of 4,4,5, 5-tetramethyl-2- (2,3,6, 7-tetrahydroxepin-4-yl) -1,3, 2-dioxaborane and 4,4,5, 5-tetramethyl-2- (2,5,6, 7-tetrahydroxepin-4-yl) -1,3, 2-dioxaborane 9d

Compound 9c (2.1g,11.86mmol) was dissolved in 1, 4-dioxane (30mL) and pinacol ester of diboronic acid (2.7g,10.63mmol), potassium acetate (3.49g,35.56mmol) and Pd (dppf) Cl were added₂Dichloromethane complex (500mg,0.61mmol), under nitrogen, was warmed to 80 ℃ and stirred for 2 hours, TLC showed the starting material to react completely. The reaction was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by crude silica gel column chromatography to give the title compound 9d as a colorless oil (1.01g, 38% yield).

¹H 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).

The fourth step (4- ((1-cyclopropyl-3- (2,3,6, 7-tetrahydrooxazepin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamic acid tert-butyl ester and (4- ((1-cyclopropyl-3- (2,5,6, 7-tetrahydrooxazepin-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamic acid tert-butyl ester mixture 9e

Intermediate 1IN-1(980mg,2.11mmol) was dissolved IN 1, 4-dioxane (20mL) and water (1.5mL) and compound 9d (947mg,4.23mmol), cesium carbonate (1.37g,4.20mmol) and Pd (dppf) Cl were added at room temperature₂Dichloromethane complex (154mg,0.19mmol), under nitrogen, heated to 90 deg.C and stirred for 16 hours, TLC showed the originalA small amount of material remained. The reaction was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by crude silica gel column chromatography to give the title compound 9e as a colorless oil (270mg, 31% yield).

LC-MS:m/z＝413.3[M+H]⁺

Fifth step tert-butyl (4- ((1-cyclopropyl-3- (oxepan-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamate 9f

Compound 9e (270mg,0.655mmol) was dissolved in dry methanol (40mL), palladium on carbon (90mg, 10%) was added, hydrogen replaced twice, stirred at room temperature for 3 hours, and TLC showed complete reaction of the starting material. The reaction was filtered through celite pad, the filter cake was washed twice with dichloromethane, the filtrate was concentrated, and the crude Prep-TLC was purified to give the title compound 9f as an oil (230mg, 84% yield).

LC-MS:m/z＝415.3[M+H]⁺

Sixth step 9g of 4- ((1-cyclopropyl-3- (oxepan-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine

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

LC-MS:m/z＝315.2[M+H]⁺

Seventh step 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

Compound 9g (180mg, crude) was dissolved in 1, 4-dioxane (7mL), and cesium carbonate (373mg,1.14mmol), Pd were added sequentially at room temperature₂(dba)₃(52mg,0.06mmol), Xantphos (66mg,0.11mmol) and Compound 1b (185mg,0.86mmol) were stirred under nitrogen at 100 ℃ for 3h, and TLC indicated complete reaction. Cooling the reaction solution to room temperature, adding water for dilution, extracting by dichloromethane, combining organic phases, washing by saturated salt water, drying by anhydrous sodium sulfate, and concentratingAfter purification by column chromatography on silica gel and Prep-TLC, the title compound 9(100mg, 38% yield in two steps) was obtained as a solid.

LC-MS:m/z＝450.3[M+H]⁺

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),1.75-1.68(m,2H),1.63-1.52(m,1H),1.44(s,6H),1.06-1.02(m,2H),0.97-0.94(m,2H).

Example 10

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

The 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

Intermediate 1IN-1(1.08g,2.32mmol) was dissolved IN 1, 4-dioxane (20mL) under nitrogen, and pinacol 4,4- (dimethylcyclohexen-1-yl) borate 10a (823mg,3.48mmol), water (2mL), cesium carbonate (1.51g,4.63mmol) and Pd (dppf) Cl were added sequentially at room temperature₂Dichloromethane complex (187mg,0.23mmol) was reacted at 90 ℃ for 5 hours. The reaction mixture 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 purified by column chromatography on a crude silica gel to give the title compound 10b (510mg, yield 52%).

Second step 4- ((1-cyclopropyl-3- (4, 4-dimethylcyclohex-1-en-1-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine 10c

Compound 10b (330mg,0.78mmol) was dissolved in trifluoroacetic acid (10mL) and reacted at room temperature for 40 min, TLC indicated completion of the reaction. The reaction was concentrated to remove trifluoroacetic acid, saturated aqueous sodium bicarbonate 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 give the title compound 10c (250mg, crude) which was used directly in the next step.

The third step is 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

Compound 10c (250mg, crude) was dissolved in 1, 4-dioxane (10mL), and compound 1b (251mg,1.16mmol), cesium carbonate (502mg,1.54mmol), Pd, was added₂(dba)₃(73mg,0.08mmol) and Xantphos (93mg,0.16mmol), heating to 100 ℃ under nitrogen for 4 hours, and TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, 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 purified by column chromatography on silica gel to give the title compound 10(77mg, 22% yield over two steps).

LC-MS:m/z＝460.3[M+H]⁺

¹H 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,1H),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).

