CDK inhibitor compound

Abstract

The present invention relates to a compound represented by formula (A), a pharmaceutical composition comprising the compound, and use of the compound represented by formula (A) in the prevention and / or treatment of cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

A CDK inhibitor compound Technical Field

[0001] The present invention relates to a compound, in particular to a highly active CDK inhibitor and use thereof. Background Art

[0002] Cyclin-dependent kinases (CDKs) are a class of serine (Ser) / threonine (Thr) kinases that can be divided into two major categories: cell cycle-related (such as CDK1 / 2 / 4 / 6) and cell transcription-related (such as CDK7 / 9 / 12).

[0003] Currently, the most studied are CDK4 and CDK6, which play key regulatory roles in the cell division cycle. They can form a CDK-cyclin complex with cyclin D, participating in cell growth, proliferation, dormancy, and apoptosis. CDK4 / 6-cyclin D is a key pathway for the transition from G1 to S phase of the cell cycle. When overexpressed, it leads to uncontrolled cell division, which can cause cancer. Several CDK4 / 6 selective inhibitors have been approved for marketing, primarily for the treatment of HR+ / HER2- breast cancer, exemplified by Palbociclib, the world's first CDK4 / 6 selective inhibitor launched by Pfizer.

[0004] Despite the tremendous success of CDK4 / 6 inhibitors, significant side effects remain in clinical practice, particularly myelosuppression. Studies have demonstrated that CDK6 is a key factor in the activation of hematopoietic stem cells, while CDK4 has a relatively minor impact on the hematopoietic system. Further research indicates that CDK4 is highly expressed in tumors, while CDK6 is less expressed. This suggests that CDK4 may be a more important oncogenic factor in breast cancer. Therefore, maintaining CDK4 activity while reducing CDK6 inhibition would be beneficial for CDK inhibitors in reducing clinical toxicity.

[0005] CDK2 is another important cell cycle regulator that can bind to cyclin E or A, playing a role in the process of entering the S phase from the G1 phase and maintaining the S phase, respectively. When CDK4 / 6 are inhibited, CDK2-cyclin E is activated, compensating for the function of CDK4 / 6 and may be one of the main reasons for CDK4 / 6 inhibitor resistance.

[0006] In summary, optimizing selectivity to further improve the therapeutic efficacy and safety of existing CDK4 / 6 inhibitors has important social significance. Summary of the Invention

[0007] The present invention provides a new class of CDK inhibitors. This class of inhibitors differs from existing CDK4 / 6 dual-target inhibitors in that they have optimized activity and selectivity, thereby achieving the goal of improving anti-tumor efficacy and reducing toxic side effects.

[0008] In one aspect, the present invention provides a compound represented by formula A or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof:

[0009] in:

[0010] A represents N or CH;

[0011] R1 represents H, D, halogen, CN, C1-C3 alkyl, fluorinated C1-C2 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy;

[0012] Ar2 represents a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

[0013] Cy2 represents a 4-8 membered heterocycloalkyl group, a 4-8 membered heterocycloalkenyl group or a 5-8 membered heteroaryl group;

[0014] X 1 and X 2 It is the bridgehead atom shared by Ar2 and Cy2, X 1 and X 2 Each independently represents C or N, X 1 and X 2 The covalent bonds between them can be single or double bonds;

[0015] R' represents H, D, F, Cl, CN, CH3, CH2F, CHF2 or CF3;

[0016] R" each independently represents H, D, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally replaced by R 20 replace;

[0017] Alternatively, R' and R" or two R" together with the atoms to which they are attached may form a 5-8 membered heterocycloalkyl group, wherein the 5-8 membered heterocycloalkyl group may be optionally replaced by R 21 replace;

[0018] Ar1 represents C 6- C 10 Aryl or 5-12 membered heteroaryl, wherein the C6-C 10Aryl, 5-12 membered heteroaryl may be optionally substituted by 1, 2, 3 or 4 R7, wherein R7 each independently represents H, D, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally substituted by R 23 replace;

[0019] L represents a bond, -CH2-, -C(O)-, -O-, or -NR a -, -S-, -S(O)- or -S(O)2-;

[0020] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C3-C 12 The cycloalkyl or 4-12 membered heterocycloalkyl may be a monocyclic, condensed, bridged or spirocyclic ring; 12 Cycloalkyl or 4-12 membered heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 R8, wherein R8 each independently represents H, D, oxo, halogen, CN, OR a NR a R a '、N(R a )COR a '、S(O)R a 、S(O)2R a 、C(O)R a 、C(O)NR a R a ', C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally R 24 replace;

[0021] R 20 、R 21 、R 23 、R 24 Each of them independently represents oxo, D, F, Cl, CN, OR a NR a R a '、N(R a )COR a '、CONR a R a ', C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl, the C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl may be optionally substituted by F, OH, C1-C2 alkyl, fluorinated C1-C2 alkyl, C1-C2 alkoxy, fluorinated C1-C2 alkoxy;

[0022] R a and R a 'Each independently represents H, D, C1-C3 alkyl;

[0023] m and n each independently represent 0, 1, 2 or 3.

[0024] In some embodiments of the present invention, X 1 and X 2 Both are C.

[0025] In some embodiments of the present invention, represents an 8-9 membered heteroaromatic ring; preferably, express or wherein Q each independently represents CR' or N, and T each independently represents CR", N, NR", O or S; more preferably, express Wherein T' represents CR" or NR".

[0026] In some embodiments of the present invention, the present invention provides a compound of formula or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof having a structure shown in Formula I:

[0027] in:

[0028] A represents N or CH;

[0029] R1 represents H, D, halogen, CN, C1-C3 alkyl, fluorinated C1-C2 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy;

[0030] U represents NR2 or CR3; R2 and R3 each independently represent H, D, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl can be arbitrarily replaced by R 20 replace;

[0031] When U represents NR2, V CR4, R4 represents C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl is separated by at least one R 21 Substituted, the 4-8 membered heterocycloalkyl group may be optionally R 21 and optionally, R2, R4 together with the atoms to which they are attached may form a 5-8 membered heterocycloalkyl group, the 5-8 membered heterocycloalkyl group being arbitrarily replaced by R 21 replace;

[0032] When U represents CR3, V represents NR5, R5 represents C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl is separated by at least one R 22 Substituted, the 4-8 membered heterocycloalkyl group may be optionally R 22 replace;

[0033] X, Y, and Z each independently represent CR6 or N, wherein R6 represents H, D, F, Cl, CN, CH3, CH2F, CHF2, or CF3;

[0034] Ar1 represents C 6- C 10 Aryl or 5-12 membered heteroaryl, wherein the C6-C 10 Aryl, 5-12 membered heteroaryl may be optionally substituted by 1, 2, 3 or 4 R7, wherein R7 each independently represents H, D, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally substituted by R 23 replace;

[0035] L represents a bond, -CH2-, -C(O)-, -O-, or -NR a -, -S-, -S(O)- or -S(O)2-;

[0036] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C3-C 12 The cycloalkyl or 4-12 membered heterocycloalkyl may be a monocyclic, condensed, bridged or spirocyclic ring; 12 Cycloalkyl or 4-12 membered heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 R8, wherein R8 each independently represents H, D, oxo, halogen, CN, OR a NR a R a '、N(R a )COR a '、S(O)R a 、S(O)2R a 、C(O)R a 、C(O)NR a R a ', C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally R 24 replace;

[0037] R20 、R 21 、R 22 、R 23 、R 24 Each of them independently represents oxo, D, F, Cl, CN, OR a NR a R a '、N(R a )COR a ', C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl, the C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl may be optionally substituted by F, OH, C1-C2 alkyl, fluorinated C1-C2 alkyl, C1-C2 alkoxy, fluorinated C1-C2 alkoxy;

[0038] R a and R a 'Each independently represents H, D, C1-C3 alkyl.

[0039] In one embodiment of the present invention, R1 represents H, D, halogen, CN, C1-C2 alkyl, fluorinated C1-C2 alkyl, cyclopropyl; preferably, R1 represents Cl, F, CN, methyl, CF3; more preferably, R1 is preferably Cl.

[0040] In one embodiment of the present invention, R2 and R3 each independently represent a C1-C6 alkyl group, and the C1-C6 alkyl group may be arbitrarily replaced by R 20 replace.

[0041] In one embodiment of the present invention, R4 represents a C1-C6 alkyl group, wherein the C1-C6 alkyl group is replaced by 1, 2 or 3 R 21 Substitution; preferably, the C1-C6 alkyl is substituted by 1, 2 or 3 OH or NH2.

[0042] In one embodiment of the present invention, R5 is preferably C1-C6 alkyl, and the C1-C6 alkyl may be optionally replaced by R 22 Substitution; preferably, the C1-C6 alkyl is substituted by 1, 2 or 3 OH or NH2.

[0043] In one embodiment of the present invention, Ar1 is preferably phenyl, and the phenyl group may be optionally substituted by R7; more preferably, Ar1 is not substituted by R7.

[0044] In one embodiment of the present invention, L represents a bond, -C(O)- or -S(O)2-.

[0045] In one embodiment of the present invention, Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C3-C 12The cycloalkyl or 4-12 membered heterocycloalkyl may be a monocyclic, condensed, bridged or spirocyclic ring; 12 Cycloalkyl or 4-12 membered heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 R8, wherein R8 each independently represents H, D, oxo, halogen, CN, OR a NR a R a '、N(R a )COR a '、S(O)R a 、S(O)2R a 、C(O)R a , C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally R 24 Substitution; preferably, Cy1 represents a 4-8 membered heterocycloalkyl group.

[0046] In one embodiment of the present invention, -L-Cy1 includes an amide or sulfonamide-containing structure.

[0047] In one embodiment of the present invention, X represents CF.

[0048] In one embodiment of the present invention, R 20 、R 21 、R 22 、R 23 、R 24 Each independently selected from F, Cl, CN, OR a NR a R a '.

[0049] In one embodiment of the present invention, X, Y and Z are each independently CR6.

[0050] In one embodiment of the present invention, when U represents NR2, V CR4, R4 represents C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl is separated by at least one R 21 Substituted, the 4-8 membered heterocycloalkyl group may be optionally R 21 replace.

[0051] In one embodiment of the present invention, U is NR2 and V is CR4.

[0052] In one embodiment of the present invention, U is CR3 and V is NR5.

[0053] In one embodiment of the present invention, the compound of formula I has a structure as shown in formula II:

[0054] wherein L represents a bond, -C(O)- or -S(O)2-; Cy1 represents a 4-8 membered heterocycloalkyl group; and R1, R2, R4, R6 and R7 are as described in any of the preceding claims.

[0055] In one aspect, the present invention provides a compound having the following structure or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof:

[0056] In another aspect, the present invention provides a compound as shown in Formula III or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof: [WH]-L1-EMB Formula III

[0057] Wherein, WH is selected from the compounds described above or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof;

[0058] The brackets [] in the general structural formula indicate that one H atom in the chemical formula of WH shown therein forms a bond and is connected to one end of L1;

[0059] L1 represents a linker, which is connected to the C, N, O or S atom on EMB through a covalent bond and WH;

[0060] EBM is an E3 ubiquitin ligase ligand fragment. Preferably, EBM is a CRBN E3 ubiquitin ligase ligand fragment or a VHL E3 ubiquitin ligase ligand fragment.

[0061] In another aspect, the present invention provides the use of the compounds described in Formula A, Formula I, Formula II and the compound list, or their pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers, for preparing the compound shown in Formula III, or its pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers.

[0062] In another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof.

[0063] In another aspect, the present invention provides the use of the aforementioned compound or its pharmaceutically acceptable salt, isotope derivative, stereoisomer or pharmaceutical composition in the preparation of a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0064] In another aspect, the present invention provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned compound or its pharmaceutically acceptable salt, isotope derivative, stereoisomer and / or pharmaceutical composition.

[0065] It is important to note that, herein, reference to a "compound" of structure (X) generally also encompasses stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopic derivatives thereof.

[0066] It is well known to those skilled in the art that salts, solvates and hydrates of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noted that when referring to the compound of formula (X) herein, it generally also includes its pharmaceutically acceptable salts, and further includes its solvates and hydrates.

[0067] Similarly, reference herein to a compound generally also includes prodrugs, metabolites, and N-oxides thereof.

[0068] Pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, or the like, within the scope of sound medical judgment, and at a reasonable benefit / risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base function may be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts formed of an amino group with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0069] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding an excess of an organic acid or an aqueous inorganic acid solution thereto to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.

[0070] The precursors or metabolites described herein may be those known in the art, as long as the precursors or metabolites are converted to compounds through in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention that, within the scope of reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and are considered to have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism or N-demethylation of the compounds of the present invention.

[0071] As used herein, "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0072] "Stereoisomerism" as used herein is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism (i.e., optical isomerism). Conformational isomerism refers to the stereoisomerism phenomenon in which the atoms or atomic groups of an organic molecule with a certain configuration have different spatial arrangements due to the rotation or distortion of carbon-carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations that occur in the structure of cyclohexane. "Stereoisomers" refer to compounds of the present invention that contain one or more asymmetric centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. The compounds of the present invention have asymmetric centers, and each asymmetric center can produce two optical isomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures, as well as pure or partially purified compounds. The compounds of the present invention may exist as tautomers, which have different hydrogen attachment points due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds of formula (I) to formula (IV) are included within the scope of the present invention.

[0073] The "isotopic derivative" of the present invention refers to a molecule in which the compound is isotopically labeled. The isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 11 C, 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and carbon 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), substitution can enhance metabolic stability and prolong half-life, thereby achieving a reduction in dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0074] The present invention also provides use of the compound of the present invention in preparing a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0075] In addition, the present invention provides a pharmaceutical composition for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases, or immune-mediated diseases, comprising a compound of the present invention as an active ingredient. The pharmaceutical composition may optionally contain a pharmaceutically acceptable carrier.

[0076] Furthermore, the present invention provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, which comprises administering a compound of the present invention to a mammal in need thereof.

[0077] Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, disease, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0078] Representative examples of cancer or tumors can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral Neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

[0079] When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for treating cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof may provide enhanced anticancer effects.

[0080] Representative examples of anticancer agents for treating cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixapram ... lon, tamoxifen, flutamide, gonadorelin analogs, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danuceritinib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib Tinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracutinib, saridegib, sorafenib, sunitinib, telatinib, tivantinib, Tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies and anti-CTLA-4 antibodies, or any combination thereof.

[0081] When the compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in combination with another therapeutic agent for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhanced therapeutic effects.

[0082] Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydroprednisolone, methylhydroprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.) and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected therefrom may be contained in the pharmaceutical composition of the present invention.

[0083] Other features of the present invention will become apparent as the present invention describes exemplary embodiments, which are given to illustrate the present invention and are not intended to be limiting thereof. The following examples were prepared, isolated, and characterized using the methods disclosed herein.

[0084] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the following methods and synthetic methods known in the field of organic synthetic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the desired transformation. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires judgment to change the order of the synthesis steps or the raw materials to obtain the desired compounds of the present invention. DETAILED DESCRIPTION

[0085] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. Unless otherwise indicated, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology will be used. Throughout this application, unless otherwise indicated, the use of "or" or "and" means "and / or."

[0086] In the specification and claims, a given chemical formula or name shall encompass all stereoisomers and optical isomers thereof and racemates thereof in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the present invention. Multiple geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they can be separated into mixtures of isomers or separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic form. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the process conditions, the final products of the present invention are obtained in free (neutral) or salt form. Both the free forms and salts of these final products are within the scope of the present invention. If desired, one form of the compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; and a mixture of isomeric compounds of the present invention can be separated into its individual isomers. The compounds of the present invention, their free forms, and salts can exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that may exist are included in the present invention.

[0087] In the present invention, when the linking group listed does not specify its connection direction, its connection direction is arbitrary, for example Where L is -C(O)NH-, in which case -C(O)NH- can be connected to form a phenyl group and a cyclohexyl group in the order of reading from left to right. It is also possible to connect phenyl and cyclohexyl groups in the reverse reading order from left to right to form Combinations of linking groups and linked groups are permitted only if they result in stable compounds. In some preferred embodiments of the present invention, the sequences are read from left to right.

[0088] Unless otherwise defined, the definitions of the substituents of the present invention are independent of each other and not interrelated. For example (listing but not exhaustive), in one aspect, for a substituent R a (or R a '), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R a ') When a definition is selected in a substituent, it does not mean that the R a (or R a') have the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NR a R a ', when R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR a R a 'In, R a (or R a ') must be hydrogen. In another aspect, when more than one R is present in a substituent a (or R a '), these R a (or R a ') are also independent of each other. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n -, when m+n is greater than or equal to 2, the m+n R a (or R a ') are independent of each other and can have the same or different meanings.

[0089] Unless otherwise defined, when a substituent is indicated as "optionally substituted", the substituent is selected, for example, from substituents such as alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, aryl In some embodiments, the present invention further comprises an alkylthiocarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, an arylalkylsulfonyl group, an aminosulfonyl group such as -SO2NH2, a substituted sulfonylamino group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group such as -CONH2, a substituted carbamoyl group such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or a case where the nitrogen has two substituents selected from alkyl, aryl or arylalkyl, an alkoxycarbonyl group, an aryl group, a substituted aryl group, a guanidino group, a heterocyclic group such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and a substituted heterocyclic group.

[0090] Unless otherwise defined, expressions herein such as "A group may be optionally substituted with Rx" or similar expressions mean that optionally, A group may be substituted with 0, 1, 2, 3, 4, 5 or 6 substituents each independently selected from Rx; preferably, A group may be substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from Rx; preferably, A group may be substituted with 0, 1, 2, 3 or 4 substituents each independently selected from Rx; preferably, A group may be substituted with 0, 1, 2 or 3 substituents each independently selected from Rx; preferably, A group may be substituted with 0, 1 or 2 substituents each independently selected from Rx; preferably, A group may be substituted with 1 Rx; preferably, A group is not substituted with Rx. The A group and Rx herein are for example only and are not specific.

[0091] Unless otherwise defined, the term "single bond," "bond," or "direct bond" as used herein means two atoms are connected by a saturated covalent bond. For example, when L represents a single bond, "ALB" means that A and B are connected by a saturated covalent bond, i.e., "AB"; for another example, when L represents a single bond, "-CH2-L-NH-" means that -CH2- and -NH- are connected by a saturated covalent bond, i.e., "-CH2-NH-."

[0092] As used herein, the term "alkyl" is intended to include side chains and straight chain saturated aliphatic hydrocarbon groups with a specified number of carbon atoms. For example, "C1-C6 alkyl" represents an alkyl group with 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl) and pentyl (such as n-pentyl, isopentyl, neopentyl). Alkyl can be unsubstituted or substituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In this article, alkyl is preferably an alkyl group with 1 to 6, more preferably 1 to 4 carbon atoms.

