Oxazolone-substituted pyrimidinamine compound, preparation method therefor, pharmaceutical composition thereof and use thereof

Abstract

Provided in the present invention are an oxazolone-substituted pyrimidinamine compound, a preparation method therefor, a pharmaceutical composition thereof and the use thereof. Specifically, provided in the present invention are a compound having a structure as shown in general formula (I), and a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof, or a mixture thereof. The compound has good IDH1 inhibitory activity, and therefore can be used for treating, preventing and relieving diseases related to IDH1 enzyme, especially for treating malignant tumors or other related diseases caused by IDH1 enzyme mutation.

Description

Oxazolone-substituted pyrimidineamine compounds, preparation methods, pharmaceutical compositions, and uses thereof Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapy, and more particularly to compounds of formula I as isocitrate dehydrogenase inhibitors, methods for preparing the compounds, pharmaceutical compositions containing the compounds, and isocitrate dehydrogenase (also known as IDH enzyme) inhibitors, particularly for treating diseases in which IDH enzyme mutations are present, such as diseases caused by IDH1 and IDH2 mutations. Background Art

[0002] Isocitrate dehydrogenases (IDH) are key rate-limiting enzymes in the tricarboxylic acid cycle (TCA) of cellular energy metabolism. They mainly catalyze the oxidative decarboxylation of isocitrate to produce α-ketoglutarate (α-KG) and carbon dioxide. They are also related to the regulation of the tricarboxylic acid cycle, fat synthesis, glutamine metabolism, and redox regulation. There are three main subtypes of IDH in the human body: IDH1, IDH2, and IDH3. However, they are located differently. IDH1 is mainly found in the cytoplasm and peroxisomes, while IDH2 and IDH3 are found in mitochondria. The IDH family is divided into two categories according to its catalytic properties: one is based on NADP + IDH1 and IDH2, which are cofactors, have highly similar structures and both exist in the form of asymmetric homodimers consisting of two monomers. + IDH3, a cofactor, is a heterotetramer composed of two α subunits, one β subunit, and one γ subunit.

[0003] Currently, high-frequency mutations of IDH have been found in many tumors. The mutations mainly occur on arginine residues that are crucial for binding to isocitrate in the conserved region of the catalytic active center of IDH1 / 2, such as arginine at position 132 of IDH1 and arginine at positions 140 and 172 of IDH2; while there are currently few reports on IDH3 mutations. At the same time, the IDH mutations detected in tumors are all heterozygous mutations, that is, one monomer in the homodimer is mutated and the other remains a wild-type monomer, which indicates that the mutation of IDH1 / 2 is not an inactivating mutation, but a gain-of-function mutation. Subsequent studies have found that mutations in arginine residues at specific sites cause changes in the spatial conformation of the IDH1 / 2 protein, increasing the steric hindrance of the catalytic site and making it unable to bind to isocitrate. Instead, the affinity for α-KG is enhanced, resulting in the loss of the original function of the mutated IDH, which can reduce α-KG to 2-hydroxyglutarate (2-HG), accompanied by the oxidation of NADPH to NADP. + ability.

[0004] A growing number of studies have shown that 2-HG, the metabolite of IDH mutant enzymes, is an oncometabolite that regulates the physiological and biochemical processes of tumor cells through multiple pathways. These pathways primarily include: 1) Due to its structural similarity to α-KG, 2-HG can competitively inhibit multiple α-KG-dependent dioxygenases, including histone demethylases (KDMs), 5-methylcytosine hydroxylases (TET1 / 2), and AlkB homologous protein (ALKBH), thereby regulating tumor cell epigenetic modifications and thereby affecting biological functions such as tumor growth, differentiation, and metastasis. 2) In the process of reducing α-KG to 2-HG, IDH mutant enzymes consume a large amount of NADPH, reducing its content. To maintain intracellular redox balance, GSH consumption increases, leading to increased intracellular reactive oxygen species (ROS) levels. 3) In addition to affecting tumor cells themselves, 2HG accumulated in tumor tissues is secreted into the tumor microenvironment, significantly affecting immune cells and endothelial cells within the tumor microenvironment.

[0005] At present, clinical IDH mutations mainly occur in gliomas, acute myeloid leukemia, chondrosarcoma and bile duct cancer, especially in patients with gliomas, accounting for about 80%. Among these mutations, about 70.7% are IDH1 mutations, and the main one is the mutation of arginine at position 132 to histidine (R132H), accounting for about 92.8% of all IDH1 mutations. Because IDH1 mutations often occur in the early stages of the development of gliomas, they are generally considered to be a driving mutation, and this mutation also plays an important role in the transformation of low-grade gliomas to high-grade gliomas. Therefore, IDH mutations are closely related to the occurrence and development of gliomas, and the design and research of glioma drugs targeting IDH mutant enzymes has attracted widespread attention from scientists at home and abroad.

[0006] Currently, the main methods for targeting IDH to treat brain gliomas include small molecule inhibitors, vaccines, and combination therapies. Small molecule inhibitors can be divided into IDH1 inhibitors, IDH2 inhibitors, and IDH1 / 2 dual inhibitors according to their mode of action. Currently, the U.S. Food and Drug Administration (FDA) has approved three small molecule drugs targeting IDH mutants for marketing, namely Ivosidenib, Enasidenib, and Olutasidenib, all of which are indicated for relapsed or refractory acute myeloid leukemia. In addition, there are multiple IDH mutant inhibitors in different stages of preclinical or clinical research.

[0007] In summary, given the important role that IDH mutations play in the development and progression of gliomas, IDH mutant enzyme inhibitors have become the most promising research direction in the field of drug development for the treatment of gliomas. However, most current drugs are concentrated in the Phase I / II clinical research stage to evaluate the safety and efficacy of the compounds. Few drugs can enter the late clinical stage. At the same time, how to balance in vivo activity and blood-brain barrier permeability is a difficulty in the development of glioma drugs. Therefore, there is still considerable room for improvement in the research and development of IDH small molecule inhibitors for the treatment of gliomas, which deserves further research. Summary of the Invention

[0008] The purpose of the present invention is to provide a small molecule inhibitor of IDH1 or its mutants.

[0009] The first aspect of the present invention provides a compound of the structure represented by general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:

[0010] in,

[0011] X can be selected from the following groups: no group (i.e., N is directly connected to ring A), CH2, C=O or SO2;

[0012] Huanhe The rings can be independently selected from the following groups: substituted or unsubstituted C6 to C 10 Aryl, substituted or unsubstituted 5- to 12-membered heteroaryl or heterocyclic group, 10- to 20-membered aromatic condensed ring;

[0013] R 1 、R 1' 、R 2 、R 2' 、R 3 and R 4 can be independently selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10 Straight chain or branched alkoxy, C2-C6 straight chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 Membered carbocyclic group, substituted or unsubstituted C6~C 10Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amino group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein the heterocyclic group is not aromatic;

[0014] R 5 and R 6 are located in Huanhe 1, 2, 3 or 4 substituents on the ring may be independently selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, thiol, -S(O)2OH, C1-C6 alkyl-sulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, aryl or heteroaromatic ring-substituted C1-C6 alkyl, C3-C 10 C1-C6 alkyl, C1-C6 alkylamino, C3-C8 cycloalkyl, C3-C8 halogenated cycloalkyl, C6-C 10 Aryl, 3-12 membered heterocyclic group, substituted or unsubstituted C1-C6 alkyl group; wherein the cycloalkane or heterocyclic group may be unsaturated or saturated, but not aromatic.

[0015] or R 4 and R 5 It can be connected end to end with the connected groups to form a 5-8 membered saturated or unsaturated heterocyclic or heteroaromatic ring;

[0016] Unless otherwise specified, the heteroaromatic ring, heterocondensed ring or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the heterocyclic group includes a saturated or partially unsaturated ring;

[0017] The substitution in the substituted or unsubstituted group means that the group is substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group, and 5- to 12-membered heteroaryl;

[0018] The halogen is F, Cl, Br or I.

[0019] In another preferred embodiment, the The ring is selected from the following group: substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted 5- to 12-membered heteroaryl;

[0020] In another preferred embodiment, the The ring is selected from the following group: substituted or unsubstituted C6~C 10 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl.

[0021] In another preferred embodiment, the R 4 and R 5 Can be connected end to end with the connected groups, thereby The rings together form a bicyclic backbone selected from the group consisting of:

[0022] Among them, R 7 Substituents can be selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, sulfhydryl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10 Straight chain or branched alkoxy, C2-C6 straight chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 a membered carbocyclic group, a substituted or unsubstituted C2-C6 acyl group, a substituted or unsubstituted C2-C6 ester group, a substituted or unsubstituted C0-C6 amino group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted C1-C6 alkyl-sulfonyl group or a substituted or unsubstituted C1-C6 alkyl-sulfinyl group; n = 0, 1, 2;

[0023] Preferably, the R 4 and R 5 Can be connected end to end with the connected groups, thereby The rings together form a bicyclic backbone selected from the group consisting of:

[0024] In another preferred embodiment, the Huanhe The rings are each independently selected from the group consisting of a substituted or unsubstituted phenyl group, and a substituted or unsubstituted 5- to 9-membered heteroaryl group.

[0025] In another preferred embodiment, the Huanhe The rings are each independently selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 9-membered heteroaryl; and R 5 and R 6are located in Huanhe 1, 2, 3 or 4 substituents on the ring may be independently selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, thiol, -S(O)2OH, C1-C6 alkyl-sulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocyclyl.

[0026] In another preferred embodiment, the compound has a structure selected from the following group:

[0027] The second aspect of the present invention provides the use of the compound according to the first aspect of the present invention, which can be used to prepare a pharmaceutical composition for treating diseases associated with IDH protease mutations.

[0028] In another preferred embodiment, the disease associated with IDH protease mutation is a tumor disease; preferably selected from the following group: glioma, acute myeloid leukemia, chondrosarcoma and bile duct cancer; more preferably, it is glioma.

