HK1230186B - Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof - Google Patents

Description

Condensed ring pyrimidine amino derivatives, their preparation methods, intermediates, pharmaceutical compositions, and applications

Technical Field

The present invention relates to a fused-ring pyrimidine amino derivative, a preparation method, an intermediate, a pharmaceutical composition and application thereof.

Background Art

The receptor tyrosine kinase anaplastic lymphoma kinase (ALK) was first discovered in anaplastic large cell lymphoma (ALCL). The fusion protein formed by a translocation of chromosomes 2 and 5 contains the 3' intracellular domain of ALK and the 5' domain of nucleophosmin (NPM). The ALK gene is located on chromosome 2p23. Under normal circumstances, human ALK is transcribed into a 6222-bp mRNA composed of 29 exons, encoding a 200-kDa type I transmembrane protein of 1620 amino acids. ALK is a receptor tyrosine kinase (RTK) and a member of the insulin superfamily of RTKs (Palmer R.H., et al., Biochem J., 2009, 420, 345-361). The complete ALK has a typical RTK three-part structure, namely the extracellular region, the lipophilic transmembrane region and the intracytoplasmic tyrosine kinase. Its extracellular region contains a special binding domain: an N-terminal signal peptide, two methyldopa, A5 protein and receptor protein tyrosine phosphatase μ (MAM, meprin, A5 protein and receptor protein tyrosine phosphatase mu) domains, a low-density lipoprotein A (LDLa, Low-density lipoprotein A) motif and a glycine-rich region (G-rich, Glycine-rich) near the cell membrane. The MAM domain and the G-rich region may be related to ALK activation. The first tyrosine residue of the YxxxYY motif in the human ALK kinase region - Tyr1604, has been shown to be related to the autologous activation of the ALK kinase region (Tartari C.J., et al., J. Bio. Chem., 2008, 283 (7), 3743-3750.).

Chromosomal translocation results in the generation of an ALK fusion gene, the encoded fusion protein of which forms a ligand-independent dimer, leading to constitutive ALK activation. Activated ALK signaling can lead to cell hyperproliferation and malignant transformation by activating downstream RAS-MEK-ERK, JAK-STAT3/5, PI3K-AKT, and PLCγ signaling pathways.

Since the ALK fusion gene was first reported in anaplastic large cell lymphoma (ALCL) in 1994, ALK has been found to fuse with a variety of genes, and these fusion genes are closely associated with the development of various tumors. For example, the NMP-ALK fusion gene is associated with anaplastic large cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL); the TPM3-ALK fusion gene is associated with anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), histiocytic tumor (Histiocytic Tumor), and renal cell carcinoma; and the EML4-ALK fusion gene is closely associated with non-small cell lung cancer (NSCLC), renal cell carcinoma, breast cancer, and colon cancer, and has become a hot topic of research (Lin E., et al., Mol. Cancer Res., 2009, 7, 1466-1476). In addition, ALK fusion genes have been detected in neuroblastoma, melanoma, rhabdomyomas, and esophageal squamous cell tumors (Webb T.R., et al., Expert Rev. Anticancer Ther., 2009, 9(3), 331-356.).

ALK is also associated with diseases of the nervous system. Recent studies have shown that ALK has the function of regulating the frontal cortex and hippocampus of the adult animal brain. ALK can be used as a new target for the treatment of mental illnesses such as schizophrenia, depression and substance (heroin) addiction (Bilsland J.G., et al., Neuropsycho-pharmacology, 2008, 33, 685-700.).

Currently available ALK inhibitors include Pfizer's Crizotinib (WO2006021881, WO2007066185, WO2008053157), Novartis' Ceritinib (WO2012106540), and Roche's Alectinib (WO2010143664). The development of ALK kinase inhibitors can effectively reduce the impact of mutated ALK genes on downstream signaling pathways, thereby affecting tumor cell invasion and proliferation, ultimately inhibiting tumor cell growth and achieving anti-tumor effects.

Summary of the Invention

The present invention provides a fused-ring pyrimidine amino derivative, its preparation method, intermediate, pharmaceutical composition and application. The fused-ring pyrimidine amino derivative of the present invention has a strong inhibitory effect on anaplastic lymphoma kinase (ALK) and is a new generation of highly effective anaplastic lymphoma kinase inhibitors.

The present invention provides a fused ring pyrimidine amino derivative as shown in general formula I, and its tautomers, mesomers, racemates, stereoisomers, pharmaceutically acceptable salts, metabolites, metabolic precursors or prodrugs:

in:

X is selected from CH, S or NR ⁴ ;

Y is selected from N or CR ⁴ ;

U is a chemical bond or CH;

V is a chemical bond or -CONH-;

W is selected from N or C;

Ring A is an aromatic ring or a heteroaromatic ring;

Ring B is an aromatic ring or a heteroaromatic ring;

^R1 is selected from hydrogen, hydroxy, halogen, alkyl, sulfonyl, alkoxy, formyl, amino, amide or heteroaryl, or two adjacent ^R1s and two atoms on the A ring to which they are connected together form a 5-7 membered carbon heterocycle; in the carbon heterocycle, the heteroatom is oxygen and/or nitrogen, the number of heteroatoms is 1-4, and the carbon atoms are 1-6;

R ² is selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, amide, cycloalkyl or heterocycloalkyl;

^R3 is selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, or two adjacent ^R3 together with the carbon atom on the B ring to which they are connected form a 5-7 membered heterocyclic group; the heterocyclic group is a heterocyclic group having one or more heteroatoms selected from oxygen, nitrogen and sulfur, with 1 to 4 heteroatoms and containing 2 to 6 carbon atoms;

R ⁴ is selected from hydrogen atom, halogen or alkyl;

n is 1 or 2;

m is 1 or 2.

In Ring A, the aromatic ring is preferably a C _6-10 aromatic ring, more preferably a benzene ring. The heteroaromatic ring is preferably a heteroaromatic ring containing 2-5 carbon atoms and having 1-3 heteroatoms as a nitrogen atom, more preferably a heteroaromatic ring containing 2-3 carbon atoms and having 1 or 2 heteroatoms as a nitrogen atom, and most preferably a pyrazole ring or a triazole ring.

In ring B, the aromatic ring is preferably a C _6-10 aromatic ring, more preferably a benzene ring. The heteroaromatic ring is preferably a heteroaromatic ring containing 2-5 carbon atoms and having 1-3 heteroatoms and a nitrogen atom as the heteroatom, more preferably a heteroaromatic ring containing 2-3 carbon atoms and having 1 or 2 heteroatoms and a nitrogen atom as the heteroatom, and most preferably a pyrazole ring.

In ^R1 , the halogen is preferably fluorine or chlorine. The alkyl group is preferably a _C1-4 alkyl group. The sulfonyl group is preferably a _C1-4 sulfonyl group; more preferably, a methylsulfonyl group. The alkoxy group is preferably a _C1-4 alkoxy group. The heteroaryl group is preferably a heteroaryl group having 1-3 heteroatoms and 2-5 carbon atoms, with a nitrogen atom as the heteroatom; more preferably, a pyrazolyl group. The carboheterocycle is preferably a heteroatom having 1 or 2 heteroatoms and 2-5 carbon atoms, with an oxygen atom as the heteroatom; more preferably, a heteroatom having 1 or 2 heteroatoms and 3-5 carbon atoms.

In ^R1 , the hydroxyl, alkyl, alkoxyl, formyl, amino, sulfonyl, or heteroaryl group may be further independently substituted by one or more of the following groups: halogen, _C1-10 alkyl, hydroxyl, amino, _C1-10 alkoxyl, _C1-4 sulfonyl, and heterocycloalkyl groups containing 3-8 carbon atoms and 1-4 heteroatoms with oxygen and/or nitrogen as the heteroatom. Among them, the halogen is preferably fluorine; the _C1-10 alkyl group is preferably _C1-4 alkyl; the _C1-10 alkoxyl group is preferably _C1-4 alkoxyl; the _C1-4 sulfonyl group is preferably methylsulfonyl; the heterocycloalkyl group is preferably heterocycloalkyl groups containing 4-6 carbon atoms and 1-4 heteroatoms with oxygen and/or nitrogen as the heteroatom; more preferably morpholinyl. The carbocyclic ring may be further substituted by one or more _C1-4 alkyl groups.

In ^R2 , the alkyl group is preferably a _C1-4 alkyl group; the alkoxy group is preferably a _C1-4 alkoxy group; the amide group is preferably a formamide group; the heterocycloalkyl group is preferably a heterocycloalkyl group having 1-4 heteroatoms and 3-8 carbon atoms, and having 1-2 heteroatoms and 4-6 carbon atoms, and having a nitrogen heteroatom; and most preferably a piperidinyl group. The heterocycloalkyl group may be further substituted with one or more of the following groups: hydroxyl, _C1-4 alkyl, or _C1-4 acyl.

In R ³ , the alkyl group is preferably a C _1-4 alkyl group; the alkoxy group is preferably a C _1-4 alkoxy group; and the heterocyclic group is preferably a heterocyclic group having oxygen as the heteroatom, 1-2 heteroatoms, and 2-4 carbon atoms.

In R ³ , the hydroxyl, alkyl or alkoxy group may be further independently substituted by one or more of the following groups: halogen (preferably fluorine), C _1-4 alkyl, hydroxyl, amino, C _1-4 alkoxy, C _1-4 sulfonyl (preferably methylsulfonyl) and amide; the heterocyclic group may be further substituted by one or more C _1-4 alkyl groups.

In R ⁴ , the halogen is preferably fluorine; and the alkyl is preferably a C _1-4 alkyl.

The ^R1 is preferably methyl, methoxy, ethoxy, trifluoromethyl, fluorine, or

The R ² is preferably

The ^R3 is preferably methoxy, isopropoxy, methyl, isopropyl,

The R ⁴ is preferably methyl or fluorine.

The preferred

The preferred

The fused ring pyrimidine amino derivative is preferably as shown in the general formula II-1 or II-2,

Wherein, A, B, R ¹ , R ² , R ³ , R ⁴ , X, Y, V, W, n and m are defined as above.

The fused ring pyrimidine amino derivative represented by the general formula II-1 is preferably represented by the general formula III-1-1 or III-1-2.

Wherein, R ¹ , R ² , R ³ , R ⁴ , n and m are defined as above.

The fused ring pyrimidine amino derivative as shown in the general formula II-2 is preferably as shown in the general formula III-2-1 or III-2-2,

Wherein, R ¹ , R ² , R ³ , R ⁴ , V, n and m are defined as above.

The fused ring pyrimidine amino derivatives as shown in the general formula I described in the present invention are preferably any of the following compounds:

In the present invention, the fused ring pyrimidine amino derivative may be a racemate or have optical activity.

The present invention also provides a method for preparing the fused ring pyrimidine amino derivative represented by general formula I, its tautomers, mesomers, racemates, stereoisomers, pharmaceutically acceptable salts, metabolites, metabolic precursors or prodrugs, which can be synthesized using commercially available raw materials by known methods, preferably comprising the following steps: in a solvent, in the presence of a catalyst containing palladium, subjecting the compound represented by general formula I-a and the compound represented by general formula I-b' to a coupling reaction as shown below, followed by a deprotection reaction to obtain the compound of general formula I;

In Formula Ia, Formula Ib and Formula I, A, B, R ¹ , R ² , R ³ , X, Y, U, V, W, n and m are defined as above; R ⁷ is boc-protected R ² .

The method and conditions of the coupling reaction can be conventional methods and conditions for such reactions in the art.

A base may be added to the coupling reaction. The base is preferably an alkali metal carbonate, more preferably sodium carbonate, potassium carbonate, or cesium carbonate. The molar ratio of the base to compound I-a is preferably 1:1 to 5:1.

The solvent is preferably an organic solvent and/or water. The organic solvent can be any commonly used organic solvent for this type of reaction in the art, preferably one or more of 1,4-dioxane, toluene, ethylene glycol dimethyl ether, and N,N-dimethylformamide, with 1,4-dioxane being more preferred. The volume-to-mass ratio of the organic solvent to the compound represented by Formula I-a is preferably 10 mL/g to 110 mL/g. The amount of water added is preferably 1-100% of the volume of the organic solvent.

The palladium-containing catalyst can be a palladium-containing catalyst commonly used in such coupling reactions, preferably one or more of tris(dibenzylideneindeneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium. The molar ratio of the palladium-containing catalyst to the compound represented by formula I-a is preferably (0.005:1) to (0.5:1), more preferably (0.01:1) to (0.10:1).

In the coupling reaction, the molar ratio of the compound represented by general formula I-a to the compound represented by general formula I-b' is preferably (0.5:1)-(2:1), more preferably (0.9:1)-(1.5:1).

The temperature of the coupling reaction is preferably 50°C-150°C, more preferably 90°C-120°C.

The progress of the coupling reaction can be monitored by TLC or HPLC, and the disappearance of the compound represented by general formula I-a is generally regarded as the end point of the reaction.

After the coupling reaction is completed, the product can be further purified by post-treatment, which preferably includes one or more of the following steps: recrystallization, silica gel thin layer chromatography plate purification, silica gel column purification, and high performance liquid chromatography preparative purification.

The deprotection reaction may be a conventional deprotection reaction in the art.

Some compounds represented by general formula I-b' can be prepared by the following method:

In a solvent, in the presence of a palladium catalyst, the compound represented by the general formula I-e and the compound represented by the general formula I-f are subjected to a coupling reaction as shown below, followed by a reduction reaction to obtain a compound represented by the general formula I-b';

Wherein, R ⁵ is halogen, preferably Cl or Br; R ⁶ is boronic acid or boronic ester; B, R ³ , V and m in general formula I-b', general formula Ie and general formula If are defined as above; R ⁷ is boc-protected R ² .

In the preparation method of the compound of formula I-b', a base may be added to the coupling reaction. The base is preferably an alkali metal carbonate, more preferably sodium carbonate, potassium carbonate, or cesium carbonate. The molar ratio of the base to compound I-e is preferably 1:1 to 5:1.

In the preparation method of the compound represented by general formula I-b', the method and conditions of the coupling reaction can be conventional methods and conditions for such reactions in the art.

In the method for preparing the compound represented by Formula I-b', the solvent is preferably an organic solvent and/or water. The organic solvent can be a commonly used organic solvent for this type of reaction in the art, preferably one or more of 1,4-dioxane, toluene, ethylene glycol dimethyl ether, and N,N-dimethylformamide, with 1,4-dioxane being more preferred. The volume-to-mass ratio of the organic solvent to the compound represented by Formula I-e is preferably 5 mL/g to 100 mL/g. The amount of water added is preferably 1-100% of the volume of the organic solvent.

In the method for preparing the compound represented by general formula I-b', the palladium-containing catalyst can be a palladium-containing catalyst commonly used in such coupling reactions, preferably one or more of tris(dibenzylideneindeneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium. The molar ratio of the palladium-containing catalyst to the compound represented by general formula I-e is preferably (0.005:1) to (0.5:1), more preferably (0.01:1) to (0.10:1).

In the preparation method of the compound represented by general formula I-b’, in the coupling reaction, the molar ratio of the compound represented by general formula I-e to the compound represented by general formula I-f is preferably (0.5:1)-(2:1), more preferably (0.9:1)-(1.5:1).

In the preparation method of the compound represented by general formula I-b', the temperature of the coupling reaction is preferably 50°C-150°C.

In the preparation method of the compound represented by general formula I-b', the progress of the coupling reaction can be monitored by TLC or HPLC, and the disappearance of the compound represented by general formula I-e is generally regarded as the end point of the reaction.

In the method for preparing the compound represented by general formula I-b', after the coupling reaction is completed, the product can be further purified by post-treatment. The post-treatment preferably comprises one or more of the following steps: recrystallization, silica gel thin layer chromatography preparative plate purification, silica gel column chromatography purification, and high performance liquid chromatography preparative purification.

In the preparation method of the compound represented by general formula I-b', the reduction reaction can be a conventional reduction reaction in the art, including nitro reduction, unsaturated olefin reduction, amino reduction or benzyl reduction reaction.

In the coupling reaction, the compound represented by the general formula I-a can be prepared by the following method: in a solvent, in the presence of a catalyst containing palladium, the compound represented by the general formula I-c and the compound represented by the general formula I-d are subjected to the coupling reaction shown below to obtain the compound represented by the general formula I-a;

wherein R ⁵ is halogen, preferably Cl or Br; and R ⁶ is boronic acid or boronic ester. In Formula Ia, Formula Ic and Formula Id, A, R ¹ , X, Y, U, W and n are as defined above.

In the preparation method of the compound of formula I-a, a base may be added to the coupling reaction. The base is preferably an alkali metal carbonate, more preferably sodium carbonate, potassium carbonate, or cesium carbonate. The molar ratio of the base to compound I-c is preferably 1.0:1 to 5:1.

In the method for preparing the compound of formula I-a, the solvent is preferably an organic solvent and/or water. The organic solvent can be any commonly used organic solvent for this type of reaction in the art, preferably one or more of 1,4-dioxane, toluene, ethylene glycol dimethyl ether, and N,N-dimethylformamide, with 1,4-dioxane being more preferred. The volume-to-mass ratio of the organic solvent to the compound of formula I-c is preferably 5 mL/g to 100 mL/g. The amount of water added is preferably 1-100% of the volume of the organic solvent.

In the method for preparing the compound of formula I-a, the palladium-containing catalyst can be a palladium-containing catalyst commonly used in such coupling reactions, preferably one or more of tris(dibenzylideneindeneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. The molar ratio of the palladium-containing catalyst to the compound of formula I-c is preferably (0.005:1) to (0.5:1), more preferably (0.01:1) to (0.10:1).

In the preparation method of the compound of general formula I-a, the molar ratio of the compound represented by general formula I-d to the compound represented by general formula I-c is preferably (0.5:1)-(2:1), more preferably (0.9:1)-(1.5:1).

In the preparation method of the compound of formula I-a, the temperature of the coupling reaction is preferably 50°C-150°C, more preferably 90°C-110°C.