[0093] As used herein, the term "alkylene" is intended to include saturated aliphatic hydrocarbon groups, branched, straight, containing or not containing cyclic alkyl groups, having a specified number of carbon atoms, which are residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. For example, "C0-C6 alkylene" means an alkylene group having 0 (i.e., a bond), 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (e.g., -(CH2)3-, -(CHCH3)CH2-, -CH(CH2CH3)-), and the like. In this article, alkylene groups are preferably alkylene groups having 0-6, 0-4, 0-3, 1-6, 1-4, or 1-3 carbon atoms. In this article, alkylene groups preferably do not contain alkylene groups that are cyclic alkyl groups.

[0094] The term "cycloalkyl" refers to a monocyclic, polycyclic or branched cyclic alkyl group. For example, C3-C 12 Cyclic alkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyls such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Herein, cycloalkyl can be a saturated or partially unsaturated carbocyclic ring, for example, a 6-membered cycloalkyl can include 0-2 double bonds, and a 12-membered cycloalkyl can include 0-5 double bonds or triple bonds. Polycyclic cycloalkyls such as bicyclic and tricyclic cycloalkyls include cycloalkyls of bridged rings, spiro rings or condensed rings. Cyclic alkyl can be unsubstituted or substituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the invention, cycloalkyl is preferably C3-C 12 Cycloalkyl, more preferably C3-C8 cycloalkyl.

[0095] Similarly, the term "heterocycloalkyl" refers to a ring structure in which at least one carbon atom of a cycloalkyl ring structure is replaced by a heteroatom selected from N, O, S and P. Herein, heterocycloalkyl can be a saturated or partially unsaturated heterocycle, for example, a 6-membered heterocycloalkyl can include 0-2 double bonds, and a 12-membered heterocycloalkyl can include 0-5 double bonds or triple bonds. The N atom can be optionally quaternized, and the N and S atoms can be optionally oxidized (i.e., NO, SO and SO2). It includes monocyclic heterocycles, bicyclic heterocycles and tricyclic heterocycle systems, wherein the bicyclic heterocycles and tricyclic heterocycle systems include spirocyclic heterocycles, annular heterocycles and bridged heterocycles. Heterocycloalkyl can be unsubstituted or substituted. When substituted, it can be substituted at any usable point of attachment, and the substituents are preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the present invention, the heterocycloalkyl group is preferably a 4- to 12-membered heterocycloalkyl group, and more preferably a 4- to 8-membered heterocycloalkyl group.

[0096] In the present invention, the term "paracyclic" refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms.

[0097] In the present invention, the term "bridged ring" refers to a polycyclic group in which two rings in the system share two or more ring atoms.

[0098] In the present invention, the term "spirocycle" refers to a polycyclic group in which single rings share a carbon atom (called a spiro atom).

[0099] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In this article, alkenyl is preferably C2-C6 alkenyl.

[0100] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl refers to a C3-C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyls include cyclic alkenyls of bridged rings, spirocycles or condensed rings.

[0101] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, etc. In this article, alkynyl is preferably C2-C6 alkynyl.

[0102] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy. In this article, alkoxy is preferably an alkoxy having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above connected by a sulfur bridge having a specified number of carbon atoms; for example, methyl-S- and ethyl-S-. Alkoxy can be unsubstituted or substituted, and when substituted, it can be substituted at any usable point of attachment, the substituent preferably being one or more selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0103] The term "carbonyl" refers to an organic functional group composed of carbon and oxygen atoms connected by a double bond (C=O).

[0104] The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. The dotted line drawn from the ring system indicates that the bond may be attached to any suitable ring atom. The aryl group may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, preferably one or more of deuterium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0105] When the term "heterocycle" is used, it refers to fully saturated, partially saturated, and fully unsaturated heteroatom-containing ring structures, including heteroaromatic rings.

[0106] The term "heteroaryl" means a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocyclic ring containing carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; it includes a structure in which a cycloalkane or heterocycloalkane is fused to an aromatic ring such as a benzene ring or a heteroaromatic ring such as pyridine, and the site of the substituent can be located on the cycloalkane, heterocycloalkane, aromatic ring, or heteroaromatic ring. The nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. The heteroaryl group may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, the substituent being preferably selected from one or more of halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.Examples of aromatic hetero groups include, but are not limited to, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isatinoyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, oxindolyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidone 4-Piperidinyl, Pteridinyl, Purinyl, Pyranyl, Pyrazinyl, Pyrazolidinyl, Pyrazolinyl, Pyrazolopyridinyl, Pyrazolyl, Pyridazinyl, Pyridooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridinyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2-Pyrrolidinonyl, 2H-Pyrrolyl, Pyrrolyl, Quinazolinyl, Quinolinyl, 4H-Qulolidinyl, Quinoxalinyl, Quinuclidinyl, Tetrazolyl, Tetrahydrofuranyl, Tetrahydroisoquinolinyl, Tetrahydroquinolinyl, 6H-1,2,5-Thiadiazinyl, 1,2,3-Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,2,5-Thiadiazolyl, 1,3,4-Thiadiazolyl, Thianthryl, Thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, dihydroindolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; the present invention also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles.

[0107] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0108] In the present disclosure, one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.

[0109] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" / "haloalkylene" is intended to include branched and straight-chain saturated alkyl / alkylene groups having a specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more fluorine atoms. "Halocycloalkyl" / "haloheterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having a specified number of carbon atoms substituted with one or more halogens. In the present invention, the halogen atom is preferably fluorine or chlorine, more preferably fluorine. In this document, unless it is specifically stated that an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl or alkylene group cannot be substituted by halogen, or it can be inferred from the context that the group does not include halogenation, or it is considered that the group is not suitable for halogenation according to common knowledge in the art, the group is considered to be halogenated.

[0110] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the specified number of carbon atoms attached via an oxygen bridge. For example, "halo C1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above having the specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0111] In this disclosure, C is used when referring to certain substituent groups. x1 -C x2, which means that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.

[0112] In the present disclosure, when referring to a cyclic group (such as an aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the number of ring atoms of the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5- or 6-membered ring, and the number of its ring atoms can be 3, 4, 5 or 6; the 3-8 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7- or 8-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7, 8 or 9-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, The term "4-7 membered ring" refers to a 4-, 5-, 6-, or 7-membered ring having 4, 5, 6, or 7 ring atoms; a 5-, 8-, or 5-membered ring refers to a 5-, 6-, 7-, or 8-membered ring having 5, 6, 7, or 8 ring atoms; a 5-, 12-, or 5-membered ring refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; and a 6-, 12-, or 6-membered ring refers to a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, such as heteroatoms selected from N, O and S.

[0113] Where nitrogen atoms (e.g., amines) are present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the invention. Thus, the shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxide to obtain the derivatives of the invention.

[0114] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0115] The term "patient" as used herein refers to an organism to be treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., mice, apes, monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably refer to humans.

[0116] As used herein, the term "effective amount" means an amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will cause a biological or medical response in a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received the above amount. An effective amount can be given in one or more administrations, applications, or dosages and is not intended to be limited by a specific formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological function.

[0117] As used herein, the term "treating" includes any effect that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, modulation, improvement, or elimination, or amelioration of the symptoms thereof.

[0118] The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response and / or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0119] As used herein, the phrase "pharmaceutically acceptable carrier" or "pharmaceutical carrier" means a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate, or stearic acid), or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0120] The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.

[0121] Specific pharmaceutical and medical terms

[0122] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0123] The term "cancer," as used herein, refers to an abnormal, uncontrolled growth of cells that can metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or blood tumors (such as non-leukemic leukemias).

[0124] The term "combination administration" or its like, as used herein, refers to the administration of several selected therapeutic agents to a single patient, using the same or different administration routes at the same or different times.

[0125] The terms "enhance" or "capable of enhancing," as used herein, refer to the ability to increase or prolong the potency or duration of a desired outcome. Thus, in the context of enhancing the therapeutic effect of a drug, the term "capable of enhancing" refers to the ability of the drug to increase or prolong the potency or duration of the drug in a system. "Potentiation," as used herein, refers to the ability of another therapeutic agent to maximize its effectiveness in an ideal system.

[0126] The term "immune disease" refers to a disease or condition that results from an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually cellular dysfunction, or the resulting damage and malfunction of, or destruction of, organs or tissues that may be responsible for the immune condition.

[0127] The term "subject" or "patient" includes both mammals and non-mammals. Mammals include, but are not limited to, mammals such as humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred aspect, the selected mammal is a human.

[0128] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing and / or treating signs caused by a disease or symptom.

[0129] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration, regardless of whether the administration is fixed or temporary, continuous or intermittent, and can be attributed to or related to the administration.

[0130] Example

[0131] General Process

[0132] When the preparation route is not included, the raw materials and reagents used in the present invention are all known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercial products. No further purification is required for the commercially available reagents used.

[0133] Room temperature refers to 20-30℃.

[0134] Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere, which means that the reaction flask was connected to a nitrogen balloon of approximately 1 L.

[0135] The hydrogenation reaction is usually carried out by evacuating the flask and filling it with hydrogen, and this operation is repeated three times. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1L.

[0136] Microwave reaction use Initiator + microwave reactor.

[0137] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using Bruker Ascend TM The NMR spectra were obtained using a 500 nm NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The following abbreviations are used for NMR signal multiplicities: s = singlet, brs = broad, d = doublet, t = triplet, and m = multiplet. Coupling constants are listed as J values ​​and are measured in Hz.

[0138] Reverse phase preparative chromatography was performed using a Thermo (UltiMate 3000) reverse phase preparative chromatograph. Flash column chromatography was performed using an Aeger (FS-9200T) automatic column machine, and silica gel prepacked columns were performed using a Santai Pre-packed columns. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for thin layer chromatography separation and purification products are 0.4mm to 0.5mm.

[0139] The LC-MS analysis method is as follows:

[0140] 1) Mass spectrometry: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameters: drying gas temperature, 350°C; drying gas flow rate, 10 L / min; MS range: 120–1000.

[0141] 2) Liquid phase conditions: Chromatographic column: Waters XBridge (3.5 μm, 50 mm × 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, linear gradient elution according to Table 1 below; flow rate: 2 mL / min; column temperature: 30°C; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0142] Table 1. Gradient elution conditions

[0143] The HPLC analysis method is as follows:

[0144] Chromatographic column: Waters XBridge phenyl (3.5 μm, 150 mm × 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, linear gradient elution according to Table 2; flow rate: 1 mL / min; column temperature: 30°C; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0145] Table 2. Gradient elution conditions

[0146] The synthetic methods of some intermediates in the invention are as follows:

[0147] Intermediate 1

[0148] Intermediate 1 was prepared by the following steps:

[0149] Step 1: Dissolve 5-bromo-1,3-difluoro-2-nitrobenzene INT-1a (4 g, 16.81 mmol) in 40 mL of tetrahydrofuran, add cesium carbonate (5.48 g, 16.81 mol), and stir for 10 minutes. Isopropylamine (0.99 g, 16.81 mmol) is added dropwise at room temperature. Stirring is continued for 16 hours. After the reaction is complete, the reaction solution is poured into 50 mL of water. The suspension is extracted with ethyl acetate (50 mL x 3). The combined organic phases are washed three times with water and concentrated under reduced pressure to yield INT-1b (4.6 g, 98% yield) as a yellow oil. ESI-MS (m / z): 277.2 [M+H] + .

[0150] Step 2: INT-1b (4.6 g, 16.60 mmol) was added to 30 mL of ethanol and 3 mL of water, followed by iron powder (3.71 g, 66.40 mmol) and ammonium chloride (1.78 g, 33.20 mmol). The mixture was stirred at 90°C for 16 hours. After the reaction was complete, the mixture was filtered, concentrated, and the filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford INT-1c (3.7 g, 90% yield) as a yellow oil. ESI-MS (m / z): 247.2 [M+H] + .

[0151] Step 3: INT-1c (3.2 g, 12.95 mmol) and INT-1d (2.33 g, 25.90 mol, 1.93 mL) were stirred at 90°C for 16 hours. After the reaction was complete, 100 mL of dichloromethane and saturated aqueous sodium bicarbonate were added. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford INT-1e (3.5 g, 89% yield) as a yellow oil. ESI-MS (m / z): 300.9 [M+H] + .

[0152] Step 4: Dissolve INT-1e (3.2 g, 10.63 mmol) in 40 mL of dichloromethane. Add Dess-Martin periodinane (5.86 g, 13.81 mmol) at 0°C, slowly warm to room temperature, and continue stirring for 16 hours. After the reaction is complete, add saturated aqueous sodium bicarbonate solution and extract with dichloromethane (50 mL x 3). The organic phases are combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain INT-1f (1.8 g, 56% yield) as a white solid. ESI-MS (m / z): 299.1 [M+H] + .

[0153] Step 5: Dissolve INT-1f (1.6 g, 5.35 mmol) in 20 mL of tetrahydrofuran under nitrogen. Add methylmagnesium bromide (3 M, 5.35 mmol, 1.78 mL) at 0°C and stir for 3 hours. Quench the mixture by adding it to a saturated aqueous ammonium chloride solution. Extract with ethyl acetate (50 mL x 3). The combined organic phases are dried and concentrated under reduced pressure. Purify by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a yellow solid INT-1g (1.5 g, 88% yield). ESI-MS (m / z): 315.0 [M+H] + .

[0154] Step 6: INT-1g (1 g, 3.17 mmol) was dissolved in 100 mL of tetrahydrofuran. Under nitrogen, n-butyllithium (2.5 mol / L in n-heptane, 6.98 mmol, 2.79 mL) was added dropwise at -78°C. After complete addition, the mixture was stirred at -78°C for 30 minutes. INT-1h (885.47 mg, 4.76 mmol, 0.97 mL) was then added dropwise, and stirring was continued at -78°C for 2 hours. After the reaction was complete, the mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) afforded INT-1i (1 g, 60% purity, 52% yield) as a yellow solid. ESI-MS (m / z): 363.2 [M+H] + .

[0155] Step 7: Compound INT-1i (1 g, 1.66 mmol), INT-1j (455.72 mg, 2.48 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (121.19 mg, 0.17 mmol), and sodium carbonate (526.66 mg, 4.97 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow solid INT-1 (630 mg, purity 53%, yield 52%). ESI-MS (m / z): 383.0 [M+H] + .

[0156] Intermediate 2

[0157] Intermediate 2 was prepared by the following steps

[0158] Step 1: Dissolve INT-1c (1.4 g, 5.67 mmol) and INT-2a (2.12 g, 11.33 mol) in 15 mL of tetrahydrofuran, add sodium dithionite (2.47 g, 14.16 mmol), and stir at 80°C for 16 hours. After the reaction is complete, dilute with dichloromethane, filter, and concentrate the filtrate. Purify by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain INT-2b (0.69 g, 29% yield) as a white solid. ESI-MS (m / z): 413.9 [M+H] + .

[0159] Step 2: Compound INT-2a (360.0 mg, 0.87 mmol), INT-2c (330.98 mg, 1.3 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (73.55 mg, 0.09 mmol), and potassium acetate (255.83 g, 2.61 mmol) were dissolved in 1,4-dioxane (5 mL) / water (0.5 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain INT-2d (330 mg, yield 82%) as a white solid. ESI-MS (m / z): 462.1 [M+H] + .

[0160] Step 3: Compound INT-2d (330.0 mg, 0.71 mmol), INT-1j (196.79 mg, 1.07 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (52.33 mg, 0.07 mmol), and sodium carbonate (227.43 mg, 2.15 mmol) were dissolved in 1,4-dioxane (2 mL) / water (0.2 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain INT-2e (300 mg, yield 86%) as a white solid. ESI-MS (m / z): 482.4 [M+H] + .

[0161] Step 4: Dissolve compound INT-2e (300.0 mg, 0.62 mmol) in N,N-dimethylformamide (5 mL), cool to 0°C in an ice-water bath, add sodium thiomethoxide (87.18 mg, 1.24 mmol), and stir at 0°C for three hours. After the reaction is complete, dilute the reaction solution with water and extract with ethyl acetate (50 mL × 3). The combined organic phases are washed three times with saturated brine, dried, and concentrated under reduced pressure to obtain a yellow solid INT-2f (300 mg, yield 97%). ESI-MS (m / z): 494.1 [M+H] + .

[0162] Step 5: Dissolve compound INT-2f (200.0 mg, 0.40 mmol) in dichloromethane (4 mL), cool to 0°C in an ice-water bath, add m-chloroperbenzoic acid (139.72 mg, 0.81 mmol), and stir at 0°C for four hours. After the reaction is complete, add saturated aqueous sodium bicarbonate solution to quench the reaction, and then extract with dichloromethane (30 mL × 3). After combining the organic phases, dry them, and concentrate under reduced pressure to obtain INT-2 (180 mg, yield 84%) as a yellow oil. ESI-MS (m / z): 526.5 [M+H] + .

[0163] Intermediate 3

[0164] Intermediate 3 was prepared by the following steps:

[0165] Step 1: Dissolve INT-1g (3 g, 9.52 mmol) in 10 mL of acetic anhydride. Add 4-dimethylaminopyridine (116.28 mg, 0.95 mmol) at room temperature and continue stirring at 80°C for 16 hours. After the reaction is complete, concentrate under reduced pressure and dilute with ethyl acetate. The organic phase is washed three times with saturated sodium bicarbonate solution, dried, and concentrated under reduced pressure to yield INT-3a (3.3 g, 97% yield) as a yellow solid. ESI-MS (m / z): 357.3 [M+H] + .

[0166] Step 2: Compound INT-3a (2.3 g, 6.44 mmol), INT-2c (2.45 g, 9.66 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (545.0 mg, 0.64 mmol), and potassium acetate (1.90 g, 19.32 mmol) were dissolved in 1,4-dioxane (20 mL) / water (2 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow solid INT-3b (2.5 g, yield 96%). ESI-MS (m / z): 405.5 [M+H] + .

[0167] Step 3: Dissolve compound INT-3b (1.1 g, 2.72 mmol), INT-1j (748.61 mg, 4.08 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (199.09 mg, 0.27 mmol), and sodium carbonate (865.15 mg, 8.16 mmol) in 1,4-dioxane (10 mL) / water (1 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction is complete, the reaction solution is filtered through celite, and the filtrate is concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow solid INT-3 (1 g, yield 86%). ESI-MS (m / z): 425.3 [M+H] + .