Example 11

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

First step 11b 4-bromopyridine-2-carboxylic acid

Methyl 4-bromopyridine-2-carboxylate 11a (10.0g,46.29mmol) was dissolved in ethanol (40mL), aqueous sodium hydroxide (30.0g,187.5mmol, 25%) was added, stirring was carried out at room temperature for 20 minutes, and TLC showed completion of the reaction. Glacial acetic acid was added to the reaction mixture, the pH was adjusted to 7-8, a large amount of solid precipitated, filtered, the filter cake washed with petroleum ether and dried to give the title compound 11b (9.7g, crude) which was used directly in the next step.

LC-MS:m/z＝201.9[M-H]^-

Second step 4-bromo-N-methoxy-N-methylpyridinomethylamide 11c

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

LC-MS:m/z＝246.9[M+H]⁺

The third step is 1- (4-bromopyridin-2-yl) ethan-1-one 11d

Compound 11c (6.1g,24.89mmol) was dissolved in tetrahydrofuran (150mL), cooled to 0 deg.C under nitrogen, methyl magnesium bromide (12.44mL,37.33mmol,3M) was added dropwise, stirred at low temperature for 10 min, warmed to room temperature and stirred for 2h, TLC indicated complete reaction. The reaction mixture was quenched with 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 purified by crude silica gel column chromatography to give the title compound 11d as a yellow oil (4.9g, 98% yield).

The fourth step 4-bromo-2- (1- ((tert-butyldimethylsilyl) oxy) vinyl) pyridine 11e

Compound 11d (1.0g,5.00mmol) was dissolved in dichloromethane (20mL), cooled to 0 ℃ under nitrogen, triethylamine (2.1mL,15.1mmol) was added, tert-butyldimethylsilyl trifluoromethanesulfonate (1.6g,6.05mmol) was added dropwise, the mixture was warmed to room temperature and stirred for 2 hours, and TLC indicated completion of the reaction. The reaction mixture was diluted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 11e as an oil (1.46g, yield 93%).

Fifth step 4-bromo-2- (1- ((tert-butyldimethylsilyl) oxy) cyclopropyl) pyridine 11f

Diethyl zinc (15mL,15.00mmol,1M) was dissolved in dichloromethane (20mL), cooled to 0 ℃ under nitrogen, chloroiodomethane (5.25g,29.76mmol) was added dropwise, stirring was carried out for 20 minutes at 0 ℃ after completion of the addition, a solution of compound 11e (1.46g,4.64mmol) in dichloromethane (10mL) was added dropwise, and stirring was carried out for 2 hours while maintaining 0 ℃ after completion of the addition, and TLC showed substantial completion of the reaction. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 11f as an oil (1.02g, yield 67%).

Sixth step 11g of 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

Compound 1f (150mg,0.50mmol) was dissolved in 1, 4-dioxane (10mL), and cesium carbonate (325mg,1.00mmol), Pd were added in that order at room temperature₂(dba)₃(45mg,0.05mmol), Xantphos (57mg,0.10mmol) and compound 11f (211mg,0.64mmol) were stirred at 100 ℃ for 3h under nitrogen and TLC indicated complete reaction. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography on a crude silica gel to give the title compound (11 g, 270mg, yield 98%).

LC-MS:m/z＝548.3[M+H]⁺

Seventh step 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

Compound 11g (270mg,0.49mmol) was dissolved in tetrahydrofuran (10mL), tetrabutylammonium fluoride (515mg,1.97mmol) was added, stirring was carried out at room temperature for 2 hours, and TLC showed completion of the reaction. The reaction mixture 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 and Prep-TLC to give the title compound 11 as a white solid (100mg, 47% yield). Chiral column resolution (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%).

Compound 11-1:

LC-MS:m/z＝434.2[M+H]⁺

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),4.22(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,2H),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).

compound 11-2:

LC-MS:m/z＝434.2[M+H]⁺

¹H 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),4.22(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,2H),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).

example 12

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

First step 1-cyclopropyl-3- (3, 4-dihydro-2H-pyran-6-yl) -1H-pyrazole 12b

Compound 12a (18g,96mmol) was dissolved in 1, 4-dioxane (200mL) and water (20mL), and cesium carbonate (47g,144mmol), Pd (dppf) Cl, was added successively at room temperature₂Dichloromethane complex (1.3g,1.6mmol), and compound 1c (20g,95mmol), under nitrogen, was allowed to warm to 80 ℃ for reaction overnight. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on a crude silica gel to give the title compound 12b (6.5g, yield 35%).

Second step 1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole 12c

Compound 12b (6.0g,31.5mmol) was dissolved in methanol (50mL), and palladium on carbon (420mg, 10%) was added thereto, followed by reaction at room temperature under a hydrogen atmosphere for 12 hours to complete the reaction. The reaction was filtered through celite and the filtrate was concentrated to give the title compound 12c (6.0g, crude) which was used directly in the next step.

The third step is 1-cyclopropyl-4-iodo-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole 12d

Under nitrogen protection, compound 12c (6.0g, crude) was dissolved in N, N-dimethylformamide (100mL), NIS (10.5g,46.7mmol) was added, the mixture was stirred at room temperature overnight, after completion of the reaction, the reaction mixture was 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 purified by silica gel column chromatography to give the title compound 12d (7.0g, 71% yield in two steps).

The fourth step (1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) boronic acid 12e

Compound 12d (7.0g,22.0mmol) was dissolved in anhydrous tetrahydrofuran (100mL), cooled to-30 ℃ under nitrogen, added with isopropyl magnesium chloride (16.5mL,33mmol,3M tetrahydrofuran solution), heated to 0 ℃ for half an hour, added with triisopropyl borate (4.9g,26.0mmol), and allowed to react at 0 ℃ for another half an hour. The reaction was quenched with saturated ammonium chloride to afford the title compound 12e (crude) which was used directly in the next step.

