Preparation method of novel Rho-associated protein kinase inhibitor and intermediate in this preparation method

Abstract

Process for preparing a novel Rho-associated protein kinase inhibitor having a structure of formula (A) and intermediates in this preparation process.

Description

Field of the Invention

[0001] The present invention relates to a method for preparing a novel Rho-associated protein kinase inhibitor and an intermediate in this preparation method. Background of the Invention

[0003] Rho-associated protein kinase (ROCK) is a serine / threonine protein kinase of the AGC kinase family, which includes two subtypes, ROCK1 and ROCK2. ROCK1 and ROCK2 are differentially expressed and regulated in specific tissues. For example, ROCK1 is ubiquitously expressed at a relatively high level, while ROCK2 is preferentially expressed in the heart, brain, and skeletal muscle. ROCK is the first Rho protein downstream effector discovered, and it achieves its biological function by phosphorylating downstream effector proteins (such as MLC, Lin-11, Isl-1, LIMK, ERM, MARCKS, CRMP-2, etc.). Studies have shown that various diseases (such as pulmonary fibrosis, cardiovascular and cerebrovascular diseases, nervous system diseases, and cancers, etc.) are related to the ROCK-mediated pathway. Therefore, in drug research and development, ROCK is considered an important target.

[0004] The present applicant has found that (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1-yl)methanone can be used as an effective Rho-associated protein kinase (ROCK) inhibitor (see PCT / CN2018 / 093713, which is incorporated herein by reference in its entirety), but there has been no report on a method suitable for preparing this compound on a larger scale. Summary of the Invention

[0006] In one aspect, the present invention provides a method for preparing a compound of formula (I)-c,

[0007]

[0008] wherein:

[0009] PG is -CH(OR 5 )R 6 , preferably -CH(OCH2CH3)CH3;

[0010] Hal 1 is a halogen, such as F, Cl, Br, or I, preferably Cl;

[0011] R a and R a’ each independently selected from H and C 1-6 alkyl each time they appear; or R a and R a’Together with the groups to which it is attached, form a 5- to 10-membered ring system (the ring system is preferably );

[0012] R is selected from H and C 1-6 alkyl;

[0013] R 1 is preferably

[0014] R 3 、R 4 、R 7 and R 8 each independently, upon each occurrence, is selected from H, halogen, -NR 5 R 6 、-OH、C 1-6 alkyl and -OR 5 ;

[0015] R 9 and R 10 each independently, upon each occurrence, is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, -C(=O)R 5 and -C 1-6 alkylene-O(P=O)(OH)2;

[0016] The above-mentioned alkylene, alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are each optionally substituted, upon each occurrence, by one or more substituents independently selected from halogen, C 1-6 alkyl and -OR 5 ;

[0017] R 5 and R 6 each independently, upon each occurrence, is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl; or R 5 and R 6 together with the atoms to which they are attached, form a 3- to 12-membered heterocyclic or heteroaromatic ring;

[0018] m is each independently an integer of 0, 1, 2 or 3 upon each occurrence; and

[0019] n is each independently an integer of 0, 1 or 2 upon each occurrence;

[0020] The method includes reacting a compound of formula (I)-a with a compound of formula (I)-b under the catalysis of a catalyst (such as a metal catalyst, preferably a palladium catalyst) (preferably in the presence of a base) to obtain a compound of formula (I)-c.

[0021] In another aspect, the present invention provides a method for preparing a compound of formula (I),

[0022]

[0023] wherein:

[0024] R 2 is selected from H and C 1-6 alkyl; and

[0025] the remaining groups are as defined above;

[0026] The method includes the following steps:

[0027] The first step: reacting a compound of formula (I)-a with a compound of formula (I)-b under the catalysis of a catalyst (such as a metal catalyst, preferably a palladium catalyst) (preferably in the presence of a base) to obtain a compound of formula (I)-c; and

[0028] The second step: removing the PG protecting group from the compound of formula (I)-c to obtain a compound of formula (I); and when R 2 is C 1-6 alkyl, it further includes the step of reacting with a reagent containing R 2 groups.

[0029] In another aspect, the present invention provides the intermediates involved in the above method.

[0030] The method of the present invention has various advantages, such as fewer by-products, higher yield of the final product; milder reaction conditions; shorter reaction cycle; and is suitable for large-scale synthesis.

[0031] Brief Description of the Drawings

[0032] Figure 1 It is the HPLC chromatogram of the reaction solution in step 9 of Example 1.

[0033] Figure 2 It is the HPLC chromatogram of the reaction solution in the comparative example. Detailed Description of the Invention

[0035] Definition

[0036] Unless otherwise defined herein, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those techniques or substitutions of equivalent techniques that are apparent to one of ordinary skill in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the present invention.

[0037] The terms "comprises," "comprising," "has," "having," "includes," "including," "involves," or other variations thereof used herein are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0038] As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene, propylene, or butylene.

[0039] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl has 1 to 12, such as 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 alkyl" refers to a linear or branched group having 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (such as CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0040] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group that contains one double bond and has 2 - 6 carbon atoms ("C 2-6 alkenyl"). The alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When a compound of the present invention contains an alkenylene group, the compound can exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0041] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0042] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.)), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15 carbon atoms. For example, the term "C 3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 6 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0043] As used herein, the terms "subcycloalkyl", "cycloalkyl" and "hydrocarbon ring" refer to a saturated (i.e., "subcycloalkyl" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3 - 10 (suitably 3 - 8, more suitably 3 - 6) ring carbon atoms, including but not limited to (sub)cyclopropyl(ring), (sub)cyclobutyl(ring), (sub)cyclopentyl(ring), (sub)cyclohexyl(ring), (sub)cycloheptyl(ring), (sub)cyclooctyl(ring), (sub)cyclononyl(ring), (sub)cyclohexenyl(ring), etc.