[0168] Intermediate 4

[0169] Intermediate 4 was prepared by the following steps:

[0170] Step 1: Dissolve INT-4a (1.0 g, 5.20 mmol) in 5 mL of formic acid and stir at 100°C for 1 hour. After the reaction is complete, concentrate under reduced pressure to obtain an oil. The oil is slurried with petroleum ether / ethyl acetate (10 / 1), filtered, and dried to obtain INT-4 (1.0 g, 87% yield) as a white solid. ESI-MS (m / z): 221.2 [M+H] + .

[0171] Intermediate 5

[0172] Intermediate 5 was prepared by the following steps:

[0173] Step 1: Compound INT-5a (700 mg, 3.51 mmol), compound INT-5b (765.68 mg, 3.51 mmol), potassium carbonate (1.45 g, 10.49 mmol), cuprous iodide (332.91 mg, 1.75 mmol), and N,N-dimethylethylenediamine (154.08 mg, 1.75 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen. The reaction mixture was stirred at 120°C for 28 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound INT-5 (900 mg, yield 88%). ESI-MS (m / z): 291.9 [M+H] + .

[0174] Intermediate 6

[0175] Intermediate 6 was prepared by the following steps:

[0176] Step 1: Dissolve compound INT-3b (200 mg, 0.49 mmol), INT-6a (123.91 mg, 0.74 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (36.02 mg, 0.049 mmol), and sodium carbonate (157.31 mg, 1.48 mmol) in 1,4-dioxane (2 mL) / water (0.2 mL) under nitrogen protection. Stir overnight at 90°C. After the reaction is complete, cool to room temperature, filter the reaction mixture through celite, and concentrate the filtrate. Purify by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain INT-6 (55 mg, 27% yield) as a yellow solid. ESI-MS (m / z): 409.4 [M+H] + .

[0177] Intermediate 7

[0178] Intermediate 7 was prepared by the following steps:

[0179] Step 1: Dissolve compound INT-7a (2.11 g, 10 mmol) in tetrahydrofuran (20 mL) and add lithium diisopropylamide (7.5 mL, 2 M in tetrahydrofuran) dropwise at -78°C under a nitrogen atmosphere. The reaction solution was stirred at -78°C for 10 minutes, followed by the dropwise addition of acetone (871 mg, 15 mmol). The reaction solution was slowly warmed to room temperature and stirred for 16 hours. After the reaction was complete, saturated aqueous ammonium chloride (30 mL) was added to quench the reaction. The product was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude compound INT-7b (2.69 g, 99% yield). ESI-MS (m / z): 269.1 [M+H] + .

[0180] Step 2: Compound INT-7b (2.69 g, 10 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of triethylsilane (5.81 g, 50 mmol) and trifluoroacetic acid (5.70 g, 50 mmol). The reaction mixture was stirred at room temperature for 48 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution (30 mL) was added to the residue. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-7c (876 mg, 35% yield) as a colorless oily liquid. ESI-MS (m / z): 253.4 [M+H] + .

[0181] Step 3: Compound INT-7c (300 mg, 1.19 mmol), INT-2c (361 mg, 1.42 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (100 mg, 118 umol), potassium acetate (349 mg, 3.56 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-7d (340 mg, yield 96%). ESI-MS (m / z): 301.5 [M+H] + .

[0182] Step 4: Compound INT-7d (180 mg, 599 umol), INT-6a (100 mg, 599 umol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (44 mg, 60 umol), and sodium carbonate (190 mg, 1.8 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). Stir at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a white solid INT-7 (134 mg, yield 74%). ESI-MS (m / z): 305.5 [M+H] + .

[0183] Intermediate 8

[0184] Intermediate 8 was prepared by the following steps:

[0185] Step 1: Dissolve compound INT-3b (180 mg, 0.45 mmol), INT-8a (123.98 mg, 0.67 mmol), bis(tri-tert-butylphosphine)palladium (90.49 mg, 0.12 mmol), and potassium carbonate (184.61 mg, 1.34 mmol) in 1,4-dioxane (2 mL) / water (0.2 mL) under nitrogen protection. Stir overnight at 90°C. After the reaction is complete, cool to room temperature, filter the reaction mixture through celite, and concentrate the filtrate. Purify by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound INT-8b (163 mg, yield 88%). ESI-MS (m / z): 428.2 [M+H] + .

[0186] Step 2: Dissolve compound INT-8b (183 mg, 0.43 mmol) in dichloromethane (2 mL), lower the temperature of the reaction system to 0°C, then add m-chloroperbenzoic acid (147 mg, 0.86 mmol), and stir at room temperature for 4 hours. After the reaction is complete, add water (5 mL) and dichloromethane (10 mL) to dilute. The organic phase is washed with saturated sodium bicarbonate aqueous solution (5 mL) and then extracted with dichloromethane (15 mL × 3). After the organic phases are combined, they are finally washed with saturated brine (20 mL). After the organic phases are combined and dried, the filtrate is concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain compound INT-8 (60 mg, yield 30%). ESI-MS (m / z): 460.2 [M+H] + .

[0187] Intermediate 9

[0188] Intermediate 9 was prepared by the following steps:

[0189] Step 1: Compound INT-9a (500 mg, 2.46 mmol), INT-9b (249 mg, 2.46 mmol), tris(dibenzylideneacetone)dipalladium (226 mg, 246 umol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (285 mg, 492 umol) and cesium carbonate (2.41 g, 7.39 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-9c (313 mg, yield 57%). ESI-MS (m / z): 224.5 [M+H] + .

[0190] Step 2: Compound INT-9c (313 mg, 1.40 mmol) was dissolved in methanol (5 mL) and palladium carbon (10% Pd, 55% Water) was added. The reaction solution was stirred at 30 ° C for 16 hours under a hydrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol=10 / 1) to give compound INT-9d (94 mg, yield 35%). ESI-MS (m / z): 194.7 [M+H] + .

[0191] Step 3: INT-9d (94 mg, 481 μmol) was dissolved in 3 mL of formic acid and stirred at 100°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to afford compound INT-9 (60 mg, 57% yield). ESI-MS (m / z): 222.9 [M+H] + .

[0192] Intermediate 10

[0193] Intermediate 10 was prepared by the following steps:

[0194] Step 1: Dissolve compound INT-10a (700 mg, 2.61 mmol), INT-5b (571.32 mg, 2.61 mmol), cuprous iodide (49.68 mg, 0.26 mmol), 1,2-bis(methylamino)ethane (22.99 mg, 0.26 mmol), and potassium carbonate (721.03 mg, 5.22 mmol) in 1,4-dioxane (20 mL) under nitrogen and stir at 120°C for 48 hours. After the reaction is complete, cool to room temperature, filter the reaction mixture through celite, and concentrate the filtrate. Purify by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain compound INT-10 (500 mg, 53% yield). ESI-MS (m / z): 360.6 [M+H] + .

[0195] Intermediate 11

[0196] Intermediate 11 was prepared by the following steps:

[0197] Step 1: At 0°C under nitrogen, INT-11a (1.00 g, 4.67 mmol) and potassium tert-butoxide (523.71 mg, 4.67 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred for one hour. INT-11b (658.54 mg, 4.67 mmol) was then added dropwise to the reaction mixture at 0°C. After complete addition, the reaction mixture was heated to 90°C and stirred overnight. After completion of the reaction, water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford the target compound, INT-11c (600 mg, 38.33% yield).

[0198] Step 2: INT-11c (600 mg, 1.79 mmol) and palladium on carbon (60 mg, 10% Pd) were dissolved in methanol (10 mL). The reaction mixture was stirred under a hydrogen atmosphere for 12 hours. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated and dried to give INT-11 (450 mg, 82.36% yield). ESI-MS (m / z): 306.3 [M+H] + .

[0199] Intermediate 12

[0200] Intermediate 12 was prepared by the following steps:

[0201] Step 1: Under a nitrogen atmosphere, INT-12a (548.53 mg, 2.74 mmol), INT-5b (600.00 mg, 2.74 mmol), N,N-dimethylethylenediamine (24.15 mg, 0.27 mmol), cuprous iodide (52.17 mg, 0.27 mmol), and cesium fluoride (1.04 g, 6.85 mmol) were dissolved in tetrahydrofuran (8 mL). The reaction solution was stirred at 60°C overnight. After completion of the reaction, the reaction solution was filtered, concentrated, and dried to obtain a crude product. The crude product was then purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford the target compound INT-12 (650 mg, 81.44% yield). ESI-MS (m / z): 292.5 [M+H] + .

[0202] Intermediate 13

[0203] Intermediate 13 was prepared by the following steps:

[0204] Step 1: Dissolve compound INT-13a (2.0 g, 8.40 mmol) in 20 mL of tetrahydrofuran, add cesium carbonate (2.74 g, 8.40 mmol), and stir the reaction at room temperature for 10 minutes. Then, add cyclobutylamine INT-13b (598 mg, 8.40 mmol) dropwise to the reaction solution. After the addition is complete, the reaction solution is stirred at room temperature for 16 hours. After the reaction is complete, the reaction solution is poured into 50 mL of water, and the suspension is extracted with ethyl acetate (50 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain INT-13c (2.43 g, 99% yield) as a yellow oil.

[0205] Step 2: INT-13c (2.43 g, 8.4 mmol) was added to a mixture of ethanol (20 mL) and water (2 mL), and iron powder (1.9 g, 34 mmol) and ammonium chloride (910 mg, 17 mmol) were added. The reaction solution was stirred at 90 ° C for 16 hours. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a black solid INT-13d (1.52 g, yield 69%). ESI-MS (m / z): 259.5 [M+H] + .

[0206] Step 3: INT-13d (1.52 g, 5.79 mmol) and INT-1d (1.04 g, 11.58 mol) were added to a single-necked eggplant-shaped flask, and the mixture was stirred at 90°C for 16 hours. After the reaction was complete, it was cooled to room temperature, and the reaction mixture was diluted with dichloromethane (100 mL). The mixture was washed with saturated brine (100 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a brown solid INT-13e (1.09 g, yield 60%). ESI-MS (m / z): 313.3 [M+H] + .

[0207] Step 4: INT-13e (900 mg, 2.87 mmol) was dissolved in 10 mL of dichloromethane, and Dess-Martin periodinane (1.58 g, 3.74 mmol) was added at 0°C, the temperature was slowly raised to room temperature, and stirring was continued for 16 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, 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 compound INT-13f (793 mg, yield 89%). ESI-MS (m / z): 311.3 [M+H] + .

[0208] Step 5: INT-13f (692 mg, 2.22 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the addition of INT-13g (297 mg, 2.45 mmol) and tetraethyl titanate (1.01 g, 4.45 mmol). The reaction mixture was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, and the reaction mixture was washed with saturated brine (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-13h (643 mg, yield 70%). ESI-MS (m / z): 414.6 [M + H] + .

[0209] Step 6: Compound INT-13h (543 mg, 1.31 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) and, under nitrogen protection, methylmagnesium bromide (1.31 mL, 3M in THF) was slowly added dropwise to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 3 hours. After the reaction was complete, saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, 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 INT-13i (200 mg, yield 36%) as a colorless oily liquid. ESI-MS (m / z): 430.2 [M+H] + .

[0210] Step 7: Compound INT-13i (180 mg, 418 umol), INT-2c (361 mg, 1.42 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (36 mg, 42 umol), potassium acetate (123 mg, 1.25 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain compound INT-13j (199 mg, yield 99%). ESI-MS (m / z): 478.8 [M+H] + .

[0211] Step 8: Compound INT-13j (199 mg, 417 umol), INT-1j (115 mg, 625 umol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (31 mg, 41 umol), and sodium carbonate (133 mg, 1.25 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). Stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain a colorless oily liquid INT-13 (155 mg, yield 75%). ESI-MS (m / z): 498.3 [M+H] + .

[0212] Intermediate 14

[0213] Intermediate 14 was prepared by the following steps:

[0214] Step 1: Dissolve compound INT-14a (420 mg, 1.85 mmol) in dichloromethane (10 mL), then add N,N-isopropylethylenediamine (836 mg, 6.47 mmol) and di-tert-butyl dicarbonate (605 mg, 2.77 mmol). Stir at room temperature for 16 hours. After the reaction is complete, dilute with water (15 mL) and dichloromethane (15 mL). Extract with dichloromethane (15 mL x 3). Combine the organic phases and finally wash with saturated brine (30 mL). Combine the organic phases, dry them, and concentrate the filtrate to obtain INT-14b (360 mg, yield 98%). ESI-MS (m / z): 215.7 [M+H] + .

[0215] Step 2: Compound INT-14b (300 mg, 1.40 mmol), compound INT-5b (306.67 mg, 1.40 mmol), potassium carbonate (580.53 mg, 4.20 mmol), cuprous iodide (26.67 mg, 0.14 mmol), and N,N-dimethylethylenediamine (12.34 mg, 0.14 mmol) were dissolved in 1,4-dioxane (8 mL) under nitrogen protection. The reaction solution was stirred at 120°C for 16 hours. After the reaction was completed, it was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-14 (240 mg, yield 56%). ESI-MS (m / z): 306.5 [M+H] + .

[0216] Intermediate 15

[0217] Intermediate 15 was prepared by the following steps:

[0218] Step 1: Compound INT-15a (500 mg, 2.11 mmol), INT-15b (213 mg, 2.11 mmol), cuprous iodide (40 mg, 210 umol), N,N-dimethylethylenediamine (19 mg, 210 umol), and potassium phosphate (896 mg, 4.22 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 120°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound INT-15 (362 mg, yield 82%). ESI-MS (m / z): 211.7 [M+H] + .

[0219] Intermediate 16

[0220] Intermediate 16 was prepared by the following steps:

[0221] Step 1: INT-1c (2.1 g, 8.5 mmol) and INT-16a (1.29 g, 17.0 mol, 1.02 mL) were stirred at 90°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and saturated aqueous sodium bicarbonate (100 mL) was added. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-16b (2.8 g, yield 81%). ESI-MS (m / z): 287.4 [M+H] + .

[0222] Step 2: INT-16b (2 g, 6.97 mmol) was dissolved in 10 mL of acetic anhydride. 4-Dimethylaminopyridine (85.10 mg, 0.69 mmol) was added at room temperature and stirred at 80°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL x 3), dried, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) afforded compound INT-16c (2.1 g, 91% yield). ESI-MS (m / z): 329.3 [M+H] + .

[0223] Step 3: Compound INT-16c (2.1 g, 6.38 mmol), INT-2c (2.43 g, 9.57 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (540.02 mg, 0.63 mmol), and potassium acetate (1.88 g, 19.14 mmol) were dissolved in 1,4-dioxane (20 mL) and stirred at 90°C overnight under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound INT-16d (2.2 g, yield 91%). ESI-MS (m / z): 377.7 [M+H] + .

[0224] Step 4: Compound INT-16d (1 g, 2.66 mmol), INT-1j (731.3 mg, 3.99 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (194.48 mg, 0.26 mmol), and sodium carbonate (845.15 mg, 7.97 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound INT-16 (660 mg, yield 62%). ESI-MS (m / z): 397.5 [M+H] + .

[0225] Intermediate 17

[0226] Intermediate 17 was prepared by the following steps:

[0227] Step 1: Compound INT-1c (500 mg, 2.02 mmol) and compound INT-17a (806 mg, 4.04 mmol) were dissolved in a mixed solvent of ethanol (5 mL) and water (2.5 mL), and sodium bisulfite (631 mg, 6.07 mmol) was added. The reaction mixture was stirred at 60 ° C for 16 hours. After the reaction was complete, it was cooled to room temperature, and the reaction mixture was added with saturated brine (30 mL). It was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 2 / 1) to obtain compound INT-17b (385 mg, yield 45%). ESI-MS (m / z): 426.8 [M+H] + .

[0228] Step 2: Compound INT-17b (330 mg, 774 umol), INT-2c (235 mg, 929 umol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (65 mg, 77 umol), potassium acetate (228 mg, 2.32 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain compound INT-17c (366 mg, yield 99%). ESI-MS (m / z): 474.7 [M+H] + .

[0229] Step 3: Compound INT-17c (366 mg, 773 umol), INT-1j (213 mg, 2.32 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (57 mg, 77 umol), and sodium carbonate (246 mg, 2.32 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). Stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a colorless oily liquid INT-17 (380 mg, yield 99%). ESI-MS (m / z): 494.6 [M+H] + .

[0230] Intermediate 18

[0231] Intermediate 18 was prepared by the following steps:

[0232] Step 1: INT-18a (395 mg, 3.04 mmol) and INT-1c (500 mg, 2.02 mmol) were added to a single-necked eggplant flask, and the mixture was stirred at 90 ° C for 16 hours. Subsequently, glacial acetic acid (5 mL) was added to the reaction mixture, and the mixture was continued to stir at 90 ° C for 16 hours. After the reaction was complete, it was cooled to room temperature, the reaction mixture was diluted with dichloromethane (50 mL), the mixed solution was washed with saturated brine (50 mL), extracted with dichloromethane (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a brown solid INT-18b (324 mg, yield 47%). ESI-MS (m / z): 341.4 [M+H] + .

[0233] Step 2: Compound INT-18b (324 mg, 950 μmol), INT-2c (290 mg, 1.14 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (80 mg, 95 μmol), potassium acetate (280 mg, 2.85 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain the crude product of compound INT-18c (368 mg, yield 99%). ESI-MS (m / z): 389.0 [M+H] + .

[0234] Step 3: Compound INT-18c (368 mg, 948 umol), INT-1j (261 mg, 1.42 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (70 mg, 95 umol), sodium carbonate (302 mg, 2.84 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). Stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid INT-18 (160 mg, yield 42%). ESI-MS (m / z): 409.7 [M+H] + .

[0235] Intermediate 19

[0236] Intermediate 19 was prepared by the following steps:

[0237] Step 1: Dissolve compound INT-5a (368.54 mg, 1.84 mmol), INT-19a (500 mg, 21.42 mmol), cuprous iodide (26.96 mg, 0.14 mmol), 1,2-bis(methylamino)ethane (24.96 mg, 0.28 mmol), and potassium carbonate (587.02 mg, 4.25 mmol) in 1,4-dioxane (10 mL) under nitrogen and stir at 120°C for 16 hours. After the reaction is complete, cool to room temperature, filter the reaction mixture through celite, and concentrate the filtrate. Purify by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain compound INT-19b (420 mg, 69% yield). ESI-MS (m / z): 426.7 [M+H] + .

[0238] Step 2: Dissolve compound INT-19b (420 mg, 0.99 mmol) in dichloromethane (2 mL), add hydrochloric acid (987.13 μL, 4 M, 1,4-dioxane solution), and stir at room temperature for 16 hours. After the reaction is complete, the reaction solution is directly concentrated to obtain compound INT-19c (350 mg, 97% yield). ESI-MS (m / z): 326.7 [M+H] + .