[0029] The third aspect of the present invention provides a pharmaceutical composition comprising: (i) a therapeutically effective amount of the compound as described in the first aspect of the present invention and its various crystal forms, or pharmaceutically acceptable inorganic or organic salts, or hydrates or solvates, and (ii) a pharmaceutically acceptable carrier.

[0030] In another preferred embodiment, the administration of the pharmaceutical composition includes but is not limited to the following: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration. DETAILED DESCRIPTION

[0031] After long and in-depth research, the present inventors have designed and prepared a class of oxazolone-substituted pyrimidineamine compounds (structure shown in Formula I). ​​The compounds have good IDH1 inhibitory activity and can be used to treat, prevent and alleviate diseases related to the IDH1 enzyme.

[0032] the term

[0033] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0034] As used herein, the term "C1-C 10 The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0035] The term "C3-C 10 "Cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 10 carbons. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "C3-C6 cycloalkyl" has a similar meaning.

[0036] The term "C3-C8 carbocycle" refers to a saturated or partially unsaturated cyclic hydrocarbon group having 3 to 8 carbon atoms, the ring skeleton of which is composed entirely of carbon atoms. The carbocycle may be saturated or partially unsaturated, but is not aromatic.

[0037] The term "5-12 membered heterocyclic group" refers to a saturated or partially unsaturated cyclic group having 5 to 12 carbon atoms, wherein one or more atoms in the backbone are selected from the group consisting of N, O, and S, wherein the ring N atom can be oxidized to NO, and the ring S atom can be oxidized to SO or SO2, and the remaining ring atoms are carbon. The heterocyclic group can be saturated or partially unsaturated, but is not aromatic.

[0038] The term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, or similar groups, and "C1-3 alkoxy" and other expressions have similar definitions.

[0039] The term "C6-C 10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, including monocyclic or polycyclic aromatic groups, such as phenyl, naphthyl, or the like.

[0040] The term "5-12 membered heteroaryl" refers to a heteroaryl group having 5-12 ring atoms (with 1-8 heteroatoms selected from N, O or S in the backbone), such as pyrrolyl, pyridyl, furyl, or the like.

[0041] The term "10-20 membered aromatic fused ring" refers to an aromatic hydrocarbon having 10-20 carbon atoms formed by two or more benzene rings fused by sharing two adjacent carbon atoms, such as naphthalene, anthracene, and phenanthrene.

[0042] The term "substituted" refers to the replacement of one or more hydrogen atoms on a group by a substituent selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, C6-C 10 aryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group and 5- to 12-membered heteroaryl.

[0043] Unless otherwise specified, all compounds mentioned in the present invention are intended to include all possible optical isomers, such as single chiral compounds or mixtures of various chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0044] As used herein, the term "compound of the present invention" refers to a compound of Formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of Formula I.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0046] Preparation of intermediates

[0047] Intermediate 1: (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0048] (S)-4-Isopropyl-oxazolidin-2-one (2.0 g, 15.48 mmol) was dissolved in 20 mL of DMF. Sodium hydride (60%, 0.805 g, 20.1 mmol) was slowly added at 0°C. The mixture was stirred at 0°C for 30 minutes. 2,4-Dichloropyrimidine (2.54 g, 17.03 mmol) was slowly added. After complete addition, the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After completion, the mixture was quenched with water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 10:1, volume ratio) afforded 1.8 g of a white solid in a 48% yield.

[0049] Intermediate 2: (S)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one

[0050] (S)-4-isopropyl-oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those of Intermediate 1.

[0051] Intermediate 3: (S)-3-(2-chloropyrimidin-4-yl)-4-methyloxazolidin-2-one

[0052] (S)-4-isopropyl-oxazolidin-2-one was replaced with (S)-4-methyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those of Intermediate 1.

[0053] Intermediate 4: 3-(2-chloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one

[0054] (S)-4-isopropyl-oxazolidin-2-one was replaced with 4,4-dimethyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those of Intermediate 1.

[0055] Intermediate 5: (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0056] Step a: Dissolve 1 (10 g, 20.46 mmol) in 100 mL of THF. Add N-methylmorpholine (2.7 mL, 24.56 mmol) and isobutyl chloroformate (3.16 mL, 24.35 mmol) at -25°C and stir at -25°C for 30 minutes. Filter the mixture with suction. Slowly add NaBH4 (1.51 g, 39.9 mmol) to the filtrate at -20°C, warm to room temperature, and stir for 1 hour. Quench with water and extract three times with DCM. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is used directly in the next step without purification.

[0057] Step b: Dissolve 2 (15 g, 50.78 mmol) in 150 mL of DMF. Slowly add sodium hydride (60%, 4.14 g, 103.6 mmol), 4-methoxybenzyl chloride (10.4 mL, 76.2 mmol), and tetrabutylammonium iodide (1.88 g, 5.08 mmol) at 0°C. Warm the mixture to room temperature and stir for 16 hours. Monitor the reaction by TLC. After completion, quench the mixture with water and extract three times with EA. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purify the mixture by column chromatography (PE:EA = 5:1, volume ratio) to obtain 14.8 g of a colorless liquid.

[0058] Step c: Dissolve 3 (15 g, 48.8 mmol) in 100 mL of DCM, add 100 mL of trifluoroacetic acid, and stir at room temperature for 2 hours. Remove the solvent under reduced pressure, dissolve in DCM, and concentrate under reduced pressure three times. Purify by column chromatography (PE:EA = 2:1, volume ratio) to obtain 8 g of a white solid.

[0059] Step d: 4 (10 g, 39.8 mmol) was dissolved in 100 mL of MeCN. Triethylamine (49 mL, 358.16 mmol), perfluorobutylsulfonyl fluoride (21.5 mL, 119.4 mmol), and triethylamine trihydrofluoride (19.5 mL, 119.4 mmol) were added at 0°C and stirred for 1 hour. The reaction was monitored by TLC. After completion, the mixture was warmed to room temperature, quenched with water, and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was then purified by column chromatography (PE:EA = 10:1, volume ratio) to obtain 7.1 g of a white solid.

[0060] Step e: 5 (9 g, 35.5 mmol) was dissolved in 120 mL of TFA, stirred at 65°C for 16 h, and the solvent was removed under reduced pressure. The product was dissolved in DCM and concentrated under reduced pressure. This process was repeated three times to remove TFA. The product was separated and purified by column chromatography (PE:EA = 10:1, volume ratio) to obtain 4 g of a light yellow solid.

[0061] Step f: Dissolve 6 (3.57 g, 26.85 mmol) in 60 mL of DMF. Slowly add sodium hydride (60%, 1.29 g, 32.22 mmol) at 0°C. Stir and react at 0°C for 30 minutes. Slowly add 2,4-dichloropyrimidine (4 g, 26.85 mmol). After complete addition, stir at room temperature and react for 4 hours. Monitor the reaction by TLC. After completion, quench with water and extract three times with EA. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purify by column chromatography (PE:EA = 5:1, volume ratio) to obtain 4.5 g of a white solid.

[0062] Intermediate 6: (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2

[0063] Step a: Dissolve 1 (10 g, 20.46 mmol) in 100 mL of THF. Add N-methylmorpholine (2.7 mL, 24.56 mmol) and isobutyl chloroformate (3.16 mL, 24.35 mmol) at -25°C and stir at -25°C for 30 minutes. Filter the filtrate with suction, slowly add NaBD4 (1.67 g, 39.9 mmol) at -20°C, and stir at room temperature for 1 hour. Quench the mixture with water and extract three times with DCM. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is used in the next step without purification.

[0064] Step b: 2 (15 g, 50.47 mmol) was dissolved in 150 mL of DMF. Sodium hydride (60%, 4.04 g, 100.9 mmol), 4-methoxybenzyl chloride (10.3 mL, 76.1 mmol), and tetrabutylammonium iodide (1.87 g, 0.507 mmol) were slowly added at 0°C. The mixture was heated to room temperature and stirred for 16 hours. The reaction was monitored by TLC. After completion, the reaction was quenched with water and extracted three times with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (PE:EA = 5:1, volume ratio) to obtain 14.2 g of a colorless liquid in a yield of 91%.

[0065] Step c: Dissolve 3 (15 g, 48.5 mmol) in 100 mL of DCM, add 100 mL of trifluoroacetic acid, and stir at room temperature for 2 hours. Remove the solvent under reduced pressure, dissolve in DCM, and concentrate under reduced pressure. Repeat this process three times. Purify by column chromatography (PE:EA = 2:1, volume ratio) to obtain 10 g of a white solid (81% yield).

[0066] Step d: 4 (10 g, 39.5 mmol) was dissolved in 100 mL of MeCN. Triethylamine (48 mL, 355.55 mmol), perfluorobutylsulfonyl fluoride (21.33 mL, 118.5 mmol), and triethylamine trihydrofluoride (19.4 mL, 118.5 mmol) were added at 0°C and stirred for 1 hour. The reaction was monitored by TLC. After completion of the reaction, the mixture was warmed to room temperature and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was separated and purified by column chromatography (PE:EA = 10:1, volume ratio) to obtain 8 g of a white solid with a yield of 79%.

[0067] Step e: Dissolve 5 (9 g, 35.3 mmol) in 120 mL of TFA and stir at 65°C for 16 hours. Remove the solvent under reduced pressure, dissolve in DCM, and concentrate under reduced pressure. Repeat this process three times to remove the TFA. The crude product can be used directly in subsequent reactions.

[0068] Step f: Dissolve crude product 6 in 100 mL of DMF. Slowly add sodium hydride (60%, 2.82 g, 70.5 mmol) at 0°C. Stir the mixture at 0°C for 30 minutes. Slowly add 2,4-dichloropyrimidine (4.8 g, 32 mmol). After complete addition, stir the mixture at room temperature for 4 hours. Monitor the reaction by TLC. After completion, quench the mixture and extract it three times with EA. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purify the mixture by column chromatography (PE:EA = 5:1, volume ratio) to obtain 3.5 g of a white solid (40% yield).