[0044] As used herein, the terms "heterocyclic group", "heterocyclylene group" and "heterocycle" refer to saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic groups having, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered (sub)heterocycle(yl)" is a saturated or partially unsaturated (sub)heterocycle(yl) having 2 to 9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclylene groups and heterocycle(yl) groups include, but are not limited to: (sub)oxiranyl, (sub)aziridinyl, (sub)azetidinyl, (sub)oxetanyl, (sub)tetrahydrofuranyl, (sub)dioxolinyl, (sub)pyrrolidinyl, (sub)pyrrolidinonyl, (sub)imidazolidinyl, (sub)pyrazolidinyl, (sub)pyrrolinyl, (sub)tetrahydropyranyl, (sub)piperidinyl, (sub)morpholinyl, (sub)dithianyl, (sub)thiomorpholinyl, (sub)piperazinyl or (sub)trithianyl. The groups also encompass bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene group and heterocycle(yl) may optionally be substituted by one or more (e.g., 1, 2, 3 or 4) suitable substituents.

[0045] As used herein, the terms "(sub)aryl" and "aryl ring" refer to fully carbon monocyclic or fused ring polycyclic aromatic groups having a conjugated π electron system. For example, as used herein, the terms "C 6-10 (sub)aryl" and "C 6-10 aryl ring" mean aromatic groups containing 6 to 10 carbon atoms, such as (sub)phenyl (benzene ring) or (sub)naphthyl (naphthalene ring). The (sub)aryl and aryl ring are optionally substituted by 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.).

[0046] As used herein, the terms “(hetero)aryl” and “heteroaromatic ring” refer to monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and containing at least one heteroatom (said heteroatom being, for example, oxygen, nitrogen or sulfur), which may be the same or different, and which may additionally be benzo-fused in each case. In particular, “(hetero)aryl” or “heteroaromatic ring” is selected from (hetero)thienyl, (hetero)furyl, (hetero)pyrrolyl, (hetero)oxazolyl, (hetero)thiazolyl, (hetero)imidazolyl, (hetero)pyrazolyl, (hetero)isoxazolyl, (hetero)isothiazolyl, (hetero)oxadiazolyl, (hetero)triazolyl, (hetero)thiadiazolyl, etc., and their benzo derivatives; or (hetero)pyridyl, (hetero)pyridazinyl, (hetero)pyrimidinyl, (hetero)pyrazinyl, (hetero)triazinyl, etc., and their benzo derivatives.

[0047] As used herein, the term “aralkyl” preferably denotes an alkyl group substituted with an aryl or heteroaryl group, wherein the aryl, heteroaryl and alkyl groups are as defined herein. Generally, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

[0048] As used herein, the term “halo” or “halogen” group is defined to include F, Cl, Br or I.

[0049] As used herein, the term “nitrogen-containing heterocycle” refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may also optionally contain one or more (e.g., one, two, three or four) ring members selected from N, O, C═O, S, S═O and S(═O)2, which is linked to the remainder of the molecule through the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle being optionally benzo-fused and preferably linked to the remainder of the molecule through the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzo ring.

[0050] The term “substituted” means that one or more (e.g., one, two, three or four) hydrogens on the specified atom are replaced by a selection from the indicated groups, provided that the normal valence of the specified atom in the present case is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variables are only permitted if such combinations result in a stable compound.

[0051] If a substituent is described as "optionally substituted", the substituent may (1) be unsubstituted or (2) be substituted. If a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced by independently selected optional substituents, individually and / or together. If a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced by an independently selected optional substituent.

[0052] If a substituent is described as "independently selected from" a group, each substituent is selected independently of the others. Thus, each substituent may be the same as or different from another (other) substituent.

[0053] As used herein, the term "one or more" means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, or 10.

[0054] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0055] When the bond of a substituent is shown as passing through a bond connecting two atoms in a ring, such a substituent may be bonded to any ring-forming atom in the ring that can be substituted.

[0056] The present invention also includes all isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominating in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g., 36 Cl); isotopes of fluorine (e.g., 18 F); isotopes of iodine (e.g., 123 I and 125 I); isotopes of nitrogen (e.g., 13 N and 15 N); isotopes of oxygen (e.g., 15 O, 17 O, and 18 O); isotopes of phosphorus (e.g., 32P); and sulfur isotopes (e.g., 35S). Certain isotopically labeled compounds of the invention (e.g., those incorporating a radioactive isotope) can be used in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because they are readily incorporated and easily detected. Substitution with a positron emitting isotope (e.g., 11 C, 18 F, 15 O and 13 N) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents in place of the previously employed unlabeled reagents. Solvates of the invention include those in which the crystallization solvent can be isotopically substituted, e.g., D2O, acetone-d6 or DMSO-d6.

[0057] The term "stereoisomers" refers to isomers formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three or four) asymmetric centers, they can give rise to racemic mixtures, single enantiomers, mixtures of diastereoisomers and individual diastereoisomers. Particular individual molecules can also exist as geometric isomers (cis / trans). Similarly, compounds of the invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0058] Solid lines (-), solid wedges or dashed wedges Depict the chemical bonds of the compounds of the present invention. The use of solid lines to depict bonds attached to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds attached to an asymmetric carbon atom is intended to indicate the presence of the depicted stereoisomer. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist in the form of stereoisomers, which include cis- and trans-isomers, optical isomers (e.g., R and S enantiomers), diastereoisomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs).

[0059] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of any proportion of more than one polymorph.

[0060] It should also be understood that certain compounds of the present invention may exist in free form or, where appropriate, in the form of their derivatives. In the present invention, said derivatives include, but are not limited to, salts, solvates. Accordingly, when referring to "compounds of the present invention" herein, it is also intended to cover the above various derivative forms of the compounds.

[0061] The salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0062] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexylsulfamate, edisylate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hippurate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethylsulfonate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinoformate.