[0239] Step 3: INT-19c (350 mg, 967.33 μmol) and N,N-diisopropylethylamine (375.06 mg, 2.90 mmol) were dissolved in dichloromethane (5 mL), acetic anhydride (148.13 mg, 1.45 mmol) was added, and stirring was continued at room temperature for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride (5 mL) was added for dilution, and dichloromethane (10 mL × 3) was used for extraction. The organic phases were combined, dried, and concentrated under reduced pressure. The residue was slurried (petroleum ether / ethyl acetate = 10 / 1, 10 mL) and filtered to obtain compound INT-19d (300 mg, yield 84%). ESI-MS (m / z): 368.5 [M+H] + .

[0240] Step 4: Dissolve INT-19d (300 mg, 816.55 μmol) in dichloromethane (3 mL) and methanol (3 mL), add palladium carbon (30 mg, 10% Pd), and continue stirring at room temperature under a hydrogen atmosphere for 16 hours. After the reaction is complete, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-19 (180 mg, yield 94%). ESI-MS (m / z): 234.5 [M+H] + .

[0241] Intermediate 20

[0242] Intermediate 20 was prepared by the following steps:

[0243] Step 1: Dissolve INT-1c (550 mg, 2.23 mmol) and INT-20a (824.51 mg, 4.45 mmol) in ethanol (10 mL) and water (1 mL). Add sodium bisulfite (579.03 mg, 5.56 mmol) and stir at 60°C for 16 hours. After the reaction is complete, add water (30 mL) and extract with dichloromethane (30 mL x 3). The organic phases are combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound INT-20b (0.77 g, yield 83%). ESI-MS (m / z): 412.3 [M+H] + .

[0244] Step 2: Sodium hydroxide (53.84 mg, 1.35 mmol, 60%) was placed in a two-necked round-bottom flask. Anhydrous N,N-dimethylformamide (2 mL) was added under a nitrogen atmosphere and cooled to 0°C. INT-20b (370 mg, 0.90 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL) and slowly added dropwise to the two-necked round-bottom flask. After half an hour, iodomethane (191.07 mg, 1.35 mmol) was added dropwise to the two-necked round-bottom flask. The system was slowly warmed to room temperature and stirred for 16 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 20c (320 mg, 83% yield).

[0245] Step 3: Compound INT-20c (320 mg, 0.75 mmol), INT-2c (270.12 mg, 1.13 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (63.54 mg, 0.075 mmol), and potassium acetate (220.99 mg, 2.25 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 90°C overnight under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound INT-20d (300 mg, yield 84%). ESI-MS (m / z): 474.8 [M+H] + .

[0246] Step 4: Compound INT-20d (300 mg, 0.63 mmol), INT-1j (174.36 mg, 0.95 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (46.37 mg, 0.063 mmol), and sodium carbonate (201.51 mg, 1.90 mmol) were dissolved in 1,4-dioxane (5 mL) / water (0.5 mL). Under a nitrogen atmosphere, the mixture was stirred at 90°C overnight. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound INT-20 (280 mg, yield 89%). ESI-MS (m / z): 495.8 [M+H] + .

[0247] Intermediate 21

[0248] Intermediate 21 was prepared by the following steps:

[0249] Step 1: Dissolve INT-21a (1 g, 4.51 mmol) in tetrahydrofuran (10 mL). Add INT-21b (1.18 g, 13.54 mmol) at room temperature and continue stirring at room temperature for 16 hours. Upon completion of the reaction, pour the reaction mixture into water (20 mL) and extract with ethyl acetate (10 mL x 3). The organic phase is washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford INT-21c (1 g, 81.4% yield) as a white solid.

[0250] Step 2: Dissolve INT-21c (1 g, 3.67 mmol) in 10 mL of methanol, add palladium on carbon (100 mg, 10% Pd) at room temperature, and continue stirring at room temperature under a hydrogen atmosphere for 16 hours. After the reaction is complete, filter to remove the palladium on carbon, and concentrate the filtrate under reduced pressure to obtain INT-21d (700 mg, 78.7% yield) as a white solid. ESI-MS (m / z): 243.3 [M+H] + .

[0251] Step 3: Dissolve INT-21d (100 mg, 0.413 mmol) in 1.5 mL of formic acid and stir at 100°C for 2 hours. After the reaction is complete, concentrate the reaction mixture under reduced pressure to obtain a yellow oil, INT-21 (100 mg, 89.6% yield). ESI-MS (m / z): 271.3 [M+H] + .

[0252] Intermediate 22

[0253] Intermediate 22 was prepared by the following steps:

[0254] Step 1: Dissolve INT-22a (1 g, 4.88 mmol) in 5 mL of formic acid and continue stirring at 100°C for 2 hours. LC-MS monitoring of the reaction completes, and the reaction solution is concentrated under reduced pressure to afford a yellow solid, INT-22b (1 g, 95.4% yield). ESI-MS (m / z): 215.6 [M+H] + .

[0255] Step 2: INT-22b (1 g, 4.65 mmol) and INT-22c (4.56 g, 46.5 mmol) were added to a microwave tube and reacted at 200°C for 2 hours. The reaction was monitored by LC-MS. The reaction mixture was directly mixed and purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain a yellow solid INT-22d (1.3 g, 89.3% yield). ESI-MS (m / z): 313.6 [M+H] + .

[0256] Step 3: Compound INT-22d (1.2 g, 3.83 mmol), INT-2c (1.26 g, 4.98 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (324.4 mg, 0.383 mmol), and potassium acetate (1.13 g, 11.5 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen protection and stirred at 100°C overnight. The reaction was monitored by LC-MS. The reaction mixture was mixed and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow solid INT-22e (1.1 g, yield 79.7%). ESI-MS (m / z): 361.7 [M+H] + .

[0257] Step 4: Compound INT-22e (250 mg, 0.69 mmol), INT-1j (191 mg, 1.04 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (50.78 mg, 0.069 mmol), and sodium carbonate (204.3 mg, 1.93 mmol) were dissolved in 1,4-dioxane (5 mL) / water (0.5 mL) under nitrogen protection and stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow solid INT-22 (220 mg, yield 83.2%). ESI-MS (m / z): 381.5 [M+H] + .

[0258] Intermediate 23

[0259] Intermediate 23 was prepared by the following steps:

[0260] Step 1: Compound INT-23a (500 mg, 2.11 mmol), compound INT-15a (234.62 mg, 2.32 mmol), potassium carbonate (834.71 mg, 6.33 mmol), cuprous iodide (401.77 mg, 2.11 mmol), and N,N-dimethylethylenediamine (185.96 mg, 2.11 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen. The reaction mixture was stirred at 120°C for 24 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound INT-23 (312 mg, yield 73%). ESI-MS (m / z): 211.8 [M+H]+ .

[0261] Intermediate 24

[0262] Intermediate 24 was prepared by the following steps:

[0263] Step 1: Dissolve compound INT-24a (2.5 g, 19.06 mmol) and sodium carbonate (6.6 g, 57.17 mmol) in acetone (30 mL) and water (30 mL). Add p-toluenesulfonyl chloride (5.5 g, 28.58 mmol) at room temperature. Then raise the temperature to 60°C and stir overnight. After the reaction is completed, extract with ethyl acetate (100 mL×3). The organic phase is dried and concentrated to obtain a yellow solid INT-24b (1 g, yield 40%).

[0264] 1 H NMR (500MHz, Chloroform-d) δ6.81(s,1H),3.68–3.55(m,2H),2.98–2.88(m,2H),2.79–2.74(m,2H),2.73–2.69(m,2H).

[0265] Step 2: Compound INT-24b (563 mg, 4.29 mmol), compound INT-5b (783 mg, 3.58 mmol), potassium carbonate (1.48 g, 10.73 mmol), cuprous iodide (681 mg, 3.58 mmol), and N,N-dimethylethylenediamine (315 mg, 3.58 mmol) were dissolved in 1,4-dioxane (8 mL) under nitrogen protection. The reaction solution was stirred at 120°C for 48 hours. After the reaction was completed, the solution was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain INT-24 (520 mg, 65% yield) as a black solid. ESI-MS (m / z): 223.6 [M+H] + .

[0266] Intermediate 25

[0267] Intermediate 25 was prepared by the following steps:

[0268] Step 1: Dissolve compound INT-3b (500 mg, 1.24 mmol), INT-25a (361.88 mg, 1.86 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (90.49 mg, 0.12 mmol), and sodium carbonate (393.25 mg, 3.72 mmol) in 1,4-dioxane (10 mL) / water (1 mL). Stir at 90°C overnight under a nitrogen atmosphere. After the reaction is complete, cool to room temperature, filter the reaction mixture through celite, and concentrate the filtrate. Purify by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound INT-25b (440 mg, yield 81%). ESI-MS (m / z): 437.4 [M+H] + .

[0269] Step 2: Dissolve compound INT-25b (440 mg, 1.01 mmol) in dichloromethane (5 mL), lower the temperature of the reaction system to 0°C, then add m-chloroperbenzoic acid (347.57 mg, 2.01 mmol), and stir at room temperature for 4 hours. After the reaction is complete, add saturated aqueous sodium bicarbonate solution (10 mL), extract with dichloromethane (15 mL × 3), combine the organic phases, dry them, and concentrate the filtrate to obtain compound INT-25 (450 mg, yield 95%). ESI-MS (m / z): 469.4 [M+H] + .

[0270] The synthesis method of the embodiment compounds of the present invention is as follows:

[0271] Example 1

[0272] 4-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0273] Example 1 was prepared by the following steps:

[0274] Step 1: Compounds INT-1 (100 mg, 0.26 mmol) and INT-4a (65 mg, 0.34 mmol) were dissolved in 1,4-dioxane (3 mL). Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (24 mg, 0.03 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (28 mg, 0.05 mmol), and cesium carbonate (170 mg, 0.52 mmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain a crude product of compound 1. The crude product was purified by preparative liquid chromatography to obtain a white solid compound 1 (20 mg, yield 14%). ESI-MS (m / z): 539.4 [M+H] + .

[0275] 1 H NMR (500MHz, DMSO-d6) δ10.06(s,1H),8.65(s,1H),8.05(s,1H),7.80(d,J=8.9Hz,2H),7.51–7.45(m,1H),7.29(d,J=8.9Hz, 2H),5.86(s,1H),5.82–5.74(m,1H),4.18(s,2H),3.99–3.94(m,2H),3.72–3.67(m,2H),1.67(s,6H),1.62(d,J=7.0Hz,6H).

[0276] Example 2

[0277] (4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone

[0278] Example 2 was prepared by the following steps:

[0279] Step 1: Compound INT-1 (100 mg, 0.26 mmol) and 4-[(4-methyl-1-piperazinyl)carbonyl]aniline 2a (74 mg, 0.34 mmol) were dissolved in 1,4-dioxane (3 mL). Methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (24 mg, 0.03 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (28 mg, 0.05 mmol), and cesium carbonate (170 mg, 0.52 mmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain a crude product of compound 2. The crude product was purified by preparative liquid chromatography to obtain a white solid compound 2 (13 mg, yield 9%). ESI-MS (m / z): 566.6 [M+H] + .

[0280] 1 H NMR (500MHz, DMSO-d6) δ10.20(s,1H),8.69(s,1H),8.05(s,1H),7.86(d,J=8.3Hz,2H),7.48(d,J=11.5Hz,1H),7.33(d,J=8.2H z,2H),5.86(s,1H),5.82–5.73(m,1H),3.59–3.40(m,4H),2.36–2.24(m,4H),2.18(s,3H),1.67(s,6H),1.63(d,J=7.0Hz,6H).

[0281] Example 3

[0282] 4-(4-((4-(2-(2-aminopropan-2-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0283] Example 3 was prepared by the following steps:

[0284] Step 1: Sodium hydroxide (8.90 mg, 0.22 mmol, 60%) was placed in a two-necked round-bottom flask. Anhydrous N,N-dimethylformamide (1 mL) was added under a nitrogen atmosphere and cooled to 0°C. INT-4 (48.98 mg, 0.22 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) and slowly added dropwise to the two-necked round-bottom flask. Half an hour later, INT-2 (90.0 mg, 0.17 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) and slowly added dropwise to the two-necked round-bottom flask. The system was slowly warmed to room temperature and stirred for 16 hours. The reaction was quenched by adding saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure to afford 3a as a yellow oil (80 mg, 73% yield). ESI-MS (m / z): 638.5 [M+H]. + .

[0285] Step 2: Dissolve 3a (80 mg, 0.125 mmol) in dichloromethane (1 mL) and add 1,4-dioxane hydrochloride solution (125.37 μL, 0.50 mmol) dropwise. Stir and react at room temperature for 16 hours. The reaction mixture was directly concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain compound 3 as a white solid (1.10 mg, 1.6% yield). ESI-MS (m / z): 538.2 [M+H] + .

[0286] 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.65(s,1H),8.03(d,J=1.3Hz,1H),7.84–7.75(m,2H),7.46(dd,J=11.6,1.3H z,1H),7.32–7.25(m,2H),6.23–6.13(m,1H),4.18(s,2H),3.99–3.93(m,2H),3.73–3.66(m,2H),1.63–1.59(m,12H).

[0287] Example 4

[0288] 2-(6-(5-chloro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol

[0289] Example 4 was prepared by the following steps:

[0290] Step 1: Compound INT-3 (70 mg, 0.16 mmol) and 4-(4-methylpiperazine)aniline 4a (38 mg, 0.20 mmol) were dissolved in 1,4-dioxane (3 mL). Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15 mg, 0.02 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (18 mg, 0.03 mmol), and cesium carbonate (107 mg, 0.33 mmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 4b (40 mg, yield 42%). ESI-MS (m / z): 580.7 [M+H] + .

[0291] Step 2: Compound 4b (40 mg, 0.07 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide (5 mg, 0.21 mmol) was added. The reaction mixture was stirred at 0°C for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 4 (14 mg, 38% yield) as a white solid. ESI-MS (m / z): 538.6 [M+H] + .

[0292] 1 H NMR (500MHz, DMSO-d6) δ9.69(s,1H),8.56(s,1H),8.02(s,1H),7.59(d,J=8.6Hz,2H),7.46(d,J=11.5Hz,1H),6.88(d,J=9.0H z,2H),5.85(s,1H),5.80–5.74(m,1H),3.09–3.04(m,4H),2.49–2.46(m,4H),2.23(s,3H),1.67(s,6H),1.62(d,J=7.0Hz,6H).

[0293] Example 5

[0294] 1-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-2-one

[0295] Example 5 was prepared by the following steps:

[0296] Step 1: Dissolve compound INT-3 (250 mg, 311.56 umol, purity 53%), INT-5 (136.16 mg, 467.34 umol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (28.24 mg, 31.16 umol), cesium carbonate (304.53 mg, 934.67 umol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (33.45 mg, 62.31 umol) in 1,4-dioxane (5 mL) and stir at 110 ° C overnight under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound 5a (80 mg, yield 37%). ESI-MS (m / z): 680.7 [M+H] + .

[0297] Step 2: Compound 5a (80 mg, 117.62 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (19.74 mg, 470.47 μmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain compound 5b (70 mg, yield 93%). ESI-MS (m / z): 638.2 [M+H] + .

[0298] Step 3: Dissolve compound 5b (70 mg, 109.7 μmol) in dichloromethane (1 mL), add hydrochloric acid (109.7 μL, 4 M, 1,4-dioxane solution), and stir at room temperature for 16 hours. After the reaction is complete, the reaction solution is directly concentrated to obtain crude product 5 (60 mg, 95% yield). 30 mg of the product is extracted and purified by preparative liquid chromatography to obtain compound 5 (12.79 mg). ESI-MS (m / z): 538.2 [M+H] + .

[0299] 1 H NMR(500MHz,DMSO-d6)δ10.03(s,1H),8.65(s,1H),8.05(s,1H),7.80–7.74(m,2H),7.48(d,J=11.5Hz,1H),7.26–7.19(m,2H), 5.86(s,1H),5.82–5.74(m,1H),3.56(t,J=5.4Hz,2H),3.36(s,2H),3.00(t,J=5.4Hz,2H),1.67(s,6H),1.63(d,J=6.9Hz,6H).

[0300] Example 6

[0301] 4-(4-((5-fluoro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0302] Example 6 was prepared by the following steps:

[0303] Step 1: Compounds INT-6 (40 mg, 0.098 mmol) and INT-4a (24.45 mg, 0.13 mmol) were dissolved in 1,4-dioxane (3 mL). Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (8.87 mg, 0.01 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (10.50 mg, 0.02 mmol), and cesium carbonate (47.82 mg, 0.15 mmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 6a (40 mg, yield 72%). ESI-MS (m / z): 565.2 [M+H] +

[0304] Step 2: Compound 6a (40 mg, 0.072 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide (8.92 mg, 0.43 mmol) was added. The reaction system was stirred at 0°C for 16 hours. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and the reaction mixture was concentrated under reduced pressure to obtain compound 6 (7.5 mg, yield 20%). ESI-MS (m / z): 523.4 [M+H] + .

[0305] 1 H NMR(500MHz, DMSO-d6)δ9.90(s,1H),8.67(d,J=3.8Hz,1H),8.29(d,J=1.3Hz,1H),7.86–7.78(m,2H),7.68(d,J=11.9Hz,1H),7.36–7.27(m, 2H),5.88(s,1H),5.84–5.76(m,1H),4.20(s,2H),3.98(t,J=6.0,4.2Hz,2H),3.72(t,J=5.9,4.2Hz,2H),1.67(s,6H),1.65(d,J=7.0Hz,6H).

[0306] Example 7

[0307] 4-(4-((5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0308] Example 7 was prepared by the following steps:

[0309] Step 1: Dissolve compound INT-7 (50 mg, 164 umol), INT-4a (41 mg, 213 umol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (15 mg, 16 umol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (17 mg, 33 umol) and cesium carbonate (107 mg, 328 umol) in 1,4-dioxane (3 mL) and stir at 100 ° C overnight under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated and purified by preparative chromatography to obtain the target compound 7 (24 mg, yield 32%). ESI-MS (m / z): 461.3 [M+H] + .

[0310] 1 H NMR(500MHz, DMSO-d6)δ9.82(s,1H),8.67–8.63(m,1H),8.59(d,J=3.9Hz,1H),7.94–7.89(m,1H),7.85–7.81(m,2H),7.69–7.64(m ,1H),7.33–7.28(m,2H),4.19(s,2H),4.15(s,3H),4.00–3.95(m,2H),3.73–3.69(m,2H),3.64–3.57(m,1H),1.51(d,J=7.0Hz,6H).