[0069] Preparation of compounds of formula I

[0070] The present invention also provides a method for preparing the compound represented by general formula I, which is carried out according to the following scheme (example):

[0071] Route 1:

[0072] where R 1 、R 1' 、R 2 、R 2' As defined above, X and Y may be independently selected from C or N.

[0073] Step a: Dissolve compound 1, (S)-tert-butylsulfenamide or (R)-tert-butylsulfenamide, and Ti(OEt)4 in a solvent, and heat to react. The solvent is tetrahydrofuran, 1,4-dioxane, toluene, ethanol, methanol, or a mixture thereof, and the heating temperature ranges from 50°C to 80°C.

[0074] Step b: Dissolve compound 2 in a solvent and slowly add 3M methylmagnesium bromide dropwise at -78°C under argon protection. After the addition, stir the reaction at -78 to -50°C, then raise the temperature to -40 to -20°C and stir the reaction. The solvent is tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, or a mixture thereof.

[0075] Step c: dissolving compound 3 in a solvent, adding dropwise a hydrogen chloride-dioxane solution, and stirring the mixture at room temperature to react. The solvent is tetrahydrofuran, 1,4-dioxane, dichloromethane or a mixed solvent thereof.

[0076] Step d: Compound 4 and the intermediate containing an oxazolidinone fragment prepared by the above method are dissolved in a solvent, DIPEA is added dropwise at room temperature, and the reaction is heated with stirring. The solvent is DMF, 1,4-dioxane, toluene, DMSO, or a mixture thereof, and the temperature range is 80-120°C.

[0077] Step e: dissolving compound 5, aromatic amine, Pd2(dba)3 and XPhos in a solvent, heating and stirring to react, the solvent being DMF, 1,4-dioxane, THF, DMSO, toluene or a mixture thereof, and the heating temperature being in the range of 80-120°C.

[0078] Route 2:

[0079] where R 1 、R 1' 、R 2 、R 2' As defined above, X may be independently selected from C or N.

[0080] Step a: Compound 1 was dissolved in NBS, which was slowly added at 0°C. After the addition, the mixture was stirred at room temperature for reaction. The solvent was tetrahydrofuran, MeCN, DCM, DMF, 1,4-dioxane or a mixed solvent thereof.

[0081] Step b: Compound 2 is dissolved in a solvent, TEA and Boc2O are added, and the mixture is stirred at room temperature. The solvent is DCM, DMF, THF, acetonitrile or a mixture thereof.

[0082] Step c: Dissolve compound 3, Pd(PPh3)4 and tributyl(1-ethoxyethylene)tin in a solvent, heat and stir to react, dissolve the crude product in a THF / H2O / AcOH mixed solvent, stir and react at room temperature, the solvent is tetrahydrofuran, MeCN, DMF, 1,4-dioxane or a mixed solvent thereof, and the temperature range is 80-120°C.

[0083] Step d: Compound 4 and NH4OAc are dissolved in a solvent, NaBH3CN is added, and the mixture is heated and stirred to react. The solvent is MeOH, DCE, THF, toluene or a mixture thereof, and the temperature range is 60-100°C.

[0084] Step e: Compound 5 and the intermediate containing an oxazolidinone fragment prepared by the above method are dissolved in a solvent, DIPEA is added dropwise at room temperature, and the reaction is heated with stirring. The solvent is DMF, 1,4-dioxane, toluene, DMSO, or a mixture thereof, and the temperature range is 80-120°C.

[0085] Step f: dissolving compound 6 in a solvent, adding hydrogen chloride-dioxane solution dropwise at room temperature, and stirring the mixture at room temperature. The solvent is tetrahydrofuran, 1,4-dioxane, dichloromethane or a mixed solvent thereof.

[0086] Step g: dissolving compound 7, an aryl halide compound, Pd2(dba)3 and XPhos in a solvent and heating the mixture for reaction. The solvent is DMF, 1,4-dioxane, THF, DMSO, toluene or a mixture thereof. The heating temperature ranges from 80 to 120°C.

[0087] Route 3:

[0088] where R 1 、R 1' 、R 2 、R 2' As defined above, X and Y may be independently selected from C or N.

[0089] Step a: Compound 1 is dissolved in a solvent, TEA and Boc2O are added, and the mixture is stirred at room temperature for 2 hours. The solvent is DCM, DMF, THF, acetonitrile or a mixture thereof.

[0090] Step b: Dissolve compound 2, Pd(PPh3)4 and tributyl(1-ethoxyethylene)tin in a solvent, heat and stir to react, dissolve the crude product in a THF / H2O / AcOH mixed solvent, stir and react at room temperature, the solvent is tetrahydrofuran, MeCN, DMF, 1,4-dioxane or a mixed solvent thereof, and the temperature range is 80-120°C.

[0091] Step c: Compound 3 and NH4OAc are dissolved in a solvent, NaBH3CN is added, and the mixture is heated and stirred for reaction. The solvent is MeOH, DCE, THF, toluene or a mixture thereof, and the temperature range is 60-100°C.

[0092] Step d: Compound 4 and the intermediate containing an oxazolidinone fragment prepared by the above method are dissolved in a solvent, DIPEA is added dropwise at room temperature, and the reaction is heated with stirring. The solvent is DMF, 1,4-dioxane, toluene, DMSO, or a mixture thereof, and the temperature range is 80-120°C.

[0093] Step e: dissolving compound 5 in a solvent, adding hydrogen chloride-dioxane solution dropwise at room temperature, and stirring at room temperature to react. The solvent is tetrahydrofuran, 1,4-dioxane, dichloromethane or a mixed solvent thereof.

[0094] Step f: dissolving compound 6, an aryl halide compound, Pd2(dba)3 and XPhos in a solvent and heating the mixture for reaction. The solvent is DMF, 1,4-dioxane, THF, DMSO, toluene or a mixture thereof. The heating temperature ranges from 80 to 120°C.

[0095] Step g: Compound 7 and DABCO are dissolved in a solvent, 5-methylfuran-2(3H)-one is added, oxygen is introduced, and the reaction mixture is stirred at room temperature. The solvent is tetrahydrofuran, 1,4-dioxane, dichloromethane or a mixed solvent thereof.

[0096] Pharmaceutical compositions and methods of administration

[0097] Since the compounds of the present invention have excellent IDH protease inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used for diseases related to IDH protease mutations.

[0098] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg / kg) of the compound of the present invention per dose, more preferably 10-2000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0099] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0100] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0101] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0102] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0103] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0104] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0105] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0106] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0107] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0108] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0109] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 6 to 600 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0110] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0111] Example 1 (S)-3-(2-(((S)-1-(4-((5-chloropyridin-3-yl)amino)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0112] 1.1 N-((5-bromopyridin-2-yl)methylene)-2-tert-butyl-2-sulfenamide

[0113] 5-Bromopyridine-2-carboxaldehyde (2 g, 10.75 mmol), (S)-tert-butylsulfenamide (1.43 g, 11.83 mmol), and Ti(OEt)4 (65%, 4.53 g, 12.9 mmol) were dissolved in 50 mL of THF and stirred at 65°C for 6 hours. The reaction was monitored by TLC. After completion, the mixture was cooled to room temperature, diluted with water and EA, filtered, and extracted three times with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 10:1, volume ratio) afforded 2.2 g of a yellow solid in a 71% yield.

[0114] 1.2 N-((S)-1-(5-bromopyridin-2-yl)ethyl)-2-tert-butyl-2-sulfenamide

[0115] N-((5-bromopyridin-2-yl)methylene)-2-tert-butyl-2-sulfenamide (2 g, 6.92 mmol) was dissolved in DCM. A 3M solution of methylmagnesium bromide in THF (3.46 mL, 10.37 mmol) was slowly added dropwise at -78°C under argon. The reaction was stirred at -78°C for 4 hours, then the temperature was raised to -40°C and stirred for 1 hour. The reaction was monitored by TLC. After completion, the reaction was warmed to room temperature and quenched with 1N aqueous hydrochloric acid. The mixture was diluted with water and extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography (PE:EA = 2:1, volume ratio) to afford 1.92 g of a white solid in a 91% yield.

[0116] 1.3(S)-1-(5-bromopyridin-2-yl)-1-ethylamine

[0117] Dissolve N-((S)-1-(5-bromopyridin-2-yl)ethyl)-2-tert-butyl-2-sulfenamide (1 g, 3.28 mmol) in 5 mL of DCM. Add 3 mL of a 4 M hydrogen chloride-dioxane solution dropwise at room temperature and stir for 6 hours. Monitor the reaction by TLC. After completion, remove the solvent under reduced pressure, dissolve in DCM, and repeat the process three times by spin drying. Adjust the pH to 7-8 with aqueous ammonia, concentrate under reduced pressure, and use the crude product directly in the next step without purification.

[0118] 1.4(S)-3-(2-(((S)-1-(5-bromopyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyl-oxazolidin-2-one

[0119] (S)-1-(5-bromopyridin-2-yl)-1-ethylamine (0.92 g, 4.55 mmol) and the intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (1 g, 4.14 mmol) were dissolved in 20 mL of DMSO. DIPEA (1.6 g, 12.41 mmol) was added dropwise at room temperature. The mixture was stirred at 110°C for 12 hours. The reaction was monitored by TLC. After completion, the mixture was cooled to room temperature, quenched with water, and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded a yellow solid in a 31% yield.