[0063] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts and zinc salts.

[0064] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing the salts of the compounds of the present invention are known to those skilled in the art.

[0065] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, especially for example water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, especially water, may be present in a stoichiometric or non-stoichiometric ratio.

[0066] The present invention also encompasses compounds of the present invention containing protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. The protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0067] The term "about" means within ±10% of the stated value, preferably within ±5% of the stated value, more preferably within ±2% of the stated value.

[0068] Preparation method

[0069] In some embodiments, the present invention provides a method for preparing a compound of formula (I)-c,

[0070]

[0071] wherein:

[0072] PG is -CH(OR 5 )R 6 , preferably -CH(OCH2CH3)CH3;

[0073] Hal 1is a halogen, such as F, Cl, Br or I, preferably Cl;

[0074] R a and R a’ each independently selected from H and C 1-6 alkyl each time it appears; or R a and R a’ together with the group to which they are attached form a 5- to 10-membered ring system (the ring system is preferably );

[0075] R is selected from H and C 1-6 alkyl;

[0076] R 1 is preferably

[0077] R 3 、R 4 、R 7 and R 8 each independently selected from H, halogen, -NR 5 R 6 、-OH、C 1-6 alkyl and -OR 5 ;

[0078] R 9 and R 10 each independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, -C(=O)R 5 and -C 1-6 alkylene-O(P=O)(OH)2;

[0079] The above-mentioned alkylene, alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are each optionally substituted by one or more substituents independently selected from halogen, C 1-6 alkyl and -OR 5 ;

[0080] R 5 and R 6 each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl; or R 5 and R6 Together with the atoms to which it is attached, it forms a 3- to 12-membered heterocyclic or heteroaromatic ring (preferably a 5- or 6-membered heterocyclic ring);

[0081] Each occurrence of m is independently an integer of 0, 1, 2, or 3; and

[0082] Each occurrence of n is independently an integer of 0, 1, or 2;

[0083] The method includes reacting a compound of formula (I)-a with a compound of formula (I)-b under the catalysis of a catalyst (such as a metal catalyst, preferably a palladium catalyst) (preferably in the presence of a base) to obtain a compound of formula (I)-c.

[0084] In some embodiments, the present invention provides a method for preparing a compound of formula (I),

[0085]

[0086] wherein:

[0087] R 2 is selected from H and C 1-6 alkyl; and

[0088] The remaining groups are as defined above;

[0089] The method includes the following steps:

[0090] The first step: Reacting a compound of formula (I)-a with a compound of formula (I)-b under the catalysis of a catalyst (such as a metal catalyst, preferably a palladium catalyst) (preferably in the presence of a base) to obtain a compound of formula (I)-c; and

[0091] The second step: Removing the PG protecting group from the compound of formula (I)-c to obtain a compound of formula (I); and when R 2 is C 1-6 alkyl, it further includes the step of reacting with a reagent containing R 2 .

[0092] In a preferred embodiment, is The above groups are connected to the pyrimidine ring at the position marked with * and to the carbonyl group at the position marked with **.

[0093] In a preferred embodiment, R is H.

[0094] In a preferred embodiment, R 2 is H.

[0095] In a preferred embodiment, R 5 and R 6Each independently selected from H, methyl, and ethyl at each occurrence; or R 5 and R 6 together with the atom to which it is attached form

[0096] In a preferred embodiment, R 3 、R 4 、R 7 and R 8 Each independently selected from H, F, Cl, Br, I, -NH2, -OH, methyl, trifluoromethyl, -CH2-Ph, methoxy, ethoxy, and -CH2OCH3 at each occurrence.

[0097] In a preferred embodiment, R 3 is H.

[0098] In a preferred embodiment, R 4 is selected from H and halogen (such as F, Cl, Br, or I), preferably H or F.

[0099] In a preferred embodiment, R 7 is selected from H and halogen (such as F, Cl, Br, or I), preferably H or F.

[0100] In a preferred embodiment, R 8 is H.

[0101] In a preferred embodiment, R 9 and R 10 Each independently selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, acetyl, -CH2CHF2, -CH20H, -CH2OCH3, -CH2CH2OCH3, -CH2-O(P=O)(OH)2 at each occurrence,

[0102] In a preferred embodiment, R 9 Each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl at each occurrence, preferably H.

[0103] In a preferred embodiment, R 10 Each independently selected from H and C 1-6 alkyl at each occurrence, preferably H, methyl, ethyl, n-propyl, or isopropyl, most preferably H or methyl.

[0104] In a preferred embodiment, the compound of formula (I)-a is compound A-51 having the following structure:

[0105]

[0106] The compound of formula (I)-b is compound A-8 having the following structure:

[0107] And

[0108] The compound of formula (I)-c is compound A-103 having the following structure:

[0109]

[0110] In a preferred embodiment, the compound of formula (I) is compound A having the following structure:

[0111]

[0112] In a preferred embodiment, the palladium catalyst is selected from dichlorobis (diphenylphosphino) ferrocene palladium, tris (dibenzylideneacetone) dipalladium, triphenylphosphine palladium and palladium acetate, and preferably dichlorobis (diphenylphosphino) ferrocene palladium.

[0113] In a preferred embodiment, the base is an inorganic base selected from potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate, and preferably potassium acetate or potassium carbonate.

[0114] In a preferred embodiment, in the reaction of the compound of formula (I)-a with the compound of formula (I)-b, the molar ratio of the compound of formula (I)-a to the compound of formula (I)-b is about 1:1 - 1:2, and preferably about 1:1 - 1:1.5.

[0115] In a preferred embodiment, in the reaction of the compound of formula (I)-a with the compound of formula (I)-b, the molar ratio of the compound of formula (I)-a to the palladium catalyst is about 200:1 - 80:1, and preferably about 150:1 - 90:1.