In the preparation method of the compound of formula I-a, the progress of the coupling reaction can be monitored by TLC or HPLC, and the disappearance of the compound represented by formula I-c is generally regarded as the end point of the reaction.

In the method for preparing the compound of formula I-a, after the coupling reaction is completed, the product can be further purified by post-treatment. The post-treatment preferably comprises one or more of the following steps: recrystallization, silica gel thin layer chromatography preparative plate purification, silica gel column chromatography purification, and high performance liquid chromatography preparative purification.

The present invention also provides a compound represented by general formula I-a,

Wherein, A, R ¹ , X, Y, U, W and n are defined as above.

The compound represented by the general formula I-a is preferably any one of the following compounds:

The present invention also provides a method for preparing the compound represented by the general formula I-a, and the steps and reaction conditions are the same as described above.

The present invention also provides the use of the fused-ring pyrimidine amino derivative, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, metabolites, metabolic precursors, or prodrugs in the preparation of drugs for preventing, alleviating, and/or treating cancer and/or anaplastic lymphoma kinase-related diseases.

The cancers generally include lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumors, breast cancer, cervical cancer, blood cancer, bone cancer, etc.

The related diseases caused by ALK generally include tumors or mental diseases.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the fused ring pyrimidine amino derivative as shown in general formula I, one or more of its tautomers, mesomers, racemates, stereoisomers, pharmaceutically acceptable salts, metabolites, metabolic precursors and drug precursors, and a pharmaceutically acceptable carrier and/or diluent.

In the present invention, the pharmaceutical composition can be prepared into various types of dosage unit forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., depending on the therapeutic purpose, preferably liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions), etc.

To form the pharmaceutical composition into tablet form, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone, and the like; disintegrants such as dry starch, sodium alginate, agar powder, kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearate, starch, and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated oil; adsorption promoters such as quaternary ammonium hydroxide and sodium lauryl sulfate; wetting agents such as glycerol and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearates, boric acid powder, and polyethylene glycol. Ordinary coating materials can be selected as needed to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film tablets and multi-layer tablets.

In order to shape the pharmaceutical composition into a pill form, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder;

In order to shape the pharmaceutical composition into a suppository form, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like.

To prepare a pharmaceutical composition in the form of an injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose, or glycerol) and prepared into an injection with an osmotic pressure equal to that of blood. Any commonly used carrier in the art can be used in the preparation of the injection. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be used. In addition, conventional solvents, buffers, and analgesics can be added.

In the pharmaceutical composition, the diluent may be a conventional diluent in the art.

The pharmaceutical composition can be in the form of oral administration or sterile injection aqueous solution, and can be prepared by any method for preparing pharmaceutical compositions known in the art.

The pharmaceutical composition can be used alone or in combination with one or more other drugs having anti-tumor activity.

Unless otherwise specified, the following terms used in this invention have the following meanings:

As used herein, "alkyl" (including when used alone and when included in other groups) means branched and straight-chain saturated aliphatic hydrocarbon groups including 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof, etc.

The term "cycloalkyl" (including when used alone or included in other groups) includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl groups, which contain 3 to 20 carbon atoms that can form a ring, preferably 3 to 10 carbon atoms, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane and cyclododecyl, cyclohexenyl.

The term "alkoxy" refers to a cyclic or acyclic alkyl group having the stated number of carbon atoms attached via an oxygen bridge. Thus, "alkoxy" encompasses the above definitions of alkyl and cycloalkyl.

The term "halogen" as used herein means fluorine, chlorine, bromine, iodine or astatine.

The term "hydroxyl" as used herein means

The term "amino" as used herein means

The term "sulfonyl" used herein means that one end is connected to the parent group, and the other end can be connected to other conventional substituents, generally including alkyl groups, for example, methylsulfonyl.

The term "acyl" used herein refers to a monovalent atomic group remaining after removing the hydroxyl group from an organic or inorganic oxygen-containing acid, one end of which is connected to the parent group, and the other end can be connected to other conventional substituents, generally including alkyl groups, for example: formyl.

The term "amide" as used herein means

As used herein, the term "heteroaryl" refers to a stable monocyclic or bicyclic ring having up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N, and S. Heteroaryl groups within this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and tetrahydroquinoline. As with the definition of heterocycle below, "heteroaryl" should also be understood to include N-oxide derivatives of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is a bicyclic substituent and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is through the aromatic ring or through a heteroatom containing ring, respectively.

As used herein, the term "carbocyclic ring," "heterocycle," or "heterocyclyl" refers to a 5-10 membered aromatic or non-aromatic heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S, and includes bicyclic groups. Thus, "heterocyclyl" includes the above-mentioned heteroaryl groups as well as their dihydro or tetrahydro analogs. Other examples of "heterocyclyl" include, but are not limited to, the following: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indazolyl, isobenzofuranyl, isoazaindenyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyrimidinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thiazolyl, thienyl , triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepine, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothiophenyl and their N-oxides.

As used herein, the term "heterocycloalkyl" when used alone or as part of another group refers to a 4-12 membered saturated or partially unsaturated ring containing 1-4 heteroatoms (such as nitrogen, oxygen and/or sulfur). In addition, any heterocycloalkyl ring can be fused to a cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.

As used herein, the term "aromatic ring" refers to any stable monocyclic or bicyclic carbon ring having up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aromatic ring units include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, or acenaphthyl. It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, attachment is via the "aromatic ring."

The term "heteroaromatic ring" as used herein is intended to denote a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N, and S. Heteroaromatic rings within the scope of this definition include, but are not limited to, acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, dihydroindole, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isoazaindene, isoquinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyrimidine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, dihydrobenzoxazole, and dihydroquinoline. As with the definition of heterocycle below, "heteroaromatic ring" should also be understood to include the N-oxide derivative of any nitrogen-containing heteroaromatic ring. In cases where the heteroaryl substituent is a bicyclic substituent and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is through the aromatic ring or through a heteroatom containing ring, respectively.

As used herein, the term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is sufficient to effectively treat a disease or condition described herein. While the amount of a compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, it can be routinely determined by one skilled in the art.

As used herein, when referring to a particular salt, pharmaceutical composition, composition, excipient, etc. as "pharmaceutically acceptable", it means that the salt, pharmaceutical composition, composition, excipient, etc. is generally non-toxic, safe, and suitable for use in subjects, preferably mammalian subjects, and more preferably human subjects.

As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1-1-methylene-bis(2-hydroxy-3-naphthoate)).

As used herein, the term "prodrug" refers to a derivative of a compound that contains a bioreactive functional group such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide the compound. Typically, a prodrug is inactive, or at least less active than the compound itself, such that its activity is not exerted until the compound is cleaved from the bioreactive functional group. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound. For example, a prodrug can contain a biohydrolyzable group. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureides.

The compounds of the present invention may contain one or more asymmetric centers ("stereoisomers"). As used herein, the term "stereoisomer" refers to cis- and trans-isomers, R- and S-enantiomers, and diastereomers. These stereoisomers can be prepared by asymmetric synthesis or chiral separation methods (e.g., separation, crystallization, thin layer chromatography, column chromatography, gas chromatography, high performance liquid chromatography). These stereoisomers can also be derived from the diastereomers of a mixture of enantiomers or racemates by reacting with an appropriate chiral compound, followed by crystallization or any other suitable conventional method.

As used herein, the term "subject" refers to any animal, preferably a mammal, and most preferably a human, that is about to be or has been administered a compound or pharmaceutical composition according to an embodiment of the present invention. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

In one embodiment, "treating" or "treating" refers to amelioration, prevention, or reversal of a disease or condition or at least one identifiable symptom thereof. In another embodiment, "treating" or "treating" refers to amelioration, prevention, or reversal of at least one measurable physical parameter of the disease or condition being treated, and the disease or condition may not have been identified in a mammal. In yet another embodiment, "treating" or "treating" refers to slowing the progression of a disease or condition, either physically, such as stabilization of an identifiable symptom, or physiologically, such as stabilization of a physical parameter, or both. In another embodiment, "treating" or "treating" refers to delaying the onset of a disease or condition.

In certain embodiments, the compounds of the present invention are administered as a preventative measure. As used herein, "prevent" or "preventing" refers to reducing the risk of acquiring a given disease or condition. In a preferred mode of embodiment, a given compound is administered as a preventative measure to a subject, for example, a subject with a family history or predisposition to cancer or an autoimmune disease.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive and progressive effect of the present invention is that the fused-ring pyrimidine amino derivative of the present invention has a significant inhibitory effect on anaplastic lymphoma kinase (ALK), and can effectively alleviate or treat cancer and other related diseases.

DETAILED DESCRIPTION

The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

The structures of the prepared compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR spectra were obtained on a Bruker Avance-500 instrument using deuterated dimethyl sulfoxide, deuterated chloroform, and deuterated methanol as solvents, and tetramethylsilane (TMS) as the internal standard. Mass spectra were obtained on an Agilent Technologies 6110 liquid chromatography-mass spectrometry (LC-MS) instrument using an ESI ion source.

The microwave reaction was carried out in an Explorer fully automatic microwave synthesizer produced by CEM Corporation of the United States. The magnetron frequency was 2450 MHz and the continuous microwave output power was 300 W.

The instrument used for HPLC preparation was Gilson 281, and the preparative column used was Xbridge, 21.2x250mmC18, 10μm.

Example 1

N-[2-(2-{[2-methoxy-4-(piperidin-4-yl)phenyl]amino}thiophene[3,2-d]pyrimidin-7-yl)phenyl-N-methylmethanesulfonamide (Compound 1)

Synthesis of compound 1-i

7-Bromo-2,4-dichlorothiopheno[3,2-d]pyrimidine (4.0 g, 14.18 mmol) was dissolved in tetrahydrofuran (60 mL) and ethanol (60 mL). The reaction mixture was cooled to 0°C, and sodium borohydride (2.7 g, 71.05 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 1 hour, followed by the addition of dichloromethane (500 mL) and water (500 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 1-i (2.5 g, 71% yield) as a yellow solid. This product did not require further purification. LC-MS (ESI): m/z = 251 [M+H] ⁺ .

Synthesis of compound 1-h

Compound 1-i (500 mg, 2.02 mmol) was dissolved in dichloromethane (5 mL), and activated manganese dioxide (270 mg, 3.04 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite, and the filter cake was washed with dichloromethane (5 mL x 4). The combined filtrates were concentrated under reduced pressure to afford 1-h as a white solid (430 mg, yield: 86%). This product did not require further purification. LC-MS (ESI): m/z = 249 [M+H] ⁺ .

Synthesis of compound 1-g

4-Nitrochlorobenzene (4.9 g, 25.9 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-pinacol borate (8.0 g, 25.9 mmol), potassium carbonate (8.28 g, 60 mmol), and tetrakis(triphenylphosphine)palladium (1.5 g, 1.3 mmol) were dissolved in dioxane (40 mL) and water (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filter cake was washed with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 1-g of a yellow solid (8.5 g, yield: 97%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.87 (d, J = 8.6 Hz, 1H), 7.01 (m, 2H), 6.17 (s, 1H), 4.12 (m, 2H), 3.98 (s, 3H), 3.66 (m, 2H), 2.53 (m, 2H), 1.50 (s, 9H) ppm

Synthesis of compound 1-f

Compound 1-g (6.68 g, 20 mmol) and 10% palladium on carbon (1.2 g) were dissolved in methanol (10 mL). The reaction mixture was replaced with hydrogen three times, followed by hydrogenation at 40°C for 3 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to obtain a pink solid 1-f (6.7 g, yield: 100%). This product did not require further purification. LC-MS (ESI): m/z = 281 [M+Ht-Bu] ⁺ .

Synthesis of compound 1-e

2-Bromoaniline (10.0 g, 58.5 mmol) was dissolved in pyridine (50 mL) and acetonitrile (50 mL). The reaction mixture was cooled to 0°C and methanesulfonyl chloride (10.0 g, 87.7 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 30 minutes, then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and diluted with water (250 mL). The separated organic phase was adjusted to pH 7 with 1 M aqueous hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 1-e (14 g, 96% yield) as a yellow solid. This product did not require further purification. LC-MS (ESI): m/z = 250 [M+H] ⁺ .

Synthesis of compound 1-d

Compound 1-e (5.0 g, 20.08 mmol) was dissolved in acetone (100 mL), and anhydrous potassium carbonate (4.2 g, 30.12 mmol) was added. Methyl iodide (4.3 g, 30.12 mmol) was slowly added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, the filter cake was washed with acetone (100 mL), and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and diluted with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 1-d (3.1 g, yield: 59%) as a light yellow solid. This product did not require further purification. LC-MS (ESI): m/z = 264 [M+H]+.

Synthesis of compound 1-c

Compound 1-d (4.0 g, 15.21 mmol), bis-pinacol boronate (5.6 g, 22.05 mmol), and anhydrous potassium acetate (4.5 g, 45.9 mmol) were suspended in dioxane (60 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.2 g, 1.52 mmol). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 1-c (3.4 g, yield: 72%) as a light yellow oil. LC-MS (ESI): m/z = 312 [M+H] ⁺ .

Synthesis of compound 1-b

Compound 1-c (1.05 g, 3.38 mmol), compound 1-h (840 mg, 3.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (316 mg, 0.38 mmol), and sodium carbonate (1.05 g, 9.92 mmol) were dissolved in 1,4-dioxane (11 mL) and water (11 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere, then heated at 90°C for 30 minutes. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to afford 1-b (610 mg, 51% yield) as a light brown solid. LC-MS (ESI): m/z = 354 [M+H] ⁺ .

Synthesis of compound 1-a

Compound 1-b (180 mg, 0.51 mmol), compound 1-f (214 mg, 0.70 mmol), palladium acetate (189 mg, 0.85 mmol), cesium carbonate (495 mg, 1.52 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (545 mg, 0.95 mmol) were dissolved in dioxane (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1-a (102 mg, yield: 33%) as a light yellow solid. LC-MS (ESI): m/z = 624 [M+H] ⁺ .

Synthesis of compound 1

Compound 1-a (102 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with saturated sodium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (mobile phase: 10 mM aqueous ammonium bicarbonate: acetonitrile = 30%-60%) to obtain a light yellow solid 1 (35 mg, yield: 41%). LC-MS (ESI): m/z = 524 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:7.88(s,1H),7.69(s,1H),7.28-7.43(m,1H),4.31-4.39(m,1H),3.81(s,2H),3.64 (s,2H),3.20-3.24(m,2H),2.76-2.86(m,6H),2.11-2.14(m,2H),1.92-1.99(m,2H)ppm

Example 2

N-[2-(2-{[2-methoxy-4-(piperidin-4-yl)phenyl]amino}-6-methylthienyl[3,2-d]pyrimidin-7-yl)phenyl-N-methylmethanesulfonamide (Compound 2)

Synthesis of compound 2-d

7-Bromo-2,4-dichloro-6-methylthiopheno[3,2-d]pyrimidine (5.0 g, 16.89 mmol) was dissolved in tetrahydrofuran (50 mL) and ethanol (50 mL). The reaction mixture was cooled to 0°C, and sodium borohydride (3.19 g, 84.5 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 3 hours. Water (500 mL) was then added and the mixture was extracted with dichloromethane (300 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 2-d (4 g, 90% yield), a yellow liquid. This product did not require further purification. LC-MS (ESI): m/z = 265 [M+H] ⁺ .

Synthesis of compound 2-c

Compound 2-d (4.0 g, 15.15 mmol) was dissolved in dichloromethane (100 mL), and activated manganese dioxide (6.6 g, 75.8 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, and the filter cake was washed with dichloromethane (50 mL x 5). The combined filtrates were concentrated under reduced pressure to afford a yellow solid 2-c (3.8 g, yield: 96%). This product did not require further purification. LC-MS (ESI): m/z = 263 [M+H].

Synthesis of compound 2-b

Compound 2-c (400 mg, 1.53 mmol), compound 1-h (474 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (132 mg, 0.16 mmol), and sodium carbonate (486 mg, 4.58 mmol) were dissolved in 1,4-dioxane (2 mL) and water (2 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere, then heated at 90°C for 30 minutes. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 1:1) to afford 2-b (170 mg, 31% yield) as a yellow solid. LC-MS (ESI): m/z = 368 (M+H) ⁺ .

Synthesis of compound 2-a

Compound 2-b (150 mg, 0.41 mmol), compound 1-f (188 mg, 0.61 mmol), palladium acetate (150 mg, 0.67 mmol), cesium carbonate (405 mg, 1.24 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (480 mg, 0.83 mmol) were dissolved in dioxane (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 40 minutes. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (ethyl acetate as the developing solvent) to obtain a light yellow solid, 2-a (75 mg, yield: 28%). LC-MS (ESI): m/z = 638 [M+H] ⁺ .

Synthesis of compound 2

Compound 2-a (50 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with saturated sodium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (mobile phase: 10 mM aqueous ammonium bicarbonate: acetonitrile = 40%-70%) to obtain a light yellow solid 2 (15 mg, yield: 36%). LC-MS (ESI): m/z = 538 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.78(s,1H),8.21(d,J＝8Hz,1H),7.65(d,J＝8Hz,1H),7.46-7.56(m,3H),7.35(d,J＝7Hz,1H),6.71(s,1H),6.61-6.63(d,J＝8Hz,1H),3.8 5(s,3H),3.17-3.20(m,2H),3.11(s,3H),2.69-2.75(m,2H),2.53(m,1 H),2.52(s,3H),2.49(s,3H),1.78-1.90(m,2H),1.61-1.64(m,2H)ppm

Example 3

7-(2,3-Dihydro-1-benzofuran-7-yl)-N-[2-methoxy-4-(piperidin-4-yl)phenyl]-6-methylthienyl[3,2-d]pyrimidin-2-amine (Compound 3)

Synthesis of compound 3-c

Compound 7-bromobenzodihydrofuran (0.4 g, 2 mmol), bis(pinacol borate) (0.78 g, 3 mmol), and anhydrous potassium acetate (0.4 g, 4 mmol) were suspended in dimethyl sulfoxide (5 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.16 g, 0.2 mmol). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 80°C for 8 hours. The reaction mixture was cooled to room temperature, diluted with ice water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain compound 3-c (0.29 g, yield: 56%).