[0120] 1.5(S)-3-(2-(((S)-1-(5-((5-chloropyridin-3-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0121] (S)-3-(2-(((S)-1-(5-bromopyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyl-oxazolidin-2-one (0.1 g, 0.246 mmol), 3-amino-5-chloropyridine (0.038 g, 0.295 mmol), Cs2CO3 (0.241 g, 0.738 mmol), Pd2(dba)3 (0.032 g, 0.035 mmol) and XPhos (0.021 g, 0.044 mmol) were dissolved in 5 mL of 1,4-Dioxane and stirred at 100°C under argon for 12 hours. The mixture was cooled to room temperature, filtered through celite, concentrated under reduced pressure, and purified by column chromatography (EA:PE = 100%, volume ratio) to obtain 0.084 g of a white solid with a yield of 75.2%. 1 H NMR (500MHz, CDCl3) δ8.37(d,J=2.4Hz,1H),8.20(d,J=4.0Hz,1H),8.17(d,J=4.0Hz,1H) ,8.10(d,J=1.8Hz,1H),7.50-7.37(m,2H),7.31(s,1H),7.25(d,J=8.4Hz,1H),6.27(s,1H ),6.03-5.88(m,1H),5.10(s,1H),4.71-4.61(m,1H),4.29(t,J=8.8Hz,1H),4.23(dd,J=8 .9,2.5Hz,1H),2.02(s,1H),1.56(d,J=6.9Hz,3H),0.77(d,J=24.7Hz,6H).LRMS(ESI)m / z 454[M+H] + .

[0122] Example 2 (S)-3-(2-(((S)-1-(4-((5-chloropyridin-3-yl)amino)phenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0123] 5-Bromopyridine-2-carboxaldehyde was replaced by p-bromobenzaldehyde. The remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0124] LRMS (ESI) m / z 453 [M+H] + .

[0125] Example 3 (S)-3-(2-(((S)-1-(5-((5-chloropyridin-3-yl)amino)-4-methylpyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0126] 5-Bromopyridine-2-carboxaldehyde was replaced with 5-bromo-4-methylpyridine-2-carboxaldehyde. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0127] 1 H NMR (500MHz, CDCl3) δ8.39 (s, 1H), 8.19 (d, J = 5.7Hz, 1H), 8.04 (dd, J = 5.6, 2.1Hz, 2H) ,7.44(d,J=5.7Hz,1H),7.18(s,1H),6.98(s,1H),5.96(d,J=7.2Hz,1H),5.70(s,1H), 5.11(s,1H),4.73-4.63(m,1H),4.29(t,J=8.7Hz,1H),4.23(dd,J=9.0,2.9Hz,1H),2 .21(s,3H),1.97(s,1H),1.56(d,J=6.9Hz,3H),0.78(d,J=24.7Hz,6H).LRMS(ESI)m / z 468[M+H] + .

[0128] Example 4 (S)-3-(2-(((S)-1-(5-((5-chloropyridin-3-yl)amino)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0129] 5-Bromopyridine-2-carboxaldehyde was replaced with 5-bromopyrazine-2-carboxaldehyde. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0130] 1H NMR(500MHz, CDCl3)δ8.50(s,1H),8.34(s,1H),8.22-8.16(m,4H),7.47(d,J=5.7Hz,1H),4.71-4.63(m,1H),4.31(t, J=9.0Hz,1H),4.25(dd,J=9.0,3.0Hz,1H),1.71(s,3H),1.58(d,J=7.0Hz,3H),0.80(d,J=36.6Hz,6H).LRMS(ESI)m / z 455[M+H] + .

[0131] Example 5 (S)-3-(2-(((R)-1-(5-((5-chloropyridin-3-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0132] (S)-tert-butylsulfenamide was replaced by (R)-tert-butylsulfenamide. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0133] 1 H NMR (500MHz, CDCl3) δ8.38(d,J=2.4Hz,1H),8.20(d,J=2.5Hz,1H),8.17(d,J=5.9Hz,1H ),8.10(d,J=2.0Hz,1H),7.47-7.38(m,2H),7.31(t,J=2.1Hz,1H),7.26(d,J=8.4Hz,1H ),6.26(s,1H),6.03(s,1H),5.06(s,1H),4.52(s,1H),4.31-4.20(m,2H),2.67-2.55(m ,1H),1.54(d,J=6.8Hz,3H),0.95(d,J=7.1Hz,3H),0.85(d,J=6.9Hz,3H).LRMS(ESI)m / z 454[M+H]+.

[0134] Example 6 (S)-3-(2-(((S)-1-(5-((5-chloropyridin-3-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-methyloxazolidin-2-one

[0135] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced with (S)-3-(2-chloropyrimidin-4-yl)-4-methyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0136] 1H NMR(500MHz, CDCl3)δ8.37(d,J=2.5Hz,1H),8.20-8.15(m,2H),8.09(d,J=2.0Hz,1H) ,7.41(dd,J=8.4,2.7Hz,1H),7.38(d,J=5.7Hz,1H),7.27(d,J=8.3Hz,2H),6.25(s,1H ),5.99(d,J=6.4Hz,1H),5.09(s,1H),4.82-4.72(m,1H),4.44(t,J=8.3Hz,1H),4.00( dd,J=8.4,2.6Hz,1H),2.00(s,1H),1.55(d,J=6.9Hz,3H),1.13(s,3H).LRMS(ESI)m / z 426[M+H] + .

[0137] Example 7 (S)-3-(2-(((S)-1-(5-((5-chloropyridin-3-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one

[0138] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced with (S)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0139] 1 H NMR (500MHz, CDCl3) δ8.29(s,1H),8.19(d,J=2.4Hz,1H),8.14(d,J=5.7Hz,1H),8.10(d,J=2.0Hz,1H),7.47(d,J=5.7Hz,1H),7.34-7.15(m,7H),6.2 4(s,1H),5.76(dd,J=8.7,3.8Hz,1H),4.75(t,J=8.7Hz,1H),4.25(dd,J=8 .6,3.8Hz,1H),1.97(s,2H),1.47(d,J=6.8Hz,3H).LRMS(ESI)m / z488[M+H] + .

[0140] Example 8 (R)-3-(2-(((S)-1-(5-((5-chloropyridin-3-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0141] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced with (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0142] 1 H NMR (500MHz, CDCl3) δ8.37(d,J=2.6Hz,1H),8.22-8.17(m,2H),8.11(d,J=2.0Hz,1H),7.47( d,J=5.7Hz,1H),7.42(dd,J=8.4,2.7Hz,1H),7.32(t,J=2.2Hz,1H),7.25(d,J=8.5Hz,1H),6 .12(d,J=110.3Hz,2H),5.04(s,1H),4.66(dd,J=26.1,6.2Hz,1H),4.50(d,J=6.3Hz,1H),4. 37(t,J=9.0Hz,1H),1.98(s,1H),1.55(d,J=6.9Hz,3H),1.18(s,3H).LRMS(ESI)m / z458[M+H] + .

[0143] Example 9 (R)-3-(2-(((S)-1-(5-((3-chlorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0144] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and 3-amino-5-chloropyridine was replaced by m-chloroaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0145] 1H NMR (500MHz, CDCl3) δ8.32 (dd, J=13.1, 2.6Hz, 1H), 8.20 (d, J=5.7Hz, 1H), 7.47 (dd, J=5 .7,1.6Hz,1H),7.43-7.37(m,1H),7.22-7.13(m,2H),7.07-6.68(m,1H),6.92-6.61(m,2 H),5.96(d,J=7.1Hz,1H),5.90-5.80(m,1H),5.01(s,1H),4.75-4.57(m,1H),4.53-4.4 4(m,1H),4.40-4.32(m,1H),1.85(s,1H),1.59-1.50(m,3H),1.15(s,3H).LRMS(ESI)m / z 457[M+H] + .

[0146] Example 10 (S)-3-(2-(((S)-1-(5-((3-chlorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0147] 3-Amino-5-chloropyridine was replaced by m-chloroaniline, and the remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0148] 1 H NMR (500MHz, CDCl3) δ8.38-8.27(m,1H),8.18(d,J=5.6Hz,1H),7.47-7.36(m,2H),7.22-7.10(m,1H),7.08-6.97(m,1H),6.91-6.81(m,2 LRMS(ESI)m / z 453[M+H] + .

[0149] Example 11 (S)-3-(2-((1-(5-((5-chloropyridin-3-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one

[0150] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced with 3-(2-chloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0151] 1 H NMR (500MHz, CDCl3) δ8.38(d,J=2.6Hz,1H),8.19(d,J=2.4Hz,1H),8.16(d,J=5.8Hz,1H),8.09(d,J=2.0Hz,1H),7.41(dd,J=8.4,2.7Hz,1H),7.31-7.23 (m,3H),6.25(s,1H),5.96(d,J=5.7Hz,1H),5.07(s,1H),4.04-3.97(m,2H), 1.97(s,1H),1.69(s,3H),1.56(d,J=6.9Hz,3H),1.34(s,3H).LRMS(ESI)m / z 440[M+H] + .

[0152] Example 12 (S)-3-(2-(((S)-1-(5-(pyridin-3-ylamino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0153] 3-Amino-5-chloropyridine was replaced by 3-aminopyridine, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0154] 1 H NMR (500MHz, CDCl3) δ8.35 (dd, J=8.6, 2.6Hz, 2H), 8.21-8.13 (m, 2H), 7.43 (d, J=5.7 Hz,1H),7.36(td,J=7.3,6.3,2.0Hz,2H),7.22-7.14(m,2H),6.17(s,1H),5.98(d,J= 6.2Hz,1H),5.07(s,1H),4.70-4.60(m,1H),4.28(t,J=8.8Hz,1H),4.22(dd,J=8.9,2 .6Hz,1H),2.10(s,1H),1.55(d,J=6.9Hz,3H),0.76(d,J=28.5Hz,6H).LRMS(ESI)m / z 420[M+H] + .

[0155] Example 13 (S)-3-(2-(((S)-1-(5-((5-fluoropyridin-3-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0156] 3-Amino-5-chloropyridine was replaced by 3-amino-5-fluoropyridine. Other required raw materials, reagents and preparation methods were the same as those in Example 1.

[0157] LRMS (ESI) m / z 438 [M+H] + .

[0158] Example 14 (S)-3-(2-(((S)-1-(5-((6-chloropyridin-2-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0159] 3-amino-5-chloropyridine was replaced by 2-amino-6-chloropyridine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0160] LRMS (ESI) m / z 454 [M+H] + .