The fifth step 1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-ol 12f

Compound 12e (crude) was dissolved in anhydrous tetrahydrofuran (30mL), urea peroxide (21.56g,229mmol) was added, and the reaction was completed after 2 hours at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on a crude silica gel to give the title compound 12f (2.3g, 50% yield in two steps).

Sixth step 2-bromo-4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridine 12H

Compound 12f (300mg,1.44mmol) was dissolved in N, N-dimethylformamide (20mL), 12g (380mg,2.16mmol) of 2-bromo-4-fluoropyridine and cesium carbonate (940mg,2.88mmol) were added at room temperature, and the reaction was completed by warming to 40 ℃ and stirring for 12 hours. The reaction mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on a crude silica gel to give the title compound (255mg, yield 48%) in 12 h.

Seventh step ethyl 2-imino-2-isopropoxyacetate hydrochloride 12j

Ethyl cyanoformate 12i (10.0g,101mmol) was dissolved in diethyl ether (100mL), isopropanol (6.0g,100mmol) was added, hydrogen chloride was bubbled through to saturation at 0 ℃ for 2 hours, and reaction was continued at 0 ℃ for 5 hours. The reaction solution was precipitated as a solid, filtered, and the filter cake was washed and dried to give the title compound 12j (15g, crude) which was used directly in the next step.

Eighth step ethyl 2-amino-2-iminoacetate hydrochloride 12k

Compound 12j (15g, crude) was suspended in diethyl ether (300mL), triethylamine (17g,168mmol) was slowly added dropwise at 0 deg.C, and after completion of the dropwise addition, the reaction was allowed to warm to room temperature for 5 hours. The reaction mixture was filtered, the filter cake was washed with ether, the filtrate was concentrated, dissolved in ethanol (200mL), and ammonium chloride (5.3g,99mmol) was added to react at room temperature overnight. The reaction mixture was filtered to remove insoluble materials, and the filtrate was the title compound 12k (200mL, ethanol solution) and used directly in the next step.

Ninth step Ethyl 4-aminopyrimidine-2-carboxylate 12m

12l (1.0g,11.4mmol) of 2-chloroacrylonitrile is added into the 12k ethanol solution (20mL, 10mmol in theory) of the compound in the last step, the temperature is reduced to 0 ℃, triethylamine (3.0g,29.6mmol) is added dropwise, and the mixture slowly rises to room temperature to react overnight. The reaction mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 12m as an oil (0.5g, 60% yield in three steps).

LC-MS:m/z＝168.1[M+H]⁺

The tenth step 2- (4-aminopyrimidin-2-yl) propan-2-ol 12n

Dissolving the compound 12M (0.5g,3.0mmol) in anhydrous tetrahydrofuran (20mL), cooling to-20 ℃ under the protection of nitrogen, dropwise adding methyl magnesium bromide (5mL,5mmol,1M), and completely heating to room temperature for reaction overnight. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic phases combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 12n as an oil (150mg, yield 33%).

LC-MS:m/z＝154.1[M+H]⁺

Eleventh step 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

Compound 12h (88.5mg,0.24mmol) was dissolved in 1, 4-dioxane (10mL) and cesium carbonate (160mg,0.49mmol), Pd were added sequentially at room temperature₂(dba)₃(22mg,0.02mmol), Xantphos (27mg,0.05mmol) and compound 12n (150mg,0.98mmol) were reacted at 100 ℃ for 3 hours under nitrogen and TLC showed completion. The reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by crude Prep-TLC to give the title compound 12(50mg, 48% yield).

LC-MS:m/z＝437.2[M+H]⁺

¹H 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).

Example 13

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

First step 3-Nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole 13b

3-Nitropyrazole 13a (10.0g,88.43mmol) was dissolved in tetrahydrofuran (150mL), cooled to 0 ℃ under nitrogen, sodium hydride (7.07g,176.8mmol, 60%) was added, stirred at 0 ℃ for 30 min, 2- (trimethylsilyl) ethoxymethyl chloride (29.5g,176.9mmol) was added dropwise, and after the addition was raised to room temperature and stirred for 2h, TLC showed completion of the reaction. The reaction was quenched with water, extracted with ethyl acetate, the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give the title compound 13b as an oil (27.0g, crude) which was used in the next step.

Second step 5-iodo-3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole 13c

Diisopropylamine (11.14g,110.0mmol) is dissolved in tetrahydrofuran (100mL), the temperature is reduced to-60 ℃ under the protection of nitrogen, n-butyllithium solution (44.0mL,110.0mmol,2.5M n-hexane solution) is added dropwise, the mixture is stirred for 1 hour after the addition is finished and the temperature is raised to-20 ℃, the mixture is reduced to-60 ℃, a tetrahydrofuran (20mL) solution of a compound 13b (13.5g, crude product) is added dropwise, the mixture is stirred for 5 hours after the addition is finished and the mixture is added dropwise into the mixture at-60 ℃, a tetrahydrofuran (20mL) solution of an iodine simple substance (16.8g,66.19mmol) is added dropwise, the mixture is slowly raised to room temperature for reaction overnight, and TLC shows the residual part. The reaction was quenched with saturated sodium sulfite solution, extracted with ethyl acetate, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 13c as an oil (6.5g, 40% yield over two steps).