1H-NMR (400MHz, CDCl3) δ: 7.53 (d, J = 8Hz, 1H), 7.27 (d, J = 8Hz, 1H), 6.83 (t, J = 8Hz, 1H), 4.63 (t, J = 8.8Hz, 1H), 3.16 (t, J = 8.8Hz, 1H), 1.36 (s, 12H) ppm

Synthesis of compound 3-b

Compound 3-c (200 mg, 0.8 mmol), compound 2-c (264 mg, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol), and sodium carbonate (210 mg, 2 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, then heated at 90°C for 8 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) to afford 3-b (130 mg, 43% yield) as a yellow solid. LC-MS (ESI): m/z = 304 [M+H] ⁺ .

Synthesis of compound 3-a

Compound 3-b (150 mg, 0.5 mmol), compound 1-f (180 mg, 0.6 mmol), tris(dibenzylideneindeneacetone)dipalladium (150 mg, 0.67 mmol), potassium carbonate (180 mg, 1.29 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (480 mg, 0.83 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 3-a (89 mg, yield: 31%) as a light yellow solid. LC-MS (ESI): m/z = 573 [M+H] ⁺ .

Synthesis of compound 3

Compound 3-a (89 mg, 0.156 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated potassium carbonate solution. A solid precipitated and was filtered. The filter cake was vacuum dried to obtain a light yellow solid 3 (26 mg, yield: 35%). LC-MS (ESI): m/z = 473 [M+H] ⁺ .

¹ H-NMR (400MHz, CD ₃ OD)δ:8.83(s,1H),8.41(d,J＝8Hz,1H),7.33(d,J＝7.2Hz,1H),8.25(d,J＝7.2Hz,1H),7.0(t,J＝8Hz,1H),6.84(s,1H),6.68(d,J＝8 Hz,1H),4.55(t,J＝8Hz,2H),3.90(s,3H),3.27(m,2H),2.85(d,J＝8Hz,2H),2.54(s,3H),1.90(m,2H),1.76(m,2H),1.33(m,4H)ppm

Example 4

N-[2-methoxy-4-(piperidin-4-yl)phenyl]-7-(1-methyl-1H-pyrazol-5-yl)thienyl[3,2-d]pyrimidin-2-amine (Compound 4)

Synthesis of compound 4-b

Compound 1-h (210 mg, 0.84 mmol), 1-methylpyrazole-5-boronic acid pinacol ester (175 mg, 0.84 mmol), bis(triphenylphosphine)palladium dichloride (3 mg, 0.05 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (33 mg, 0.08 mmol), and 2M aqueous sodium carbonate solution (3.4 mL, 6.72 mmol) were dissolved in 1,4-dioxane (7 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 90°C for 6 hours. The reaction mixture was cooled to room temperature, diluted with ice water (100 mL), and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by HPLC to obtain a yellow solid 4-b (100 mg, yield: 48%). LC-MS (ESI): m/z = 251 [M+H] ⁺ .

Synthesis of compound 4-a

Compound 4-b (50 mg, 0.2 mmol), compound 1-f (92 mg, 0.3 mmol), palladium acetate (5 mg, 0.02 mmol), cesium carbonate (194 mg, 0.6 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol) were dissolved in dioxane (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere, and then heated at 110°C for 40 minutes. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 20:1) to afford 4-a (25 mg, 24% yield) as a yellow solid. LC-MS (ESI): m/z = 521 [M+H] ⁺ .

Synthesis of compound 4

Compound 4-a (25 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL) and diluted with saturated sodium carbonate solution (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain a yellow solid 4 (35 mg, yield: 41%). LC-MS (ESI): m/z = 421 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.89(s,1H),8.40(d,J＝8Hz,1H),7.84(s,1H),7.81(s,1H),7.56(d,J＝2Hz,1H),7.19(s,1H),6.77(dd,J＝2Hz,J＝8Hz,1H ),6.71(d,J＝8Hz,1H),6.56(d,J＝8Hz,1H),3.89(s,3H),3.85(s,3H),3.32(m,2H),2.80(m,2H),2.59(m,1H),1.88(m,4H)ppm

Example 5

7-(2-Methylsulfonylphenyl)-N-[2-methoxy-4-(piperidin-4-yl)phenyl]thiophene[3,2-d]pyrimidin-2-amine (Compound 5)

Synthesis of compound 5-b

Compound 1-h (671 mg, 1.64 mmol), 2-methylsulfonylphenylboronic acid (328 mg, 1.64 mmol), bis(triphenylphosphine)palladium dichloride (69 mg, 0.09 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (63 mg, 0.15 mmol), and 2M aqueous sodium carbonate solution (6.5 mL, 13 mmol) were dissolved in 1,4-dioxane (13 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 90°C for 6 hours. The reaction mixture was cooled to room temperature, diluted with ice water (100 mL), and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 40:1) to afford a yellow solid 4-b (130 mg, yield: 24%). LC-MS (ESI): m/z = 325 [M+H] ⁺ .

Synthesis of compound 5-a

Compound 5-b (60 mg, 0.19 mmol), compound 1-f (68 mg, 0.22 mmol), cesium carbonate (180 mg, 0.56 mmol), palladium acetate (5 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22 mg, 0.04 mmol) were dissolved in dioxane (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere, and then heated at 110°C for 40 minutes. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 25:1) to afford 5-a (48 mg, 43% yield) as a yellow solid. LC-MS (ESI): m/z = 595 [M+H] ⁺ .

Synthesis of compound 5

Compound 5-a (50 mg, 0.08 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL) and diluted with saturated sodium carbonate solution (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain a yellow solid 5 (8 mg, yield: 19%). LC-MS (ESI): m/z = 495 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.98(s,1H),8.30(d,J=8Hz,1H),8.25(m,2H),7.77(m,2H),7.70(m,1H),7.63(m,1H),6.74( s,1H),6.62(d,J＝8Hz,1H),3.89(s,3H),3.35(s,2H),2.83(m,2H),2.61(m,1H),1.83(m,4H)ppm

Example 6

N-[2-methoxy-4-(piperidin-4-yl)phenyl]-3-(2-methoxyphenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-amine (Compound 6)

Synthesis of compound 6-b

Dissolve 3-bromo-5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (200 mg, 0.81 mmol), o-anisylboronic acid (184 mg, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (59 mg, 0.08 mmol), and sodium carbonate (170 mg, 1.6 mmol) in 1,4-dioxane (8 mL) and water (2 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere, then heated at 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford a white solid 6-b (90 mg, yield: 40%). LC-MS (ESI): m/z = 275 [M+H] ⁺ .

Synthesis of compound 6-a

Compound 6-b (70 mg, 0.25 mmol), compound 1-f (86 mg, 0.28 mmol), cesium carbonate (122 mg, 0.37 mmol), tris(dibenzylideneindeneacetone)dipalladium (23 mg, 0.02 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (16 mg, 0.02 mmol) were dissolved in toluene (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain 6-a (110 mg, yield: 79%) as a yellow solid. LC-MS (ESI): m/z = 545 [M+H] ⁺ .

Synthesis of compound 6

Compound 6-a (110 mg, 0.2 mmol) was dissolved in dichloromethane (3 mL). The reaction solution was cooled to 0°C, trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 8-9 with saturated aqueous sodium carbonate solution and then extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (mobile phase: 10 mM aqueous ammonium bicarbonate solution: acetonitrile = 30%-40%) to obtain a yellow solid 6 (79 mg, yield: 88%). LC-MS (ESI): m/z = 445 [M+H] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ )δ:8.81(s,1H),8.69(d,J＝8.3Hz,1H),7.95(dd,J＝7.5,1.5Hz,1H),7.86(s,1H), 7.47–7.37(m,1H),7.11(dd,J＝18.0,7.9Hz,2H),6.83(d,J＝8.3Hz,1H),6.77(s,1 H),4.16(s,3H),3.91(d,J＝7.5Hz,6H),3.25(d,J＝11.7Hz,2H),3.06(s,1H),2.77 (t,J＝11.5Hz,2H),2.60(s,1H),1.87(d,J＝12.0Hz,2H),1.72(d,J＝10.1Hz,2H)ppm

Example 7

N-[2-methoxy-4-(piperidin-4-yl)phenyl]-3-(2-methoxyphenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine (Compound 7)

Synthesis of compound 7-c

2,3-Dichloro-4-nitropyrimidine (5.8 g, 30 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and the reaction mixture was cooled to -78°C. 2-Methoxyaniline (3.7 g, 30 mmol) and diisopropylethylamine (3.9 g, 30 mmol) were then added to the solution, and stirring was continued for 2 hours. The reaction mixture was warmed to room temperature, and 1M aqueous hydrochloric acid (50 mL) was added, followed by extraction with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 7-c (6.9 g, 82% yield) as a yellow solid. This product did not require further purification. LC-MS (ESI): m/z = 289 [M+H] ⁺ .

Synthesis of compound 7-b

Compound 7-c (0.84 g, 3 mmol), compound 1-f (1.0 g, 3 mmol), and diisopropylethylamine (0.78 g, 6 mmol) were dissolved in tetrahydrofuran (100 mL). The reaction mixture was stirred at 40°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to 1M aqueous hydrochloric acid (2 mL), followed by extraction with dichloromethane (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 7-b (1.3 g, yield: 79%) as a yellow solid. This product did not require further purification. LC-MS (ESI): m/z = 551 [M+H] ⁺ .

Synthesis of compound 7-a

Compound 7-b (750 mg, 1.5 mmol) and 10% palladium on carbon (150 mg) were dissolved in methanol (10 mL). The reaction mixture was replaced with hydrogen three times, then hydrogenated at 40°C for 3 hours. The reaction mixture was cooled to room temperature, filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to afford a yellow solid 7-a (610 mg, yield: 78%). This product did not require further purification. LC-MS (ESI): m/z = 521 [M+H] ⁺ .

Synthesis of compound 7

Compound 7-a (260 mg, 0.5 mmol) was added to a 4M aqueous hydrochloric acid solution (2 mL) and acetic acid (2 mL). The reaction solution was cooled to -5°C. Sodium nitrite (70 mg, 1 mmol) was then slowly added to the solution, and stirring was continued for 2 hours. Saturated aqueous sodium bicarbonate solution (8 mL) was added to the reaction solution, and a solid precipitated. This solid was filtered, washed with water (5 mL x 3), and then dried under vacuum to obtain a yellow solid 7 (130 mg, yield: 60%). LC-MS (ESI): m/z = 432 [M+H] ⁺ .

¹ H-NMR (400MHz, CD ₃ OD)δ:9.26(s,1H),8.25(d,J＝8Hz,1H),7.68(t,J＝8Hz,1H),7.64(d,J＝8Hz,1H),7.36(d,J＝8Hz,1H),7.25(t,J＝8Hz,1H),6.90(s ,1H),6.74(d,J＝8Hz,1H),3.94(s,3H),3.84(s,3H),3.17(m,2H),2.77(t,J＝12Hz,2H),2.66(m,1H),1.83(m,2H),1.69(m,2H)ppm

Example 8

N-[2-methoxy-4-(piperidin-4-yl)phenyl]-7-(2-methoxyphenyl)-6-methylthienyl[3,2-d]pyrimidin-2-amine (Compound 8)

Synthesis of compound 8-b

Compound 2-c (380 mg, 1.5 mmol), o-anisylboronic acid (150 mg, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (82 mg, 0.1 mmol), and sodium carbonate (210 mg, 2 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, then heated at 110°C for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove a portion of the dioxane. The residue was filtered through celite, and the filter cake was washed with ethyl acetate (20 mL x 3). The organic phase was washed sequentially with water (20 mL x 3) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 8-b (239 mg, yield: 40%) as a yellow solid. LC-MS (ESI): m/z = 277 [M+H] ⁺ .

Synthesis of compound 8-a

Compound 8-b (145 mg, 0.5 mmol), compound 1-f (150 mg, 0.5 mmol), tris(dibenzylideneindeneacetone)dipalladium (74 mg, 0.13 mmol), potassium carbonate (180 mg, 1.29 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (60 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL). The organic phase was washed sequentially with water (20 mL x 3) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford a light yellow solid 8-a (61 mg, yield: 22%). LC-MS (ESI): m/z = 561 [M+H] ⁺ .

Synthesis of compound 8

Compound 8-a (56 mg, 0.1 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL), followed by the addition of 1 M aqueous hydrochloric acid (30 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (10 mL x 3) and then dried under vacuum to yield a light yellow solid 8 (16 mg, yield: 34.7%). LC-MS (ESI): m/z = 461 [M+H] ⁺ .

¹ H-NMR (400MHz, CD ₃ OD)δ:8.70(s,1H),8.20(m,1H),7.39(t,J＝8Hz,1H),7.20(d,J＝8Hz,1H),7.07(m,2H),6.70(s,1H),6.51(d, J＝7.2Hz,1H),3.78(s,3H),3.65(s,3H),3.08(m,1H),2.60(m,2H),2.35(s,3H),1.73(m,2H),1.53(m,2H)ppm

Example 9

7-(5-methylsulfonyl-2-methoxyphenyl)-N-[2-methoxy-4-(piperidin-4-yl)phenyl]thiophene[3,2-d]pyrimidin-2-amine (Compound 9)

Synthesis of compound 9-d

2-Bromo-4-methylsulfonylphenol (2.0 g, 7.96 mmol) and iodomethane (3.39 g, 23.9 mmol) were dissolved in tetrahydrofuran (30 mL), and cesium carbonate (7.79 g, 23.9 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was added to water (15 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-d (2 g, yield: 94.7%). This product did not require further purification. LC-MS (ESI): m/z = 267 [M+H] ⁺ .

Synthesis of compound 9-c

Compound 9-d (400 mg, 1.51 mmol), pinacol bisboronate (1.15 g, 4.53 mmol), anhydrous potassium acetate (445 mg, 4.53 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (110 mg, 0.15 mmol) were dissolved in 1,4-dioxane (15 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 9-c (341 mg, yield: 72%). LC-MS (ESI): m/z = 348 [M+H] ⁺ .

Synthesis of compound 9-b

Compound 9-c (200 mg, 0.8 mmol), compound 1-h (300 mg, 0.96 mmol), sodium carbonate (24 mg, 2.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (117 mg, 0.16 mmol) were dissolved in 1,4-dioxane (12 mL) and water (2 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 9-b (140 mg, yield: 49%). LC-MS (ESI): m/z = 355 [M+H] ⁺ .

Synthesis of compound 9-a

Compound 9-b (140 mg, 0.39 mmol), compound 1-f (133 mg, 0.43 mmol), cesium carbonate (381 mg, 0.43 mmol), tris(dibenzylideneindeneacetone)dipalladium (14 mg, 0.01 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (15 mg, 0.02 mmol) were dissolved in toluene (15 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain compound 9-a (150 mg, yield: 63%). LC-MS (ESI): m/z = 625 [M+H] ⁺ .

Synthesis of compound 9

Compound 9-a (155 mg, 0.25 mmol) was dissolved in dichloromethane (6 mL). The reaction solution was cooled to 0°C, trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 8-9 with saturated aqueous sodium carbonate solution and then extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (mobile phase: 10 mM aqueous ammonium bicarbonate solution: acetonitrile = 38%-48%) to obtain compound 9 (10 mg, yield: 7.7%). LC-MS (ESI): m/z = 525 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.95(s,1H),8.44-8.39(m,2H),8.14(s,1H),8.00(dd,J＝8.7,2.4Hz,1H),7.82(s,1H),7.19(d,J＝8.8Hz,1H),6.80(d,J＝8.3Hz,1H),6.7 5(s,1H),3.91(d,J＝12.4Hz,6H),3.34(d,J＝12.2Hz,2H),3.08(s,3H),2.83(t,J＝10.8Hz,2H),2.63(s,1H),1.86(dd,J＝30.8,10.5Hz,4H)ppm

Example 10

7-(2,3-Dihydro-1-benzofuran-7-yl)-N-[4-(piperidin-4-yl)-2-isopropoxyphenyl]-6-methylthienyl[3,2-d]pyrimidin-2-amine (Compound 10)

Synthesis of compound 10-d

2-Fluoro-4-bromonitrobenzene (5.0 g, 22.83 mmol) was dissolved in isopropanol (100 mL), and cesium carbonate (37.2 g, 114.16 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (150 mL), followed by the addition of water (150 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from petroleum ether (100 mL) to obtain a yellow solid 10-d (4.7 g, yield: 79%). This product did not require further purification.

Synthesis of compound 10-c

Compound 10-d (1.2 g, 4.63 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-pinacol boronate (1.72 g, 5.56 mmol), sodium carbonate (147 g, 13.89 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (375 mg, 0.46 mmol) were dissolved in dioxane (15 mL) and water (15 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL). The organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 10-c (1.17 g, yield: 71%) as a light yellow solid. LC-MS(ESI): m/z=307[M+Ht-Bu] ⁺ .

Synthesis of compound 10-b

Compound 10-c (610 mg, 1.68 mmol) and 10% palladium on carbon (150 mg) were dissolved in ethanol (20 mL). The reaction mixture was replaced with hydrogen three times and then hydrogenated at room temperature for 16 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to obtain a purple oil 10-b (435 mg, yield: 84%). This product did not require further purification. LC-MS (ESI): m/z = 335 [M+H] ⁺ .

Synthesis of compound 10-a

Compound 10-b (132 mg, 0.39 mmol), compound 3-b (120 mg, 0.39 mmol), potassium carbonate (168 mg, 1.22 mmol), tris(dibenzylideneindeacetone)dipalladium (72 mg, 0.13 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (72 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The filtrate was washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a yellow solid 10-a (71 mg, yield: 30%). LC-MS (ESI): m/z = 601 [M+H] ⁺ .