[0161] Example 15 (S)-3-(2-(((S)-1-(5-((2-(trifluoromethyl)pyridin-4-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0162] 3-amino-5-chloropyridine was replaced by 2-trifluoromethyl-4-aminopyridine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0163] 1 H NMR (500MHz, CDCl3) δ8.46(d,J=2.5Hz,1H),8.35(d,J=5.7Hz,1H),8.18(d,J=5.7Hz,1H),7.52( dd,J=8.4,2.6Hz,1H),7.45(d,J=5.7Hz,1H),7.33(d,J=8.4Hz,1H),7.12(d,J=2.3Hz,1H),6.91 -6.83(m,2H),6.01-5.87(m,1H),5.14(s,1H),4.72-4.62(m,1H),4.29(t,J=8.8Hz,1H),4.23(d d,J=9.0,2.5Hz,1H),1.91(s,1H),1.58(d,J=6.9Hz,3H),0.76(d,J=27.4Hz,6H).LRMS(ESI)m / z 488[M+H] + .

[0164] Example 16 (S)-3-(2-(((S)-1-(5-((1H-indol-6-yl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0165] 3-amino-5-chloropyridine was replaced by 6-aminoindole, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0166] 1 H NMR (500MHz, CDCl3) δ8.45(s,1H),8.27(d,J=2.6Hz,1H),8.17(d,J=5.8Hz,1H),7.54(d,J=8.4Hz,1H),7.42(d ,J=5.7Hz,1H),7.26(dd,J=8.4,2.8Hz,2H),7.13(t,J=2.6Hz,1H),7.09(d,J=8.9Hz,2H),6.85(dd,J=8.4,1.9 Hz,1H),6.51-6.47(m,1H),5.96(d,J=7.1Hz,1H),5.78(s,1H),4.65-4.60(m,1H),4.25(t,J=8.7Hz,1H),4.21 (dd,J=9.0,3.1Hz,1H),3.70(s,1H),1.94(s,1H),1.54(d,J=6.9Hz,3H),0.76(d,J=26.9Hz,6H).LRMS(ESI)m / z 458[M+H] + .

[0167] Example 17 (S)-3-(2-(((S)-1-(5-((3-methoxyphenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0168] 3-amino-5-chloropyridine was replaced by m-aminoanisole, and the remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0169] LRMS (ESI) m / z 449 [M+H] + .

[0170] Example 18 (S)-3-(2-(((S)-1-(5-((3-(trifluoromethoxy)phenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0171] 3-Amino-5-chloropyridine was replaced by m-trifluoromethoxyaniline, and the remaining raw materials, reagents and preparation methods were the same as in Example 1. LRMS (ESI) m / z 503 [M+H] + .

[0172] Example 19 (S)-3-(2-(((S)-1-(5-((3-(trifluoromethyl)phenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0173] 3-Amino-5-chloropyridine was replaced by m-aminobenzotrifluoride, and the remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0174] 1 H NMR (600MHz, CDCl3) δ8.37(s,1H),8.18(d,J=4.8Hz,1H),7.45(d,J=5.7Hz,1H),7. 41(dd,J=8.4,2.6Hz,1H),7.35(t,J=7.9Hz,1H),7.22(d,J=9.1Hz,2H),7.16(t,J= 6.7Hz,2H),6.06(s,1H),5.08(s,1H),4.66(s,1H),4.29(t,J=8.8Hz,1H),4.23(d, J=6.7Hz,1H),2.26-2.15(m,1H),1.57(d,J=6.9Hz,3H),0.73(s,6H).LRMS(ESI)m / z 487[M+H] + .

[0175] Example 20 (S)-3-(2-(((S)-1-(5-((3-fluorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0176] 3-Amino-5-chloropyridine was replaced by m-fluoroaniline, and the remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0177] 1 H NMR (400MHz, CDCl3) δ8.33(d,J=2.5Hz,1H),8.17(d,J=5.8Hz,1H),7.47-7.38(m,2H),7.21-7.14(m,2H),6.79-6.67(m,2H),6.64-6.56 (m,1H),6.08(s,1H),5.06(s,1H),4.69-4.61(m,1H),4.33-4.18(m,2H),2.37(s,1H),1.55(d,J=6.9Hz,3H),0.72(s,6H).LRMS(ESI)m / z 437[M+H] + .

[0178] Example 21 (S)-3-(2-(((S)-1-(5-((2-chlorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0179] 3-amino-5-chloropyridine was replaced by o-chloroaniline, and the remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0180] LRMS (ESI) m / z 453 [M+H] + .

[0181] Example 22 (S)-3-(2-(((S)-1-(5-((4-chlorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0182] 3-Amino-5-chloropyridine was replaced by p-chloroaniline, and the remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0183] 1 H NMR (600MHz, CDCl3) δ8.31(d,J=2.5Hz,1H),8.17(d,J=5.8Hz,1H),7.45(d,J=5.8Hz,1H),7.3 4(dd,J=8.4,2.7Hz,1H),7.22(d,J=8.8Hz,2H),7.18(d,J=8.4Hz,1H),6.95(d,J=8.8Hz,2H),6 .05(s,1H),5.83(s,1H),5.07(s,1H),4.74-4.62(m,1H),4.28(t,J=8.8Hz,1H),4.23(dd,J=8. 9,2.6Hz,1H),2.31-2.17(m,1H),1.56(d,J=6.9Hz,3H),0.76(d,J=27.9Hz,6H).LRMS(ESI)m / z 453[M+H] + .

[0184] Example 23 (S)-3-(2-(((S)-1-(5-((3-chloro-2-fluorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0185] 3-Amino-5-chloropyridine was replaced by 3-chloro-2-fluoroaniline. The remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0186] 1H NMR (500MHz, CDCl3) δ8.39(d,J=2.3Hz,1H),8.19(d,J=5.7Hz,1H),7.45(d,J=5.7 Hz,1H),7.40(dd,J=8.4,2.6Hz,1H),7.23(d,J=8.4Hz,1H),7.07-7.03(m,1H),6.9 3(d,J=5.6Hz,2H),5.95(d,J=6.7Hz,1H),5.87(s,1H),5.09(s,1H),4.65(s,1H), 4.32-4.20(m,2H),1.91(S,1H),1.56(d,J=6.9Hz,3H),0.73(S,6H).LRMS(ESI)m / z 471[M+H] + .

[0187] Example 24 (S)-3-(2-(((S)-1-(5-((5-chloro-2-fluorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0188] 3-amino-5-chloropyridine was replaced by 5-chloro-2-fluoroaniline, and the remaining raw materials, reagents and preparation method were the same as those in Example 1.

[0189] 1 H NMR (500MHz, CDCl3) δ8.40(d,J=2.5Hz,1H),8.20(d,J=5.7Hz,1H),7.46(d,J=5.7Hz,1H),7.4 3(dd,J=8.4,2.7Hz,1H),7.26(d,J=8.3Hz,1H),7.11(dd,J=7.4,2.4Hz,1H),7.02(dd,J=10.8, 8.7Hz,1H),6.83-6.79(m,1H),5.92(d,J=7.1Hz,1H),5.83(d,J=2.2Hz,1H),5.16-5.02(m,1H ),4.66(s,1H),4.31-4.21(m,2H),1.58(d,J=6.9Hz,3H),0.75(s,6H).LRMS(ESI)m / z471[M+H] + .

[0190] Example 25 (S)-3-(2-(((S)-1-(5-((3-chloro-4-fluorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0191] 3-Amino-5-chloropyridine was replaced by 3-chloro-4-fluoroaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0192] 1 H NMR (600MHz, CDCl3) δ8.29(s,1H),8.17(d,J=5.0Hz,1H),7.45(d,J=5.7Hz,1H ),7.31(dd,J=8.4,2.4Hz,1H),7.19(d,J=8.3Hz,1H),7.09-7.02(m,2H),6.89 -6.85(m,1H),6.02(s,1H),5.78(s,1H),5.06(s,1H),4.66(s,1H),4.37-4.17 (m,2H),2.12-1.94(m,1H),1.56(d,J=6.9Hz,3H),0.74(s,6H).LRMS(ESI)m / z 471[M+H]+.

[0193] Example 26 (S)-3-(2-(((S)-1-(5-((4-fluoro-3-methylphenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0194] 3-amino-5-chloropyridine was replaced by 2-fluoro-5-aminotoluene, and the remaining raw materials, reagents and preparation methods were the same as in Example 1. LRMS (ESI) m / z 451 [M+H] + .

[0195] Example 27 (R)-3-(2-(((S)-1-(5-((3-methoxyphenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0196] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced with (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and 3-amino-5-chloropyridine was replaced with m-aminoanisole. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0197] LRMS (ESI) m / z 453 [M+H] + .

[0198] Example 28 (R)-3-(2-(((S)-1-(5-((3-(trifluoromethoxy)phenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0199] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and 3-amino-5-chloropyridine was replaced by m-trifluoromethoxyaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0200] LRMS (ESI) m / z 507 [M+H] + .

[0201] Example 29 (R)-3-(2-(((S)-1-(5-((3-(trifluoromethyl)phenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0202] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and 3-amino-5-chloropyridine was replaced by m-aminotrifluorotoluene. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0203] LRMS (ESI) m / z 491 [M+H] + .

[0204] Example 30 (R)-3-(2-(((S)-1-(5-((3-fluorophenyl)amino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0205] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and 3-amino-5-chloropyridine was replaced by m-fluoroaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1.

[0206] LRMS (ESI) m / z 441 [M+H] + .