[0311] Example 8

[0312] 1-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-4-(oxetan-3-yl)piperazin-2-one

[0313] Example 8 was prepared by the following steps:

[0314] Step 1: Compound 5 (30 mg, 55.76 μmol) and compound 8a (12.05 mg, 167.28 μmol) were dissolved in dichloromethane (2 mL). Acetic acid (0.1 mL) was added and stirred at room temperature for half an hour. Sodium triacetoxyborohydride (17.73 mg, 83.64 μmol) was then added and stirred at room temperature for 16 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution (2 mL) was added to quench the reaction. The reaction solution was extracted with dichloromethane (10 mL x 3). The organic phase was concentrated and purified by preparative liquid chromatography to obtain the target compound 8 (14.84 mg, 44% yield). ESI-MS (m / z): 594.1 [M+H] + .

[0315] 1 H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.66(s,1H),8.05(s,1H),7.79(d,J=8.8Hz ,2H),7.47(d,J=11.5Hz,1H),7.24(d,J=8.9Hz,2H),5.87(s,1H),5.81–5.73(m,1 H),4.59(t,J=6.6Hz,2H),4.50(t,J=6.1Hz,2H),3.64(t,J=5.3Hz,2H),3.62–3.5 5(m,1H),3.10(s,2H),2.70(t,J=5.3Hz,2H),1.67(s,6H),1.63(d,J=7.0Hz,6H).

[0316] Example 9

[0317] 4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)-2-((4-(3-oxomorpholino)phenyl)amino)pyrimidine-5-carbonitrile

[0318] Example 9 was prepared by the following steps:

[0319] Step 1: Sodium hydroxide (15.67 mg, 0.39 mmol, 60%) was placed in a two-necked round-bottom flask. Anhydrous N,N-dimethylformamide (1 mL) was added under a nitrogen atmosphere and cooled to 0°C. INT-4 (37.38 mg, 0.17 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) and slowly added dropwise to the two-necked round-bottom flask. Half an hour later, INT-8 (60.0 mg, 0.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) and slowly added dropwise to the two-necked round-bottom flask. The system was slowly warmed to room temperature and stirred for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure to afford 9a (75 mg, 95% yield). ESI-MS (m / z): 572.2 [M+H]. + .

[0320] Step 2: Compound 9a (75 mg, 0.13 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide (16.55 mg, 0.39 mmol) was added. The reaction system was stirred at 0°C for 2 hours. After the reaction was complete, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 9 as a white solid (14 mg, yield 38%). ESI-MS (m / z): 530.2 [M+H] + .

[0321] 1 H NMR (500MHz, DMSO-d6) δ10.62(s,1H),8.98(s,1H),8.26(s,1H),7.80(s,2H),7.61(d,J=11.5Hz,1H),7.41–7.32(m,2H),5.92(s ,1H),5.79(p,J=7.0Hz,1H),4.20(s,2H),3.98(t,J=6.0,4.1Hz,2H),3.72(t,J=5.0Hz,2H),1.68(s,6H),1.65(d,J=7.0Hz,6H).

[0322] Example 10

[0323] 4-(6-((4-(2-(2-aminopropan-2-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)pyridin-3-yl)morpholin-3-one

[0324] Example 10 was prepared by the following steps:

[0325] Step 1: Sodium hydride (11 mg, 271 μmol, 60%) was placed in a two-necked round-bottom flask. Anhydrous N,N-dimethylformamide (1 mL) was added under a nitrogen atmosphere and cooled to 0°C. INT-9 (60 mg, 271 μmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) and slowly added dropwise to the two-necked round-bottom flask. The reaction was stirred at 0°C for 30 minutes. INT-2 (110 mg, 208 μmol) was then dissolved in anhydrous N,N-dimethylformamide (1 mL) and slowly added dropwise to the two-necked round-bottom flask. The system was slowly warmed to room temperature and stirred for 16 hours. Upon completion of the reaction, saturated aqueous ammonium chloride (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound 10a (30 mg, 23% yield). ESI-MS (m / z): 639.1 [M+H] + .

[0326] Step 2: Dissolve 10a (30 mg, 47 μmol) in dichloromethane (1 mL) and add a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) dropwise. Stir and react at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to afford the formate salt 10 (3 mg, 12% yield) as a white solid. ESI-MS (m / z): 539.3 [M+H] + .

[0327] 1 H NMR (500MHz, DMSO-d6) δ10.38(s,1H),8.72(s,1H),8.36(d,J=2.6Hz,1H),8.31(s,1H),8.26(d,J=8.9Hz,1H),8.07(d,J=1.3Hz,1H ),7.80–7.76(m,1H),7.51–7.48(m,1H),6.20–6.15(m,1H),4.22(s,2H),4.00–3.97(m,2H),3.78–3.74(m,2H),1.63–1.54(m,12H).

[0328] Example 11

[0329] 3-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-3,9-diazaspiro[5.5]undecan-2-one

[0330] Example 11 was prepared by the following steps:

[0331] Step 1: Compound INT-3 (120 mg, 149.55 μmol), INT-10 (69.88 mg, 194.41 μmol), tris(dibenzylidene indeneacetone)dipalladium (13.69 mg, 14.95 μmol), cesium carbonate (146.18 mg, 448.64 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17.31 mg, 29.91 μmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 110° C. for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain compound 11a (60 mg, yield 53%). ESI-MS (m / z): 748.1 [M+H] + .

[0332] Step 2: Compound 11a (60 mg, 80.18 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (13.46 mg, 320.73 μmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain compound 11b (50 mg, yield 88%). ESI-MS (m / z): 706.4 [M+H] + .

[0333] Step 3: Dissolve compound 11b (50 mg, 70.8 μmol) in dichloromethane (1 mL), add hydrochloric acid (70.8 μL, 4 M, 1,4-dioxane solution), and stir at room temperature for 16 hours. After the reaction is complete, the reaction solution is directly concentrated and purified by preparative liquid chromatography to obtain the target compound 11 (7.81 mg, 18% yield). ESI-MS (m / z): 606.3 [M+H] + .

[0334] 1 H NMR(500MHz,DMSO-d6)δ10.00(s,1H),8.65(s,1H),8.05(d,J=1.3Hz,1H),7.75(d ,J=8.7Hz,2H),7.47(d,J=11.5Hz,1H),7.16(d,J=8.5Hz,2H),5.85(s,1H),5.81–5 .73(m,1H),3.56(t,J=6.3Hz,2H),2.73–2.65(m,3H),2.48–2.44(m,1H),2.26(s, 2H),1.79(t,J=6.4Hz,2H),1.67(s,6H),1.62(d,J=7.0Hz,6H),1.44–1.36(m,4H).

[0335] Example 12

[0336] 4-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepan-5-one

[0337] Example 12 was prepared by the following steps:

[0338] Step 1: Compound INT-3 (150 mg, 0.32 mmol) and compound INT-11 (118.48 mg, 0.38 mmol) were dissolved in 1,4-dioxane (2 mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (31.97 mg, 0.03 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (18.93 mg, 0.03 mmol) and cesium carbonate (229 mg, 0.71 mmol) were added in sequence. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 12a (110 mg, yield 49%). ESI-MS (m / z): 694.9 [M+H] + .

[0339] Step 2: Compound 12a (110 mg, 0.16 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide (19.95 mg, 0.47 mmol) was added. The reaction system was stirred at 0°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and the reaction mixture was concentrated under reduced pressure to obtain compound 12b (100 mg, yield 98%). ESI-MS (m / z): 652.1 [M+H] + .

[0340] Step 3: Dissolve 12b (100 mg, 0.15 mmol) in dichloromethane (1 mL) and add dropwise a 4M 1,4-dioxane hydrochloride solution (153.32 μL, 0.61 mmol). Stir and react at room temperature for 4 hours. After the reaction is complete, the reaction solution is directly concentrated under reduced pressure. The crude product is purified by preparative liquid chromatography to obtain compound 12 as a white solid (30 mg, 35% yield). ESI-MS (m / z): 552.3 [M+H] + .

[0341] 1 H NMR (500MHz, DMSO-d6) δ10.00(s,1H),8.64(s,1H),8.05(d,J=1.3Hz,1H),7.77–7.71(m,2H),7.47(d,J=11.5Hz,1H),7.16–7.09(m,2 H),5.85(s,1H),5.77(q,J=7.0Hz,1H),3.78–3.73(m,2H),3.03–2.95(m,4H),2.72–2.67(m,2H),1.67(s,6H),1.63(d,J=7.0Hz,6H).

[0342] Example 13

[0343] 3-amino-1-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)pyrrolidin-2-one

[0344] Example 13 was prepared by the following steps:

[0345] Step 1: Compound INT-3 (137 mg, 0.32 mmol) and compound INT-12 (98.55 mg, 0.38 mmol) were dissolved in 1,4-dioxane (2 mL). Tris(dibenzylideneindeneacetone) (29.50 mg, 0.03 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (37.28 mg, 0.06 mmol), and potassium phosphate (205 mg, 0.96 mmol) were added sequentially. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 13a (200 mg, 90% yield). ESI-MS (m / z): 680.1 [M+H] + .

[0346] Step 2: Compound 13a (200 mg, 0.29 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide (21.13 mg, 0.88 mmol) was added. The reaction system was stirred at 0°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and the reaction mixture was concentrated under reduced pressure to obtain compound 13b (100 mg, yield 56%). ESI-MS (m / z): 638.4 [M+H] + .

[0347] Step 3: Dissolve 13b (100 mg, 0.15 mmol) in dichloromethane (1 mL) and add dropwise 4M 1,4-dioxane hydrochloride solution (156.32 μL, 0.61 mmol). Stir and react at room temperature for 4 hours. After the reaction is complete, the reaction solution is directly concentrated under reduced pressure. The crude product is purified by preparative liquid chromatography to obtain compound 13 as a white solid (50 mg, 59% yield). ESI-MS (m / z): 538.5 [M+H] + .

[0348] 1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),8.63(s,1H),8.06(s,1H),7.78(d,J=9 .0Hz,2H),7.61(d,J=9.0Hz,2H),7.49(d,J=11.5Hz,1H),5.85(s,1H),5.78( q,J=7.0Hz,1H),3.73–3.64(m,2H),3.52(dd,J=10.2,8.2Hz,1H),2.38–2.32 (m,1H),2.07(s,2H),1.78–1.71(m,1H),1.68(s,6H),1.63(d,J=6.9Hz,6H).

[0349] Example 14

[0350] 2-(6-(5-chloro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol

[0351] Example 14 was prepared by the following steps:

[0352] Step 1: Compound INT-3 (100 mg, 0.24 mmol) and compound 14a (42 mg, 0.24 mmol) were dissolved in 1,4-dioxane (2 mL). Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (21.32 mg, 0.024 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (12.62 mg, 0.024 mmol), and cesium carbonate (230 mg, 0.70 mmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 11 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain compound 14b (83 mg, yield 62%). ESI-MS (m / z): 567.7 [M+H] + .

[0353] Step 2: Compound 14b (83 mg, 0.15 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide (18.43 mg, 0.44 mmol) was added. The reaction system was stirred at 0°C for 4 hours. After the reaction was complete, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 14 as a white solid (13 mg, yield 16%). ESI-MS (m / z): 525.5 [M+H] + .

[0354] 1 H NMR (500MHz, DMSO-d6) δ9.64(s,1H),8.50(s,1H),7.96(s,1H),7.54(d,J=8.6Hz,2H),7.40(d,J=11.6Hz,1H),6.85–6.78 (m,2H),5.79(s,1H),5.71(p,J=7.0Hz,1H),3.66(t,J=4.8Hz,4H),2.97–2.93(m,4H),1.60(s,6H),1.56(d,J=7.0Hz,6H).

[0355] Example 15

[0356] 4-acetyl-1-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)piperazin-2-one

[0357] Example 15 was prepared by the following steps:

[0358] Step 1: Dissolve compound 5a (120 mg, 176.43 μmol) in dichloromethane (1 mL). Add hydrochloric acid (176.43 μL, 4 M, 1,4-dioxane solution). Stir at room temperature for 16 hours. After the reaction is complete, the reaction mixture is concentrated to obtain the target compound 15a (100 mg, 91% yield). ESI-MS (m / z): 580.8 [M+H] + .

[0359] Step 2: Compound 15a (45 mg, 77.58 μmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (30.08 mg, 232.74 μmol) and acetic anhydride (10.30 mg, 100.85 μmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain compound 15b (45 mg, yield 93%). ESI-MS (m / z): 622.3 [M+H] + .

[0360] Step 3: Compound 15b (45 mg, 72.34 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (9.11 mg, 217.01 μmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, concentrated, and purified by preparative liquid chromatography to obtain compound 15 (10.99 mg, yield 26%). ESI-MS (m / z): 580.4 [M+H] + .

[0361] 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.66(s,1H),8.06(s,1H),7.79(d,J=8. 9Hz,2H),7.47(d,J=11.4Hz,1H),7.25(dd,J=9.0,2.7Hz,2H),5.86(s,1H),5. 81–5.74(m,1H),4.25(s,1H),4.14(s,1H),3.85–3.80(m,1H),3.79–3.72(m,2 H),3.68–3.63(m,1H),2.10–2.04(m,3H),1.67(s,6H),1.63(d,J=7.0Hz,6H).

[0362] Example 16

[0363] 1-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-4-(methylsulfonyl)piperazin-2-one

[0364] Example 16 was prepared by the following steps:

[0365] Step 1: Dissolve compound 15a (45 mg, 77.58 μmol) in dichloromethane (2 mL). Add N,N-diisopropylethylamine (30.08 mg, 232.74 μmol) and methanesulfonic anhydride (17.57 mg, 100.85 μmol) sequentially. Stir at room temperature for 16 hours. After the reaction is complete, dilute the reaction solution with water (5 mL) and extract with dichloromethane (10 mL x 3). The organic phases are combined, dried, and concentrated to obtain compound 16a (48 mg, 94% yield). ESI-MS (m / z): 658.2 [M+H] + .

[0366] Step 2: Compound 16a (48 mg, 72.93 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (9.18 mg, 218.8 μmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, concentrated, and purified by preparative liquid chromatography to obtain compound 16 (12.69 mg, yield 28%). ESI-MS (m / z): 616.4 [M+H] + .

[0367] 1 H NMR (500MHz, DMSO-d6) δ10.06(s,1H),8.66(s,1H),8.06(s,1H),7.80(d,J=8.8Hz,2H),7.48(d,J=11.6Hz,1H),7.26(d,J=8.9Hz,2H) ,5.85(s,1H),5.82–5.74(m,1H),3.94(s,2H),3.78–3.72(m,2H),3.58–3.53(m,2H),3.05(s,3H),1.67(s,6H),1.63(d,J=6.9Hz,6H).

[0368] Example 17

[0369] 4-(4-((4-(2-(2-aminopropan-2-yl)-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0370] Example 17 was prepared by the following steps:

[0371] Step 1: Dissolve compound INT-13 (104 mg, 209 umol), INT-4a (52 mg, 271 umol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (19 mg, 21 umol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (22 mg, 42 umol) and cesium carbonate (136 mg, 417 umol) in 1,4-dioxane (3 mL) and stir at 100 ° C overnight under nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 17a (78 mg, yield 57%). ESI-MS (m / z): 654.8 [M+H] + .

[0372] Step 2: Dissolve 17a (78 mg, 119 μmol) in dichloromethane (1 mL) and add a 1,4-dioxane hydrochloric acid solution (2 mL, 4 M) dropwise. Stir and react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 17 as a white solid (10 mg, 15% yield). ESI-MS (m / z): 550.6 [M+H] + .

[0373] 1 H NMR (500MHz, DMSO-d6) δ10.06(s,1H),8.67(s,1H),8.26(s,1H),7.80(d,J=8.8Hz,2H),7.50(d,J=11.5Hz,1H),7.29(d,J=8.9Hz,2H),6.56( d,J=11.5Hz,1H),4.18(s,2H),3.99–3.93(m,2H),3.71–3.67(m,2H), 3.00–2.92(m,2H),2.47–2.43(m,2H),2.04–1.84(m,2H),1.60(s,6H).

[0374] Example 18

[0375] 4-amino-1-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)piperidin-2-one

[0376] Example 18 was prepared by the following steps:

[0377] Step 1: Compound INT-3 (50.64 mg, 0.12 mmol) and compound INT-12 (40 mg, 0.13 mmol) were dissolved in 1,4-dioxane (5 mL). Tris(dibenzylideneindeneacetone) (10.9 mg, 0.012 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (6.89 mg, 0.012 mmol), and cesium carbonate (116.4 mg, 0.36 mmol) were added sequentially. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 18a (60 mg, 72% yield). ESI-MS (m / z): 694.4 [M+H] + .

[0378] Step 2: Compound 18a (60 mg, 0.086 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide (10.88 mg, 0.26 mmol) was added. The reaction system was stirred at 0°C for 8 hours. After the reaction was complete, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and the reaction mixture was concentrated under reduced pressure to obtain compound 18b (56 mg, yield 94%). ESI-MS (m / z): 652.9 [M+H] + .

[0379] Step 3: Dissolve 18b (40 mg, 0.06 mmol) in dichloromethane (2 mL) and add 4M 1,4-dioxane hydrochloride solution (0.5 mL) dropwise. Stir and react at room temperature for 4 hours. After the reaction is complete, the reaction solution is directly concentrated under reduced pressure. The crude product is purified by preparative liquid chromatography to obtain compound 18 as a white solid (15 mg, 44% yield). ESI-MS (m / z): 553.0 [M+H] + .

[0380] 1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.64(s,1H),8.05(s,1H),7.77–7.72(m,2H),7 .47(d,J=11.5Hz,1H),7.17–7.14(m,2H),5.85(s,1H),5.80–5.75(m,1H),3.65–3.6 0(m,1H),3.56–3.51(m,1H),3.25–3.19(m,2H),2.55–2.53(m,1H),2.15(d,J=8.1Hz ,1H),2.12(d,J=8.1Hz,1H),2.00–1.92(m,2H),1.67(s,6H),1.63(d,J=7.0Hz,6H).

[0381] Example 19

[0382] 4-(4-((4-(2-(2-aminopropan-2-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)-3-fluorophenyl)morpholin-3-one

[0383] Example 19 was prepared by the following steps:

[0384] Step 1: Dissolve compound INT-2e (100 mg, 207 umol), INT-15 (48 mg, 228 umol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (19 mg, 21 umol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (22 mg, 42 umol) and cesium carbonate (136 mg, 417 umol) in 1,4-dioxane (3 mL) and stir at 100 ° C overnight under nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give compound 19a (20 mg, yield 15%). ESI-MS (m / z): 656.8 [M+H] + .