Synthesis of compound 10

Compound 10-a (71 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL), followed by addition of saturated aqueous sodium carbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain a light yellow solid 10 (35 mg, yield: 39%). LC-MS (ESI): m/z = 501 [M+H] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ )δ:8.77(s,1H),8.59(d,J＝8Hz,1H),7.80(s,1H),7.37(d,J＝8Hz,1H),7.31(d d,J＝8Hz,J＝2Hz,1H),6.73(m,1H),6.69(s,1H),6.67(dd,J＝8Hz,J＝2Hz,1H),4 .56-4.65(m,3H),3.57-3.60(m,2H),3.31-3.36(m,2H),2.98-3.04(m,1H),2. 57(s,3H),2.07-2.13(m,2H),2.00-2.07(m,2H),1.37(s,3H),1.38(s,3H)ppm

Example 11

7-(2-Methylphenyl)-N-[4-(piperidin-4-yl)-2-isopropoxyphenyl]-6-methylthienyl[3,2-d]pyrimidin-2-amine (Compound 11)

Synthesis of compound 11-a

Compound 10-b (242 mg, 0.73 mmol), compound 8-b (210 mg, 0.73 mmol), potassium carbonate (300 mg, 2.17 mmol), tris(dibenzylideneacetone)dipalladium (124 mg, 0.22 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (101 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 11-a (145 mg, yield: 34%) as a light yellow solid. LC-MS (ESI): m/z = 589 [M+H] +.

Synthesis of compound 11

Compound 11-a (145 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL), followed by addition of saturated aqueous sodium carbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain a light yellow solid 11 (125 mg, yield: 100%). LC-MS (ESI): m/z = 488 [M+H] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ )δ:8.76(s,1H),8.46(d,J=8Hz,1H),7.74(s,1H),7.42-7.47(m,2H),7.10- 7.14(m,1H),7.06(d,J＝8Hz,1H),6.72(d,J＝2Hz,1H),6.63(dd,J＝8Hz,J＝2H z,1H),4.56-4.61(m,1H),3.78(s,3H),3.20-3.23(m,2H),2.73-2.78(m,2H ),2.51-2.55(m,1H),2.50(s,3H),1.76-1.83(m,4H),1.35(d,J＝8Hz,6H)ppm

Example 12

2-[4-(4-{[7-(2-methylphenyl)-6-methylthienyl[3,2-d]pyrimidin-2-yl]amino}-3-isopropoxyphenyl)piperidin-1-yl]acetamide (Compound 12)

Synthesis of compound 12

Compound 11 (50 mg, 0.11 mmol) and bromoacetamide (21 mg, 0.16 mmol) were dissolved in anhydrous ethanol (3 mL), followed by the addition of potassium carbonate (22 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 16 hours, then filtered. The filter cake was washed with ethyl acetate (10 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 12 (35 mg, yield: 63%). LC-MS (ESI): m/z = 546 [M+H] ⁺ .

1H-NMR (400MHz, CDCl3) δ: 8.76 (s, 1H), 8.46 (d, J = 8Hz, 1H), 7.74 (s, 1H), 7.43-7.47 (m, 2H), 7.10-7.14(m,1H),7.06(d,J＝8Hz,1H),6.72(d,J＝2Hz,1H),6.63(dd,J＝8Hz,J＝2Hz,1H),5.62 (br,1H),4.56-4.61(m,1H),3.78(s,3H),3.03(s,2H),2.97-3.01(m,2H),2.50(s,3H),2.40- 2.43(m,1H),2.24-2.30(m,2H),1.81-1.85(m,2H),1.69-1.76(m,2H),1.35(d,J＝8Hz,6H)ppm

Example 13

7-(2-Methylphenyl)-N-[5-methyl-4-(piperidin-4-yl)-2-isopropoxyphenyl]-6-methylthienyl[3,2-d]pyrimidin-2-amine (Compound 13)

Synthesis of compound 13-d

2-Chloro-4-fluoro-5-nitrobenzene (25 g, 131 mmol) was dissolved in isopropanol (250 mL), and cesium carbonate (208 g, 659 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (250 mL), followed by addition of water (250 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 19:1) to obtain a yellow solid 13-d (28.7 g, yield: 95%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 7.90 (d, J = 0.6Hz, 1H), 7.52 (s, 2H), 7.86 (m, 1H), 2.30 (s, 3H), 1.27 (d, J = 6Hz, 6H) ppm

Synthesis of compound 13-c

Compound 13-d (2.75 g, 12 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-pinacol borate (4.65 g, 15 mmol), potassium carbonate (4.97 g, 24 mmol), tris(dibenzylideneindeneacetone)dipalladium (375 mg, 0.46 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.5 g, 1.2 mmol) were dissolved in dioxane (40 mL) and water (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 150°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove a portion of the dioxane. The residue was dissolved in ethyl acetate (50 mL) and filtered through celite. The filtrate was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a yellow solid 13-c (3.15 g, yield: 70%). LC-MS (ESI): m/z = 376 [M+H] ⁺ .

Synthesis of compound 13-b

Compound 13-c (3.15 g, 8.4 mmol) and 10% palladium on carbon (0.5 g) were dissolved in methanol (10 mL). The reaction mixture was replaced with hydrogen three times, followed by hydrogenation at 40°C for 3 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to afford 13-b (2.8 g, 88% yield), a white solid. This product did not require further purification. LC-MS (ESI): m/z = 378 [M+H] ⁺ .

Synthesis of compound 13-a

Compound 13-b (144 mg, 0.41 mmol), compound 8-b (120 mg, 0.41 mmol), potassium carbonate (173 mg, 1.25 mmol), tris(dibenzylideneindeacetone)dipalladium (72 mg, 0.13 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (59 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The filtrate was washed with water (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow oil 13-a (67 mg, yield: 27%). LC-MS (ESI): m/z = 603 [M+H] ⁺ .

Synthesis of compound 13

Compound 13-a (67 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL), followed by addition of saturated aqueous sodium carbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain a light yellow solid 13 (15 mg, yield: 27%). LC-MS (ESI): m/z = 503 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.76(s,1H),8.36(s,1H),7.76(s,1H),7.41-7.45(m,2H),7.05-7.13(m,2H),6.72(s,1H),4.55-4.60(m,1H),3.77(s,3H) ,3.50-3.53(m,2H),2.99-3.05(m,2H),2.80-2.89(m,1H),2.49(s,3H),2.08(s,3H),1.90-2.04(m,4H),1.37(d,J＝8Hz,6H)ppm

Example 14

7-(2,3-Dihydro-1-benzofuran-7-yl)-N-[5-methyl-4-(piperidin-4-yl)-2-isopropoxyphenyl]-6-methylthienyl[3,2-d]pyrimidin-2-amine (Compound 14)

Synthesis of compound 14-a

Compound 13-b (98 mg, 0.28 mmol), compound 3-b (85 mg, 0.28 mmol), potassium carbonate (116 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium (48 mg, 0.09 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (39 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL × 3). The filtrate was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 14-a (45 mg, yield: 26%) as a yellow oil. LC-MS (ESI): m/z = 615 [M+H] ⁺ .

Synthesis of compound 14

Compound 14-a (45 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL), followed by addition of saturated aqueous sodium carbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain a light yellow solid 14 (26 mg, yield: 69%). LC-MS (ESI): m/z = 515 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.75(s,1H),8.40(s,1H),7.75(s,1H),7.405(d,J＝8Hz,1H),7.26(d,J ＝8Hz,1H),7.02(t,J＝8Hz,1H),6.75(s,1H),4.52-4.59(m,1H),3.28-3.32 (m,2H),3.17-3.20(m,2H),2.71-2.78(m,3H),2.55(s,3H),2.16(s,3H),1 .84(br,2H),1.71-1.74(m,2H),1.57-1.64(m,2H),1.34(d,J＝8Hz,6H)ppm

Example 15

7-(2-Methylphenyl)-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]-6-methylthienyl[3,2-d]pyrimidin-2-amine (Compound 15)

Synthesis of compound 15-d

7-Aminobenzo-2,3-dihydrofuran (3 g, 22.22 mmol) was dissolved in N,N-dimethylformamide (7 mL), and the reaction mixture was cooled to 0°C. A solution of N-bromosuccinimide (3.93 g, 22.22 mmol) in N,N-dimethylformamide (7 mL) was then added dropwise to the solution over 30 minutes. Stirring was continued for 30 minutes after the addition was complete. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 15-d (2.5 g, yield: 53%) as a yellow solid. LC-MS (ESI): m/z = 214 (M+H).

Synthesis of compound 15-c

Compound 15-d (2.2 g, 10 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-pinacol borate (3.1 g, 10 mmol), sodium carbonate (2.12 g, 20 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.55 g, 1 mmol) were dissolved in dioxane (40 mL) and water (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove a portion of the dioxane. The residue was dissolved in ethyl acetate (50 mL) and filtered through celite. The filtrate was washed sequentially with water (20 mL x 3) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a yellow solid 15-c (1.7 g, yield: 53.8%). LC-MS (ESI): m/z = 317 [M+H] ⁺ .

Synthesis of compound 15-b

Compound 15-c (1.7 g, 5.38 mmol) and 10% palladium on carbon (0.3 g) were dissolved in methanol (10 mL). The reaction mixture was replaced with hydrogen three times, followed by hydrogenation at 40°C for 3 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to obtain a pink solid 15-b (1.5 g, yield: 87.7%). This product did not require further purification. LC-MS (ESI): m/z = 263 [M+Ht-Bu] ⁺ .

Synthesis of compound 15-a

Compound 15-b (160 mg, 0.5 mmol), compound 8-b (150 mg, 0.5 mmol), potassium carbonate (140 mg, 0.05 mmol), tris(dibenzylideneindeacetone)dipalladium (46 mg, 0.05 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (24 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The filtrate was washed with water (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a yellow oil 15-a (180 mg, yield: 63%). LC-MS (ESI): m/z = 573 [M+H] ⁺ .

Synthesis of compound 15

Compound 15-a (180 mg, 0.31 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL), followed by the addition of 1 M aqueous hydrochloric acid (30 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (10 mL x 3) and then dried under vacuum to afford 15 (110 mg, yield: 74%) as a light yellow solid. LC-MS (ESI): m/z = 473 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ )δ:8.94(s,1H),8.00(s,1H),7.56(d,J＝8Hz,1H),7.44(t,J＝8Hz,1H),7.30(d,J＝8Hz,1H),7.06(t,J＝8 Hz,1H),6.51(d,J＝8Hz,1H),4.51(t,J＝8Hz,2H),3.71(s,3H),3.18(m,4H),2.40(s,3H),1.62(m,4H)ppm

Example 16

7-(2-Ethoxyphenyl)-6-methyl-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]thiophene[3,2-d]pyrimidin-2-amine (Compound 16)

Synthesis of compound 16-b

Compound 2-c (620 mg, 2 mmol), o-ethoxyphenylboronic acid (330 mg, 2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg, 0.14 mmol), and sodium carbonate (500 mg, 4.7 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 16-b (300 mg, yield: 49%) as a white solid. LC-MS (ESI): m/z = 305 [M+H] +.

Synthesis of compound 16-a

Compound 15-b (300 mg, 0.98 mmol), compound 15-b (3.2 g, 1 mmol), potassium carbonate (400 mg, 2.89 mmol), tris(dibenzylideneindeacetone)dipalladium (70 mg, 0.07 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (50 mg, 0.1 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid 16-a (200 mg, yield: 34%). LC-MS (ESI): m/z = 578 [M+H] ⁺ .

Synthesis of compound 16

Compound 16-a (200 mg, 0.34 mmol) was dissolved in dichloromethane (10 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with potassium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 16 (70 mg, yield: 42%) as a yellow solid. LC-MS (ESI): m/z = 487 [M+H]+.

¹ H-NMR (400MHz, CD ₃ OD) δ: 8.60 (s, 1H), 7.87 (d, J = 8.4Hz, 1H), 7.29-7.24 (m, 1H), 7.15 (dd, J ₁ = 7.6Hz, J ₂ ＝1.6Hz,1H),6.95-6.90(m,2H),6.36(d,J＝8.4Hz,1H),4.37(t,J＝8.4Hz,2H),7.29-7.24(m,1H),3.92-3.74(m,2H),3.11-3.07 (m,2H),3.00(t,J＝8.4Hz,2H),2.70-2.63(m,2H),2.53-2.45(m,1H),2.30(s,1H),1.60-1.50(m,4H),1.01(t,J＝7.6Hz,2H)ppm

Example 17

4-[7-({7-[2-methoxy-4-trifluoromethylphenyl]-6-methylthien[3,2-d]pyrimidin-2-yl}amino)-2,3-dihydro-1-benzofuran-4-yl]piperidin-3-ol (Compound 17)

Synthesis of compound 17-c

At 0°C, a 1M borane solution in tetrahydrofuran (15.8 mL) was added dropwise to a solution of compound 15-c (1 g, 3.16 mmol) in tetrahydrofuran (10 mL). After the addition was complete, the reaction solution was warmed to room temperature and stirred for 30 minutes. The reaction solution was cooled to 0°C again, and a 2M aqueous sodium hydroxide solution was added dropwise to adjust the pH of the reaction solution to 10. Then, 30% hydrogen peroxide (1 mL) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a light yellow solid 17-c (653 mg, yield: 62%). LC-MS (ESI): m/z = 279 [M+Ht-Bu] ⁺ .

Synthesis of compound 17-b

Compound 2-c (3.1 g, 10 mmol), o-methoxy-p-trifluoromethylphenylboronic acid (2.2 g, 10 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (700 mg, 1 mmol), and sodium carbonate (3.0 g, 30 mmol) were dissolved in 1,4-dioxane (60 mL) and water (15 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 120°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (50 mL), and extracted with dichloromethane (150 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 17-b (2.25 g, yield: 63%) as a white solid. LC-MS (ESI): m/z = 359 [M+H] ⁺ .

Synthesis of compound 17-a

Compound 17-b (500 mg, 1.4 mmol), compound 17-c (466 mg, 1.4 mmol), potassium carbonate (580 mg, 4.2 mmol), tris(dibenzylideneindeneacetone)dipalladium (100 mg, 0.14 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (650 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (20 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid 17-a (200 mg, yield: 22%). LC-MS (ESI): m/z = 657 [M+H] ⁺ .

Synthesis of compound 17

Compound 17-a (200 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with saturated aqueous potassium carbonate. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 17 (40 mg, yield: 21%) as a yellow solid. LC-MS (ESI): m/z = 557 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.78(s,1H),8.11(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.19(s,1H),6.65(d,J＝8.0Hz ,1H),4.61(t,J＝8.4Hz,1H),3.83(s,4H),3.46-3.12(m,4H),2.78-2.50(m,3H),2.48(s,3H),2.07-1.95(m,2H)ppm

Example 18

7-[2-Methoxy-4-trifluoromethylphenyl]-6-methyl-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]thiophene[3,2-d]pyrimidin-2-amine (Compound 18)

Synthesis of compound 18-a

Compound 17-b (400 mg, 1.12 mmol), compound 15-b (355 mg, 1.12 mmol), potassium carbonate (460 mg, 3.33 mmol), tris(dibenzylideneindeneacetone)dipalladium (80 mg, 0.11 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (460 mg, 3.33 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (20 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid 18-a (100 mg, yield: 14%). LC-MS (ESI): m/z = 641 [M+H].

Synthesis of compound 18

Compound 18-a (200 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL). The reaction solution was cooled to 0°C, trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with saturated aqueous potassium carbonate. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a yellow solid 18 (24 mg, yield: 28%). LC-MS (ESI): m/z = 541 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.77(s,1H),8.05(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.16(s,1H),6.59(d,J＝8.0Hz,1H),4.6 0(t,J＝8.4Hz,1H),3.82(s,4H),3.28-3.18(m,4H),2.79-2.72(m,2H),2.62-2.52(m,1H),2.49(s,3H),1.82-1.65(m,4H)ppm

Example 19

N-[2-(2-{[2-methoxy-4-(piperidin-4-yl)phenyl]amino}quinazolin-8-yl)phenyl]-N-methylmethanesulfonamide (Compound 19)

Synthesis of compound 19-f

2-Amino-3-bromobenzoic acid (5.0 g, 23.26 mmol) and urea (7.0 g, 116.28 mmol) were mixed and heated at 210°C for 2 hours. The reaction mixture was cooled to 90°C, and then water (50 mL) was added and stirred for 30 minutes. The reaction mixture was cooled to room temperature, filtered, and the filter cake was dried under vacuum to yield a yellow solid 19-f (5.5 g, yield: 98%). This product did not require further purification. LC-MS (ESI): m/z = 241 [M+H] ⁺ .

Synthesis of compound 19-e

Compound 19-f (5.5 g, 22.9 mmol) was dissolved in phosphorus oxychloride (30 mL), and N,N-dimethylaniline (5 mL) was added. The reaction mixture was heated at 110°C for 18 hours. After cooling to room temperature, the phosphorus oxychloride was removed by concentration under reduced pressure. The residue was concentrated to dryness, dissolved in dichloromethane (500 mL), and washed with water (500 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:dichloromethane = 3:1) to obtain 19-e (2.5 g, yield: 40%) as a light yellow solid. LC-MS (ESI): m/z = 277 [M+H] ⁺ .

Synthesis of compound 19-d

Compound 19-e (1.2 g, 4.35 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of a 7 M methanolic ammonia solution (50 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added with water (50 mL). A solid precipitated, which was filtered and the filter cake washed with water (50 mL). After vacuum drying, a yellow solid 19-d (1.5 g, yield: 100%) was obtained. This product was used directly in the next reaction without further purification.

Synthesis of compound 19-c

Compound 19-d (1.5 g, 5.84 mmol) was dissolved in tetrahydrofuran (20 mL), and tert-amyl nitrite (2.7 g, 23.36 mmol) was added. The reaction mixture was heated at 70°C for 18 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:dichloromethane = 3:1) to afford 19-c (0.79 g, yield: 56%) as a light yellow solid. LC-MS (ESI): m/z = 243 [M+H] ⁺ .