The third step is 3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -5-vinyl-1H-pyrazole 13d

Compound 13c (6.5g,17.60mmol) was dissolved in 1, 4-dioxane (80mL) and water (10mL), potassium vinyltrifluoroborate (4.72g,35.24mmol) was added sequentially at room temperature,potassium phosphate (7.47g,35.20mmol) and Pd (dppf) Cl₂Dichloromethane complex (645mg,0.88mmol), warmed to 100 ℃ and stirred for 15 hours, TLC showed completion of the reaction. The reaction was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 13d as an oil (4.4g, yield 93%).

The fourth step is 3-nitro-5-vinyl-1H-pyrazole 13e

Compound 13d (4.3g,15.96mmol) was dissolved in dichloromethane (50mL), trifluoroacetic acid (10mL) was added, the mixture was stirred at room temperature for 15 hours, and TLC indicated completion of the reaction. The reaction was concentrated to give the title compound 13e as a solid (3.7g, crude) which was used directly in the next step.

LC-MS:m/z＝138.0[M-H]^-

The fifth step is 1-allyl-3-nitro-5-vinyl-1H-pyrazole 13f

Compound 13e (3.7g, crude) was dissolved in N, N-dimethylformamide (50mL), 3-bromopropene (6.4g,52.90mmol) and cesium carbonate (17.3g,53.10mmol) were added, stirred at room temperature for 2 hours and TLC indicated complete reaction of starting materials. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 13f as an oil (1.8g, two-step yield 63%).

LC-MS:m/z＝180.1[M+H]⁺

¹H 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).

Sixth step 13g of 2-nitro-6H-pyrrolo [1,2-b ] pyrazole

Compound 13f (730mg,4.07mmol) was dissolved in toluene (50mL), Grubbs's second generation catalyst (346mg,0.41mmol) was added, the temperature was raised to 100 ℃ under nitrogen and stirred for 3 hours, TLC indicated that the starting material was not reacted completely. The reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography on a crude silica gel to give the title compound (13 g, 270mg, yield 44%) as a gray solid.

LC-MS:m/z＝152.1[M+H]⁺

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

Seventh step 5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-amine 13H

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

LC-MS:m/z＝124.2[M+H]⁺

Eighth step 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

Compound 12h (88mg,0.24mmol) was dissolved in 1, 4-dioxane (10mL), and cesium carbonate (160mg,0.49mmol), Pd were added sequentially at room temperature₂(dba)₃(22mg,0.02mmol), Xantphos (27mg,0.05mmol) and compound 13h (60mg,0.49mmol) were stirred at 100 ℃ under nitrogen and TLC showed complete reaction. The reaction mixture 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 purified by column chromatography on a crude silica gel to give the title compound 13(50mg, yield 51%).

LC-MS:m/z＝407.2[M+H]⁺

¹H 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).

Example 14

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-methylpropanenitrile 14

Compound 7c (85mg,0.28mmol) and compound 5e (127mg,0.56mmol) were dissolved in 1, 4-dioxane (5mL), and cesium carbonate (185mg,0.57mmol), Pd, were added sequentially at room temperature₂(dba)₃(26mg,0.03mmol) and Xantphos (33mg,0.06mmol), heating to 100 ℃ under nitrogen for 2 hours, and TLC showed the reaction was complete. The reaction was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the combined organic phases were washed with water, saturated laboratory wash, dried over anhydrous sodium sulfate, concentrated, and crude product was purified by column chromatography on silica gel to give the title compound 14(26mg, yield 21%) as a white solid.

LC-MS:m/z＝443.2[M+H]⁺

¹H 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).

Example 15

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

First step 2- (6-Bromopyridin-2-yl) propan-2-ol 15b

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

Second step 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

Compound 1f (200mg,0.67mmol) was dissolved in 1, 4-dioxane (10mL), and compound 15b (285mg,1.32mmol), Pd, was added sequentially at room temperature₂(dba)₃(61mg,0.07mmol), Xantphos (77mg,0.13mmol) and cesium carbonate (433mg,1.33mmol) were reacted at 100 ℃ for 1 hour under nitrogen protection and TLC checked for completion. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 15(180mg, yield 62%) as a white solid.

LC-MS:m/z＝436.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ9.56(br,1H),8.09(d,J＝5.2Hz,1H),7.86(s,1H),7.69-7.51(m,2H),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).

Example 16

2- (2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-methylpropanenitrile 16

First step tert-butyl 2- (2-chloropyrimidin-4-yl) -2-cyanoacetate 16c

2, 4-dichloropyrimidine 16a (2.0g,13.4mmol) and tert-butyl cyanoacetate 16b (4.8mL,33.6mmol) were dissolved in anhydrous tetrahydrofuran (20mL), cooled to 0 deg.C, and sodium hydride (1.3g,32.5mmol, 60%) was added in portions, warmed to room temperature and reacted for 2 hours, and TLC indicated completion of the reaction. The reaction mixture was added with 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 subjected to crude silica gel column chromatography to give the title compound 16c (2.2g, yield 64%) as a yellow solid.

Second step 2- (2-Chloropyrimidin-4-yl) acetonitrile 16d

Compound 16c (2.2g,8.67mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (10mL) was added and the reaction was allowed to proceed at room temperature for 1 hour and TLC indicated completion. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate solution was added, extraction was performed with dichloromethane, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and crude silica gel column chromatography gave the title compound 16d as a yellow solid (370mg, yield 27%).