[0207] Example 31 (S)-3-(2-(((S)-1-(5-(3-chlorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0208] 1.1 6-Bromo-1,2,3,4-tetrahydro-1,5-naphthyridine

[0209] 6-Bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (10 g, 74.5 mmol) was dissolved in 100 mL of MeCN. NBS (13.4 g, 75.3 mmol) was slowly added at 0°C. After complete addition, the mixture was stirred at room temperature for 90 minutes. The reaction was monitored by TLC. After completion, the solvent was evaporated under reduced pressure, the mixture was diluted with DCM, washed three times with saturated Na2SO3 solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by column chromatography (PE:EA = 5:1, volume ratio) to obtain 15 g of a white solid in a yield of 94.5%.

[0210] 1.2 tert-Butyl 6-bromo-3,4-dihydro-1,5-naphthyridinecarboxylate

[0211] 6-Bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (10 g, 46.9 mmol) was dissolved in 100 mL of MeCN. TEA (26 mL, 187.7 mmol), DMAP (1.72 g, 14 mmol), and Boc2O (21.6 mL, 93.9 mmol) were added and stirred at 80°C for 18 hours. The reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure and the product was purified by column chromatography (PE:EA = 15:1, volume ratio) to afford 13.3 g of a yellow solid in a 90.5% yield.

[0212] 1.3 tert-Butyl 6-acetyl-3,4-dihydro-1,5-naphthyridinecarboxylate

[0213] Tert-butyl 6-bromo-3,4-dihydro-1,5-naphthyridinecarboxylate (10 g, 31.9 mmol), Pd(PPh3)4 (3.7 g, 3.2 mmol), and tributyl(1-ethoxyethylene)tin (19.3 g, 53.3 mmol) were dissolved in 150 mL of PhMe and stirred at 115°C for 12 hours. The reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure, 100 mL of 5 M KF solution was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and extracted three times with EA. The organic phases were combined and concentrated under reduced pressure. The crude product was dissolved in 90 mL of a 3 / 1 THF / H2O mixture, 30 mL of AcOH was added, and the mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After completion, the mixture was quenched with water, extracted three times with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography (PE:EA = 5:1, volume ratio) to obtain 8.12 g of a yellow solid in a yield of 92%.

[0214] 1.4 tert-Butyl 6-(1-aminoethyl)-3,4-dihydro-1,5-naphthyridinecarboxylate

[0215] Dissolve tert-butyl 6-acetyl-3,4-dihydro-1,5-naphthyridinecarboxylate (10 g, 36.2 mmol) and NH₄OAc (33.5 g, 434.3 mmol) in 150 mL of MeOH. Add 3 drops of glacial acetic acid and stir at room temperature for 1 hour. Add NaBH₃CN (9 g, 144.8 mmol) and stir at 65°C for 12 hours. Monitor the reaction by TLC. After completion, remove the solvent under reduced pressure, dilute with water, adjust the pH to 8-9 with anhydrous sodium carbonate, and extract three times with DCM. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Use directly in the next step without purification.

[0216] 1.5 tert-Butyl 6-(1-((4-((S)-4-isopropyl-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

[0217] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (0.795 g, 3.29 mmol), tert-butyl 6-(1-aminoethyl)-3,4-dihydro-1,5-naphthyridinecarboxylate (1 g, 3.62 mmol), DIPEA (1.28 g, 9.87 mmol), and DMSO (20 mL) were subjected to the same procedures as step 1.4 of Example 1.

[0218] 1.6(4S)-3-(2-((1-(5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)4-isopropyl-oxazolidin-2-one

[0219] Tert-butyl 6-(1-((4-((S)-4-isopropyl-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (1 g, 2.07 mmol), DCM (5 ml), and a 4M hydrogen chloride-dioxane solution (3 ml) were stirred at room temperature for 6 hours. The reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure, dissolved in DCM, and concentrated under reduced pressure three times. The pH was adjusted to 7-8 with aqueous ammonia, and the product was separated and purified by column chromatography. The product was obtained as a white solid with a yield of 76%.

[0220] 1.8(S)-3-(2-(((S)-1-(5-(3-chlorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyl-2-oxazolidinone

[0221] (4S)-3-(2-((1-(5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)4-isopropyl-oxazolidin-2-one (0.1 g, 0.262 mmol), m-chloroiodobenzene (0.068 g, 0.288 mmol), Cs2CO3 (0.256 g, 0.784 mmol), Pd2(dba)3 (0.036 g, 0.039 mmol), and XPhos (0.023 g, 0.047 mmol) were dissolved in 5 mL of 1,4-Dioxane and stirred at 100°C under argon for 12 hours. The mixture was cooled to room temperature, filtered through celite, concentrated under reduced pressure, and purified by column chromatography (EA:PE = 100%, volume ratio) to afford 0.046 g of a white solid (36% yield).

[0222] 1 H NMR (600MHz, CDCl3) δ8.18(d,J=5.7Hz,1H),7.42(d,J=5.7Hz,1H),7.26-7.21(m,1H),7.14( s,1H),7.07-6.99(m,3H),6.85(d,J=8.4Hz,1H),6.04(d,J=6.2Hz,1H),4.96(s,1H),4.68(d, J=7.3Hz,1H),4.29(t,J=8.8Hz,1H),4.25-4.20(m,1H),3.64-3.55(m,2H),3.00(t,J=6.2Hz, 2H),2.13-2.08(m,2H),1.94(s,1H),1.53(d,J=6.8Hz,3H),0.94-0.67(m,6H).LRMS(ESI)m / z 494[M+H] + .

[0223] Example 32 (S)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0224] Meta-chloroiodobenzene was replaced with meta-iodotrifluorotoluene. The remaining raw materials, reagents and preparation methods were the same as those in Example 31.

[0225] 1H NMR (400MHz, CDCl3) δ8.15 (d, J = 5.5Hz, 1H), 7.43-7.38 (m, 3H), 7.34-7.27 (m, 2H) ,7.01(d,J=8.5Hz,1H),6.86(d,J=8.5Hz,1H),6.21(s,1H),4.97(s,1H),4.70-4.6 3(m,1H),4.30-4.20(m,2H),3.65-3.59(m,2H),3.01(t,J=6.5Hz,2H),2.59(s,1H ),2.13-2.08(m,2H),1.52(d,J=6.8Hz,3H),0.76(d,J=15.3Hz,6H).LRMS(ESI)m / z 527[M+H] + .

[0226] Example 33 (S)-3-(2-(((S)-1-(5-(3-methoxyphenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0227] Substitute 3-iodoanisole for m-chloroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 31.

[0228] 1 H NMR (400MHz, CDCl3) δ8.15(d,J=5.7Hz,1H),7.39(d,J=5.7Hz,1H),7.22(t,J=8.1Hz,1H),6.99(d,J=8 .5Hz,1H),6.81(d,J=8.5Hz,1H),6.73(d,J=8.0Hz,1H),6.69(t,J=2.1Hz,1H),6.64(dd,J=8.2,2.3Hz, 1H),6.22(s,1H),4.95(s,1H),4.69-4.63(m,1H),4.31-4.19(m,2H),3.76(s,3H),3.61-3.57(m,2H), 3.00(t,J=6.5Hz,2H),2.13-2.06(m,2H),1.52(d,J=6.8Hz,3H),0.76(d,J=13.1Hz,6H).LRMS(ESI)m / z 489[M+H] + .

[0229] Example 34 (S)-3-(2-(((S)-1-(5-(3-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0230] Substitute m-chloroiodobenzene with m-trifluoromethoxyiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 31.

[0231] LRMS (ESI) m / z 543 [M+H] + .

[0232] Example 35 (S)-3-(2-(((S)-1-(5-(3-fluorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0233] Substitute m-chloroiodobenzene with m-fluoroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 31.

[0234] 1 H NMR (400MHz, CDCl3) δ8.14(d,J=5.7Hz,1H),7.39(d,J=5.7Hz,1H),7.26-7.20(m,1H),7.07(d ,J=8.5Hz,1H),6.90(dd,J=8.1,1.4Hz,1H),6.87-6.80(m,2H),6.73(td,J=8.2,2.2Hz,1H),6 .25(s,1H),4.95(s,1H),4.70-4.62(m,1H),4.29-4.19(m,2H),3.62-3.55(m,2H),2.98(t,J= 6.6Hz,2H),2.64(s,1H),2.10-2.05(m,2H),1.52(d,J=6.8Hz,3H),0.73(s,6H).LRMS(ESI)m / z 477[M+H] + .

[0235] Example 36 (S)-3-(2-(((S)-1-(5-(2-chlorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0236] Replace m-chloroiodobenzene with o-chloroiodobenzene; the remaining raw materials, reagents and preparation methods are the same as those in Example 31.

[0237] LRMS (ESI) m / z 494 [M+H] + .

[0238] Example 37 (S)-3-(2-(((S)-1-(5-(4-chlorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0239] Replace m-chloroiodobenzene with p-chloroiodobenzene; the remaining raw materials, reagents and preparation methods are the same as those in Example 31.

[0240] LRMS (ESI) m / z 494 [M+H] + .

[0241] Example 38 (S)-3-(2-(((S)-1-(5-(5-chloropyridin-3-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0242] Substitute 3-chloro-5-iodopyridine for m-chloroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 31.

[0243] LRMS (ESI) m / z 495 [M+H] + .

[0244] Example 39 (S)-3-(2-(((S)-1-(5-(2-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0245] Substitute 4-iodo-2-(trifluoromethyl)pyridine for m-chloroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 31.

[0246] LRMS (ESI) m / z 528 [M+H] + .

[0247] Example 40 (S)-3-(2-(((S)-1-(5-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0248] Substitute m-chloroiodobenzene with 2-chloro-1-fluoro-4-iodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 31.

[0249] LRMS (ESI) m / z 512 [M+H] + .

[0250] Example 41 (S)-3-(2-(((S)-1-(5-(3-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0251] Substitute 3-chloro-2-fluoroiodobenzene for m-chloroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 31.

[0252] LRMS (ESI) m / z 512 [M+H] + .

[0253] Example 42 (S)-3-(2-(((S)-1-(5-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0254] Substitute 5-chloro-2-fluoroiodobenzene for m-chloroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 31.