Synthesis of compound 19-b

Compound 19-c (300 mg, 1.24 mmol), compound 1-c (384 mg, 1.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (144 mg, 0.17 mmol), and sodium carbonate (396 mg, 3.74 mmol) were dissolved in 1,4-dioxane (5 mL) and water (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, then heated at 90°C for 30 minutes. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain 19-b (158 mg, yield: 37%) as a light yellow solid. LC-MS (ESI): m/z = 348 [M+H] ⁺ .

Synthesis of compound 19-a

Compound 19-b (100 mg, 0.29 mmol), compound 1-f (132 mg, 0.43 mmol), cesium carbonate (280 mg, 0.86 mmol), palladium acetate (102 mg, 0.46 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (332 mg, 0.58 mmol) were dissolved in dioxane (2 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 40 minutes. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 19-a (61 mg, yield: 35%) as a yellow solid. LC-MS (ESI): m/z = 618 [M+H] ⁺ .

Synthesis of compound 19

Compound 19-a (61 mg, 0.1 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with saturated sodium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (mobile phase: 10 mM aqueous ammonium bicarbonate: acetonitrile = 35%-65%) to obtain 19 (30 mg, yield: 59%) as a yellow solid. LC-MS (ESI): m/z = 518 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.09(s,1H),7.99(d,J＝8Hz,1H),7.92(s,1H),7.85(dd,J＝5Hz,J＝2Hz,1H),7.76(dd,J＝5Hz,J＝2Hz,1H),7.40-7.61(m,5H),6.70(d,J＝2Hz,1H), 6.40(dd,J＝5Hz,J＝2Hz,1H),3.87(s,3H),3.21(m,2H),2.92(s,3H),2.72 -2.78(m,2H),2.52-2.57(m,4H),1.79-1.82(m,2H),1.63-1.70(m,2H)ppm

Example 20

N-[2-methoxy-4-(piperidin-4-yl)phenyl]-8-(2-methoxyphenyl)quinazolin-2-amine (Compound 20)

Synthesis of compound 20-b

Compound 19-c (600 mg, 2.48 mmol), 2-methoxyphenylboronic acid pinacol ester (415 mg, 2.73 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (204 mg, 0.25 mmol), and sodium carbonate (804 mg, 7.44 mmol) were dissolved in 1,4-dioxane (5 mL) and water (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:dichloromethane = 3:1) to obtain 20-b (450 mg, yield: 67%) as a white solid. LC-MS (ESI): m/z = 271 [M+H] +.

Synthesis of compound 20-a

Compound 19-b (150 mg, 0.37 mmol), compound 1-f (255 mg, 0.56 mmol), cesium carbonate (362 mg, 1.11 mmol), tris(dibenzylideneindeneacetone)dipalladium (64 mg, 0.12 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (75 mg, 0.12 mmol) were dissolved in dioxane (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere, and then heated at 110°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filter cake was washed with dichloromethane (50 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 20-a (98 mg, yield: 33%) as a yellow solid. LC-MS (ESI): m/z = 541 [M+H] ⁺ .

Synthesis of compound 20

Compound 20-a (98 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with saturated aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain a yellow solid 20 (22 mg, yield: 28%). LC-MS (ESI): m/z = 441 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.09(s,1H),8.35(d,J＝8Hz,1H),7.95(s,1H),7.78(dd,J＝8Hz,J＝2Hz,1 H),7.75(dd,J＝8Hz,J＝2Hz,1H),7.49-7.53(m,1H),7.38-7.41(m,2H),7.10 -7.14(m,1H),6.71(d,J＝2Hz,1H),6.53(dd,J＝8Hz,J＝2Hz,1H),3.88(s,3H) ,3.68(s,3H),3.58(m,2H),3.02(m,2H),2.69(m,1H),1.99-2.14(m,4H)ppm

Example 21

N-[2,2-dimethyl-4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]-6-fluoro-8-(2-methoxyphenyl)quinazolin-2-amine (Compound 21)

Synthesis of compound 21-k

2-Nitro-5-bromophenol (1.0 g, 4.61 mmol) was dissolved in water (10 mL), and sodium hydroxide (185 mg, 4.61 mmol) and 3-bromo-2-methylpropene (803 mg, 5.99 mmol) were added to the solution. The mixture was heated at 60°C for 5 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The separated organic phase was washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 21-k (1.1 g, yield: 88%) as a yellow solid. LC-MS (ESI): m/z = 599 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:7.75(d,J＝9Hz,1H),7.21(d,J＝2Hz,1H),7.17(dd,J＝9Hz,J＝2Hz,1H),5.17(s,1H),5.06(t,J＝2Hz,1H),4.56(s,2H),1.85(s,3H)ppm

Synthesis of compound 21-j

Compound 21-k (1.1 g, 4.06 mmol) and anhydrous magnesium chloride (110 mg) were mixed and heated to 190°C for 3 hours. The mixture was then cooled to room temperature and ethyl acetate (50 mL) was added, resulting in the precipitation of a solid. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford 21-j (1.1 g, 100% yield) as a white solid.

Synthesis of compound 21-i

Compound 21-j (1.1 g, 4.06 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.51 g, 48.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (341 mg, 0.43 mmol), and sodium carbonate (1.3 g, 12.25 mmol) were dissolved in 1,4-dioxane (15 mL) and water (15 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 80°C for 16 hours. The reaction was cooled to room temperature, diluted with ice water (100 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a light yellow solid 21-i (565 mg, yield: 37%).

¹ H-NMR (400MHz, CDCl ₃ )δ:7.90(d,J＝9Hz,1H),8.08(d,J＝9Hz,1H),6.77(d,J＝9Hz,1H),5.88(s,1H),4 .08-4.11(m,2H),3.61-3.64(m,2H),3.09(s,2H),2.44(s,2H),1.50(s,9H)ppm

Synthesis of compound 21-h

Compound 21-i (565 mg, 1.51 mmol) and 10% palladium on carbon (150 mg) were dissolved in ethanol (20 mL). The reaction mixture was replaced with hydrogen three times and then hydrogenated at room temperature for 16 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to obtain a purple oil 21-h (435 mg, yield: 84%). This product did not require further purification. LC-MS (ESI): m/z = 291 [M+H] ⁺ .

Synthesis of compound 21-g

At 0°C, 2-amino-5-fluorobenzoic acid (20 g, 129 mmol) was dissolved in glacial acetic acid (250 mL). N-bromosuccinimide (25 g, 140 mmol) was then added portionwise to the solution. The mixture was stirred at room temperature for 16 hours and then filtered. The filter cake was washed with petroleum ether (100 mL x 3). The filter cake was dried in vacuo to yield 21-g of a white solid (18.8 g, yield: 62%). This product did not require further purification. LC-MS (ESI): m/z = 234 [M+H] ⁺ .

Synthesis of compound 21-f

At 0°C, a solution of borane in tetrahydrofuran (240 mL, 240 mmol) was added dropwise to a solution of compound 21-g (18.8 g, 80 mmol) in tetrahydrofuran (160 mL). The reaction was stirred at room temperature for 16 hours. Methanol (10 mL) was added to quench the reaction, and the reaction solution was then concentrated under reduced pressure to remove the organic solvent. The residue was dissolved in ethyl acetate (200 mL), and the solution was washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 21-f as a white solid (17.2 g, yield: 97%). LC-MS (ESI): m/z = 220 [M+H] ⁺ .

Synthesis of compound 21-e

At 0°C, manganese dioxide (34 g, 390 mmol) was added portionwise to a solution of compound 21-f (17.2 g, 78 mmol) in chloroform (300 mL). The reaction was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 21-e (16.5 g, yield: 95%). This product did not require further purification. LC-MS (ESI): m/z = 218 [M+H] ⁺ .

Synthesis of compound 21-d

Compound 21-f (16.5 g, 76 mmol) was mixed with urea (64 g, 1070 mmol) and heated at 185°C for 30 minutes. The reaction mixture was cooled to room temperature, and then water (200 mL) was added and stirred for 30 minutes. The reaction mixture was filtered, and the filter cake was dried under vacuum to yield a white solid 21-d (18 g, yield: 97%). This product did not require further purification. LC-MS (ESI): m/z = 243 [M+H] ⁺ .

Synthesis of compound 21-c

At 0°C, compound 21-d (18 g, 74 mmol) was dissolved in phosphorus oxychloride (120 mL, 860 mmol). The reaction mixture was heated at 105°C for 16 hours. After cooling to room temperature, the phosphorus oxychloride was removed by concentration under reduced pressure. The residue was added to water (100 mL) and stirred. The reaction mixture was filtered, and the filter cake was dried under vacuum to obtain a white solid 21-c (5 g, yield: 26%). This product did not require further purification. LC-MS (ESI): m/z = 261 [M+H] ⁺ .

Synthesis of compound 21-b

Compound 21-c (1.03 g, 3.93 mmol), o-anisylboronic acid (600 mg, 3.95 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (150 mg, 0.2 mmol), and sodium carbonate (1.2 g, 11.3 mmol) were dissolved in 1,4-dioxane (30 mL) and water (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 120°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 21-b (0.49 g, yield: 43%) as a white solid. LC-MS (ESI): m/z = 599 [M+H] ⁺ .

Synthesis of compound 21-a

Compound 21-b (140 mg, 0.48 mmol), compound 21-h (112 mg, 0.32 mmol), potassium carbonate (220 mg, 1.6 mmol), tris(dibenzylideneindeneacetone)dipalladium (11 mg, 0.015 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (11 mg, 0.023 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid 21-a (120 mg, yield: 42%). LC-MS (ESI): m/z = 499 [M+H] ⁺ .

Synthesis of compound 21

Compound 21-a (120 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (5 mL, 43 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with potassium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a yellow solid 21 (20 mg, yield: 20%). LC-MS (ESI): m/z = 499 [M+H] ⁺ .

¹ H-NMR (400MHz, CD ₃ OD) δ: 9.17 (s, 1H), 7.95 (d, J = 8.4Hz, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.52-7.47 (m, 1H), 7.37 (dd, J ₁ = 7.6Hz, J ₂ ＝1.6Hz,1H),7.16(d,J＝8.4Hz,1H),7.11(t,J＝7.4Hz,1H),6.40(d,J＝8.4Hz,1H),3.69(s,3H),3 .53-3.46(m,2H),3.16-3.08(m,4H),2.85-2.76(m,1H),2.05-1.97(m,2H),1.95-1.83(m,2H)ppm

Example 22

6-Fluoro-8-(2-methoxyphenyl)-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 22)

Synthesis of compound 22-a

Compound 21-b (170 mg, 0.59 mmol), compound 15-b (190 mg, 0.60 mmol), tris(dibenzylideneindeneacetone)dipalladium (20 mg, 0.02 mmol), potassium carbonate (250 mg, 1.8 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (10 mg, 0.02 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 130 ° C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid 22-a (200 mg, yield: 59%). LC-MS (ESI): m/z = 571 [M+H] ⁺ .

Synthesis of compound 22

Compound 22-a (200 mg, 0.35 mmol) was dissolved in dichloromethane (10 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (5 mL, 43 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with potassium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 22 (70 mg, yield: 42%) as a yellow solid. LC-MS (ESI): m/z = 471 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.02(s,1H),8.00(d,J＝8.4Hz,1H),7.59-7.56(m,1H),7.52-7.47(m,1H),7.41(d,J＝6.8Hz,1H),7.36-7.32(m,2H),7.13-7.07(m,2H),6 .46(d,J＝8.4Hz,1H),4.60(t,J＝8.8Hz,1H),3.69(s,3H),3.25-3.15(m,4H),2.72(t,J＝8.8Hz,1H),2.57-2.45(m,1H),1.78-1.64(m,4H)ppm

Example 23

8-(2-Methoxyphenyl)-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 23)

Synthesis of compound 23-a

Compound 20-b (170 mg, 0.59 mmol), compound 15-b (160 mg, 0.5 mmol), potassium carbonate (140 mg, 1 mmol), tris(dibenzylideneindeneacetone)dipalladium (46 mg, 0.05 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (24 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110 ° C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The combined filtrates were washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford a light yellow solid 23-a (161 mg, yield: 58%). LC-MS (ESI): m/z = 553 [M+H] ⁺ .

Synthesis of compound 23

Compound 23-a (160 mg, 0.29 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL), followed by the addition of 1 M aqueous hydrochloric acid (30 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (50 mL x 3) and then dried under vacuum to afford a light yellow solid 23 (62 mg, yield: 47.3%). LC-MS (ESI): m/z = 453 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.06(s,1H),8.06(d,J＝8Hz,1H),7.76(d,J＝8Hz,1H),7.71(d,J＝8Hz,1H),7.43(m,4H),7.10(m,2H),6.46(d,J＝8Hz,1H),6.56( d,J＝8Hz,1H),4.60(t,J＝8Hz,2H),3.68(s,3H),3.21(t,J＝8Hz,2H),3.20(m,2H),2.73(t,J＝8Hz,2H),2.53(m,1H),1.73(m,4H)ppm

Example 24

N-[2,2-dimethyl-4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]-8-(2-methoxyphenyl)quinazolin-2-amine (Compound 24)

Synthesis of compound 24-a

Compound 21-h (143 mg, 0.41 mmol), 20-b (120 mg, 0.41 mmol), cesium carbonate (401 mg, 1.23 mmol), tris(dibenzylideneindeneacetone)dipalladium (71 mg, 0.13 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (58 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (50 mL x 3). The filtrate was washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a light yellow solid 24-a (98 mg, yield: 40%). LC-MS (ESI): m/z = 601 [M+H] ⁺ .

Synthesis of compound 24

Compound 24-a (98 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL, 25.8 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL) and diluted with saturated aqueous sodium carbonate (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain a light yellow solid 24 (35 mg, yield: 43%). LC-MS (ESI): m/z = 501 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.76(s,1H),8.21(d,J＝8Hz,1H),7.45-7.50(m,1H),7.40(dd,J＝8Hz,J＝2Hz,1H),7.23(s,1H),7.12-7.15(m,1H),7.08(d,J＝8Hz,1H),6 .56(d,J=8Hz,1H),3.79(s,3H),3.56(m,2H),3.03(s,2H),2.98(m,2H),2.63(m,1H),2.50(s,3H),2.13(m,2H),1.97(m,2H),1.47(s,6H)ppm

Example 25

8-(2-Methoxyphenyl)-N-[3-(piperidin-4-yl)-1-isopropyl-1H-pyrazol-5-yl]quinazolin-2-amine (Compound 25)

Synthesis of compound 25-c

Dissolve anhydrous acetonitrile (1.18 g, 28.81 mmol) in anhydrous tetrahydrofuran (50 mL) and cool the reaction mixture to -78°C. Then, add a 2.5 M solution of n-butyllithium in n-hexane (11.5 mL, 28.75 mmol) dropwise to the solution and continue stirring for 4 hours. Add a solution of methyl N-Boc-4-piperidinylcarboxylate (7.0 g, 28.81 mmol) in anhydrous tetrahydrofuran (50 mL) dropwise to the reaction mixture. Stir at -78°C for 30 minutes, slowly warm to room temperature, continue stirring for 2 hours, and then dilute with a saturated aqueous solution of ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a light yellow solid 25-c (3.1 g, yield: 42%). LC-MS (ESI): m/z = 197 [M+Ht-Bu] ⁺ .

Synthesis of compound 25-b

Compound 25-c (1.6 g, 6.35 mmol) and isopropylhydrazine hydrochloride (769 mg, 6.99 mmol) were dissolved in anhydrous ethanol (20 mL), and triethylamine (962 mg, 9.53 mmol) was added. The reaction mixture was heated under reflux for 16 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a light yellow solid 25-b (1.3 g, yield: 67%). This product did not require further purification. LC-MS (ESI): m/z = 309 [M+H] ⁺ .

Synthesis of compound 25-a

Compound 25-b (189 mg, 0.62 mmol), 20-b (150 mg, 0.56 mmol), tris(dibenzylideneindeneacetone)dipalladium (97 mg, 0.17 mmol), potassium carbonate (232 mg, 1.68 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (78 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and ice water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a light yellow solid 25-a (208 mg, yield: 69%). LC-MS (ESI): m/z = 543 [M+H] ⁺ .

Synthesis of compound 25

Compound 25-a (208 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL, 25.8 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain 25 (130 mg, yield: 76%) as a yellow solid. LC-MS (ESI): m/z = 543 [M+H] ⁺ .

¹ H-NMR (400MHz, CD ₃ OD)δ:9.21(s,1H),7.87(dd,J＝8Hz,J＝2Hz,1H),7.69(dd,J＝8Hz,J＝2Hz,1H),7.38-7.46(m,2H),7.25-7.27(dd,J＝8Hz,J＝2Hz,1H),7.04-7.11(m,2H ), 6.08(s,1H),4.49-4.52(m,1H),3.64(s,3H),3.15-3.20(m,2H),2.69- 2.81(m,3H),1.83-1.86(m,2H),1.55-1.59(m,2H),1.31(d,J＝7Hz,6H)ppm

Example 26

6-Fluoro-8-(2-methoxyphenyl)-N-[3-(piperidin-4-yl)-1-isopropyl-1H-pyrazol-5-yl]quinazolin-2-amine (Compound 26)

Synthesis of compound 26-a

Compound 21-b (170 mg, 0.59 mmol), compound 25-b (160 mg, 0.52 mmol), tris(dibenzylideneindeneacetone)dipalladium (20 mg, 0.02 mmol), potassium carbonate (210 mg, 1.5 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (10 mg, 0.02 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen from the system, and then heated at 130 ° C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain a yellow solid 26-a (200 mg, yield: 68%). LC-MS (ESI): m/z = 561 [M+H] ⁺ .