The third step is 2- (2-chloropyrimidin-4-yl) -2-methylpropanenitrile 16e

Sodium hydride (65mg,1.63mmol, 60%) was dispersed in N, N-dimethylformamide (5mL), cooled to 0 deg.C, and Compound 16d (100mg,0.65mmol) was added in portions, iodomethane (274mg,1.93mmol) was added, warmed to room temperature and reacted for 1 hour, and TLC showed completion of the reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound 16e (110mg, crude) which was used directly in the next step.

The fourth step 2- (2- ((4- ((1-cyclopropyl-3- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) amino) pyrimidin-4-yl) -2-methylpropanenitrile 16-1,2

Compound 1e-1(100mg,0.33mmol) was dissolved in 1, 4-dioxane (8mL) under nitrogen, and compound 16e (91mg,0.50mmol), cesium carbonate (215mg,0.66mmol), Pd, and palladium were added at room temperature₂(dba)₃(27mg,0.03mmol) and Xantphos (35mg,0.06mmol), and was allowed to warm to 100 ℃ for 2 hours and TLC showed completion. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography on a crude silica gel, slurried with methyl tert-butyl ether, filtered, and the filter cake was washed and dried to give the title compound 16-1 as a solid (47mg, yield 33%).

LC-MS:m/z＝446.3[M+H]⁺

¹H 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).

Compound 1e-2(100mg,0.33mmol) was dissolved in 1, 4-dioxane (7mL) under nitrogen, and compound 16e (91mg,0.50mmol), cesium carbonate (215mg,0.66mmol), Pd were added at room temperature₂(dba)₃(27mg,0.03mmol) and Xantphos (35mg,0.06mmol), and was allowed to warm to 100 ℃ for 2 hours and TLC showed completion. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography on a crude silica gel, slurried with methyl tert-butyl ether, filtered, and the filter cake was washed and dried to give the title compound 16-2 as a solid (63mg, yield 42%).

LC-MS:m/z＝446.3[M+H]⁺

¹H 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).

Example 17

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

First step 3-Methyltetrahydropyran-4-one 17b

Diisopropylamine (14.2g,0.14mol) was dissolved in anhydrous tetrahydrofuran (150mL), cooled to-60 ℃ under nitrogen, n-butyllithium (52mL,0.13mol,2.5M tetrahydrofuran solution) was added dropwise, stirred for 2 hours at-20 ℃ after completion of the dropwise addition, cooled to-60 ℃ and then added dropwise with a tetrahydrofuran (50mL) solution of tetrahydropyran-4-one 17a (10.0g,0.10mol), followed by hexamethylphosphoric triamide (17.9g,0.10mol), stirred for 30 minutes at-60 ℃, added dropwise with methyl iodide (31mL,0.50mol), stirred for 2 hours after completion of the dropwise addition to room temperature, and TLC indicated that a small amount of starting material remained. The reaction was quenched with water, concentrated to remove tetrahydrofuran, the crude product was dissolved in ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on crude silica gel to give the title compound 17b as an oil (1.6g, 14% yield).

Second step 3-methyl-3, 6-dihydro-2H-pyran-4-yl-trifluoromethanesulfonate 17c

Dissolving the compound 17b (1.6g,14.0mmol) in anhydrous tetrahydrofuran (80mL), cooling to-60 ℃ under the protection of nitrogen, dropwise adding lithium bis (trimethylsilyl) amide (18.0mL,18.0mmol,1M tetrahydrofuran solution), stirring for 3 hours at-60 ℃ after dropwise adding, dropwise adding a tetrahydrofuran (40mL) solution of N-phenyl bis (trifluoromethane) sulfimide (6.0g,16.8mmol), stirring for 20 minutes at low temperature after dropwise adding, heating to room temperature and stirring for 3 hours, and TLC shows that the reaction is complete. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude silica gel column chromatography to give the title compound 17c as an oil (1.55g, yield 45%).

The third step is 4,4,5, 5-tetramethyl-2- (3-methyl-3, 6-dihydro-2H-pyran-4-yl) -1,3, 2-dioxaborane 17d

Compound 17c (1.5g,6.09mmol) was dissolved in 1, 4-dioxane (30mL) and pinacol ester of diboronic acid (1.7g,6.69mmol), potassium acetate (1.3g,13.25mmol) and Pd (dppf) Cl were added sequentially at room temperature₂(490mg,0.67mmol), under nitrogen, warm to 80 ℃ and stir for 3 hours, TLC showed substantial completion of the reaction. The reaction mixture 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 purified by column chromatography on crude silica gel to give the title compound 17d (724mg, 48% yield).

The fourth step (4- ((1-cyclopropyl-3- (3-methyl-3, 6-dihydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamic acid tert-butyl ester 17e-1,2

Intermediate 1IN-1(1.0g,2.15mmol) was dissolved IN 1, 4-dioxane(15mL) and water (1.3mL) were added cesium carbonate (1.4g,4.30mmol), Pd (dppf) Cl in that order at room temperature₂(157mg,0.21mmol) and compound 17d (724mg,3.23mmol) were heated to 90 ℃ under nitrogen and stirred for 16 h, TLC showed substantial reaction completion. 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 purified by crude silica gel column chromatography to give solid compound 17e (160mg, yield 18%). Chiral resolution (DAICEL AD-H,30 × 250mm,5um,30mL/min, IPA: Hexane ═ 20:80) gave title compound 17e-1 (peak 1, RT:9.8min) (60mg, yield 38%) and title compound 17e-2 (peak 2, RT:12.5min) (65mg, yield 41%).