[0255] LRMS (ESI) m / z 512 [M+H] + .

[0256] Example 43 (R)-3-(2-(((S)-1-(5-(3-chlorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0257] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and m-chloroiodobenzene was replaced by m-chloroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those required in Example 31.

[0258] LRMS (ESI) m / z 497 [M+H] + .

[0259] Example 44 (R)-3-(2-(((S)-1-(5-(3-fluorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0260] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and m-chloroiodobenzene was replaced by m-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those required in Example 31.

[0261] LRMS (ESI) m / z 481 [M+H] + .

[0262] Example 45 (R)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0263] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and m-chloroiodobenzene was replaced by m-iodotrifluorotoluene. The remaining raw materials, reagents and preparation methods were the same as those in Example 31.

[0264] LRMS (ESI) m / z 531 [M+H] + .

[0265] Example 46 (R)-3-(2-(((S)-1-(5-(3-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0266] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and m-chloroiodobenzene is replaced by m-trifluoromethoxyiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 31.

[0267] LRMS (ESI) m / z 547 [M+H] + .

[0268] Example 47 (R)-3-(2-(((S)-1-(5-(3-methoxyphenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0269] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and m-chloroiodobenzene was replaced by 3-iodoanisole. The remaining raw materials, reagents and preparation methods were the same as those in Example 31.

[0270] LRMS (ESI) m / z 493 [M+H] + .

[0271] Example 48 (R)-3-(2-(((S)-1-(5-(3-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0272] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and m-chloroiodobenzene was replaced by 3-chloro-2-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those required in Example 31.

[0273] LRMS (ESI) m / z 515 [M+H] + .

[0274] Example 49 (R)-3-(2-(((S)-1-(5-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0275] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and m-chloroiodobenzene was replaced by 5-chloro-2-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those required in Example 31.

[0276] LRMS (ESI) m / z 515 [M+H] + .

[0277] Example 50 (R)-3-(2-(((S)-1-(5-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0278] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and m-chloroiodobenzene was replaced by 2-chloro-1-fluoro-4-iodobenzene. The remaining raw materials, reagents and preparation methods were the same as those required in Example 31.

[0279] LRMS (ESI) m / z 515 [M+H] + .

[0280] Example 51 (S)-3-(2-(((S)-1-(1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0281] 6-Bromo-1,2,3,4-tetrahydro-1,5-naphthyridine was replaced with 1,2,3,4-tetrahydroquinoline. The remaining raw materials, reagents and preparation methods were the same as those in Example 31.

[0282] LRMS (ESI) m / z 493 [M+H] +.

[0283] Example 52 (S)-3-(2-(((S)-1-(1-(3-fluorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0284] Replace 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine with 1,2,3,4-tetrahydroquinoline, and replace m-chloroiodobenzene with m-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those in Example 31.

[0285] LRMS (ESI) m / z 476 [M+H] + .

[0286] Example 53 (S)-3-(2-(((S)-1-(1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0287] 6-Bromo-1,2,3,4-tetrahydro-1,5-naphthyridine was replaced by 1,2,3,4-tetrahydroquinoline, and m-chloroiodobenzene was replaced by m-iodotrifluorotoluene. The remaining raw materials, reagents and preparation methods were the same as those in Example 31.

[0288] LRMS (ESI) m / z 526 [M+H] + .

[0289] Example 54 (S)-3-(2-(((S)-1-(1-(3-methoxyphenyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0290] Replace 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine with 1,2,3,4-tetrahydroquinoline, and replace m-chloroiodobenzene with 3-iodoanisole. The remaining raw materials, reagents and preparation methods are the same as those in Example 31.

[0291] LRMS (ESI) m / z 488 [M+H] + .

[0292] Example 55 (S)-3-(2-(((S)-1-(1-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0293] Replace 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine with 1,2,3,4-tetrahydroquinoline, and replace m-chloroiodobenzene with m-trifluoromethoxyiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those in Example 31.

[0294] LRMS (ESI) m / z 542 [M+H] + .

[0295] Example 56 (S)-3-(2-(((S)-1-(2-(3-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0296] 1.1 tert-Butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0297] Dissolve 6-bromo-1,2,3,4-tetrahydroisoquinoline (10 g, 47.2 mmol) in a solvent, add TEA (14.3 g, 141.5 mmol) and Boc2O (10.5 g, 48.1 mmol), and stir at room temperature for 2 hours. Monitor the reaction by TLC. After completion, remove the solvent under reduced pressure, and purify by column chromatography to obtain a white oil in a 95.1% yield.

[0298] 1.2 tert-Butyl 6-acetyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0299] tert-Butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (12.7 g, 40.7 mmol), Pd(PPh3)4 (4.5 g, 4.1 mmol), and tributyl(1-ethoxyethylene)tin (24.6 g, 68.0 mmol) were dissolved in 150 mL of PhMe and stirred at 115°C for 12 hours. The reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure, and 100 mL of 5M KF solution was added. The mixture was stirred at room temperature for 2 hours, filtered, and extracted three times with EA. The organic phases were combined and concentrated under reduced pressure. The crude product was dissolved in 90 mL of a 3 / 1 THF / H2O mixture, and 30 mL of AcOH was added. The mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After completion, the mixture was quenched with water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a white oil in a 90% yield.

[0300] 1.3 tert-Butyl 6-(1-aminoethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0301] Dissolve tert-butyl 6-acetyl-3,4-dihydro-1,5-naphthyridinecarboxylate (12.8 g, 46.3 mmol) and NH₄OAc (42.9 g, 556.1 mmol) in 150 mL of MeOH. Add 3 drops of glacial acetic acid and stir at room temperature for 1 hour. Add NaBH₃CN (4 g, 185.4 mmol) and stir at 65°C for 12 hours. Monitor the reaction by TLC. After completion, remove the solvent under reduced pressure, dilute with water, adjust the pH to 8-9 with anhydrous sodium carbonate, and extract three times with DCM. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Use directly in the next step without purification.

[0302] 1.4 tert-Butyl 6-(1-((4-((S)-4-isopropyl-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0303] The same procedure as step 1.4 of Example 1 was used to remove tert-butyl 6-(1-aminoethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.5 g, 9.1 mmol), intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (2.4 g, 10.0 mmol), DIPEA (3.5 g, 27.1 mmol) and DMSO (30 mL).

[0304] 1.5(4S)-3-(2-((1-(1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyl-oxazolidin-2-one

[0305] Tert-butyl 6-(1-((4-((S)-4-isopropyl-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.7 g, 3.53 mmol) was stirred in DCM (10 ml) and a 4M hydrogen chloride-dioxane solution (6 ml) at room temperature for 6 hours. The reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure, dissolved in DCM, and concentrated under reduced pressure three times. The pH was adjusted to 7-8 with aqueous ammonia, and the product was purified by column chromatography. The product was a white solid with an 81.7% yield.

[0306] 1.6(S)-3-(2-(((S)-1-(2-(3-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0307] (4S)-3-(2-((1-(1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyl-oxazolidin-2-one (0.1 g, 0.262 mmol), m-chloroiodobenzene (0.068 g, 0.288 mmol), Cs2CO3 (0.256 g, 0.784 mmol), Pd2(dba)3 (0.036 g, 0.039 mmol), and XPhos (0.023 g, 0.047 mmol) were dissolved in 5 mL of 1,4-Dioxane and stirred at 100°C under argon for 12 hours. The mixture was cooled to room temperature, filtered through celite, concentrated under reduced pressure, and purified by column chromatography to obtain 0.04 g of a white solid, with a yield of 31%.

[0308] 1 H NMR(500MHz, CDCl3)δ8.14(d,J=5.8Hz,1H),7.42(d,J=5.8Hz,1H),7.18-7.13(m,2H),7.11- 7.07(m,2H),6.88(t,J=2.1Hz,1H),6.79(dd,J=8.4,2.4Hz,1H),6.76-6.74(m,1H),4.99(s, 1H),4.57(s,1H),4.36(s,2H),4.26(t,J=8.8Hz,1H),4.19(dd,J=8.9,2.8Hz,1H),3.52(td, J=6.5,2.4Hz,2H),2.91(t,J=5.8Hz,2H),1.53(d,J=6.9Hz,3H),0.63(s,6H).LRMS(ESI)m / z 493[M+H] + .

[0309] Example 57 (S)-3-(2-(((S)-1-(2-(3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0310] Replace m-chloroiodobenzene with m-fluoroiodobenzene; the remaining raw materials, reagents and preparation methods are the same as those in Example 56. 1 H NMR (400MHz, CDCl3) δ8.15(d,J=5.8Hz,1H),7.43(d,J=5.8Hz,1H),7.21-7.09(m,4H),6.68( dd,J=8.4,2.1Hz,1H),6.60(dt,J=12.6,2.2Hz,1H),6.47(td,J=8.2,2.1Hz,1H),6.00(s,1H ),5.00(s,1H),4.37(s,2H),4.27(t,J=8.8Hz,1H),4.19(dd,J=8.9,2.8Hz,1H),3.53(t,J=6 .0Hz,2H),2.92(t,J=5.7Hz,2H),1.95(s,1H),1.54(d,J=6.9Hz,3H),0.63(s,6H).(ESI)m / z 476[M+H] + .

[0311] Example 58 (S)-3-(2-(((S)-1-(2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0312] Substitute meta-chloroiodobenzene with meta-iodotrifluorotoluene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 56.

[0313] 1 H NMR (500MHz, CDCl3) δ8.16(d,J=5.7Hz,1H),7.43(d,J=5.8Hz,1H),7.35(t,J=8.0Hz,1H ),7.17-7.09(m,4H),7.07(dd,J=8.4,2.3Hz,1H),7.02(d,J=7.6Hz,1H),5.83(s,1H),5. 01(s,1H),4.57(s,1H),4.41(s,2H),4.27(t,J=8.8Hz,1H),4.19(dd,J=8.9,2.7Hz,1H) ,3.59-3.55(m,2H),2.95(t,J=5.8Hz,2H),1.54(d,J=6.9Hz,3H),0.63(s,6H).(ESI)m / z 526[M+H]+ .