[0385] Step 2: Dissolve 19a (20 mg, 31 μmol) in dichloromethane (1 mL) and add a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) dropwise. Stir and react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to afford compound 19 as a white solid (8 mg, 46% yield). ESI-MS (m / z): 556.4 [M+H] + .

[0386] 1 H NMR(500MHz,DMSO-d6)δ9.60(s,1H),8.59(s,1H),7.98(d,J=1.3Hz,1H),7.70(t,J=8.8Hz,1H),7.46–7.39(m,2H),7.25–7 .19(m,1H),6.22–6.13(m,1H),4.21(s,2H),4.00–3.95(m,2H),3.77–3.72(m,2H),2.30–2.19(m,2H),1.64–1.55(m,12H).

[0387] Example 20

[0388] 4-(4-((5-chloro-4-(4-fluoro-2-(hydroxymethyl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0389] Example 20 was prepared by the following steps:

[0390] Step 1: Compounds INT-16 (660 mg, 1.66 mmol) and INT-4a (319.36 mg, 1.66 mmol) were dissolved in 1,4-dioxane (10 mL). Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (75.31 mg, 0.083 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (89.18 mg, 0.166 mmol), and cesium carbonate (1.62 g, 4.98 mmol) were added sequentially. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 20a (800 mg, yield 87%). ESI-MS (m / z): 553.2 [M+H] + .

[0391] Step 2: Compound 20a (800 mg, 1.45 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), and lithium hydroxide monohydrate (242.81 mg, 5.79 mmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, concentrated, and then purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 20 (540 mg, yield 73%). ESI-MS (m / z): 511.4 [M+H] + .

[0392] 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.66(s,1H),8.07(d,J=1.3Hz,1H),7.88–7.75(m,2H),7.49(d,J=11.6Hz,1H),7.35–7.22 (m,2H),5.77(s,1H),5.12–4.94(m,1H),4.78(s,2H),4.18(s,2H),4.01–3.93(m,2H),3.72–3.62(m,2H),1.63(d,J=6.9Hz,6H).

[0393] Example 21

[0394] 4-(4-((5-chloro-4-(4-fluoro-1-isopropyl-2-(morpholinomethyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0395] Example 21 was prepared by the following steps:

[0396] Step 1: Dissolve 20 (50 mg, 97.86 μmol) and N,N-diisopropylethylamine (37.94 mg, 293.57 μmol) in dichloromethane (10 mL). Add methanesulfonic anhydride (25.57 mg, 146.79 μmol) at 0°C and continue stirring at room temperature for 16 hours. After the reaction is complete, dilute with saturated aqueous ammonium chloride (5 mL) and extract with dichloromethane (10 mL x 3). The organic phases are combined, dried, and concentrated under reduced pressure to yield compound 21a (50 mg, 86% yield). ESI-MS (m / z): 589.3 [M+H] + .

[0397] Step 2: Dissolve 21a (50 mg, 84.88 μmol) and 21b (22.19 mg, 254.65 μmol) in dichloromethane (2 mL) and continue stirring at room temperature for 4 hours. After the reaction is complete, add saturated aqueous ammonium chloride (5 mL) to dilute the mixture, extract with dichloromethane (10 mL x 3), combine the organic phases, dry, concentrate, and purify by preparative liquid chromatography to obtain compound 21 (6.65 mg, 13% yield). ESI-MS (m / z): 580.7 [M+H] + .

[0398] 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.66(s,1H),8.07(s,1H),7.80(d,J=8.9Hz,2H),7.49(d,J=11.6Hz,1H),7.29(d,J=8.8Hz,2H),5.1 8–5.06(m,1H),4.18(s,2H),4.00–3.92(m,2H),3.86(s,2H),3.69(t,2H),3.57(t,J=4.4Hz,4H),2.45–2.40(m,4H),1.63(d,J=6.8Hz,6H).

[0399] Example 22

[0400] (S)-4-(4-((5-chloro-4-(4-fluoro-1-isopropyl-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0401] Example 22 was prepared by the following steps:

[0402] Step 1: Dissolve compound INT-17 (100 mg, 202 umol), INT-4a (43 mg, 223 umol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (19 mg, 21 umol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (22 mg, 41 umol) and cesium carbonate (132 mg, 405 umol) in 1,4-dioxane (3 mL) and stir at 100 ° C overnight under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 22a (82 mg, yield 63%). ESI-MS (m / z): 650.5 [M+H] + .

[0403] Step 2: Dissolve 22a (82 mg, 126 μmol) in dichloromethane (1 mL) and add a 1,4-dioxane hydrochloric acid solution (2 mL, 4 M) dropwise. Stir and react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 22 as a white solid (16 mg, 23% yield). ESI-MS (m / z): 550.7 [M+H] + .

[0404] 1H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.65(s,1H),8.04(s,1H),7.79(d,J=8.5Hz, 2H),7.48(d,J=11.7Hz,1H),7.29(d,J=8.6Hz,2H),5.16–5.08(m,1H),4.47(t,J=7 .2Hz,1H),4.18(s,2H),3.96(t,J=5.0Hz,2H),3.69(t,J=5.0Hz,2H),3.00–2.94(m ,1H),2.89–2.81(m,1H),2.26–2.10(m,2H),1.91–1.74(m,2H),1.65–1.56(m,6H).

[0405] Example 23

[0406] 1-acetyl-4-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepan-5-one

[0407] Example 23 was prepared by the following steps:

[0408] Step 1: Dissolve compound 12a (35 mg, 0.052 mmol) in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL), and add lithium hydroxide (3.62 mg, 0.15 mmol). The reaction system was stirred at 0°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried. The reaction solution was concentrated under reduced pressure to obtain compound 23a (30 mg, yield 94%). ESI-MS (m / z): 652.5 [M+H] + .

[0409] Step 2: Dissolve 23a (30 mg, 0.05 mmol) in dichloromethane (1 mL) and add dropwise 4M 1,4-dioxane hydrochloride solution (148.32 μL, 0.61 mmol). Stir and react at room temperature for 4 hours. After completion, quench the reaction with water (5 mL). Extract with dichloromethane (10 mL x 3). The organic phases are combined and dried. The reaction mixture is concentrated under reduced pressure to obtain compound 23b (25 mg, 97% yield). ESI-MS (m / z): 552.7 [M+H] + .

[0410] Step 3: Compound 23b (25 mg, 0.045 mmol) was dissolved in dichloromethane (2 mL), and N,N-isopropylethylenediamine (17.56 mg, 0.13 mmol) and acetic anhydride (6.93 mg, 0.067 mmol) were added. The reaction system was stirred at 0°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain compound 23 as a white solid (14 mg, yield 52%). ESI-MS (m / z): 594.7 [M+H] + .

[0411] 1 H NMR(500MHz,DMSO-d6)δ10.01(d,J=5.5Hz,1H),8.65(d,J=2.1Hz,1H),8.05(s,1H),7. 76(dd,J=8.6,6.3Hz,2H),7.48(d,J=11.5Hz,1H),7.12(t,J=9.2Hz,2H),5.86(s,1H), 5.78(p,J=6.9Hz,1H),3.85–3.80(m,1H),3.74(s,2H),3.73–3.65(m,3H),2.83–2.79( m,1H),2.70–2.65(m,1H),2.07(d,J=18.9Hz,3H),1.68(s,6H),1.63(d,J=6.9Hz,6H).

[0412] Example 24

[0413] 4-(4-((5-chloro-4-(2-((dimethylamino)methyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0414] Example 24 was prepared by the following steps:

[0415] Step 1: Dissolve 21a (75 mg, 127.33 μmol) and 24a (21.81 mg, 381.98 μmol) in dichloromethane (2 mL) and continue stirring at room temperature for 4 hours. After the reaction is complete, add saturated aqueous ammonium chloride (5 mL) to dilute the mixture, extract with dichloromethane (10 mL x 3), combine the organic phases, dry, concentrate, and purify by preparative liquid chromatography to obtain compound 24 (13.18 mg, 18% yield). ESI-MS (m / z): 550.8 [M+H] + .

[0416] 1 H NMR(500MHz,DMSO-d6)δ10.04(s,1H),8.65(s,1H),8.05(d,J=1.3Hz,1H),7.80(d,J =9.0Hz,2H),7.49(d,J=11.6Hz,1H),7.29(d,J=8.9Hz,2H),5.11–4.92(m,1H),4.19 (s,2H),4.08(d,J=6.1Hz,2H),4.01–3.91(m,2H),3.75–3.66(m,2H),3.01–2.90(m, 1H),2.24–2.13(m,1H),1.60(d,J=6.9Hz,6H),0.40–0.34(m,2H),0.27–0.18(m,2H).

[0417] Example 25

[0418] 4-(4-((5-chloro-4-(2-((cyclopropylamino)methyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0419] Example 25 was prepared by the following steps:

[0420] Step 1: Dissolve 21a (75 mg, 127.33 μmol) and dimethylamine (26.49 μL, 2 M, tetrahydrofuran) in dichloromethane (2 mL) and continue stirring at room temperature for 4 hours. After the reaction is complete, dilute with saturated aqueous ammonium chloride (5 mL) and extract with dichloromethane (10 mL x 3). The organic phases are combined, dried, concentrated, and purified by preparative liquid chromatography to afford compound 25 (15.43 mg, 22% yield). ESI-MS (m / z): 538.7 [M+H] + .

[0421] 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.66(s,1H),8.07(s,1H),7.80(d,J=8.7Hz,2H),7.49(d,J=11.5Hz,1H),7.29(d,J=8.7Hz ,2H),5.18–5.05(m,1H),4.18(s,2H),3.98–3.94(m,2H),3.75(s,2H),3.69(t,J=5.1Hz,2H),2.22(s,6H),1.61(d,J=6.9Hz,6H).

[0422] Example 26

[0423] 4-(4-((5-chloro-4-(4-fluoro-2-(1-hydroxycyclopentyl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0424] Example 26 was prepared by the following steps:

[0425] Step 1: Dissolve compound INT-18 (45 mg, 110 umol), INT-4a (23 mg, 121 umol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (10 mg, 11 umol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (12 mg, 22 umol) and cesium carbonate (72 mg, 220 umol) in 1,4-dioxane (3 mL) and stir at 100 ° C overnight under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated, and the residue was purified by preparative liquid chromatography to obtain white solid compound 26 (6 mg, yield 10%). ESI-MS (m / z): 565.0 [M+H] + .

[0426] 1H NMR(500MHz,DMSO-d6)δ10.04(s,1H),8.65(s,1H),8.05(d,J=1.3Hz,1H),7.83 –7.77(m,2H),7.47(d,J=11.5Hz,1H),7.33–7.26(m,2H),5.75(s,1H),5.60–5.5 2(m,1H),4.18(s,2H),3.99–3.94(m,2H),3.72–3.67(m,2H),2.41–2.34(m,2H), 2.12–2.05(m,2H),1.89–1.82(m,2H),1.75–1.69(m,2H),1.62(d,J=6.9Hz,6H).

[0427] Example 27

[0428] 2-((4-(4-acetyl-2-oxopiperazin-1-yl)phenyl)amino)-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidine-5-carbonitrile

[0429] Example 27 was prepared by the following steps:

[0430] Step 1: Compounds INT-8 (50 mg, 108.82 μmol) and INT-19 (33 mg, 141.46 μmol) were dissolved in 2,2,2-trifluoroethanol (2 mL) and one drop of trifluoroacetic acid was added. The reaction mixture was reacted at 100°C under microwave irradiation for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and the filtrate was concentrated to obtain compound 27a (50 mg, 75% yield). ESI-MS (m / z): 613.8 [M+H] + .

[0431] Step 2: Compound 27a (50 mg, 81.61 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.2 mL), and lithium hydroxide monohydrate (13.70 mg, 326.45 μmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, concentrated, and purified by preparative liquid chromatography to obtain compound formate 27 (0.81 mg, yield 1.7%). ESI-MS (m / z): 571.3 [M+H] + .

[0432] 1 H NMR(500MHz,DMSO-d6)δ10.62(s,1H),8.99(s,1H),8.45(s,1H),8.27(s,1H),7.8 1(d,J=6.1Hz,2H),7.61(d,J=11.5Hz,1H),7.34(dd,J=9.0,2.9Hz,2H),5.89(s,1H ),5.83–5.74(m,1H),4.27(s,1H),4.15(s,1H),3.88–3.81(m,1H),3.81–3.76(m,2 H),3.72–3.64(m,1H),2.07(d,J=13.9Hz,3H),1.68(s,6H),1.65(d,J=7.0Hz,6H).

[0433] Example 28

[0434] 4-(4-((5-chloro-4-(4-fluoro-1-isopropyl-2-(1-(methylamino)cyclopropyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0435] Example 28 was prepared by the following steps:

[0436] Step 1: Compounds INT-20 (50 mg, 101.14 μmol) and INT-4a (25.27 mg, 131.48 μmol) were dissolved in 1,4-dioxane (5 mL). Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (4.58 mg, 5.06 μmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (5.43 mg, 10.11 μmol), and cesium carbonate (98.86 mg, 303.41 μmol) were added sequentially. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 28a (20 mg, yield 30%). ESI-MS (m / z): 650.7 [M+H] + .

[0437] Step 2: Dissolve compound 28a (20 mg, 30.76 μmol) in dichloromethane (1 mL), add hydrochloric acid (30.76 μL, 4 M, 1,4-dioxane solution), and stir at room temperature for 16 hours. After the reaction is complete, the reaction solution is directly concentrated and purified by preparative liquid chromatography to obtain the target compound 28 (7.81 mg, 39% yield). ESI-MS (m / z): 550.3 [M+H] + .

[0438] 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.65(s,1H),8.03(d,J=1.3Hz,1H),7.80(d,J=8.9Hz,2H),7.46(d,J=11.5Hz,1H),7.29(d,J=9.0Hz,2H), 5.54–5.39(m,1H),4.18(s,2H),3.99–3.93(m,2H),3.73–3.67(m,2H),2 .19(s,3H),1.62(d,J=7.0Hz,6H),1.18–1.14(m,2H),1.05–0.99(m,2H).

[0439] Example 29

[0440] 4-(4-((4-(2-(1-aminocyclopropyl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0441] Example 29 was prepared by the following steps:

[0442] Step 1: Dissolve compound INT-20b (400 mg, 0.97 mmol), INT-2c (349.13 mg, 1.46 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (82.12 mg, 0.097 mmol), and potassium acetate (285.64 mg, 2.91 mmol) in 1,4-dioxane (5 mL) and stir at 90°C overnight under a nitrogen atmosphere. After the reaction is complete, the reaction solution is filtered through celite, and the filtrate is concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 29a (400 mg, yield 89%). ESI-MS (m / z): 460.6 [M+H] + .

[0443] Step 2: Compound 29a (400 mg, 0.87 mmol), INT-1j (239.58 mg, 1.31 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (63.71 mg, 0.087 mmol), and sodium carbonate (276.88 mg, 2.61 mmol) were dissolved in 1,4-dioxane (5 mL) / water (0.5 mL). The mixture was stirred at 90°C overnight under a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 29b (380 mg, yield 90%). ESI-MS (m / z): 480.6 [M+H] + .

[0444] Step 3: Compound 29b (80 mg, 166.54 μmol) and INT-4a (41.61 mg, 216.5 μmol) were dissolved in 1,4-dioxane (5 mL). Methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (7.55 mg, 8.33 μmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (8.94 mg, 16.65 μmol), and cesium carbonate (162.79 mg, 499.62 μmol) were added sequentially. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 29c (60 mg, yield 56%). ESI-MS (m / z): 636.7 [M+H] + .

[0445] Step 4: Dissolve compound 29c (60 mg, 94.32 μmol) in dichloromethane (1 mL), add hydrochloric acid (94.32 μL, 4 M, 1,4-dioxane solution), and stir at room temperature for 16 hours. After the reaction is complete, the reaction solution is directly concentrated and purified by preparative liquid chromatography to obtain the target compound 29 (13.19 mg, 26% yield). ESI-MS (m / z): 536.2 [M+H] + .

[0446] 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.65(s,1H),8.02(d,J=1.3Hz,1H),7.80(d,J=8.9Hz,2H),7.46(d,J=11.5Hz,1H),7.29(d,J=8.9Hz ,2H),5.51–5.34(m,1H),4.18(s,2H),4.01–3.92(m,2H),3.74–3.66(m,2H),1.64(d,J=7.0Hz,6H),1.23–1.15(m,2H),1.06–0.98(m,2H).

[0447] Example 30

[0448] 4-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-1-cyclopropyl-1,4-diazepan-5-one

[0449] Example 30 was prepared by the following steps:

[0450] Step 1: Dissolve 12a (40 mg, 0.057 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL) dropwise, and stir at room temperature for 4 hours. After the reaction is complete, quench with saturated sodium bicarbonate (5 mL) and extract with ethyl acetate (10 mL x 3). The organic phases are combined, dried, and the reaction mixture is concentrated under reduced pressure to obtain compound 30a (30 mg, yield 85%). ESI-MS (m / z): 594.6 [M+H] + .

[0451] Step 2: 30a (30 mg, 0.057 mmol) was dissolved in methanol (2 mL), and 1-ethoxy-1-trimethylsilyloxycyclopropane (58.68 mg, 0.34 mmol) and sodium acetate borohydride (12.69 mg, 0.2 mmol) were added. The reaction system was stirred at 60°C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched with saturated sodium bicarbonate (5 mL). The mixture was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and the reaction mixture was concentrated under reduced pressure to obtain compound 30b (32 mg, 74% yield). ESI-MS (m / z): 634.8 [M+H] + .

[0452] Step 3: Compound 30b (32 mg, 0.05 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide (4.5 mg, 0.19 mmol) was added. The reaction system was stirred at 0°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain compound 30 (2 mg, 6% yield) as a white solid. ESI-MS (m / z): 592.5 [M+H] + .

[0453] 1 H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.64(s,1H),8.05(s,1H),7.74(d,J=8.4Hz,2H ),7.47(d,J=11.5Hz,1H),7.11(d,J=8.2Hz,2H),5.85(s,1H),5.80–5.74(m,1H),3. 72(d,J=5.4Hz,2H),2.82(dd,J=20.9,7.3Hz,4H),2.65(d,J=9.0Hz,2H),1.82(s,1H ),1.67(s,6H),1.63(d,J=7.1Hz,6H),0.48(d,J=5.9Hz,2H),0.35(d,J=3.7Hz,2H).