LC-MS:m/z＝413.2[M+H]⁺

Fifth step tert-butyl (4- ((1-cyclopropyl-3- (3-methyltetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-yl) carbamate 17f-1,2

Compound 17e-1(200mg,0.48mmol) was dissolved in methanol (10mL), palladium on carbon (100mg, 10%) was added, and the mixture was stirred at room temperature for 3 hours, whereupon the starting material disappeared. The reaction was filtered through celite and the filtrate was concentrated to give the title compound 17f-1 as an oil (190mg, crude) which was used directly in the next step.

Compound 17e-2(230mg,0.56mmol) was dissolved in methanol (10mL), palladium on carbon (100mg, 10%) was added, and the mixture was stirred at room temperature for 3 hours, whereupon the starting material disappeared. The reaction was filtered through celite and the filtrate was concentrated to give the title compound 17f-2 as an oil (200mg, crude) which was used directly in the next step.

Sixth step 4- ((1-cyclopropyl-3- (3-methyltetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) oxy) pyridin-2-amine 17g-1,2

Compound 17f-1(190mg, crude) was dissolved in trifluoroacetic acid (10mL), stirred at room temperature for 3 hours and TLC showed disappearance of starting material. The reaction mixture was concentrated, and then saturated aqueous sodium bicarbonate was added to adjust the pH to basic, followed by extraction with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 17g-1(140mg, crude product) as an oily title compound which was used in the next step.

Compound 17f-2(200mg, crude) was dissolved in trifluoroacetic acid (10mL), stirred at room temperature for 3 hours and TLC showed disappearance of starting material. The reaction mixture was concentrated, and then saturated aqueous sodium bicarbonate was added to adjust the pH to basicity, followed by extraction with ethyl acetate, and then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 17g-2(150mg, crude product) as an oily title compound which was used in the next step.

Seventh step 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

Compound 17g-1(140mg, crude) was dissolved in 1, 4-dioxane (15mL), and cesium carbonate (400mg,1.23mmol), Pd were added in that order at room temperature₂(dba)₃(50mg,0.05mmol), Xantphos (72mg,0.12mmol) and compound 1b (264mg,1.22mmol) were stirred at 100 ℃ for 2h under nitrogen and TLC indicated complete reaction. The reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by crude Prep-TLC to give the title compound 17-1 as a pale yellow solid (70mg, 32% yield in three steps).

LC-MS:m/z＝450.3[M+H]⁺

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),3.30-3.27(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),1.57-1.54(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).

Compound 17g-2(150mg, crude) was dissolved in 1, 4-dioxane (15mL), and cesium carbonate (400mg,1.23mmol), Pd were added in that order at room temperature₂(dba)₃(50mg,0.05mmol), Xantphos (72mg,0.12mmol) and compound 1b (264mg,1.22mmol) were stirred at 100 ℃ for 2h under nitrogen and TLC indicated complete reaction. The reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by crude Prep-TLC to give the title compound 17-2 as a pale yellow solid (100mg, 40% yield in three steps).

LC-MS:m/z＝450.3[M+H]⁺

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),3.30-3.27(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),1.58-1.54(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).

Example 18

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

First step 5- (4-chlorobutyryl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione 18c

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

Second step Ethyl 6-chloro-3-oxohexanoate 18d

Compound 18c (30.0g, crude) was dissolved in ethanol (200mL), warmed to 95 deg.C and stirred for 24 h, TLC indicated complete reaction. The reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography on a crude silica gel to give the title compound 18d (21.2g, 53% yield in two steps).

The third step is 5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-ol 18e

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

The fourth step is 5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl trifluoromethanesulfonate 18f

Compound 18e (5.5g,44.30mmol) was dissolved in dichloromethane (200mL), triethylamine (8.97g,88.64mmol) was added at room temperature, cooled to 0 deg.C, trifluoromethanesulfonic anhydride (18.75g,66.45mmol) was slowly added dropwise, and the reaction was completed by stirring at 0 deg.C for 1 hour. The reaction mixture was poured into ice water, separated by extraction, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on a crude silica gel to give the title compound 18f (9.5g, yield 84%).

The fifth step 18g of 2- (3, 4-dihydro-2H-pyran-6-yl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole

Compound 18f (1.5g,5.85mmol) was dissolved in 1, 4-dioxane (50mL) and 2- (3, 4-dihydro-2H-pyran-6-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxine 1c (2.48g,11.80mmol), Pd (dppf) Cl was added sequentially at room temperature₂(489mg,0.67mmol), cesium carbonate (4.8g,14.76mmol) and water (5mL) under nitrogen, warmed to 100 ℃ and stirred overnight, TLC indicated complete reaction. The reaction mixture 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 purified by column chromatography on a crude silica gel to give 18g (1.1g, yield 99%) of the title compound.