Synthesis of compound 26

Compound 26-a (200 mg, 0.35 mmol) was dissolved in dichloromethane (10 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (5 mL, 43 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with potassium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a yellow solid 26 (33 mg, yield: 20%). LC-MS (ESI): m/z = 461 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 9.07 (s, 1H), 7.57 (dd, J ₁ = 9.2 Hz, J ₂ ＝2.8Hz,1H),7.45-7.32(m,3H),7.09-7.02(m,2H),6.93-6.85(m,1H),6.04(s,1H),4.34-4.25(m,1H),3.67( s,3H),3.21-3.12(m,2H),2.77-2.65(m,3H),1.88-1.80(m,2H),1.55-1.45(m,2H),1.35(d,J＝6.8Hz,1H)ppm

Example 27

8-(4-Fluoro-2-methoxyphenyl)-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 27)

Synthesis of compound 27-b

Compound 19-c (900 mg, 3.72 mmol), 2-methoxy-4-fluorophenylboronic acid (885 mg, 5.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (245 mg, 1.16 mmol), and sodium carbonate (1.19 g, 11.16 mmol) were dissolved in 1,4-dioxane (5 mL) and water (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (50 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to afford compound 27-b (335 mg, yield: 31%) as a white solid. LC-MS (ESI): m/z = 289 [M+H] ⁺ .

Synthesis of compound 27-a

Compound 27-b (150 mg, 0.52 mmol), compound 15-b (166 mg, 0.52 mmol), potassium carbonate (216 mg, 1.56 mmol), tris(dibenzylideneindeacetone)dipalladium (90 mg, 0.16 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (73 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ice water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a light yellow solid 27-a (98 mg, yield: 33%). LC-MS (ESI): m/z = 571 [M+H] ⁺ .

Synthesis of compound 27

Compound 27-a (98 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL), followed by the addition of 1 M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (10 mL x 3) and then dried under vacuum to afford 27 as a light yellow solid (31 mg, yield: 39%). LC-MS (ESI): m/z = 471 [M+H] ⁺ .

¹ H-NMR (400 MHz, CD ₃ OD)δ:9.16(s,1H),7.94(d,J＝8Hz,1H),7.85(dd,J＝1Hz,J＝8Hz,1H),7.72(dd,J＝H z,J＝8Hz,1H),7.42(d,J＝1Hz,J＝8Hz,1H),7.31(d,J＝1Hz,J＝8Hz,1H),6.92(d,J＝1 Hz,J＝8Hz,1H),6.82(m,1H),6.47(d,J＝8Hz,1H),4.62(t,J＝8Hz,2H),3.64(s,3H) ,3.26(t,J＝8Hz,2H),3.31(m,2H),2.92(m,2H),2.73(m,1H),1.76-1.89(m,4H)ppm

Example 28

8-(4-Fluoro-2-methoxyphenyl)-N-[3-(piperidin-4-yl)-1-isopropyl-1H-pyrazol-5-yl]quinazolin-2-amine (Compound 28)

Synthesis of compound 28-a

Compound 25-b (161 mg, 0.52 mmol), compound 27-b (150 mg, 0.52 mmol), tris(dibenzylideneindeneacetone)dipalladium (90 mg, 0.16 mmol), potassium carbonate (216 mg, 1.56 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (73 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and ice water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a light yellow solid 28-a (128 mg, yield: 44%). LC-MS (ESI): m/z = 561 [M+H] ⁺ .

Synthesis of compound 28

Compound 28-a (128 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL, 25.8 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain a yellow solid 28 (86 mg, yield: 82%). LC-MS (ESI): m/z = 461 [M+H] ⁺ .

¹ H-NMR (400MHz, MeOD) δ: 9.27 (s, 1H), 7.88 (dd, J = 2Hz, J = 8Hz, 1H), 7.70 (dd, J = 2Hz, J = 8Hz, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 6.92 (m, 1H), 6.78(m,1H),6.07(s,1H),4.53(s,1H),3.64(m,3H),3.17(m,2H),2.67-2.77(m,3H),1.84(m,2H),1.55(m,2H),1.32(d,J＝8Hz,6H)ppm

Example 29

8-(5-Fluoro-2-methoxyphenyl)-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 29)

Synthesis of compound 29-b

Compound 19-c (1.02 g, 4.20 mmol), 2-methoxy-5-fluorophenylboronic acid (1.0 g, 5.88 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (343 mg, 0.42 mmol), and sodium carbonate (1.34 g, 12.6 mmol) were dissolved in 1,4-dioxane (10 mL) and water (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain a white solid 29-b (137 mg, yield: 12%). LC-MS (ESI): m/z = 289 [M+H] ⁺ .

Synthesis of compound 29-a

Compound 29-b (137 mg, 0.48 mmol), compound 15-b (151 mg, 0.48 mmol), potassium carbonate (197 mg, 1.43 mmol), tris(dibenzylideneindeacetone)dipalladium (82 mg, 0.14 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (67 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ice water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to afford a light yellow solid 29-a (80 mg, yield: 30%). LC-MS (ESI): m/z = 571 [M+H] ⁺ .

Synthesis of compound 29

Compound 29-a (80 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain 29 (37 mg, yield: 67%) as a yellow solid. LC-MS (ESI): m/z = 471 [M+H] ⁺ .

¹ H-NMR (400MHz, CD ₃ OD)δ:9.17(s,1H),7.95(d,J＝8Hz,1H),7.87(dd,J＝1Hz,J＝8Hz,1H),7.76(dd,J＝Hz,J＝8Hz,1H),7.43(d,J＝1Hz,J＝8Hz,1H),7 .10-1.79(m,3H),6.48(d,J=8Hz,1H),4.63(m,2H),3.63(s,3H),3.26(m,4H),2.87(m,2H),2.73(m,1H),1.73-1.85(m,4H)ppm

Example 30

8-[2-methoxy-4-(trifluoromethyl)phenyl])-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 30)

Synthesis of compound 30-b

Compound 19-c (1.0 g, 4.13 mmol), 2-methoxy-4-trifluoromethylphenylboronic acid (1.1 g, 4.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (335 mg, 0.41 mmol), and sodium carbonate (1.31 g, 12.4 mmol) were dissolved in 1,4-dioxane (10 mL) and water (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain compound 30-b (280 mg, yield: 21%) as a white solid. LC-MS (ESI): m/z = 339 [M+H] ⁺ .

Synthesis of compound 30-a

Compound 30-b (110 mg, 0.33 mmol), compound 15-b (87 mg, 0.33 mmol), potassium carbonate (135 mg, 0.98 mmol), tris(dibenzylideneindeacetone)dipalladium (56 mg, 0.1 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (46 mg, 0.1 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford a light yellow solid 30-a (80 mg, yield: 30%). LC-MS (ESI): m/z = 621 [M+H] ⁺ .

Synthesis of compound 30

Compound 30-a (85 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain 30 as a yellow solid (47 mg, yield: 67%). LC-MS (ESI): m/z = 521 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.08(s,1H),7.88(d,J＝8Hz,2H),7.75(dd,J＝1Hz,J＝8Hz,1H),7.49(d,J＝8Hz,1H),7.36-7.41(m,3H),7.26(d,J＝8Hz,1H),6.42(d ,J＝8Hz,1H),4.60(t,J＝8Hz,2H),3.71(s,3H),3.19-3.23(m,4H),2.69-2.76(m,2H),2.53(m,1H),2.13(m,1H),1.58-1.76(m,4H)ppm

Example 31

4-[7-({8-[2-methoxy-4-(trifluoromethyl)phenyl]quinazolin-2-yl}amino)-2,3-dihydro-1-benzofuran-4-yl]-piperidin-3-ol (Compound 31)

Synthesis of compound 31-a

Compound 17-c (148 mg, 0.45 mmol), compound 30-b (150 mg, 0.45 mmol), potassium carbonate (183 mg, 1.33 mmol), tris(dibenzylideneindeacetone)dipalladium (76 mg, 0.13 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (62 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford a light yellow solid 31-a (87 mg, yield: 31%). LC-MS (ESI): m/z = 637 [M+H] ⁺ .

Synthesis of compound 31

Compound 31-a (87 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain a light yellow solid 31 (31 mg, yield: 43%). LC-MS (ESI): m/z = 537 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.08(s,1H),7.93(d,J＝8Hz,1H),7.76(m,1H),7.49(d,J＝8Hz,1H),7.28-7.42(m,3H),7.26(d,J＝8Hz,1H),6.47 (d,J＝8Hz,1H),4.61(t,J＝8Hz,2H),3.71(s,3H),3.71(m,1H),3.24-3.39(m,4H),2.53-2.67(m,1H),1.75(m,2H)ppm

Example 32

8-{2-methoxy-4-[(morpholin-4-yl)carbonyl]phenyl}-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 32)

Synthesis of compound 32-d

4-Bromo-3-methoxybenzoic acid (1.16 g, 5 mmol), morpholine (650 mg, 7.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g, 6 mmol), 4-dimethylaminopyridine (60 mg, 0.5 mmol), and triethylamine (2 mL, 15 mmol) were dissolved in dichloromethane (20 mL). The reaction mixture was stirred at 20°C for 16 hours, then diluted with ice water (20 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 32-d (1.15 g, yield: 76%) as a white solid. LC-MS (ESI): m/z = 300 [M+H] ⁺ .

Synthesis of compound 32-c

Compound 32-d (1.15 g, 3.85 mmol), pinacol bisboronate (1.5 g, 5.77 mmol), anhydrous potassium acetate (1.14 g, 11.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (135 mg, 0.19 mmol) were dissolved in 1,4-dioxane (20 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere and then stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (20 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to afford 32-c (800 mg, 60% yield) as a white solid. LC-MS (ESI): m/z = 348 [M+H] ⁺ .

Synthesis of compound 32-b

Compound 32-c (800 mg, 2.3 mmol), 2-chloro-8-bromoquinazoline (600 mg, 2.46 mmol), anhydrous sodium carbonate (700 mg, 6.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (70 mg, 0.1 mmol) were dissolved in 1,4-dioxane (30 mL) and water (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (20 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 32-b (340 mg, yield: 38%) as a white solid. LC-MS (ESI): m/z = 587 [M+H] ⁺ .

Synthesis of compound 32-a

Compound 32-b (340 mg, 0.89 mmol), compound 15-b (260 mg, 0.81 mmol), tris(dibenzylideneindeneacetone)dipalladium (80 mg, 0.1 mmol), potassium carbonate (380 mg, 3.0 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (50 mg, 0.1 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen from the system, and then heated at 130 ° C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain a yellow solid 32-a (300 mg, yield: 50%). LC-MS (ESI): m/z = 666 [M+H] ⁺ .

Synthesis of compound 32

Compound 32-a (300 mg, 0.45 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (2 mL, 25.9 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The mixture was adjusted to pH 10 with potassium carbonate solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 32 (5 mg, yield: 2%) as a yellow solid. LC-MS (ESI): m/z = 566 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.07(s,1H),7.97(d,J＝8.8Hz,1H),7.73(t,J＝6Hz,1H),7.36-7.40(m,3H),7.15(s,1H),7.08(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H),4.59 (t,J＝8.0Hz,2H),3.62-3.98(m,13H),3.22(t,J＝8.0Hz,2H),3.02(t,J＝8.0Hz,2H),2.62-2.72(m,1H),2.11-2.24(m,2H),1.86-1.96(m,2H)ppm

Example 33

3-Methoxy-4-(2-{[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]amino}quinazolin-8-yl)benzamide (Compound 33)

Synthesis of compound 33-d

At 0°C, 4-bromo-3-fluorobenzonitrile (1.06 g, 5 mmol) and potassium carbonate (10.35 g, 7.5 mmol) were dissolved in dimethyl sulfoxide (5 mL). 30% hydrogen peroxide (2.5 g, 6.5 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with ice water (10 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 33-d as a yellow solid (1.05 g, yield: 91%). This product did not require further purification. LC-MS (ESI): m/z = 230 (M+H) ⁺ .

Synthesis of compound 33-c

Compound 33-d (1.05 g, 4.56 mmol), pinacol bisboronate (1.95 g, 7.65 mmol), anhydrous potassium acetate (1.5 g, 15.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg, 0.142 mmol) were dissolved in 1,4-dioxane (20 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the atmosphere, and then stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (20 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 33-c (800 mg, 63% yield) as a white solid. LC-MS (ESI): m/z = 278 (M+H) ⁺ .

Synthesis of compound 33-b

Compound 33-c (800 mg, 2.81 mmol), 2-chloro-8-bromoquinazoline (562 mg, 2.31 mmol), anhydrous sodium carbonate (920 mg, 8.67 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg, 0.142 mmol) were dissolved in 1,4-dioxane (15 mL) and water (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (20 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 33-b (160 mg, yield: 18%) as a white solid. LC-MS (ESI): m/z = 314 [M+H] ⁺ .

Synthesis of compound 33-a

Compound 33-b (340 mg, 0.89 mmol), compound 15-b (143 mg, 0.45 mmol), tris(dibenzylideneindeneacetone)dipalladium (46 mg, 0.05 mmol), potassium carbonate (208 mg, 1.5 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (30 mg, 0.064 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen from the system, and then heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain a yellow solid 33-a (70 mg, yield: 23%). LC-MS (ESI): m/z = 596 [M+H] ⁺ .

Synthesis of compound 33

Compound 33-a (70 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (2 mL, 25.9 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The mixture was adjusted to pH 10 with 1 M potassium carbonate aqueous solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 33 (6 mg, yield: 10%) as a yellow solid. LC-MS (ESI): m/z = 496 [M+H] ⁺ .

¹ H-NMR (400 MHz, CD ₃ OD)δ:9.05(s,1H),7.77(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.65(d,J＝6 .8Hz,1H),7.55(s,1H),7.53(d,J＝8.0Hz,1H),7.32(t,J＝8.0Hz,1H),7.28(d ,J＝8.0Hz,1H),6.31(d,J＝8.0Hz,1H),4.48(t,J＝8.8Hz,2H),3.55(s,3H),3. 36-3.44(m,2H),2.98-3.15(m,4H),2.64-2.74(m,1H),1.74-1.94(m,4H)ppm

Example 34

8-(4-Methylsulfonyl-2-methoxyphenyl)-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 34)

Synthesis of compound 34-g

2-Methoxy-4-fluoronitrobenzene (5.0 g, 29.24 mmol) was dissolved in N,N-dimethylformamide (35 mL), followed by the addition of 50% sodium thiomethoxide (6.1 g, 43.86 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was a solid, which was washed with a solvent (petroleum ether:ethyl acetate = 10:1, 50 mL) and dried under vacuum to obtain 34-g of a yellow solid (2.8 g, yield: 48%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.89 (d, J = 9Hz, 1H), 6.86 (s, 1H), 6.83 (d, J = 9Hz, 1H), 3.97 (s, 3H), 2.54 (s, 3H) ppm

Synthesis of compound 34-f

Compound 34-g (3.0 g, 15.09 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (7.8 g, 37.74 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C and filtered. The filter cake was washed with 0°C dichloromethane (20 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain 34-f (1.7 g, yield: 49%) as a yellow solid. LC-MS (ESI): m/z = 232 [M+H] ⁺ .

Synthesis of compound 34-e

Compound 34-f (1.7 g, 7.36 mmol) was dissolved in a mixture of ethanol (20 mL) and water (20 mL). Ammonium chloride (2.0 g, 36.79 mmol) and zinc powder (2.4 g, 36.79 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (200 mL). The organic phase was washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 34-e (1 g, yield: 68%) as a brown oil. This product did not require further purification. LC-MS (ESI): m/z = 202 [M+H] ⁺ .

Synthesis of compound 34-d

Compound 34-e (1.0 g, 4.98 mmol) was dissolved in acetonitrile (10 mL), copper bromide (1.9 g, 7.50 mmol) was added, and tert-butyl nitrite (0.73 mL) was slowly added. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 34-d (540 mg, yield: 41%) as a light yellow solid. LC-MS (ESI): m/z = 202 [M+H] ⁺ .

Synthesis of compound 34-c

Compound 34-d (300 mg, 1.14 mmol), bis(pinacol boronate) (433 mg, 1.71 mmol), and anhydrous potassium acetate (281 mg, 3.42 mmol) were suspended in dioxane (5 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (98 mg, 0.15 mmol). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 85°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and filtered through celite. The filtrate was concentrated under reduced pressure to yield 34-c (350 mg) as a black oil, which did not require further purification.

Synthesis of compound 34-b

Compound 19-c (387 mg, 1.61 mmol), 2-methoxy-4-methylsulfonylphenylboronic acid pinacol ester (500 mg, 1.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (374 mg, 0.5 mmol), and sodium carbonate (512 mg, 4.83 mmol) were dissolved in 1,4-dioxane (5 mL) and water (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to afford a light yellow solid 34-b (148 mg, yield: 27%). LC-MS (ESI): m/z = 349 [M+H] ⁺ .

Synthesis of compound 34-a

Compound 34-b (148 mg, 0.43 mmol), compound 15-b (113 mg, 0.43 mmol), potassium carbonate (176 mg, 1.28 mmol), tris(dibenzylideneindeacetone)dipalladium (73 mg, 0.13 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (60 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford a light yellow solid 34-a (40 mg, yield: 17%). LC-MS (ESI): m/z = 579 [M+H] ⁺ .

Synthesis of compound 34

Compound 34-a (40 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain a light yellow solid 34 (18 mg, yield: 55%). LC-MS (ESI): m/z = 479 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.09(s,1H),7.88(d,J＝8Hz,2H),7.74-7.78(m,2H),7.67-7.69(m,1H),7.59-7.61(m,2H),7.36-7.41(m,2H),6.47(d,J＝8Hz,1 H),4.61(t,J＝8Hz,2H),3.76(s,3H),3.17-3.25(m,7H),2.69-2.741(m,2H),2.51-2.57(m,1H),2.73(m,1H),1.55-1.65(m,4H)ppm

Example 35

8-(4-Methylsulfonyl-2-methoxyphenyl)-N-[2-methyl-4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 35)

Synthesis of compound 35-e

3-Bromopropene (2.5 g, 20.74 mmol) was added to a 50 mL solution of 2-nitro-5-bromophenol (3.0 g, 13.82 mmol) and sodium hydroxide (830 mg, 20.74 mmol). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford 35-e (1.1 g, yield: 37%) as a yellow solid.