[0116] In a preferred embodiment, in the reaction of the compound of formula (I)-a with the compound of formula (I)-b, the molar ratio of the compound of formula (I)-a to the base is about 1:1 - 1:5, and preferably about 1:1 - 1:3.

[0117] In a preferred embodiment, the reaction of the compound of formula (I)-a with the compound of formula (I)-b is carried out in a mixed solvent of an amide having 1-10 carbon atoms (such as N,N-dimethylformamide or N,N-dimethylacetamide) and water, wherein the volume ratio of the amide solvent to water is preferably about 10:1 - 1:1, more preferably about 5:1 - 1:1.

[0118] In a preferred embodiment, the reaction of the compound of formula (I)-a with the compound of formula (I)-b is carried out at a temperature of about 100 - 20 °C, preferably about 60 - 50 °C.

[0119] In a preferred embodiment, the PG protecting group in the compound of formula (I)-c is removed in the presence of an acid, and the acid is preferably hydrochloric acid.

[0120] In a preferred embodiment, the reaction for removing the PG protecting group in the compound of formula (I)-c is carried out in an alcohol solvent having 1 - 10 carbon atoms, and the alcohol solvents include but are not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol, and tert-butanol.

[0121] In a preferred embodiment, the reaction for removing the PG protecting group in the compound of formula (I)-c is carried out at a temperature of about 50 - 10 °C, preferably about 30 - 20 °C.

[0122] In a preferred embodiment, the compound of formula (I)-a is prepared by the following method:

[0123]

[0124] Hal 2 is a halogen, such as F, Cl, Br, or I, preferably Cl; and

[0125] the remaining groups are as defined above;

[0126] The method includes the following steps:

[0127] Step A: Introduce a PG protecting group into the compound of formula (I)-a-1 to obtain the compound of formula (I)-a-2;

[0128] Step B: React the compound of formula (I)-a-2 under reducing conditions to obtain the compound of formula (I)-a-3; and when R is not H, this step further includes a reaction with a reagent containing R; and

[0129] Step C: React the compound of formula (I)-a-3 with the compound of formula (I)-a-4 to obtain the compound of formula (I)-a;

[0130] Preferably, in step A, the compound of formula (I)-a-1 is reacted with vinyl ethyl ether to introduce a protecting group of -CH(OCH2CH3)CH3, wherein the molar ratio of the compound of formula (I)-a-1 to vinyl ethyl ether is preferably about 1:1 - 1:2, more preferably about 1:1 - 1:1.5;

[0131] Preferably, step A is carried out in an ether solvent (such as an ether having 3 - 10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane);

[0132] Preferably, step A is carried out in the presence of an acid, and the acid is preferably a dioxane solution of hydrochloric acid;

[0133] Preferably, step A is carried out at a temperature of about 50 - 10 °C, more preferably about 30 - 20 °C;

[0134] Preferably, the reducing agent used in step B is sodium sulfide, and the molar ratio of the compound of formula (I)-a-2 to sodium sulfide is about 1:1 - 1:5, more preferably about 1:1 - 1:3;

[0135] Preferably, the reaction solvent for step B is an alcohol solvent having 1 - 10 carbon atoms (including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), water or a mixed solvent of the alcohol solvent and water;

[0136] Preferably, step B is carried out at a temperature of about 100 - 20 °C, more preferably about 80 - 70 °C;

[0137] Preferably, the molar ratio of the compound of formula (I)-a-3 to the compound of formula (I)-a-4 in step C is about 1:1 - 1:2, more preferably about 1:1 - 1:1.5;

[0138] Preferably, step C is carried out in the presence of a base, and the base is preferably an organic base selected from imidazole, triethylamine, pyridine, 2,6-dimethylpyridine, DBU and DIEA, most preferably DIEA; the molar ratio of the compound of formula (I)-a-3 to the base is preferably about 1:1 - 1:5, more preferably about 1:1 - 1:2;

[0139] Preferably, step C is carried out in an alcohol solvent having 1 - 10 carbon atoms, and the alcohol solvent includes but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol;

[0140] Preferably, step C is carried out at a temperature of about 120 - 20 °C, preferably about 80 - 70 °C.

[0141] In a preferred embodiment, the compound of formula (I)-a-1 is compound A-2 having the following structure:

[0142]

[0143] In a preferred embodiment, the compound of formula (I)-a-2 is compound A-21 having the following structure:

[0144]

[0145] In a preferred embodiment, the compound of formula (I)-a-3 is compound A-31 having the following structure:

[0146]

[0147] In a preferred embodiment, the compound of formula (I)-b is prepared by the following method:

[0148]

[0149] Hal 3 is a halogen, such as F, Cl, Br or I, preferably Cl;

[0150] LG is a leaving group, such as -OH or a halogen selected from F, Cl, Br and I; and

[0151] the remaining groups are as defined above;

[0152] The method comprises the following steps:

[0153] Step I: Reacting a compound of formula (I)-b-1 with a reagent containing an R 1 group to obtain a compound of formula (I)-b-2;

[0154] Step II: Reacting a compound of formula (I)-b-2 with a reagent containing an R 10 group to obtain a compound of formula (I)-b-3; provided that when R 10 is H, step II is not required; and

[0155] Step III: Reacting a compound of formula (I)-b-3 with boric acid or a borate in the presence of a catalyst (such as a metal catalyst, preferably a palladium catalyst) (preferably in the presence of a base) to obtain a compound of formula (I)-b;

[0156] Preferably, the reagent containing an R 1 group is or its hydrochloride;

[0157] Preferably, the molar ratio of the compound of formula (I)-b-1 to the reagent containing the R 1 group in Step I is about 1:1 - 1:2, preferably about 1:1 - 1:1.5;