[0454] Example 31

[0455] 2-(6-(5-chloro-2-((4-(morpholinosulfonyl)phenyl)amino)pyrimidin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol

[0456] Example 31 was prepared by the following steps:

[0457] Step 1: Sodium hydroxide (17.06 mg, 0.43 mmol, 60%) was placed in a two-necked round-bottom flask. Anhydrous N,N-dimethylformamide (2 mL) was added under a nitrogen atmosphere and cooled to 0°C. INT-21 (75 mg, 0.277 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) and slowly added dropwise to the two-necked round-bottom flask. Half an hour later, INT-25 (100 mg, 0.213 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL) and slowly added dropwise to the two-necked round-bottom flask. The system was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was directly subjected to reverse preparative purification to obtain 31 (35.85 mg, 28.5% yield) as a white solid. ESI-MS (m / z): 589.7 [M+H] + .

[0458] 1 H NMR (500MHz, DMSO-d6) δ10.54(s,1H),8.76(s,1H),8.09–8.04(m,3H),7.68–7.62(m,2H),7.50(dd,J=11.4,1. 3Hz,1H),5.82–5.74(m,1H),3.62(t,J=4.7Hz,4H),2.83(t,J=4.7Hz,4H),1.68(s,6H),1.63(d,J=7.0Hz,6H).

[0459] Example 32

[0460] 4-acetyl-1-(4-((4-(2-(2-aminopropan-2-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)phenyl)piperazin-2-one

[0461] Example 32 was prepared by the following steps:

[0462] Step 1: Compounds INT-2e (100 mg, 207.31 μmol) and INT-19 (62.86 mg, 269.5 μmol) were dissolved in 1,4-dioxane (5 mL). Methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (9.4 mg, 10.37 μmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (11.13 mg, 20.73 μmol), and cesium carbonate (202.63 mg, 621.92 μmol) were added sequentially. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 32a (60 mg, yield 42%). ESI-MS (m / z): 679.6 [M+H] + .

[0463] Step 2: Dissolve compound 32a (60 mg, 88.34 μmol) in dichloromethane (1 mL), add hydrochloric acid (88.34 μL, 4 M, 1,4-dioxane solution), and stir at room temperature for 16 hours. After the reaction is complete, the reaction solution is directly concentrated and purified by preparative liquid chromatography to obtain the target compound 32 (7.9 mg, 15% yield). ESI-MS (m / z): 579.6 [M+H] + .

[0464] 1 H NMR (500MHz, DMSO-d6) δ10.04 (s, 1H), 8.65 (s, 1H), 8.03 (d, J = 1.4Hz, 1H), 7. 86–7.76(m,2H),7.46(d,J=11.5Hz,1H),7.25(dd,J=8.9,2.6Hz,2H),6.24–6. 14(m,1H),4.25(s,1H),4.14(s,1H),3.86–3.80(m,1H),3.78–3.72(m,2H),3. 68–3.60(m,1H),2.26(s,2H),2.07(d,J=13.7Hz,3H),1.61(t,J=3.5Hz,12H).

[0465] Example 33

[0466] 4-(4-((5-chloro-4-(5-fluoro-3-hydroxy-1,1,3-trimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0467] Example 33 was prepared by the following steps:

[0468] Step 1: Compounds INT-22 (150 mg, 0.393 mmol) and INT-4a (58.8 mg, 0.305 mmol) were dissolved in 1,4-dioxane (5 mL). Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (10.7 mg, 0.012 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (12.6 mg, 0.024 mmol), and cesium carbonate (230 mg, 0.705 mmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by preparative liquid chromatography to obtain compound 33 as a white solid (15.68 mg, yield 12.4%). ESI-MS (m / z): 537.2 [M+H] + .

[0469] 1 H NMR (500 MHz, DMSO-d6) δ 1 H NMR(500MHz,DMSO-d6)δ10.06(s,1H),8.66(s,1H),8.00(d,J=1.4Hz,1H),7.82–7.75(m,2H),7.51(dd,J=11.9,1.4Hz,1 H),7.32–7.25(m,2H),5.86(s,1H),4.18(s,2H),4.00–3.92(m,2H),3.74–3.65(m,2H),2.62(s,2H),1.73–1.64(m,9H).

[0470] Example 34

[0471] 4-(4-((4-(2-(2-aminopropan-2-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-chloropyrimidin-2-yl)amino)-2-fluorophenyl)morpholin-3-one

[0472] Example 34 was prepared by the following steps:

[0473] Step 1: Compound INT-2e (40 mg, 0.083 mmol) and compound INT-23 (19.17 mg, 0.091 mmol) were dissolved in 1,4-dioxane (2 mL). Tris(dibenzylideneindeneacetone) (7.59 mg, 0.008 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (9.6 mg, 0.016 mmol), and potassium phosphate (52.81 mg, 0.25 mmol) were added sequentially. The reaction mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 34a (40 mg, 73% yield). ESI-MS (m / z): 656.1 [M+H] + .

[0474] Step 2: Dissolve 34a (40 mg, 0.061 mmol) in dichloromethane (2 mL) and add 4M 1,4-dioxane hydrochloride solution (0.5 mL) dropwise. Stir and react at room temperature for 4 hours. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain compound 34 as a white solid (20 mg, 59% yield). ESI-MS (m / z): 556.2 [M+H] + .

[0475] 1H NMR (500MHz, DMSO-d6) δ10.27(s,1H),8.71(s,1H),8.03(d,J=1.3Hz,1H),7.94(dd,J=13.2,2.3Hz,1H),7.52(dd,J=8.8,2.3Hz,1H),7.45(dd,J=11.6, 1.2Hz,1H),7.34(t,J=8.7Hz,1H),6.22–6.13(m,1H),4.21(s,2H),3.97(dd ,J=6.0,4.2Hz,2H),3.63(dd,J=6.0,4.2Hz,2H),1.62(s,9H),1.60(s,3H).

[0476] Example 35

[0477] 4-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-1,4-thiazepan-5-one 1,1-dioxide

[0478] Example 35 was prepared by the following steps:

[0479] Step 1: Compound INT-3 (229.57 mg, 0.54 mmol) and compound INT-24 (100 mg, 0.45 mmol) were dissolved in 1,4-dioxane (2 mL). Tris(dibenzylideneindeneacetone) (41.19 mg, 0.045 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (52.06 mg, 0.09 mmol), and potassium phosphate (286.46 mg, 1.35 mmol) were added sequentially. The reaction mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to obtain compound 35a (200 mg, 72% yield). ESI-MS (m / z): 611.1 [M+H] + .

[0480] Step 2: Compound 35a (150 mg, 0.25 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide (30.9 mg, 0.74 mmol) was added. The reaction system was stirred at 0°C for 1 hour. After the reaction was complete, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain compound 35b (120 mg, 85% yield) as a white solid. ESI-MS (m / z): 569.2 [M+H] + .

[0481] Step 3: Compound 35b (120 mg, 0.21 mmol) was dissolved in dichloromethane (4 mL), cooled to 0°C in an ice-water bath, and m-chloroperbenzoic acid (72.78 mg, 0.42 mmol) was added. The mixture was stirred at 0°C for 16 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction. The mixture was then extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain compound 35 as a white solid (50 mg, yield 39%). ESI-MS (m / z): 601.2 [M+H] + .

[0482] 1 H NMR (500MHz, DMSO-d6) δ10.02(s,1H),8.65(s,1H),8.08–8.04(m,1H),7.79–7.73(m,2H),7.47(d,J=11.5Hz,1H),7.29–7.20(m,2H),5.85(s ,1H),5.81–5.76(m,1H),4.10–4.03(m,2H),3.51–3.45(m,2H),3.43(d ,J=9.0Hz,2H),2.95–2.91(m,2H),1.68(s,6H),1.63(d,J=7.0Hz,6H).

[0483] Example 36

[0484] (S)-1-(6-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one

[0485] Example 36 was prepared by the following steps:

[0486] Step 1: Compound 36a (1 g, 4.67 mmol), 2-amino-5-iodopyridine (1.03 g, 4.67 mmol), potassium phosphate (2.97 g, 14.0 mmol), cuprous iodide (88.89 mg, 0.47 mmol), and N,N-dimethylethylenediamine (82.28 mg, 0.93 mmol) were dissolved in 1,4-dioxane (10 mL). Under a nitrogen atmosphere, the reaction solution was stirred at 120°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to obtain 36b (0.7 g, 48% yield). ESI-MS (m / z): 307.0 [M+H] + .

[0487] Step 2: Compound 36b (108.05 mg, 0.35 mmol) and compound INT-3 (100 mg, 0.24 mmol) were dissolved in 1,4-dioxane (5 mL). Tris(dibenzylideneindeneacetone) (21.53 mg, 0.024 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (21.94 mg, 0.047 mmol), and cesium carbonate (229.84 mg, 0.71 mmol) were added sequentially. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 36c (50 mg, 30% yield). ESI-MS (m / z): 694.8 [M+H] + .

[0488] Step 3: Dissolve 36c (50 mg, 0.072 mmol) in dichloromethane (1 mL), add 4M 1,4-dioxane hydrochloride solution (0.07 mL) dropwise, and stir at room temperature for 16 hours. The reaction solution is directly concentrated under reduced pressure to give compound 36d (35 mg, 77% yield). ESI-MS (m / z): 594.5 [M+H] + .

[0489] Step 4: Compound 36d (35 mg, 0.055 mmol) was dissolved in dichloromethane (1 mL) and methanol (1 mL), and aqueous formaldehyde solution (0.006 mL, 0.22 mmol, 37%) was added to the reaction solution. The reaction mixture was stirred at room temperature for 30 minutes. Sodium acetate borohydride (35.24 mg, 0.17 mmol) was then added to the reaction solution. The reaction mixture was continued to stir at room temperature for 3 hours. After the reaction was complete, the reaction solution was quenched with saturated aqueous ammonium chloride solution (5 mL), extracted with dichloromethane (10 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 36e (30 mg, yield 86%). ESI-MS (m / z): 622.6 [M+H] + .

[0490] Step 5: Compound 36e (30 mg, 0.05 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (8.08 mg, 0.19 mmol) was added. The reaction system was stirred at room temperature for 16 hours. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain compound 36 (2.88 mg, yield 9%) as a white solid. ESI-MS (m / z): 580.6 [M+H] + .

[0491] 1 H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.72(s,1H),8.32(s,1H),8.26–8.18(m,2H),8 .09(d,J=1.3Hz,1H),7.66(dd,J=8.8,2.7Hz,1H),7.51(dd,J=11.6,1.3Hz,1H),5.85( s,1H),5.82–5.73(m,1H),3.66–3.59(m,2H),2.73–2.67(m,1H),2.38–2.34(m,1H),2 .22(s,6H),2.11–2.06(m,1H),1.86–1.73(m,2H),1.67(s,6H),1.63(d,J=6.9Hz,7H).

[0492] Example 37

[0493] (S)-1-(4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-4-(dimethylamino)piperidin-2-one

[0494] Example 37 was prepared by the following steps:

[0495] Step 1: Compound 36a (1 g, 4.67 mmol), p-iodoaniline (1.23 g, 5.6 mmol), potassium carbonate (1.29 g, 9.33 mmol), cuprous iodide (88.89 mg, 0.47 mmol), and N,N-dimethylethylenediamine (82.28 mg, 0.93 mmol) were dissolved in 1,4-dioxane (10 mL). Under a nitrogen atmosphere, the reaction solution was stirred at 120°C for 24 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 37a (1.3 g, yield 91%). ESI-MS (m / z): 306.4 [M+H] + .

[0496] Step 2: Compound 37a (107.71 mg, 0.35 mmol) and compound INT-3 (100 mg, 0.24 mmol) were dissolved in 1,4-dioxane (5 mL). Methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (21.32 mg, 0.024 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (25.24 mg, 0.047 mmol), and cesium carbonate (229.84 mg, 0.71 mmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 37b (50 mg, yield 30%). ESI-MS (m / z): 693.0 [M+H] + .

[0497] Step 3: Dissolve 37b (50 mg, 0.072 mmol) in dichloromethane (1 mL), add 4M 1,4-dioxane hydrochloride solution (0.07 mL) dropwise, and stir at room temperature for 16 hours. The reaction mixture was directly concentrated under reduced pressure to give compound 37c (40 mg, 88% yield). ESI-MS (m / z): 593.3 [M+H] + .

[0498] Step 4: Compound 37c (40 mg, 0.067 mmol) was dissolved in dichloromethane (1 mL) and methanol (1 mL), and aqueous formaldehyde solution (0.007 mL, 0.27 mmol, 37%) was added to the reaction solution. The reaction mixture was stirred at room temperature for 30 minutes. Sodium acetate borohydride (42.81 mg, 0.20 mmol) was then added to the reaction solution. The reaction mixture was continued to stir at room temperature for 3 hours. After the reaction was complete, the reaction solution was quenched with saturated aqueous ammonium chloride solution (5 mL), extracted with dichloromethane (10 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 37d (35 mg, yield 83%). ESI-MS (m / z): 621.9 [M+H] + .

[0499] Step 5: Compound 37d (35 mg, 0.056 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (9.44 mg, 0.23 mmol) was added. The reaction system was stirred at room temperature for 16 hours. After the reaction was complete, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain compound 37 (14.9 mg, yield 45%) as a white solid. ESI-MS (m / z): 579.7 [M+H] + .

[0500] 1 H NMR(500MHz,DMSO-d6)δ10.00(s,1H),8.64(s,1H),8.05(d,J=1.3Hz,1H),7.83–7.7 0(m,2H),7.47(d,J=11.6Hz,1H),7.23–7.09(m,2H),5.95–5.81(m,1H),5.81–5.74(m ,1H),3.62–3.52(m,2H),2.69–2.62(m,1H),2.55–2.52(m,1H),2.40–2.34(m,1H),2. 21(s,6H),2.10–2.02(m,1H),1.81–1.73(m,1H),1.67(s,6H),1.63(d,J=6.9Hz,6H).

[0501] Example 38

[0502] (S)-1-(4-((5-chloro-4-(9-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidin-7-yl)pyrimidin-2-yl)amino)phenyl)-4-(dimethylamino)piperidin-2-one

[0503] Example 38 was prepared by the following steps:

[0504] Step 1: Compound 37a (1.3 g, 4.26 mmol), benzyloxycarbonyl succinimide (1.38 g, 5.53 mmol), and potassium carbonate (1.18 g, 8.51 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction solution was stirred at 50°C for 16 hours. After the reaction was completed, it was cooled to room temperature and diluted with water (30 mL). The reaction solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by slurrying with ethyl acetate / petroleum ether (10 / 1) to obtain 38a (1.6 g, yield 85%). ESI-MS (m / z): 440.5 [M+H] + .

[0505] Step 2: Compound 38a (1.6 g, 3.64 mmol) was dissolved in dichloromethane (10 mL) and a 1,4-dioxane hydrochloride solution (4 mol / L, 3.64 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was directly concentrated to obtain compound 38b (1.2 g, yield 87%). ESI-MS (m / z): 339.8 [M+H] + .

[0506] Step 3: Compound 38b (1.2 g, 3.19 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and aqueous formaldehyde solution (0.35 mL, 12.77 mmol, 37%) was added to the reaction solution. The reaction mixture was stirred at room temperature for 30 minutes. Sodium acetate borohydride (2.03 g, 9.58 mmol) was then added to the reaction solution. The reaction mixture was continued to stir at room temperature for 4 hours. After the reaction was complete, the reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by ethyl acetate / petroleum ether (10 / 1) to give 38c (1 g, yield 85%). ESI-MS (m / z): 368.4 [M+H] + .

[0507] Step 4: Compound 38c (1 g, 2.72 mmol) was dissolved in methanol (10 mL), and palladium on carbon (100 mg, 0.94 mmol) was added. The reaction system was stirred overnight under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain compound 38d (600 mg, yield 94%). ESI-MS (m / z): 234.4 [M+H] + .

[0508] Step 5: Compound 38e (5 g, 21.01 mmol) and cesium carbonate (6.85 g, 21.01 mmol) were dissolved in tetrahydrofuran (50 mL). 3-Chloropropylamine hydrochloride (2.73 g, 21.01 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 16 hours. After the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 38f (5.83 g, yield 89%). ESI-MS (m / z): 310.8 [M+H] + .

[0509] Step 6: Compound 38f (6.3 g, 20.22 mmol) and 4,4'-bipyridine (1.58 g, 10.11 mmol) were dissolved in N,N-dimethylformamide (60 mL). The reaction mixture was stirred at room temperature. Tetrahydroxydiboron (5.44 g, 60.67 mmol) was then added and the reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 38g (5.6 g, 98% yield).

[0510] 1 H NMR (500MHz, DMSO-d6) δ6.63–6.58(m,1H),6.38(t,J=1.7Hz,1H),5.11(t,J=5.4H z,1H),4.64(s,2H),3.77(t,J=6.5Hz,2H),3.19–3.13(m,2H),2.04–2.00(m,2H).

[0511] Step 7: Compound 38g (5.2 g, 18.47 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of N,N'-carbonyldiimidazole (7.49 g, 46.17 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 38h (4.68 g, 82% yield).

[0512] 1 H NMR(500MHz,DMSO-d6)δ11.63(s,1H),7.33(d,J=1.6Hz,1H),7.20(dd,J=9.9,1 .6Hz,1H),3.91(t,J=6.9Hz,2H),3.67(t,J=6.4Hz,2H),2.07(p,J=6.7Hz,2H).

[0513] Step 8: Compound 38h (2 g, 6.5 mmol) was dissolved in phosphorus oxychloride (3 mL), and the reaction mixture was stirred at 100°C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was slowly added dropwise to water (30 mL). The mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 38i (1.28 g, yield 60%). ESI-MS (m / z): 325.6 [M+H] + .

[0514] Step 9: Compound 38i (1 g, 3.07 mmol) was dissolved in ethanol (10 mL), followed by the addition of methylamine hydrochloride (2.07 g, 30.68 mmol) and N,N-diisopropylethylamine (4.76 g, 36.81 mmol). The reaction mixture was stirred at 80°C for 12 hours. After the reaction was complete, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 38j (346 mg, 40% yield). ESI-MS (m / z): 283.7 [M+H] + .

[0515] Step 10: Compound 38j (300 mg, 1.06 mmol) and pinacol diboron (348.56 mg, 1.37 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (77.18 mg, 0.11 mmol) and potassium acetate (311.87 mg, 3.17 mmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 38k (94 mg, 27% yield). ESI-MS (m / z): 331.6 [M+H] + .

[0516] Step 11: Compound 38k (66 mg, 199.28 μmol) and 2,4,5-trichloropyrimidine (33.23 mg, 181.16 μmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.3 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13.24 mg, 18.12 μmol) and sodium carbonate (38.4 mg, 362.33 μmol) were then added sequentially. The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through celite. 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 compound 38l (44 mg, yield 69%). ESI-MS (m / z): 352.3 [M+H] + .