Synthesis of compound 35-d

Compound 35-e (1.1 g, 4.29 mmol) and anhydrous magnesium chloride (100 mg) were mixed, heated to 200°C for 2 hours, and then cooled to room temperature. 0.1 M aqueous hydrochloric acid solution (50 mL) was added to the mixture, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford 35-d (250 mg, 23% yield) as a yellow solid.

¹ H-NMR (400MHz, CDCl ₃ )δ:7.81(d,J＝8Hz,1H),7.06(d,J＝8Hz,1H),5.27(m,1H),3.42(dd,J＝8Hz,16Hz,1H),2.90(dd,J＝8Hz,16Hz,1H),1.59(d,J＝6Hz,3H)ppm

Synthesis of compound 35-c

Compound 35-e (250 mg, 0.97 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-pinacol boronate (360 mg, 1.17 mmol), sodium carbonate (308 mg, 2.91 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (236 mg, 0.29 mmol) were dissolved in dioxane (5 mL) and water (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 35-c (190 mg, yield: 54%) as a light yellow solid. LC-MS(ESI): m/z=305[M+H-t-Bu]+.

Synthesis of compound 35-b

Compound 35-c (190 mg, 0.53 mmol) and 10% palladium on carbon (150 mg) were dissolved in ethanol (10 mL). The reaction mixture was replaced with hydrogen three times and then hydrogenated at room temperature for 16 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to obtain a purple oil 35-b (143 mg, yield: 82%). This product did not require further purification. LC-MS (ESI): m/z = 333 [M+H] ⁺ .

Synthesis of compound 35-a

Compound 34-b (150 mg, 0.43 mmol), compound 35-b (143 mg, 0.43 mmol), potassium carbonate (178 mg, 1.29 mmol), tris(dibenzylideneindeacetone)dipalladium (74 mg, 0.13 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (60 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford a light yellow solid 35-a (183 mg, yield: 66%). LC-MS (ESI): m/z = 645 [M+H] ⁺ .

Synthesis of compound 35

Compound 35-a (183 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain a light yellow solid 35 (121 mg, yield: 79%). LC-MS (ESI): m/z = 545 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.09(s,1H),7.88(d,J＝8Hz,2H),7.74-7.78(m,2H),7.67-7.69(m,1H),7.60-7.62(m,2H),7.37-7.41(m,2H),6.45(d,J＝8Hz,1H), 4.97(m,1H),3.34(m,1H),3.32(s,3H),3.21(m,2H),2.83(m,1H),2.71(m,2H),2.53(m,1H),1.55-1.65(m,4H),1.25(d,J＝8Hz,3H)ppm

Example 36

7-{[8-(4-methylsulfonyl-2-methoxyphenyl)quinazolin-2-yl]amino}-2,3-dihydro-1-benzofuran-4-carboxamide (Compound 36)

Synthesis of compound 36-d

Compound 15-d (1.07 g, 5 mmol), benzyl bromide (2.66 g, 15 mmol), and potassium carbonate (2.8 g, 15 mmol) were dissolved in acetonitrile (30 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (50 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 36-d (1.8 g, yield: 91%) as a yellow solid. LC-MS (ESI): m/z = 394 [M+H] ⁺ .

Synthesis of compound 36-c

Compound 36-d (2.4 g, 6.1 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and the reaction mixture was cooled to -78°C. A 2.5 M solution of n-butyllithium in n-hexane (5 mL, 12.5 mmol) was then added dropwise to the solution. Stirring was continued for 3 hours after the addition was complete. The reaction mixture was poured into dry ice (5 g), diluted with ice water (50 mL), and the pH was adjusted to 3 with 1.0 M hydrochloric acid. The mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 36-c (1.5 g, yield: 63%) as a white solid. LC-MS (ESI): m/z = 360 [M+H] ⁺ .

Synthesis of compound 36-b

Aqueous ammonia (1 mL) was added dropwise to a solution of 1-hydroxybenzotriazole (740 mg, 5.48 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 30 minutes, then filtered. The filter cake was dried under vacuum to obtain a solid (960 mg). This solid, compound 36-c (1.5 g, 4.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.3 mmol), and triethylamine (1.5 mL, 12.6 mmol) were dissolved in dichloromethane (30 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ice water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a white solid 36-b (1.1 g, yield: 73%). LC-MS (ESI): m/z = 359 [M+H] ⁺ .

Synthesis of compound 36-a

Compound 36-b (1.1 g, 3.07 mmol) and 10% palladium on carbon (100 mg) were dissolved in methanol (20 mL). The reaction mixture was replaced with hydrogen three times and then hydrogenated at room temperature for 16 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 36-a (500 mg, yield: 91%) as a white solid. LC-MS (ESI): m/z = 179 [M+H] ⁺ .

Synthesis of compound 36

Compound 36-a (86 mg, 0.48 mmol), compound 34-b (166 mg, 0.48 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.024 mmol), potassium carbonate (207 mg, 1.5 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (10 mg, 0.024 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a white solid 36 (25 mg, yield: 10%). LC-MS (ESI): m/z = 491 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.13(s,1H),7.80-7.83(m,3H),7.69-7.71(m,1H),7.44-7.60(m,5H),6.97(d,J＝ 8.8Hz,1H),4.64(t,J＝8.8Hz,2H),3.71(s,3H),3.62(t,J＝8.8Hz,2H),3.25(s,3H)ppm

Example 37

4-[7-({8-[2-methoxy-4-trifluoromethylphenyl]quinazolin-2-yl}amino)-2,3-dihydro-1-benzofuran-4-yl]piperidin-4-ol (Compound 37)

Synthesis of compound 37-c

Compound 36-d (3.6 g, 9.1 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and the reaction mixture was cooled to -78°C. A 2.5 M solution of n-butyllithium in n-hexane (7.5 mL, 18.75 mmol) was then added dropwise to the solution, and stirring continued for 3 hours. A solution of N-Boc-piperidone (3.62 g, 18.7 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise to the reaction mixture. The reaction was stirred at room temperature for 16 hours, then diluted with saturated aqueous ammonium chloride (50 mL). The mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 37-c (2.5 g, yield: 53%) as a white solid. LC-MS (ESI): m/z = 515 [M+H] ⁺ .

Synthesis of compound 37-b

Compound 37-b (2.5 g, 4.86 mmol) and 10% palladium on carbon (200 mg) were dissolved in methanol (30 mL). The reaction mixture was replaced with hydrogen three times, then hydrogenated at room temperature for 16 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 37-b as a white solid (700 mg, yield: 43%). LC-MS (ESI): m/z = 357 [M+Na] ⁺ .

Synthesis of compound 37-a

Compound 37-b (300 mg, 0.94 mmol), compound 30-b (300 mg, 0.86 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol), potassium carbonate (300 mg, 2.17 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (90 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 37-a as a white solid (250 mg, yield: 40%). LC-MS (ESI): m/z = 637 [M+H] ⁺ .

Synthesis of compound 37

Compound 37-a (250 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (2 mL, 25.9 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The mixture was adjusted to pH 10 with 1 M potassium carbonate aqueous solution. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 37 (42 mg, yield: 10%) as a yellow solid. LC-MS (ESI): m/z = 537 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.10(s,1H),7.90(d,J＝8.4Hz,1H),7.76-7.79(m,2H),7.38-7.50(m,4H),7.29(s,1H),6.56(d,J＝8.0Hz,1H),4.58(t,J＝8 .8Hz,2H),3.72(s,3H),3.48(t,J＝8.8Hz,2H),3.12-3.18(m,2H),2.98-3.06(m,2H),1.99-2.09(m,2H),1.78-1.85(m,2H)ppm

Example 38

8-[2-Methoxy-4-trifluoromethylphenyl]-N-[(2R)-2-methyl-4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]quinazolin-2-amine (Compound 38)

Synthesis of compound 38-h

At 0°C, sodium hydroxide (289 mg, 7.22 mmol) was slowly added to a solution of 2-hydroxy-3-bromoaniline (300 mg, 1.60 mmol) in N,N-dimethylformamide (3 mL). The mixture was stirred for 2 hours before benzyl bromide (1.23 g, 7.22 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1) to obtain 38-h (690 mg, yield: 94%) as a light brown solid. LC-MS (ESI): m/z = 458 [M+H] ⁺ .

Synthesis of compound 38-g

Compound 38-h (3 g, 6.56 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and the reaction mixture was cooled to -78°C. A 2.5 M solution of n-butyllithium in n-hexane (7.5 mL, 18.75 mmol) was then added dropwise to the solution, and stirring continued for 30 minutes. A solution of S-propylene oxide (580 mg, 9.84 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise to the reaction mixture, followed by a solution of boron trifluoride in ether (1.4 g, 9.84 mmol). The resulting yellow solution was slowly warmed to room temperature and stirred for 16 hours before being diluted with a saturated aqueous solution of ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 38-g (2.1 g, yield: 66%) of a light yellow oil. LC-MS (ESI): m/z = 438 [M+H] ⁺ .

Synthesis of compound 38-f

Compound 38-g (1.6 g, 3.66 mmol) and 10% palladium on carbon (200 mg) were dissolved in ethanol (50 mL). The reaction mixture was replaced with hydrogen three times and then hydrogenated at room temperature for 16 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to obtain a brown oil 38-f (460 mg, yield: 61%). This product did not require further purification. LC-MS (ESI): m/z = 168 [M+H] ⁺ .

Synthesis of compound 38-e

Compound 38-f (460 mg, 2.75 mmol) and triphenylphosphine (1.08 g, 4.12 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). The reaction solution was cooled to 0°C, and diisopropyl azodicarboxylate (838 mg, 4.15 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a light brown solid 38-e (190 mg, yield: 46%). LC-MS (ESI): m/z = 150 [M+H] ⁺ .

Synthesis of compound 38-d

Compound 38-e (190 mg, 1.28 mmol) was dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was cooled to 0°C, and N-bromosuccinimide (237 mg, 1.34 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light brown solid 38-d (261 mg, yield: 90%). This product did not require further purification.

Synthesis of compound 38-c

Compound 38-d (250 mg, 1.11 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-pinacol borate (510 mg, 1.65 mmol), anhydrous sodium carbonate (350 mg, 3.31 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50 mg, 0.06 mmol) were suspended in 1,4-dioxane (5 mL) and water (5 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (20 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to afford a light brown solid 38-c (140 mg, yield: 39%). LC-MS (ESI): m/z = 331 [M+H] ⁺ .

Synthesis of compound 38-b

Compound 38-c (140 mg, 0.42 mmol) and 10% palladium on carbon (150 mg) were dissolved in ethanol (10 mL). The reaction mixture was replaced with hydrogen three times and then hydrogenated at room temperature for 16 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to obtain a brown solid 38-b (128 mg, yield: 91%). This product did not require further purification. LC-MS (ESI): m/z = 277 [M+Ht-Bu] ⁺ .

Synthesis of compound 38-a

Compound 38-b (128 mg, 0.39 mmol), compound 30-b (130 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium (66 mg, 0.12 mmol), potassium carbonate (159 mg, 1.16 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (54 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (10 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a yellow solid 38-a (82 mg, yield: 34%). LC-MS (ESI): m/z = 635 [M+H] ⁺ .

Synthesis of compound 38

Compound 38-a (82 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL, 38.85 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain 38 as a yellow solid (15 mg, yield: 22%). LC-MS (ESI): m/z = 535 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.08(s,1H),7.88(d,J＝8Hz,2H),7.76(dd,J＝1Hz,J＝8Hz,1H),7.49(d,J＝8Hz,1H),7.36-7.41(m,3H),7.26(d,J＝8Hz,1H),6.40(d,J＝8Hz,1H),4 .60(t,J＝8Hz,2H),3.73(s,3H),3.35(m,1H),3.21(m,2H),2.76(m,1H),2 .73(m,2H),2.53(m,1H),1.71(m,1H),1.46(d,J=8Hz,3H),1.25(m,2H)ppm

Example 39

7-({8-[2-methoxy-4-trifluoromethylphenyl]quinazolin-2-yl}amino)-N-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-4-carboxamide (Compound 39)

Synthesis of compound 39-j

5-Chlorobenzo-2,3-dihydrofuran (1.84 g, 10 mmol) was dissolved in acetic acid (15 mL). The reaction mixture was cooled to 0°C and a solution of liquid bromine (0.62 mL, 12 mmol) in acetic acid (5 mL) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 16 hours. The pH of the reaction mixture was adjusted to 8 with saturated aqueous sodium carbonate solution, then extracted with petroleum ether (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 39-j (2.5 g, 90% yield) as a yellow oil. This product did not require further purification.

Synthesis of compound 39-i

Compound 39-j (2.5 g, 10.5 mmol), _BocNH₂ (1.5 g, 12.8 mmol), sodium tert-butoxide (3.2 g, 32.6 mmol), tris(dibenzylideneindeneacetone)dipalladium (66 mg, 0.12 mmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.06 mmol) were dissolved in toluene (30 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system and then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (50 mL x 2). The combined filtrates were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 39-i (2 g, yield: 71%) as a yellow solid. LC-MS(ESI): m/z=214[M+Ht-Bu] ⁺ .

Synthesis of compound 39-h

Compound 39-i (540 mg, 2 mmol) was dissolved in N,N-dimethylformamide (2 mL). The reaction solution was cooled to 0°C, and N-bromosuccinimide (360 mg, 2 mmol) was added portionwise. The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 39-h as a yellow solid (650 mg, yield: 93%). This product did not require further purification. LC-MS (ESI): m/z = 292 [M+Ht-Bu] ⁺ .

Synthesis of compound 39-g

Compound 39-h (2.8 g, 5.16 mmol) was dissolved in dichloromethane (30 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (10 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous potassium carbonate (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 39-g (1.8 g, yield: 91%). This product did not require further purification. LC-MS (ESI): m/z = 248 [M+H] ⁺ .

Synthesis of compound 39-f

Compound 39-g (1.8 g, 7.28 mmol), benzyl bromide (4.4 g, 25.5 mmol), and potassium carbonate (3.52 g, 25.5 mmol) were dissolved in acetonitrile (50 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, then heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 39-f (2 g, yield: 64%) as a light yellow solid. LC-MS (ESI): m/z = 428 [M+H] ⁺ .

Synthesis of compound 39-e

Compound 39-f (2.0 g, 4.68 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and the reaction mixture was cooled to -78°C. A 2.5 M solution of n-butyllithium in n-hexane (2.8 mL, 7 mmol) was then added dropwise to the solution, and stirring continued for 1 hour. A solution of formylpiperidine (795 mg, 7.03 mmol) in tetrahydrofuran (1 mL) was added dropwise to the solution, and stirring continued for 1 hour. The reaction mixture was warmed to room temperature and quenched with saturated aqueous ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 39-e (680 mg, yield: 39%) as a light yellow solid. LC-MS (ESI): m/z = 378 [M+H] ⁺ .

Synthesis of compound 39-d

Compound 39-e (350 mg, 0.93 mmol), dimethyl sulfoxide (88 mg, 1.12 mmol), and concentrated sulfuric acid (51 mg, 0.51 mmol) were dissolved in acetonitrile (3 mL) and water (1 mL). The reaction mixture was cooled to 0°C, and a solution of sodium chlorite (116 mg, 1.39 mmol) in water (2 mL) was added dropwise. The reaction mixture was stirred at this temperature for 30 minutes and then warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 39-d (170 mg, yield: 47%) as a light yellow solid. This product did not require further purification. LC-MS (ESI): m/z = 394 [M+H] ⁺ .

Synthesis of compound 39-c

Compound 39-d (400 mg, 1.02 mmol), N-Boc-4-aminopiperidine (244 mg, 1.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g, 6 mmol), 4-dimethylaminopyridine (60 mg, 0.5 mmol), triethylamine (2 mL, 15 mmol), and 1-hydroxybenzotriazole (137 mg, 1.02 mmol) were dissolved in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 16 hours, then diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 39-c (375 mg, yield: 65%) as a white solid. LC-MS (ESI): m/z = 576 [M+H] ⁺ .

Synthesis of compound 39-b

Compound 39-c (375 mg, 0.65 mmol) and 10% palladium on carbon (100 mg) were dissolved in isoethanol (10 mL). The reaction mixture was replaced with hydrogen three times and then hydrogenated at room temperature for 16 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to obtain a light brown solid 39-b (270 mg, yield: 100%). LC-MS (ESI): m/z = 306 [M+Ht-Bu] ⁺ .

Synthesis of compound 39-a

Compound 39-b (150 mg, 0.42 mmol), compound 30-b (140 mg, 0.42 mmol), potassium carbonate (172 mg, 1.25 mmol), tris(dibenzylideneacetone)dipalladium (72 mg, 0.13 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (58 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (ethyl acetate as the developing solvent) to obtain a yellow solid 39-a (20 mg, yield: 7%). LC-MS (ESI): m/z = 664 [M+H] ⁺ .

Synthesis of compound 39

Compound 39-a (20 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with saturated aqueous sodium bicarbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (mobile phase: 0.05% aqueous TFA: acetonitrile = 35%-45%) to obtain 39 as a light yellow solid (5 mg, yield: 30%). LC-MS (ESI): m/z = 564 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.14(s,1H),7.96(d,J＝8Hz,1H),7.78-7.82(m,1H),7.55(s,1H),7.41-7.52(m,3H),7.29(m,1H),6.63(d,J＝9Hz,1H),5.88(d,J＝8Hz, 1H),4.66(t,J＝8Hz,2H),4.15(m,1H),3.74(m,1H),3.70(s,3H),3.58(m,2H),3.02(m,1H),2.18(m,1H),2.09(m,2H),1.58-1.76(m,2H)ppm

Example 40

7-{[8-(4-Fluoro-2-methoxyphenyl)quinazolin-2-yl]amino}-N-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-4-carboxamide (Compound 40)

Synthesis of compound 40-a

Compound 39-b (150 mg, 0.42 mmol), compound 27-b (120 mg, 0.42 mmol), potassium carbonate (172 mg, 1.25 mmol), tris(dibenzylideneacetone)dipalladium (72 mg, 0.13 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (58 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (ethyl acetate as the developing solvent) to obtain a yellow solid 40-a (21 mg, yield: 8%). LC-MS (ESI): m/z = 614 [M+H] ⁺ .