[0158] Preferably, Step I is carried out in the presence of a carboxylic acid activating reagent (preferably CDI), and the molar ratio of the compound of formula (I)-b-1 to the carboxylic acid activating reagent is preferably about 1:1 - 1:2, preferably about 1:1 - 1:1.5;

[0159] Preferably, Step I is carried out in an amide solvent having 1 - 10 carbon atoms (such as N,N-dimethylformamide or N,N-dimethylacetamide);

[0160] Preferably, Step I is carried out at a temperature of -10°C to 60°C, preferably 10 to 30°C;

[0161] Preferably, the molar ratio of the compound of formula (I)-b-2 to the reagent containing the R 10 group in Step II is about 1:1 - 1:15, preferably about 1:1 - 1:10;

[0162] Preferably, when R 10 is C 1-6 alkyl, the reagent containing the R 10 group is an alkylating reagent, and the alkylating reagent is preferably dimethyl carbonate;

[0163] Preferably, Step II is carried out in an amide solvent having 1 - 10 carbon atoms (such as N,N-dimethylformamide or N,N-dimethylacetamide);

[0164] Preferably, Step II is carried out in the presence of a base, and the base is preferably an organic base selected from TMED, imidazole, triethylamine, pyridine, 2,6-dimethylpyridine, DBU and DIEA, most preferably TMED; the molar ratio of formula (I)-b-2 to the base is preferably about 5:1 - 1:1, preferably about 2:1 - 1:1;

[0165] Preferably, Step II is carried out at a temperature of about 150 - 80°C, preferably about 130 - 100°C;

[0166] Preferably, the palladium catalyst in Step III is selected from dichlorobis(diphenylphosphino)ferrocene palladium(II), tris(dibenzylideneacetone) dipalladium(0), triphenylphosphine palladium and palladium acetate, preferably dichlorobis(diphenylphosphino)ferrocene palladium(II);

[0167] Preferably, the base is an inorganic base selected from potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate, preferably potassium acetate or potassium carbonate;

[0168] Preferably, the borate ester is pinacol diborate;

[0169] Preferably, in step III, the molar ratio of the compound of formula (I)-b-3 to the boric acid or borate ester is about 1:1 - 1:2, preferably about 1:1 - 1:1.5;

[0170] Preferably, the molar ratio of the compound of formula (I)-b-3 to the palladium catalyst is about 200:1 - 80:1, preferably about 150:1 - 90:1;

[0171] Preferably, the molar ratio of the compound of formula (I)-b-3 to the base is about 1:1 - 1:5, preferably about 1:1 - 1:3;

[0172] Preferably, step III is carried out in an ether solvent (such as an ether having 3 - 10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane);

[0173] Preferably, step III is carried out at a temperature of about 110 - 20 °C, preferably about 90 - 70 °C.

[0174] In a preferred embodiment, the compound of formula (I)-b-1 is compound A-SM3 having the following structure:

[0175]

[0176] In a preferred embodiment, the compound of formula (I)-b-2 is compound A-6 having the following structure:

[0177]

[0178] In a preferred embodiment, the compound of formula (I)-b-3 is compound A-7 having the following structure:

[0179]

[0180] The present invention encompasses any combination of the above embodiments.

[0181] Intermediate

[0182] In some embodiments, the present invention provides a compound or a salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, said compound having the structure of formula (I)-c:

[0183]

[0184] Wherein each group is as defined above; and

[0185] The compound is preferably compound A-103 having the following structure:

[0186] Example

[0187] The present invention will be further described below in conjunction with examples, but providing these examples is not intended to limit the scope of the present invention.

[0188] The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).

[0189] The chemical shift (δ) is given in parts per million (ppm). 1 The measurement of 1H NMR was carried out on a Bruker BioSpin GmbH 400 nuclear magnetic resonance spectrometer, and the test solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterodimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS).

[0190] Thin layer chromatography (TLC) was carried out using a Huanghai brand HSGF 254 (5×20 cm) silica gel plate, and preparative thin layer chromatography was carried out using a silica gel plate with a specification of GF 254 (0.4 - 0.5 nm) produced in Yantai.

[0191] The reaction was detected by thin layer chromatography (TLC), and the developing agent systems used included dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems, and the developing agent system was adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvents or adding triethylamine, etc.).

[0192] Unless otherwise stated, the raw materials and reagents used in the examples are commercially available or obtained according to the methods disclosed in WO 2019 / 001572 (which is incorporated herein by reference).

[0193] The abbreviations in the present invention have the following meanings:

[0194]

[0195]

[0196] Example 1.

[0197]

[0198] Step 1: Preparation of (E)-N-(3-(dimethylamino)-2-(4-nitrophenyl)allylidene)-N-methylmethanaminium tetrafluoroborate (A-11)

[0199] Add DMF (400 ml) to the reaction flask, cool the temperature to 0 - 10 °C, and slowly add POCl3 (203.0 g, 1.32 mol) dropwise to the reaction flask. After the addition is complete, add 2-(4-nitrophenyl)acetic acid (A-SM1) (80.0 g, 0.44 mol) to the reaction flask. After the addition is complete, heat the reaction solution to 80 °C and react at this temperature. When TLC detection shows that the raw materials have completely reacted, cool the reaction solution to 20 - 30 °C, slowly add ice water (800 ml) dropwise to the reaction solution. After the addition is complete, slowly add a solution of NaBF4 (72.7 g, 0.66 mol) in water (160 ml) dropwise to precipitate a solid. Cool the reaction system to 0 - 10 °C and stir for 1 h. Filter the reaction solution, wash the filter cake with water (160 ml), and vacuum dry the collected filter cake at 25 ± 5 °C to obtain 135.0 g of a yellow solid with a purity of 100% and a yield of 91.2%.

[0200] MS m / z (ESI): 248.29M +

[0201] 1 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J = 8.7 Hz, 2H), 7.79 (s, 2H), 7.60 (d, J = 8.7 Hz, 2H), 3.28 (s, 6H), 2.47 (s, 6H).