Sixth step 2- (tetrahydro-2H-pyran-2-yl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole 18H

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

Seventh step 3-iodo-2- (tetrahydro-2H-pyran-2-yl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole 18i

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

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

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

Ninth step 2- (tetrahydro-2H-pyran-2-yl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-ol 18k

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

Tenth step 18l of 3- ((2-bromopyridin-4-yl) oxy) -2- (tetrahydro-2H-pyran-2-yl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole

Compound 18k (2.0g, crude) was dissolved in N, N-dimethylformamide (30mL), 12g (1.69g,9.60mmol) of 2-bromo-4-fluoropyridine and cesium carbonate (6.26g,19.20mmol) were added at room temperature, the mixture was stirred at 50 ℃ for 2 hours, and TLC indicated complete reaction of the starting materials. The reaction mixture 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 purified by column chromatography on a crude silica gel to give 18l (870mg, 11% yield in three steps) of the title compound.

Eleventh step methyl 4- ((4- ((2- (tetrahydro-2H-pyran-2-yl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) oxy) pyridin 2-yl) amino) picolinate 18n

Compound 18l (250mg,0.69mmol) was dissolved in 1, 4-dioxane (20mL), and cesium carbonate (270mg,0.83mmol), Pd were added successively at room temperature₂(dba)₃(80mg,0.08mmol), methyl 4-aminopyridinecarboxylate 18m (158mg,1.04mmol) and Xantphos (90mg,0.16mmol) were stirred at 100 ℃ for 3h under nitrogen and TLC indicated complete reaction. The reaction mixture 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 purified by column chromatography on a crude silica gel to give the title compound 18n (300mg, yield 84%).

Twelfth step 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

Compound 18n (300mg,0.69mmol) was dissolved in anhydrous tetrahydrofuran (20mL), cooled to 0 ℃ under nitrogen, methylmagnesium bromide (0.46mL,1.38mmol,3M in tetrahydrofuran) was slowly added dropwise, and the reaction was completed by stirring at 0 ℃ for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give title compound 18(65mg, yield 22%).

LC-MS:m/z＝436.2[M+H]⁺

¹H 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).

Test example 1 test of inhibitory Effect of Compounds on TGF-beta R1(ALK5) kinase Activity

The detection of the in vitro inhibition of TGF β R1(ALK5) kinase activity by the compounds of the present invention was determined by the following method:

(1) preparation of compound: compounds were diluted 5-fold with DMSO (Sigma, D2650) to the desired maximum concentration, 4-fold over a total of 6 concentration gradients. Transfer 1ul to 384 well plates (Corning, 4512).

(2) Kinase reaction: a384-well plate (Corning,4512) containing the compound was added with a 2uL ALK5 kinase (SignalChem, T07-11G-10) solution, a mixed solution of 2uL ATP (Promega, V9102) and ALK5 substrate polypeptide (SignalChem, T36-58), and left at room temperature for 2 hours, then a 5uL ADP-Glo (Promega, V9102) solution was added to each well, and left at room temperature for 30 minutes, then 10uL Detection Reagent (Promega, V9102) was added to each well, and left at room temperature for 30 minutes.

(3) And (3) detection: chemiluminescence signal values were measured using a Synergy H1(BioTek) multifunctional microplate reader.

(4) And (3) calculating: IC50 values were calculated from compound concentrations and corresponding signal values using Graphpad prism 5.0 software. And (3) test results: see table 1.

And (4) conclusion: the compounds of the embodiment of the invention have obvious inhibition effect on TGF beta R1(ALK5) kinase activity, and most of the compounds have higher inhibition activity than LY 3200882.

Test example 2 Effect of the Compounds on inhibition of NIH3T3 cell proliferation

The effect of the compounds of the present invention on the inhibition of proliferation of NIH3T3 cells (cell Bank of Chinese academy: GNM 6) in vitro was determined by the following method:

(1) cell inoculation: NIH3T3 cells with good log phase growth were seeded at 3000 cells/well in 96-well plates at 37 ℃ with 5% CO₂Incubated under conditions overnight.

(2) Administration: the cells cultured overnight were replaced with 90uL of DMEM containing 10% FBS, 1% PS, and 5ng/mL of TGF-beta R1(novoprotein, CK33) recombinant protein, and the compound was diluted with the above medium in a 4-fold gradient and placed at 37 ℃ in 5% CO₂Cell cultureThe culture was carried out in a chamber for 72 hours.

(3) And (3) detection: adding 10uL of CCK8 (Japan Co., Ltd., CK04) solution into each well, and keeping the temperature at 37 ℃ and 5% CO₂After incubation for 1 hour in the cell incubator, the Synergy H1(BioTek) multifunctional microplate reader reads the OD450 value.

And (4) 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 equivalent to or even higher than that of LY 3200882.

TABLE 1

Test example 3 assay of Smad Signaling pathway inhibitory Activity of Compounds on MDA-MB-231 cells

The effect of the compounds of the invention on inhibition of the Smad signalling pathway in MDA-MB-231 cells in vitro (ATCC:70015968) was determined by the following method:

(1) cell inoculation: taking MDA-MB-231 cells with good logarithmic phase growth state by 2 x 10⁵One/well was inoculated into six-well plates at 37 ℃ with 5% CO₂Incubated under conditions overnight.

(2) Administration: the overnight cultured cells were replaced with 2mL DMEM medium containing compound, 10% FBS, 1% PS, and 5ng/mL TGF-. beta.R 1 recombinant protein (novoprotein, CA59), and placed at 37 ℃ in 5% CO₂The cells were cultured in a cell incubator for 1 hour.