Synthesis of compound 40

Compound 40-a (21 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with saturated aqueous sodium bicarbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (ethyl acetate as the developing solvent) to obtain a light yellow solid 40 (4 mg, yield: 23%). LC-MS (ESI): m/z = 514 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.12(s,1H),8.13(d,J＝8Hz,1H),7.76(dd,J＝8Hz,2H),7.57(s,1H),7.42(m,1H),7.34(m,1H),6.77-6.86(m,3H),5.90(m, 1H),4.66(t,J＝8Hz,2H),4.05(s,3H),3.67(s,3H),3.57(t,J＝8Hz,2H),3.14(m,2H),2.76(m,2H),2.06(m,2H),1.47(m,2H)ppm

Example 41

4-(7-{[8-(4-fluoro-2-methoxyphenyl)quinazolin-2-yl]amino}-2,3-dihydro-1-benzofuran-4-yl)piperidin-4-ol (Compound 41)

Synthesis of compound 41-a

Compound 37-b (394 mg, 1.18 mmol), compound 27-b (400 mg, 1.18 mmol), tris(dibenzylideneindeneacetone)dipalladium (204 mg, 0.36 mmol), potassium carbonate (492 mg, 3.56 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (166 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was purged with nitrogen three times to remove oxygen from the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with ice water (10 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 41-a (236 mg, yield: 34%) as a white solid. LC-MS (ESI): m/z = 587 (M+H) ⁺ .

Synthesis of compound 41

Compound 41-a (236 mg, 0.41 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL, 38.85 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The separated organic phase was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (mobile phase: 0.05% aqueous TFA: acetonitrile = 35%-45%) to obtain a light yellow solid 41 (54 mg, yield: 28%). LC-MS (ESI): m/z = 487 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:9.08(s,1H),8.06(d,J＝8Hz,1H),7.74(dd,J＝1Hz,J＝8Hz,2H),7.47(s,1H),7.33-7.41(m,2H),6.83(s,1H),6.81(d,J＝8Hz,1H) ,6.65(d,J＝8Hz,1H),4.58(t,J＝8Hz,2H),3.67(s,3H),3.48(t,J＝8Hz,2H),3.17(m,2H),3.03(m,2H),2.09(m,2H),1.76(m,2H)ppm

Example 42

N-[7-(2-methoxyphenyl)-6-methylthienyl[3,2-d]pyrimidin-2-yl]-3-(piperidin-4-yl)-1-isopropyl-1-H-pyrazol-5-amine (Compound 42)

Synthesis of compound 42-a

Compound 25-b (175 mg, 0.57 mmol), compound 8-b (150 mg, 0.52 mmol), tris(dibenzylideneindeneacetone)dipalladium (89 mg, 0.16 mmol), potassium carbonate (216 mg, 1.56 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (73 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and ice water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a light yellow solid 42-a (179 mg, yield: 44%). LC-MS (ESI): m/z = 563 [M+H] ⁺ .

Synthesis of compound 42

Compound 42-a (179 mg, 0.32 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL, 25.8 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and diluted with 1M aqueous hydrochloric acid (50 mL). The separated aqueous phase was adjusted to pH 10 with saturated aqueous potassium carbonate. A solid precipitated and was filtered. The filter cake was washed with water (20 mL x 3) and the solid was dried under vacuum to obtain 42 (80 mg, yield: 54%) as a yellow solid. LC-MS (ESI): m/z = 463 [M+H] ⁺ .

¹ H-NMR (400MHz, CD ₃ OD)δ:8.83(s,1H),7.41-7.45(m,1H),7.25(dd,J＝8Hz,J＝1Hz,1H),7.13(d,J＝8Hz,2H),7.05-7.09(m,1H),6.12(s,1H),4.44-4.51( m,1H),3.73(s,3H),3.17-3.21(m,2H),2.71-2.83(m,3H),2.46(s,3H),1.89-1.93(m,2H),1.58-1.68(m,2H),1.32(d,J＝7Hz,6H)ppm

Example 43

N-[2,2-dimethyl-4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]-7-(2-methoxyphenyl)-6-methylthienyl[3,2-d]pyrimidin-2-amine (Compound 43)

Synthesis of compound 43-a

Compound 21-h (143 mg, 0.41 mmol), compound 8-b (120 mg, 0.41 mmol), cesium carbonate (401 mg, 1.23 mmol), tris(dibenzylideneindeneacetone)dipalladium (71 mg, 0.13 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (58 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to afford a light yellow solid 43-a (98 mg, yield: 40%). LC-MS (ESI): m/z = 601 [M+H] ⁺ .

Synthesis of compound 43

Compound 43-a (98 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL) and washed with saturated aqueous potassium carbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain 43 (35 mg, yield: 43%) as a light yellow solid. LC-MS (ESI): m/z = 501 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ:8.76(s,1H),8.21(d,J＝8Hz,1H),7.45-7.50(m,1H),7.40(dd,J＝8Hz,J＝2Hz,1H),7.23(s,1H),7.12-7.15(m,1H),7.08(d,J＝8Hz,1H),6 .56(d,J=8Hz,1H),3.79(s,3H),3.56(m,2H),3.03(s,2H),2.98(m,2H),2.63(m,1H),2.50(s,3H),2.13(m,2H),1.97(m,2H),1.47(s,6H)ppm

Example 44

1-[4-(7-{[8-(4-fluoro-2-methoxyphenyl)quinazolin-2-yl]amino}-2,3-dihydro-1-benzofuran-4-yl)piperidin-1-yl]prop-2-en-1-one (Compound 44)

Synthesis of compound 44

Compound 27 (300 mg, 0.64 mmol) was dissolved in dichloromethane (10 mL). The reaction mixture was cooled to 0°C, and acryloyl chloride (86 mg, 0.96 mmol) and triethylamine (130 mg, 1.28 mmol) were added. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (dichloromethane:methanol = 40:1) and further purified by HPLC (mobile phase: ₁₀ mM aqueous _NH₄CO₃ :acetonitrile = 25%-75%) to obtain a yellow solid 44 (26 mg, yield: 8%). LC-MS (ESI): m/z = 525 (M+H) ⁺ .

¹ H-NMR (400MHz, DMSO) δ: 9.26 (s, 1H), 8.19 (s, 1H), 7.89 (d, J = 7.0Hz, 1H), 7.69 (d, J = 7.0Hz, 1H) ,7.63(d,J＝8.6Hz,1H),7.39(t,J＝7.5Hz,1H),7.27(t,1H),7.07(dd,J＝2.4Hz,1H),6.87(m,2H) ,6.46(d,J＝8.3Hz,1H),6.14(dd,J＝2.4Hz,1H),5.70(dd,J＝2.4Hz,1H),4.59(m,1H),4.51(t,2H ),4.18(d,1H),3.59(s,3H),3.22-3.15(m,3H),2.76-2.66(m,2H),1.77(m,2H),1.50(m,2H)ppm

Example 45

7-[4-Fluoro-2-methoxyphenyl]-6-methyl-N-[4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]thiophene[3,2-d]pyrimidin-2-amine (Compound 45)

Synthesis of compound 45-e

2,4-Dichloro-6-methylthiopheno[3,2-d]pyrimidine (10 g, 45.6 mmol) was dissolved in tetrahydrofuran (100 mL) and ethanol (100 mL). The reaction mixture was cooled to 0°C, and sodium borohydride (12.5 g, 198 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. Water (500 mL) was added to dilute the mixture, and the pH was adjusted to 7 with 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phase was washed sequentially with water (100 mL x 3) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 45-e as a white solid (7.5 g, yield: 88%). This product did not require further purification. LC-MS (ESI): m/z = 187 [M+H] ⁺ .

Synthesis of compound 45-d

Compound 45-e (7.5 g, 40 mmol) was dissolved in chloroform (300 mL) at 0°C. Activated manganese dioxide (35 g, 400 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was filtered through celite, and the filter cake was washed with chloroform (100 mL x 3). The combined filtrates were concentrated under reduced pressure to afford 45-d (6.6 g, yield: 89%) as a white solid. This product did not require further purification. LC-MS (ESI): m/z = 185 [M+H].

Synthesis of compound 45-c

Compound 45-d (3.1 g, 16.8 mmol) was dissolved in trifluoroacetic acid (30 mL) at 0°C. N-iodosuccinimide (5.7 g, 25.3 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. Water (50 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 45-c as a white solid (4.9 g, yield: 94%). This product did not require further purification. LC-MS (ESI): m/z = 311 [M+H] ⁺ .

Synthesis of compound 45-b

Compound 45-c (615 mg, 1.98 mmol), 2-methoxy-4-fluorophenylboronic acid (405 mg, 2.38 mmol), and sodium carbonate (630 mg, 5.94 mmol) were suspended in dioxane (5 mL) and water (5 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (163 mg, 0.2 mmol) was added. The atmosphere was purged with nitrogen three times and heated to 80°C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to afford 45-b (240 mg, yield: 39%) as a white solid. LC-MS (ESI): m/z = 309 [M+H] ⁺ .

Synthesis of compound 45-a

Compound 45-b (300 mg, 0.97 mmol), compound 15-b (309 mg, 0.97 mmol), potassium carbonate (402 mg, 2.91 mmol), tris(dibenzylideneindeneacetone)dipalladium (44 mg, 0.048 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (23 mg, 0.048 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was replaced with nitrogen three times to remove oxygen in the system, and then heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water (20 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid 45-a (274 mg, yield: 48%). LC-MS (ESI): m/z = 591 [M+H] ⁺ .

Synthesis of compound 45

Compound 45-a (276 mg, 0.46 mmol) was dissolved in dichloromethane (8 mL). The reaction solution was cooled to 0°C, trifluoroacetic acid (3 mL) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 10 with saturated aqueous potassium carbonate. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain compound 45 (126 mg, yield: 56%). LC-MS (ESI): m/z = 491 [M+H] ⁺ .

^1H NMR(400MHz, DMSO)δ:8.93(s,1H),8.05(s,1H),7.53(d,J＝8.2Hz,1H),7.35–7.27(t,1H),7.11-7.00(m,1H),6.90(m,1H),6.55(d,J＝8.3Hz,1 H),4.51(t,J＝8.4Hz,2H),3.73(s,3H),3.18(t,J＝8.6Hz,3H),3.08(d,J＝11.7Hz,2H),2.67-2.61(m,3H),2.40(s,3H),1.70-1.50(m,4H)ppm.

Effect Example: IC ₅₀ Evaluation Experiment of Anaplastic Lymphoma Kinase ALK Enzyme Activity Inhibition

Buffer configuration: 50 mM HEPES, pH 7.5, 0.00015% Brij-35.

Compounds were prepared in 100% DMSO in a concentration gradient and added to a 384-well plate, with a final DMSO concentration of 2%.

1. ALK enzyme (purchased from Carna Biosciences, Inc.) was diluted to the optimal concentration in the following buffer: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, 2 mM DTT. The enzyme was transferred to a 384-well plate and incubated with the compound for a specified time.

2. Dilute the substrate to the optimal concentration using the following buffer: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, mM MgCl ₂ , ATP at Km. Add the substrate to a 384-well plate to initiate the reaction and incubate at 28°C for 1 hour.

3. Read the conversion rate using Caliper Reader and calculate the inhibition rate as the average of two tests.

The compounds of the present invention were tested for their inhibitory activity against ALK according to the above test, and the results are as follows (Table 1):

Table 1 IC50 values of some compounds of the present invention for inhibition of ALK activity

Compound IC50(nM) Compound IC50(nM) 1 5.5 3 14 8 6.4 11 27.7 15 3.3 16 9.3 17 2.1 18 9.1 20 12.8 twenty two 34 twenty three 12 twenty four 36 25 27 27 5.1 28 34 29 14 30 14 31 2.3 32 35 33 2.5 34 14 35 3.4 37 3.3 40 12 42 2.7 43 10.9

Claims (22)

1. A fused-ring pyrimidine amino derivative as shown in general formula I, or a pharmaceutically acceptable salt thereof: in: X is S; Y is CR ⁴ ; U represents a chemical bond; V represents a chemical bond; W is C; Ring A is a _C6-10 aromatic ring; Ring B is a _C6-10 aromatic ring; ^R1 is selected from a hydrogen atom, a _C1-4 alkyl group, or a _C1-4 alkoxy group; the _C1-4 alkyl group may be further substituted with one or more halogens; ^R2 is a heterocyclic alkyl group with nitrogen as the heteroatom, having 1-2 heteroatoms and containing 4-6 carbon atoms; the heterocyclic alkyl group may be further replaced by one or more hydroxyl groups; The two adjacent ^{R3 atoms} together with the carbon atoms on the B ring they are connected to form a heterocyclic group with oxygen as the heteroatom, 1-2 heteroatoms, and 2-4 carbon atoms; the heterocyclic group may be further replaced by one or more _C1-4 alkyl groups; ^R4 is a _C1-4 alkyl group; n is 1 or 2; m is 2. 2. The fused-ring pyrimidine amino derivative or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that: the fused-ring pyrimidine amino derivative as shown in general formula I is as shown in general formula III-1-1. 3. The fused-ring pyrimidine amino derivative or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that: in ring A, the aromatic ring of _C6-10 is a benzene ring; In ring B, the aromatic ring of _C6-10 is a benzene ring. 4. The fused-ring pyrimidine amino derivative or a pharmaceutically acceptable salt thereof as described in claim 3, characterized in that: in ^R2 , the heterocyclic alkyl group is piperidinyl. 5. The fused-ring pyrimidine amino derivative or a pharmaceutically acceptable salt thereof as described in claim 4, characterized in that: the halogen in the substituent of ^R1 is fluorine. 6. The fused-ring pyrimidine amino derivative or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that: ^R1 is methoxy, ethoxy, or trifluoromethyl; ^R2 is ^R3 is ^R4 is a methyl group. 7. The fused-ring pyrimidine amino derivative or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that: the derivative is... 8. The fused-ring pyrimidine amino derivative of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: the fused-ring pyrimidine amino derivative as represented by general formula I is any of the following compounds: 9. A method for preparing a fused-ring pyrimidine amino derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, comprising the following steps: in a solvent, under the action of a palladium-containing catalyst, performing a coupling reaction as shown below on the compound represented by general formula I-a and the compound represented by general formula I-b', followed by a deprotection reaction to obtain the compound of general formula I; In general formulas Ia, Ib and I, the definitions of A, B, ^R1 , ^R2 , ^R3 , X, Y, U, V, W, n and m are as described in any one of claims 1 to 8; ^R7 is ^R2 protected by boc. 10. The preparation method according to claim 9, characterized in that: a base is added to the coupling reaction; the base is sodium carbonate, potassium carbonate or cesium carbonate; the molar ratio of the base to compound I-a is 1:1 to 5:1. 11. The preparation method according to claim 9 or 10, characterized in that: the solvent is an organic solvent and/or water; the organic solvent is one or more selected from 1,4-dioxane, toluene, ethylene glycol dimethyl ether, and N,N-dimethylformamide; the volume-to-mass ratio of the organic solvent to the compound represented by general formula I-a is 10 mL/g to 110 mL/g; and the amount of water added is 1-100% of the volume of the organic solvent. 12. The preparation method according to claim 9 or 10, characterized in that: the palladium-containing catalyst is one or more of tris(dibenzylindeneacetone)palladium, palladium acetate, tetra(triphenylphosphine)palladium, and [1,1’-bis(diphenylphosphine)ferrocene]palladium dichloride; the molar ratio of the palladium-containing catalyst to the compound represented by general formula I-a is (0.005:1)-(0.5:1). 13. The preparation method according to claim 9 or 10, characterized in that: in the coupling reaction, the molar ratio of the compound represented by general formula I-a to the compound represented by general formula I-b’ is (0.5:1)-(2:1). 14. The preparation method according to claim 9 or 10, wherein the temperature of the coupling reaction is 50℃-150℃. 15. The preparation method according to claim 9 or 10, characterized in that: the coupling reaction includes the following steps: in a solvent, under the action of a palladium-containing catalyst, the compounds represented by general formula I-c and the compounds represented by general formula I-d are subjected to the coupling reaction shown below to obtain the compound of general formula I-a; ^R5 is a halogen; ^R6 is boric acid or borate ester. 16. The preparation method according to claim 15, characterized in that: in the preparation method of compound of general formula I-a, the coupling reaction further includes the addition of a base; the base is sodium carbonate, potassium carbonate or cesium carbonate; the molar ratio of the base to compound I-c is 1.3:1 to 5:1. 17. The preparation method according to claim 15, characterized in that: in the preparation method of the compound of general formula I-a, the solvent is an organic solvent and/or water; the organic solvent is one or more selected from 1,4-dioxane, toluene, ethylene glycol dimethyl ether, and N,N-dimethylformamide; the volume-to-mass ratio of the organic solvent to the compound represented by general formula I-c is 5 mL/g to 100 mL/g; and the amount of water added is 1-100% of the volume of the organic solvent. 18. The preparation method according to claim 15, characterized in that: in the preparation method of the compound of general formula I-a, the palladium-containing catalyst is one or more of tris(dibenzylindeneacetone)palladium, palladium acetate, tetra(triphenylphosphine)palladium and [1,1’-bis(diphenylphosphine)ferrocene]palladium dichloride; the molar ratio of the palladium-containing catalyst to the compound represented by general formula I-c is (0.005:1)-(0.5:1). 19. The preparation method according to claim 15, characterized in that: in the preparation method of the compound of general formula I-a, the molar ratio of the compound of general formula I-d to the compound of general formula I-c is (0.5:1)-(2:1). 20. The preparation method according to claim 15, characterized in that: in the preparation method of the compound of general formula I-a, the temperature of the coupling reaction is 50℃-150℃. 21. A pharmaceutical composition comprising a therapeutically effective amount of a fused-ring pyrimidine amino derivative as shown in any one of claims 1 to 8 and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or diluent. 22. The use of the fused-ring pyrimidine amino derivative of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, in the preparation of a medicament for the prevention, relief and/or treatment of cancer and/or diseases related to anaplastic lymphoma kinase.