[0202] Step 2: Preparation of 4-(4-nitrophenyl)-1H-pyrazole (A-2)

[0203] Add ethanol (670 ml), A-11 (134.0 g, 0.40 mol) and acetic acid (20 ml) to the reaction flask. After the addition is complete, heat the reaction system to 70 - 80 °C, and slowly add 55% hydrazine hydrate (43.7 g, 0.48 mol) dropwise to the reaction system. After the addition is complete, react at this temperature. When TLC detection shows that the raw materials have completely reacted, stop the reaction, cool the reaction solution to 45 ± 5 °C, slowly add water (1340 ml) dropwise to the reaction system. After the addition is complete, cool the reaction system to 0 - 10 °C, stir for 1 h, filter, wash the filter cake with water (268 ml), collect the filter cake, and vacuum dry it at 45 ± 5 °C to obtain 74.0 g of a yellow solid with a purity of 99.07% and a yield of approximately 97.8%.

[0204] MS m / z (ESI): 190.12[M+H] +

[0205] 1 1H NMR (400 MHz, DMSO-d6): δ 13.20 (s, 1H), 8.29 (s, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H).

[0206] Step 3: Preparation of 1-(1-ethoxyethyl)-4-(4-nitrophenyl)-1H-pyrazole (A-21)

[0207] Add THF (365 ml), A-2 (73.0 g, 0.38 mol) and a 1,4-dioxane solution of 4M HCl (2.4 ml, 9.6 mmol) to a reaction flask. After addition, at 25 ± 5 °C, add vinyl ethyl ether (41.9 g, 0.579 mol) dropwise. After the dropwise addition, stir the reaction. After TLC detection shows that the raw materials have completely reacted, add sodium bicarbonate (1.3 g, 15.4 mmol) to the reaction system, stir for 1 h, add water (365 ml) and ethyl acetate (365 ml), separate and collect the organic phase. Wash the organic phase once with water (365 ml), collect the organic phase, concentrate it to about 150 ml, add n-heptane (365 ml), a large amount of solid precipitates, cool to 0 - 10 °C, stir for 1 h, and filter. Wash the filter cake with n-heptane (150 ml), collect the filter cake, and dry it under vacuum at 45 ± 5 °C to obtain 89.5 g of a light brown solid with a purity of 99.1% and a yield of about 88.7%.

[0208] MS m / z (ESI): 262.08 [M + H] + , 190.20 [M - 72] +

[0209] 1 1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 1H), 8.25 - 8.20 (m, 2H), 8.14 (s, 1H), 7.95 - 7.89 (m, 2H), 5.58 (q, J = 6.0 Hz, 1H), 3.52 - 3.41 (m, 1H), 3.31 - 3.23 (m, 1H), 1.64 (d, J = 6.0 Hz, 3H), 1.06 (t, J = 7.04 Hz, 3H).

[0210] Step 4: Preparation of 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)aniline (A-31)

[0211] Add ethanol (264 ml) and A-21 (88.0 g, 0.34 mol) to the reaction flask, heat up to 70 - 80 °C, and add dropwise a solution of Na2S·9H2O (222.5 g, 0.93 mol) in water (880 ml) to the reaction flask. After the addition is complete, carry out the reaction at this temperature. When TLC detection shows that the raw materials have completely reacted, cool the reaction solution to 40 - 50 °C, concentrate the reaction solution to remove ethanol, add 2-methyltetrahydrofuran (352 ml) to the reaction system, separate and collect the organic phase, wash the organic phase with saturated NaCl solution (440 ml), collect and concentrate the organic phase to about 220 ml, cool to 0 - 10 °C, a large amount of solid will precipitate. Add dropwise n-heptane (440 ml) to the system. After the addition is complete, control the temperature at 0 - 10 °C and stir for 1 h. Filter, wash the filter cake with n-heptane (176 ml), collect the solid, and dry it under vacuum at 40 - 50 °C to obtain 73.6 g of yellow solid with a purity of 99.2% and a yield of about 94.4%.

[0212] MS m / z (ESI): 232.29 [M+H] +

[0213] 1 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.72 (s, 1H), 7.29 - 7.23 (m, 2H), 6.59 - 6.53 (m, 2H), 5.49 (q, J = 6.0 Hz, 1H), 5.01 (s, 2H), 3.46 - 3.37 (m, 1H), 3.26 - 3.17 (m, 1H), 1.60 (d, J = 6.0 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H).

[0214] Step 5: Preparation of 2-chloro-N-(4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-amine (A-51)

[0215] Add A-31 (70.0 g, 0.30 mol), ethanol (350 ml), 2,4-dichloropyrimidine (49.6 g, 0.33 mol) and DIEA (78.2 g, 0.60 mol) to the reaction kettle. After adding, heat the reaction solution to 75 ± 5 °C and stir the reaction overnight at this temperature. After TLC detection shows that the raw materials have completely reacted, cool the reaction solution to 45 ± 5 °C and concentrate until no distillate flows out. Add ethyl acetate (350 ml) and water (350 ml) to the system, separate and collect the organic phase. Wash the organic phase with saturated sodium chloride solution (350 ml), collect the organic phase, concentrate it to about 210 ml at 45 ± 5 °C, add methyl tert-butyl ether (350 ml), concentrate it to about 210 ml, add methyl tert-butyl ether (700 ml), heat to 50 ± 5 °C, stir for 1 h, cool to 5 ± 5 °C, stir for 1 h, filter, wash the filter cake with methyl tert-butyl ether (140 ml), collect the filter cake, and dry it under vacuum at 45 ± 5 °C to obtain 93.3 g of yellow solid with a purity of 99.4% and a yield of about 91.6%.