(3) Protein extraction and quantification: discarding the cell culture medium, washing with PBS for 3 times, blotting out residual liquid, adding 80uL of cell lysate to each well, placing on ice, shaking by a shaking table for 10 minutes, collecting cell suspension to a 1.5mL centrifuge tube, centrifuging at 12000g for 5min, and collecting supernatant, namely total protein solution; the BCA method measures protein concentration.

(4) WB detection and imaging are carried out, and the results are shown in FIG. 1.

And (4) conclusion: the compounds of the embodiment of the invention have obvious inhibition effect on Smad2/3 phosphorylation, and most of the compounds have stronger Smad phosphorylation inhibition effect than LY 3200882.

The applicant states that the invention is illustrated by the above examples to show one aminopyridyl radical pyrazole derivative of the invention, its preparation method and application, but the invention is not limited by the above examples, i.e. it does not mean that the invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.

It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.

Claims

1. An aminopyridyl radical pyrazole derivative is characterized in that the structure of the aminopyridyl radical pyrazole derivative is shown in formula (I):

wherein, AR¹Selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-or 6-membered heteroaryl; said substituted phenyl, substituted 5-or 6-membered heteroaryl is independently substituted with at least 1R^cSubstituted phenyl, 5-or 6-membered heteroaryl; 2 of said R^cOptionally forming a saturated or partially saturated 3-7 membered cycloalkyl or 4-7 membered heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted1-3R^cSubstitution; said heterocyclyl or heteroaryl independently contains 1-3 heteroatoms selected from N, O or S;

R^cindependently selected from alkyl, hydroxy, halo, cyano, alkoxy, cycloalkyl, heterocyclyl, ═ O, alkenyl, or amino, said alkyl, alkoxy, cycloalkyl, heterocyclyl, or amino optionally substituted with at least 1 substituent independently selected from alkyl, hydroxy, halo, cyano, amino, or alkoxy;

R²selected from tetrahydropyran-2-yl, 3, 6-dihydro-2H-pyran-4-yl, oxepan-4-yl, cyclohex-1-en-1-yl, and 1-3R^cSubstituted tetrahydropyran-4-yl; said tetrahydropyran-2-yl, cyclohex-1-en-1-yl being optionally substituted with 1-3R^cSubstituted;

R³selected from H or C1-C3 alkyl;

R⁴selected from cyclopropyl or C1-C3 alkyl, wherein R³And C atom and R to which they are attached⁴And the N atom to which they are attached are optionally joined to form a 5-7 membered heterocyclic ring.

2. Aminopyridyloxypyrazole-based derivative according to claim 1, wherein the aminopyridyl-based derivative has the structure shown in formula (II):

wherein, AR¹And R^cHaving the same limits as in claim 1; n is 0 to 3.

3. Aminopyridyloxypyrazole-based derivative according to claim 1, wherein the aminopyridyl-based derivative has the structure shown in formula (III):

wherein, AR¹Having the same limits as in claim 1.

4. Aminopyridyloxypyrazole-based derivative according to claim 1, wherein the aminopyridyl-based derivative has the structure shown in formula (IV):

wherein, AR¹Having the same limits as in claim 1;

preferably, the structure of the aminopyridyl radical pyrazole derivative is shown as the formula (V):

wherein, AR¹And R^cHaving the same limits as in claim 1; m is 1-3;

preferably, the structure of the aminopyridyl radical pyrazole derivative is shown as the formula (VI):

wherein, AR¹And R^cHaving the same limits as in claim 1; x is 0-3;

wherein, AR¹And R²Having the same limits as in claim 1.

5. Aminopyridyloxypyrazole-based derivative according to claim 1, wherein the aminopyridyl-oxy pyrazole-based derivative is selected from any one of the following structures:

6. stereoisomers, tautomers or pharmaceutically acceptable salts thereof of aminopyridinyloxypyrazole derivatives according to any of claims 1 to 5.

7. Process for the preparation of aminopyridinyloxypyrazole derivatives according to any of claims 1 to 5, wherein the process comprises: reacting a compound with a general formula (I-A) with a compound with a general formula (I-B) to obtain the aminopyridyl radical pyrazole derivative, wherein the reaction process is as follows:

wherein X is halogen, AR¹、R²、R³And R⁴Having the same limits as in claim 1.

8. Process for the preparation of aminopyridinyloxypyrazole derivatives according to any of claims 1 to 5, wherein the process comprises: reacting a compound with a general formula (I-Aa) and a compound with a general formula (I-Bb) to obtain the aminopyridinyloxy pyrazole derivative, wherein the reaction process is as follows:

9. Pharmaceutical composition comprising a stereoisomer, a tautomer, a pharmaceutically acceptable salt of an aminopyridinyloxypyrazole derivative according to any of claims 1 to 5 and/or of an aminopyridinyloxypyrazole derivative according to claim 6;

10. Use of an aminopyridinyloxypyrazole derivative according to any of claims 1 to 5, a stereoisomer, a tautomer, a pharmaceutically acceptable salt of an aminopyridinyloxypyrazole derivative according to claim 6 and a pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of cancer or fibrosis-related diseases or for the preparation of a TGF- β R1 inhibitor;

preferably, the cancer comprises colon cancer, hepatocellular carcinoma, pancreatic cancer, renal cancer, breast cancer, myelodysplastic syndrome, brain glioma, gastric cancer or lung cancer;