[0517] Step 12: Compound 38l (20 mg, 57 μmol) and compound 38d (20 mg, 85 μmol) were dissolved in 1,4-dioxane (3 mL). Palladium acetate (1 mg, 6 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (7 mg, 11 μmol), and cesium carbonate (56 mg, 170 μmol) were added sequentially. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by preparative chromatography to obtain compound 38 (13 mg, 42% yield). ESI-MS (m / z): 549.2 [M+H] + .

[0518] 1 H NMR(500MHz,DMSO-d6)δ9.93(s,1H),8.58(s,1H),7.74(d,J=8.8Hz,2H),7.55(d,J=1 .4Hz,1H),7.43–7.39(m,1H),7.19–7.16(m,2H),4.05(t,J=6.0Hz,2H),3.60–3.55(m ,2H),3.41(t,J=5.7Hz,2H),3.14(s,3H),2.69–2.64(m,1H),2.55–2.53(m,1H),2.40 –2.34(m,1H),2.21(s,6H),2.20–2.16(m,2H),2.10–2.03(m,1H),1.81–1.73(m,1H).

[0519] CDK2 / Cyclin E1 kinase activity inhibition assay

[0520] The purpose of this study was to evaluate the inhibitory ability of small molecule compounds on CDK2 / Cyclin E1 kinase activity (% inhibition and IC 50 First, the enzyme, ATP, substrate, and compound were diluted to the desired concentration using kinase buffer, which consists of 40mM Tris-HCl, pH 7.5; 20mM MgCl2; 0.01% Triton X-100; and 1mM DTT. The experiment was performed in a 384-well plate. First, 2μL of CDK2 / Cyclin E1 and 1μL of the test compound (generally, the starting concentration of the compound was 10μM, and 3-fold dilutions provided 9 concentration gradients) were added to the 384-well plate. After centrifugation, the plate was incubated at room temperature for 10 minutes. 2μL of a mixture of substrate Histone H1 and ATP was added, and after centrifugation, the plate was incubated at room temperature in the dark for 60 minutes. 5μL of ADP-Glo ​​was added. TMReagent (Promega, V9102) was incubated at room temperature for 120 minutes to terminate the reaction and consume the remaining ATP. Then 10 μL Kinase Detection Reagent (Promega, V9102) was added and incubated at room temperature for 30 minutes to convert ADP into ATP. The ATP was detected using a multifunctional microplate reader ( The fluorescence signal value was read by i3x, Molecular devices, and then the signal value was normalized. The curve was fitted using a four-parameter regression equation to calculate the half maximal inhibitory concentration (IC) of the compound on the kinase activity. 50 ).

[0521] CDK4 / Cyclin D3 kinase activity inhibition assay

[0522] The purpose of this study was to evaluate the inhibitory ability of small molecule compounds on CDK4 / Cyclin D3 kinase activity (% inhibition and IC 50 ). First, the enzyme, ATP, substrate, and compound were diluted to the required concentration using kinase buffer. The kinase buffer composition is 40mM Tris-HCl, pH 7.5; 20mM MgCl2; 0.01% Triton X-100; 1mM DTT. The experiment was performed in a 384-well plate. First, 2μL CDK4 / Cyclin D3 and 1μL of the test compound (generally, the starting concentration of the compound is 10μM, and 3-fold dilutions are 9 concentration gradients) were added to the 384-well plate. After centrifugation, the plate was incubated at room temperature for 5 minutes. 2μL of a mixture of substrate DYRKtide (RRRFRPASPLRGPPK) and ATP was added. After centrifugation, the plate was incubated at room temperature in the dark for 60 minutes. 5μL ADP-Glo ​​was added. TM Reagent (Promega, V9102) was incubated at room temperature for 60 minutes to terminate the reaction and consume the remaining ATP. Then 10 μL Kinase Detection Reagent (Promega, V9102) was added and incubated at room temperature for 30 minutes to convert ADP into ATP. The ATP was detected using a multifunctional microplate reader ( The fluorescence signal value was read by i3x, Molecular devices, and then the signal value was normalized. The curve was fitted using a four-parameter regression equation to calculate the half maximal inhibitory concentration (IC) of the compound on the kinase activity. 50 ).

[0523] CDK6 / Cyclin D3 kinase activity inhibition assay

[0524] The purpose of this study was to evaluate the inhibitory ability of small molecule compounds on CDK6 / Cyclin D3 kinase activity (% inhibition and IC 50 ). First, the enzyme, ATP, substrate, and compound were diluted to the required concentration using kinase buffer. The kinase buffer composition is 40mM Tris-HCl, pH 7.5; 20mM MgCl2; 0.01% Triton X-100; 1mM DTT. The experiment was performed in a 384-well plate. First, 2μL CDK6 / Cyclin D3 and 1μL of the test compound (generally, the starting concentration of the compound is 10μM, and 3-fold dilutions are 9 concentration gradients) were added to the 384-well plate. After centrifugation, the plate was incubated at room temperature for 5 minutes. 2μL of a mixture of substrate DYRKtide (RRRFRPASPLRGPPK) and ATP was added. After centrifugation, the plate was incubated at room temperature in the dark for 60 minutes. 5μL ADP-Glo ​​was added. TM Reagent (Promega, V9102) was incubated at room temperature for 120 minutes to terminate the reaction and consume the remaining ATP. Then 10 μL Kinase Detection Reagent (Promega, V9102) was added and incubated at room temperature for 30 minutes to convert ADP into ATP. The ATP was detected using a multifunctional microplate reader ( The fluorescence signal value was read by i3x, Molecular devices, and then the signal value was normalized. The curve was fitted using a four-parameter regression equation to calculate the half maximal inhibitory concentration (IC) of the compound on the kinase activity. 50 ).

[0525] The inhibitory activities of the compounds of the present invention on CDK2, CDK4 and CDK6 are shown in Table 3.

[0526] Table 3

[0527] Conclusion: The compounds of the present invention have certain activity and selectivity against CDK2, 4 and 6.

[0528] Cell Titer-Glo cell viability assay

[0529] To evaluate the inhibitory activity of the test compounds on tumor cell viability, we used The cells were tested using Luminescent Cell Viability Assay (G7570, Promega).

[0530] 1. Cell Lines

[0531] The tumor cell lines to be tested, their culture conditions, and plating densities are as shown in the table below. All cells were cultured in a humidified cell culture incubator at 37°C, 5% CO2, and the assay was performed when the cells reached 80-90% of their normal density.

[0532] 2. Experimental reagents and equipment

[0533] 3. Experimental Procedure

[0534] 1) CellTiter-Glo TM Reagent preparation: CellTiter-Glo TM Thaw the buffer at room temperature, fully equilibrate, and then add CellTiter-Glo TM Add the substrate and mix by inversion until the substrate is completely dissolved.

[0535] 2) Cell plating: Digest and count cells in the logarithmic growth phase. Dispense the cell suspension into a 96-well plate at a final volume of 180 μL per well. After plating, place the plate in a 37°C, 5% CO2 incubator and culture overnight.

[0536] 3) Cell administration: The test compound was dissolved in DMSO and diluted with culture medium to 10X the highest test concentration. A serial dilution (1:3, for a total of 10 concentration points) was then performed. A blank control well was set up without compound. The compound was added to the cells at 20 μL / well. The DMSO concentration in the system was maintained at 0.1%.

[0537] 4) CellTiter-Glo TM Detection: 7 days after cell administration, take the cells out of the incubator and centrifuge at room temperature (100g, 5min); remove 80μL supernatant from each well and add 20μL CellTiter-Glo TM Reagent, incubate in the dark at room temperature for 10 min, then transfer 80 μL of cell lysate to a white opaque 96-well plate (OptiPlate-96), and detect the corresponding chemiluminescent signal intensity using a multi-function microplate reader (SpectraMax i3x).

[0538] 5) Data processing: The signal value of the blank control group was subtracted from the signal value of all experimental groups to correct for background noise, and the cell viability was calculated. Graphpad Prism or Excel xLift plug-in was used to draw the compound concentration-cell inhibition rate curve and calculate the IC50 value.

[0539] To ensure the accuracy and reliability of the experimental data, all experiments were arranged with two biological replicates, and positive and negative controls were set up.

[0540] The inhibitory activities of the compounds of the present invention on various cells are shown in Table 4.

[0541] Table 4

[0542] Conclusion: The compounds of the present invention have good activity against the tested cells.

[0543] Detection of Rb phosphorylation

[0544] In order to evaluate the effects of compounds on the phosphorylation level of intracellular retinoblastoma protein (Rb) and to verify the inhibitory ability of compounds on CDK-mediated Rb phosphorylation, we used the homogeneous time-resolved fluorescence (HTRF) method to evaluate and screen compounds. The test method refers to the HTRF Human & Mouse Phospho-Rb (Ser780) Detection Kit (64RBS780PEG, revvity). First, the MCF-7 cells in the logarithmic growth phase (culture conditions MEM + 10% FBS + 1% PS + 1% MEM NEAA + 1mM Sodium Pyruvate) were digested and counted and then plated into a 96-well plate, 2*10^4 cells per well. The cells were cultured in a cell culture incubator overnight; the compound was gradiently diluted with DMSO to the required concentration and then added to the 96-well plate and incubated with the cells for 24 hours; then centrifuged at 100g for 5 minutes, the supernatant was removed, and 50μL lysis buffer (1X) was immediately added, and the cells were shaken and lysed at 350rpm at 25°C for 30 minutes. After the lysis was completed, 16μL of cell lysate was transferred from the 96-well plate to the 384-well plate, and then 4μL of antibody was added to each well (20X was diluted with detection buffer). Eu and d2 antibodies were diluted to 1X, the plates were sealed with sealing film, centrifuged at 2000g for 1 minute, and incubated overnight at 4°C. Detection was performed using a multi-function microplate reader (SpectraMax i3x) with an excitation wavelength set to 340 nm. Signals at 665 nm and 616 nm were read in TR-FRET mode. LANCE signal was calculated using HTRF ratio = (the signal at 665 nm / the signal at 615 nm) × 10,000. Four-parameter curve fitting was performed using Graphpad Prism to calculate IC50 values. To ensure experimental reliability, two biological replicates were performed for each concentration, along with positive controls (control lysis) and negative controls (lysis buffer).

[0545] The inhibitory activity of the compounds of the present invention on Rb phosphorylation in MCF-7 is shown in Table 5.

[0546] Table 5

[0547] Conclusion: The compounds of the present invention can effectively inhibit Rb phosphorylation in MCF-7 cells.

Claims

1. The compound represented by formula A or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof: in: A represents N or CH; R1 represents H, D, halogen, CN, C1-C3 alkyl, fluorinated C1-C2 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy; Ar2 represents a 6-membered aromatic ring or a 6-membered heteroaromatic ring; Cy2 represents a 4-8 membered heterocycloalkyl group, a 4-8 membered heterocycloalkenyl group or a 5-8 membered heteroaryl group; X 1 and X 2 It is the bridgehead atom shared by Ar2 and Cy2, X 1 and X 2 Each independently represents C or N, X 1 and X 2 The covalent bonds between them can be single or double bonds; R' represents H, D, F, Cl, CN, CH3, CH2F, CHF2 or CF3; R" each independently represents H, D, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally replaced by R 20 replace; Alternatively, R' and R" or two R" together with the atoms to which they are attached may form a 5-8 membered heterocycloalkyl group, wherein the 5-8 membered heterocycloalkyl group may be optionally replaced by R 21 replace; Ar1 represents C6-C 10 Aryl or 5-12 membered heteroaryl, wherein the C6-C 10 Aryl, 5-12 membered heteroaryl may be optionally substituted by 1, 2, 3 or 4 R7, wherein R7 each independently represents H, D, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally substituted by R 23 replace; L represents a bond, -CH2-, -C(O)-, -O-, or -NR a -, -S-, -S(O)- or -S(O)2-; Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C3-C 12 The cycloalkyl or 4-12 membered heterocycloalkyl may be a monocyclic, condensed, bridged or spirocyclic ring; 12 Cycloalkyl or 4-12 membered heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 R8, wherein R8 each independently represents H, D, oxo, halogen, CN, OR a NR a R a '、N(R a )COR a '、S(O)R a 、S(O)2R a 、C(O)R a 、C(O)NR a R a ', C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally R 24 replace; R 20 、R 21 、R 23 、R 24 Each of them independently represents oxo, D, F, Cl, CN, OR a NR a R a '、N(R a )COR a '、CONR a R a ', C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl, the C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl may be optionally substituted by F, OH, C1-C2 alkyl, fluorinated C1-C2 alkyl, C1-C2 alkoxy, fluorinated C1-C2 alkoxy; R a and R a 'Each independently represents H, D, C1-C3 alkyl; m and n each independently represent 0, 1, 2 or 3.

2. The compound according to claim 1 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Both are C.

3. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: represents an 8-9 membered heteroaromatic ring.

4. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: express or wherein Q each independently represents CR′ or N, and T each independently represents CR″, N, NR″, O or S.

5. The compound according to claim 4 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: express Wherein T' represents CR" or NR".

6. A compound according to any preceding claim, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, having the structure shown in Formula I: in: A represents N or CH; R1 represents H, D, halogen, CN, C1-C3 alkyl, fluorinated C1-C2 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy; U represents NR2 or CR3; R2 and R3 each independently represent H, D, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl can be arbitrarily replaced by R 20 replace; When U represents NR2, V represents CR4, R4 represents C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl is separated by at least one R 21 Substituted, the 4-8 membered heterocycloalkyl group may be optionally R 21 and optionally, R2, R4 together with the atoms to which they are attached may form a 5-8 membered heterocycloalkyl group, the 5-8 membered heterocycloalkyl group being arbitrarily replaced by R 21 replace; When U represents CR3, V represents NR5, R5 represents C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl is separated by at least one R 22 Substituted, the 4-8 membered heterocycloalkyl group may be optionally R 22 replace; X, Y, and Z each independently represent CR6 or N, wherein R6 represents H, D, F, Cl, CN, CH3, CH2F, CHF2, or CF3; Ar1 represents C6-C 10 Aryl or 5-12 membered heteroaryl, wherein the C6-C 10 Aryl, 5-12 membered heteroaryl may be optionally substituted by 1, 2, 3 or 4 R7, wherein R7 each independently represents H, D, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally substituted by R 23 replace; L represents a bond, -CH2-, -C(O)-, -O-, or -NR a -, -S-, -S(O)- or -S(O)2-; Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C3-C 12 The cycloalkyl or 4-12 membered heterocycloalkyl may be a monocyclic, condensed, bridged or spirocyclic ring; 12 Cycloalkyl or 4-12 membered heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 R8, wherein R8 each independently represents H, D, oxo, halogen, CN, OR a NR a R a '、N(R a )COR a '、S(O)R a 、S(O)2R a 、C(O)R a 、C(O)NR a R a ', C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally R 24 replace; R 20 、R 21 、R 22 、R 23 、R 24 Each of them independently represents oxo, D, F, Cl, CN, OR a NR a R a '、N(R a )COR a ', C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl, the C3-C8 cycloalkyl, 3-6 membered heterocycloalkyl may be optionally substituted by F, OH, C1-C2 alkyl, fluorinated C1-C2 alkyl, C1-C2 alkoxy, fluorinated C1-C2 alkoxy; R a and R a 'Each independently represents H, D, C1-C3 alkyl.

7. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R1 represents H, D, halogen, CN, C1-C2 alkyl, fluorinated C1-C2 alkyl, cyclopropyl; preferably, R1 represents Cl, F, CN, methyl, CF3; more preferably, R1 is preferably Cl.

8. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Ar1 is preferably phenyl, which may be optionally substituted by R7; more preferably, Ar1 is not substituted by R7.

9. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: L represents a bond, -C(O)- or -S(O)2-.

10. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C3-C 12 The cycloalkyl or 4-12 membered heterocycloalkyl may be a monocyclic, condensed, bridged or spirocyclic ring; 12 Cycloalkyl or 4-12 membered heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 R8, wherein R8 each independently represents H, D, oxo, halogen, CN, OR a NR a R a '、N(R a )COR a '、S(O)R a 、S(O)2R a 、C(O)R a , C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl may be optionally R 24 Substitution; preferably, Cy1 represents a 4-8 membered heterocycloalkyl group.

11. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: -L-Cy1 includes an amide or sulfonamide structure.

12. The compound according to any one of claims 6 to 11, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R2 and R3 each independently represent a C1-C6 alkyl group, and the C1-C6 alkyl group may be optionally replaced by R 20 replace.

13. The compound according to any one of claims 6 to 12, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R4 represents a C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by 1, 2 or 3 R 21 Substitution; preferably, the C1-C6 alkyl is substituted by 1, 2 or 3 OH or NH2.

14. The compound according to any one of claims 6 to 13, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R5 is preferably a C1-C6 alkyl group, which may be optionally replaced by R 22 Substitution; preferably, the C1-C6 alkyl is substituted by 1, 2 or 3 OH or NH2.

15. The compound according to claim 6-14 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: X represents CF.

16. The compound according to claim 6-15 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R 20 、R 21 、R 22 、R 23 、R 24 Each of which is independently selected from F, Cl, CN, OR a NR a R a '.

17. The compound according to claim 6-16 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: X, Y and Z are each independently CR6.

18. The compound according to claim 6-17 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: When U represents NR2, V represents CR4, R4 represents C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl is separated by at least one R 21 Substituted, the 4-8 membered heterocycloalkyl group may be optionally R 21 replace.

19. The compound according to claim 6-18 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: U is NR2, V is CR4, and R4 represents a C1-C6 alkyl group, a C3-C8 cycloalkyl group, or a 4-8 membered heterocycloalkyl group.

20. The compound according to claim 6-17 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: U is CR3 and V is NR5.

21. The compound according to any preceding claim, or its isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, having the structure shown in Formula II: L represents a bond, -C(O)- or -S(O)2-; Cy1 represents a 4-8 membered heterocycloalkyl group; R1, R2, R4, R6, and R7 are as described in any of the preceding claims.

22. A compound having the following structure or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt:

23. The compound represented by formula III or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof [WH]-L1-EMB Formula III in, WH is selected from the compound according to any one of claims 1 to 22, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof; The brackets [] in the general structural formula indicate that one H atom in the chemical formula of WH shown therein forms a bond and is connected to one end of L1; L1 represents a linker, which is connected to the C, N, O or S atom on EMB through a covalent bond and WH; EBM is the E3 ubiquitin ligase ligand fragment.

24. Use of the compound according to any one of claims 1 to 22, or its isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, for preparing the compound according to claim 23, or its isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 24 or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof.

26. Use of the compound according to any one of claims 1 to 24 or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof, and the pharmaceutical composition according to claim 25 in the preparation of a medicament for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Images