[0216] MS m / z(ESI): 344.29[M+H] +

[0217] 1 H NMR(400MHz, DMSO-d6): δ10.02(s, 1H), 8.32(s, 1H), 8.15(d, J = 5.88Hz, 1H), 7.91(s, 1H), 7.66 - 7.56(m, 4H), 6.75(d, J = 5.88Hz, 1H), 5.54(q, J = 5.96Hz, 1H), 3.50 - 3.39(m, 1H), 3.30 - 3.20(m, 1H), 1.63(d, J = 6.0Hz, 3H), 1.05(t, J = 7.04Hz, 3H).

[0218] Step 6: Preparation of (6-bromo-1H-indol-2-yl)(3,3-difluoroazetidin-1-yl)methanone (A-6)

[0219] Add 6-bromo-1H-indole-2-carboxylic acid (80.0 g, 0.33 mol) and DMF (560 ml) to a reaction flask, add CDI (64.5 g, 0.40 mol), and stir the reaction at 25 - 30 °C. After TLC detection shows that the raw materials are completely converted into intermediates, add 3,3-difluoroazetidine hydrochloride (47.5 g, 0.36 mol) to the reaction system. After TLC detection shows that the raw materials have completely reacted, stop the reaction, add water (1120 ml) to the system, stir for 0.5 h, filter, wash the filter cake with water (160 ml), collect the filter cake, and dry it at 40 - 50 °C to obtain 99.5 g of an off-white solid with a purity of 99.0% and a yield of about 94.7%.

[0220] MS m / z(ESI): 315.24[M+H] +

[0221] 1 H NMR(400MHz, DMSO-d6): δ11.80(s, 1H), 7.60(m, 2H), 7.19(m, 1H), 6.94(m, 1H), 4.73(brs, 4H).

[0222] Step 7: Preparation of (6-bromo-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1-yl)methanone (A-7)

[0223] Add A-6 (98.0 g, 0.31 mol), dimethyl carbonate (224.0 g, 2.49 mol), DMF (490 ml) and TMED (18.0 g, 0.15 mol) to a reaction kettle. After adding, heat the reaction solution to 110 °C and stir the reaction. After TLC detection shows that the raw materials have completely reacted, stop the reaction, cool the reaction solution to 55 ± 5 °C, concentrate it under reduced pressure until no distillate flows out, cool the reaction solution to 25 ± 5 °C, add water (980 m1), cool the reaction solution to 0 - 10 °C, stir for 1 h, filter, wash the filter cake with water (198 m1), collect the filter cake, and dry it under vacuum at 45 ± 5 °C to obtain 96.2 g of a brown-yellow solid with a purity of 91.0% and a yield of about 94.0%.

[0224] MS m / z(ESI): 329.27[M+H] +

[0225] 1 H NMR(400MHz, DMSO-d6): δ7.84(s, 1H), 7.58(d, J = 8.4Hz, 1H), 7.24(dd, J = 8.4Hz, 1.7Hz, 1H), 7.02(s, 1H), 3.92(s, 3H), 4.67(brs, 4H).

[0226] Step 8: Preparation of (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)methanone (A-8)

[0227] Add A-7 (95.0 g, 0.29 mol), KOAc (70.8 g, 0.72 mol), bis(pinacolato)diboron (80.6 g, 0.32 mol) and 1,4-dioxane (950 ml) into the reaction kettle. After addition, displace with nitrogen for 3 times, and add Pd(dppf)Cl2 (2.1 g, 2.9 mmol). After addition, heat the reaction solution to 80 °C for reaction. When TLC detection shows that the raw materials have completely reacted, stop the reaction, cool to 25 ± 5 °C, filter, wash the filter cake with ethyl acetate (475 ml), collect and combine the filtrate, wash the filtrate twice with 10% NaCl (475 ml × 2), collect the organic phase, concentrate at 45 ± 5 °C until no distillate flows out, add ethyl acetate (143 ml), heat to 50 ± 5 °C, the solution becomes clear, dropwise add n-heptane (760 ml), cool to 0 - 10 °C, stir for 1 h, filter, wash the filter cake with n-heptane (190 ml), collect the filter cake, and dry it under vacuum at 45 ± 5 °C to obtain 81.5 g of yellow solid, with a purity of 98.0% and a yield of about 75.0%.

[0228] MS m / z (ESI): 377.22 [M+H] +

[0229] 1 1H NMR (400 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.62 (d, J = 8 Hz, 1H), 7.41 (d, J = 8 Hz, 1H), 7.01 (s, 1H), 4.75 (brs, 4H), 3.91 (s, 3H), 1.32 (s, 12H).

[0230] Step 9: Preparation of (3,3-difluoroazetidin-1-yl)(6-(4-((4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)methanone (A-103)

[0231] Add A-51 (60.0 g, 0.17 mol), A-8 (72.3 g, 0.19 mol), potassium carbonate (72.4 g, 0.52 mol), DMF (300 ml) and water (60 ml) into the reaction flask. Replace the air with nitrogen for 6 times, and then add Pd(dppf)Cl2 (1.28 g, 1.74 mmol). After adding, heat the reaction solution to 55 ± 5 °C and stir for reaction. After TLC detection shows that the raw materials have completely reacted, take the reaction solution for HPLC detection. The HPLC chromatogram is as shown in Figure 1 shown below. The retention times and peak area percentages of the reaction raw materials and products are shown in the following table:

[0232] Compound Retention time Percentage of chromatographic peak area A-103 11.736 min 91.26％ A-51 12.462 min 1.95％ A-8 14.870 min 1.77％

[0233] Add ethyl acetate (600 ml) and water (600 ml) to the reaction solution, let it stand for liquid separation at a temperature of 60 ± 5 °C, collect the organic phase. Then add water (300 ml) to the reaction solution, separate the aqueous phase at a temperature of 60 ± 5 °C, collect the organic phase, concentrate it under reduced pressure to about 300 ml at 45 ± 5 °C, add ethyl acetate (300 ml), heat to 60 ± 5 °C until the solid dissolves clearly, add n-heptane (600 ml), cool to 5 ± 5 °C, stir for 1 h, filter, wash the filter cake with n-heptane (120 ml), collect the filter cake, and dry it under vacuum at 45 ± 5 °C to obtain 71.2 g of yellow solid, with a purity of 98.0% and a yield of about 73.0%.

[0234] MS m / z(ESI): 558.23[M + H] +

[0235] 1 1H NMR(400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.58 (s, 1H), 8.43 (d, J = 5.4 Hz, 1H), 8.37 (s, 1H), 8.22 (dd, J = 8.4 Hz, 1.4 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.09 (s, 1H), 6.74 (d, J = 5.8 Hz, 1H), 5.58 (q, J = 6.04 Hz, 1H), 4.77 (brs, 4H), 4.07 (s, 3H), 3.53 - 3.44 (m, 1H), 3.32 - 3.25 (m, 1H), 1.67 (d, J = 6.04 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H).

[0236] Step 10: Preparation of (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1-yl)methanone (A)

[0237] Add ethanol (600 ml) and A-103 (60.0 g, 0.11 mol) to a reaction flask. Dropwise add concentrated hydrochloric acid (33.6 g, 0.32 mol) at a temperature of 20 - 30 °C, and stir for reaction. After TLC detection shows that the raw materials have completely reacted, add triethylamine (43.4 g, 0.43 mol) to the reaction system and stir for 1 h. Add water (600 ml) to the reaction system, cool to 0 - 10 °C, stir for 1 h, filter, wash with water (120 ml), collect the filter cake, and dry it under vacuum at 40 - 50 °C to obtain 47.2 g of a yellow solid with a yield of 90.3%.

[0238] MS m / z (ESI): 486.23 [M + H] +

[0239] 1 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.49 (s, 1H), 8.41 (d, J = 6.9 Hz, 1H), 8.13 (s, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.76 (m, 4H), 7.16 (s, 1H), 6.96 (d, J = 7.2 Hz, 1H), 4.90 (s, 2H), 4.56 (s, 2H), 4.05 (s, 3H).

[0240] Comparative Example

[0241]

[0242] Add A-5 (1.5 g, 4.03 mmol), A-8 (1.67 g, 4.44 mmol), potassium carbonate (1.71 g, 12.3 mmol), DMF (10 ml) and water (2 ml) to a reaction flask. Replace the air with nitrogen 6 times, add Pd(dppf)Cl2 (30.3 mg, 41.2 μmol). After addition, heat the reaction solution to 55 ± 5 °C and stir for reaction for 22 h. Perform HPLC detection on the reactants. The HPLC chromatogram is as Figure 2 shown, and the retention times and peak areas of the main peaks are shown in the following table.

[0243]

[0244]

[0245] As can be seen by HPLC detection, the reaction of raw material A-5 is complete, but the reaction products are very complex. Among them, the target product A-111 (retention time 10.104 min) only accounts for 25.66%, the deprotected product A-4 of raw material A-5 (retention time 9.936 min) accounts for 25.96%, the raw material A-8 (retention time 14.492 min) accounts for 16.48%, and the compound A (retention time 9.839 min) accounts for 0.25%.

[0246] Except those described herein, various modifications of the present invention will be apparent to those skilled in the art in light of the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other publications) are incorporated herein by reference in their entirety.

Claims

1. A method for preparing compound A-103, wherein: the method comprises reacting compound A-51 with compound A-8 in the presence of a palladium catalyst and in the presence of a base to obtain compound A-103.

2. A method for preparing compound A, wherein the method comprises the following steps: The first step: Reacting compound A-51 with compound A-8 in the presence of a palladium catalyst and in the presence of a base to obtain compound A-103; and The second step: Removing the -CH(OCH2CH3)CH3 protecting group in compound A-103 to obtain compound A.

3. The method according to claim 1 or 2, wherein the palladium catalyst is selected from dichlorobis(η5-cyclopentadienyl)bis(diphenylphosphine)iron(II) palladium, tris(dibenzylideneacetone)dipalladium(0), triphenylphosphine palladium, and palladium acetate.

4. The method according to claim 3, wherein the palladium catalyst is dichlorobis(η5-cyclopentadienyl)bis(diphenylphosphine)iron(II) palladium.

5. The method according to claim 1 or 2, wherein the base is selected from potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

6. The method according to claim 5, wherein the base is potassium acetate or potassium carbonate.

7. The method according to claim 2, wherein the -CH(OCH2CH3)CH3 protecting group in compound A-103 is removed in the presence of an acid.

8. The method according to claim 7, wherein the acid is hydrochloric acid.

9. The method according to claim 1 or 2, wherein compound A-51 is prepared by the following method: The method comprises the following steps: Step A: Introducing a -CH(OCH2CH3)CH3 protecting group into compound A-2 to obtain compound A-21; Step B: Reacting compound A-21 under reducing conditions to obtain compound A-31; and Step C: Reacting compound A-31 with compound A-SM2 to obtain compound A-51.

10. The method according to claim 1 or 2, wherein compound A-8 is prepared by the following method: The method comprises the following steps: Step I: React the compound of formula A-SM3 with to obtain compound A-6; Step II: Reacting compound A-6 with dimethyl carbonate to obtain compound A-7; and Step III: Reacting compound A-7 with bis(pinacolato)diboron in the presence of a catalyst to obtain compound A-8.

11. The method according to claim 10, wherein the catalyst in step III is a metal catalyst.

12. The method according to claim 11, wherein the metal catalyst is a palladium catalyst.

13. The method according to claim 10, wherein the reaction in step III is carried out in the presence of a base.

14. A compound or its salt or stereoisomer, wherein the compound is compound A-103 having the following structure:

Images