[0314] Example 59 (S)-3-(2-(((S)-1-(2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0315] Substitute m-chloroiodobenzene with m-trifluoromethoxyiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 56.

[0316] 1 H NMR (500MHz, CDCl3) δ8.13(d,J=5.7Hz,1H),7.43(d,J=5.8Hz,1H),7.24(t,J=8.3Hz,1H),7.16(d, J=7.8Hz,1H),7.13-7.08(m,,2H),6.82(dd,J=8.4,2.2Hz,1H),6.73(s,1H),6.63(d,J=8.1Hz,1H), 5.02(s,1H),4.69-4.51(m,1H),4.37(s,2H),4.26(t,J=8.8Hz,1H),4.19(dd,J=8.9,2.6Hz,1H),3 .56-3.49(m,2H),2.91(t,J=5.5Hz,2H),1.96(s,1H),1.55(d,J=7.0Hz,3H),0.63(s,6H).(ESI)m / z 542[M+H] + .

[0317] Example 60 (S)-3-(2-(((S)-1-(2-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0318] Substitute 3-iodoanisole for m-chloroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 56.

[0319] 1H NMR (500MHz, CDCl3) δ8.15(d,J=5.7Hz,1H),7.42(d,J=5.7Hz,1H),7.18(t,J=8.2Hz,1H),7.13(d,J=8.1Hz,1 H),7.10-7.07(m,2H),6.57(dd,J=8.3,2.0Hz,1H),6.49(t,J=2.1Hz,1H),6.38(dd,J=8.1,2.0Hz,1H),5.84(s ,1H),4.99(s,1H),4.57(d,J=3.3Hz,1H),4.37(s,2H),4.26(t,J=8.8Hz,1H),4.19(dd,J=8.8,2.5Hz,1H),3.8 0(s,3H),3.55-3.51(m,2H),2.92(t,J=5.7Hz,2H),1.96(s,1H),1.53(d,J=6.9Hz,3H),0.64(s,6H).(ESI)m / z 488[M+H] + .

[0320] Example 61 (S)-3-(2-(((S)-1-(2-(m-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0321] Substitute meta-chloroiodobenzene with meta-iodotoluene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 56.

[0322] LRMS (ESI) m / z 472 [M+H] + .

[0323] Example 62 (S)-3-(2-(((S)-1-(2-(5-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0324] Substitute 5-chloro-2-fluoroiodobenzene for m-chloroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 56.

[0325] LRMS (ESI) m / z 511 [M+H] + .

[0326] Example 63 (S)-3-(2-(((S)-1-(2-(3-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0327] Substitute 3-chloro-2-fluoroiodobenzene for m-chloroiodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 56.

[0328] LRMS (ESI) m / z 511 [M+H] + .

[0329] Example 64 (S)-3-(2-(((S)-1-(2-(3-chloro-4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0330] Substitute m-chloroiodobenzene with 2-chloro-1-fluoro-4-iodobenzene; the remaining raw materials, reagents, and preparation methods are the same as those in Example 56.

[0331] LRMS (ESI) m / z 511 [M+H] + .

[0332] Example 65 (S)-3-(2-(((S)-1-(6-(3-chlorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0333] 6-Bromo-1,2,3,4-tetrahydroisoquinoline was replaced with 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine. The remaining raw materials, reagents and preparation methods were the same as those in Example 56.

[0334] LRMS (ESI) m / z 494 [M+H] + .

[0335] Example 66 (S)-3-(2-(((S)-1-(6-(3-fluorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0336] Replace 6-bromo-1,2,3,4-tetrahydroisoquinoline with 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and replace m-chloroiodobenzene with m-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 56.

[0337] LRMS (ESI) m / z 477 [M+H] + .

[0338] Example 67 (S)-3-(2-(((S)-1-(6-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0339] 6-Bromo-1,2,3,4-tetrahydroisoquinoline was replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and m-chloroiodobenzene was replaced by m-iodotrifluorotoluene. The remaining raw materials, reagents and preparation methods were the same as those in Example 56.

[0340] LRMS (ESI) m / z 527 [M+H] + .

[0341] Example 68 (S)-3-(2-(((S)-1-(5-(pyridin-3-ylamino)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0342] 6-Bromo-1,2,3,4-tetrahydroisoquinoline was replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and m-chloroiodobenzene was replaced by m-trifluoromethoxyiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those in Example 56.

[0343] LRMS (ESI) m / z 543 [M+H] + .

[0344] Example 69 (S)-3-(2-(((S)-1-(6-(3-methoxyphenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0345] 6-Bromo-1,2,3,4-tetrahydroisoquinoline was replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and m-chloroiodobenzene was replaced by 3-iodoanisole. The remaining raw materials, reagents and preparation methods were the same as those in Example 56.

[0346] LRMS (ESI) m / z 489 [M+H] + .

[0347] Example 70 (S)-3-(2-(((S)-1-(6-(m-phenylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0348] Replace 6-bromo-1,2,3,4-tetrahydroisoquinoline with 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and replace m-chloroiodobenzene with m-iodotoluene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 56.

[0349] LRMS (ESI) m / z 473 [M+H] + .

[0350] Example 71 (S)-3-(2-(((S)-1-(6-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0351] Replace 6-bromo-1,2,3,4-tetrahydroisoquinoline with 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and replace m-chloroiodobenzene with 5-chloro-2-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 56.

[0352] LRMS (ESI) m / z 512 [M+H] + .

[0353] Example 72 (S)-3-(2-(((S)-1-(6-(3-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0354] Replace 6-bromo-1,2,3,4-tetrahydroisoquinoline with 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and replace m-chloroiodobenzene with 3-chloro-2-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 56.

[0355] LRMS (ESI) m / z 512 [M+H] + .

[0356] Example 73 (S)-3-(2-(((S)-1-(6-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0357] Replace 6-bromo-1,2,3,4-tetrahydroisoquinoline with 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and replace m-chloroiodobenzene with 2-chloro-1-fluoro-4-iodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 56.

[0358] LRMS (ESI) m / z 512 [M+H] + .

[0359] Example 74 (S)-3-(2-(((S)-1-(1-carbonyl-2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0360] (S)-3-(2-(((S)-1-(2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one, Example 59, has been prepared as described above.

[0361] Example 59 (100 mg, 0.185 mmol) and DABCO (62 mg, 0.554 mmol) were dissolved in THF, and 5-methylfuran-2(3H)-one (5 mg, 0.046 mmol) was added. Oxygen was introduced, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was monitored by TLC. After completion, the reaction was quenched with water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded a white solid in a yield of 48.7%.

[0362] 1 H NMR(600MHz, CDCl3)δ.15(d,J=5.7Hz,1H),8.08(d,J=8.0Hz,1H),7.44(d,J=5.8Hz,1H), 7.40(t,J=8.2Hz,1H),7.34-7.30(m,2H),7.28(s,1H),7.20(s,1H),7.10-7.07(m,1H),6. 02(s,1H),5.05(s,1H),4.56(s,1H),4.26(t,J=8.8Hz,1H),4.19(d,J=6.7Hz,1H),3.98-3 .93(m,2H),3.12-3.06(m,2H),2.24(s,1H),1.55(d,J=7.0Hz,3H),0.64(s,6H).(ESI)m / z 556[M+H] + .

[0363] Example 75 (S)-3-(2-(((S)-1-(2-(3-methoxyphenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0364] Trifluoromethoxyiodobenzene was replaced with 3-iodoanisole. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0365] 1H NMR (500MHz, CDCl3) δ8.17(d,J=5.8Hz,1H),8.09(d,J=8.0Hz,1H),7.46(d,J=5.8Hz,1H),7 .32-7.28(m,2H),7.18(s,1H),6.96-6.91(m,2H),6.82-6.77(m,1H),5.72(s,1H),5.05(s, 1H),4.57(s,1H),4.27(t,J=8.8Hz,1H),4.20(dd,J=8.9,2.7Hz,1H),3.94(t,J=6.5Hz,2H) ,3.81(s,3H),3.11-3.05(m,2H),1.94(s,1H),1.56(d,J=7.0Hz,3H),0.66(s,6H).(ESI)m / z 502[M+H] + .

[0366] Example 76 (S)-3-(2-(((S)-1-(1-carbonyl-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0367] Trifluoromethoxyiodobenzene was replaced by meta-iodotrifluorotoluene. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0368] 1 H NMR (500MHz, CDCl3) δ8.18(d,J=5.8Hz,1H),8.09(d,J=8.0Hz,1H),7.64(s,1H),7.59(d,J=7 .6Hz,1H),7.53-7.48(m,2H),7.47(d,J=5.8Hz,1H),7.33(d,J=8.0Hz,1H),7.21(s,1H),5.7 4(s,1H),5.06(s,1H),4.57(s,1H),4.28(t,J=8.8Hz,1H),4.21(d,J=8.6Hz,1H),3.99(t,J= 6.5Hz,2H),3.12(t,J=6.4Hz,2H),1.98(s,1H),1.56(d,J=7.0Hz,3H),0.66(s,6H).(ESI)m / z 540[M+H] + .

[0369] Example 77 3-(6-((S)-1-((4-((S)-4-isopropyl-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-1-carbonyl-3,4-dihydroisoquinolin-2(1H)-yl)benzonitrile

[0370] Trifluoromethoxyiodobenzene was replaced with 3-iodobenzonitrile. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0371] 1 H NMR (600MHz, CDCl3) δ8.14(d,J=5.8Hz,1H),8.05(d,J=8.0Hz,1H),7.69(d,J=1.0Hz, 1H),7.65-7.61(m,1H),7.50-7.47(m,2H),7.43(d,J=5.8Hz,1H),7.32(d,J=8.0Hz,1H ),7.20(s,1H),5.05(s,1H),4.56(s,1H),4.26(t,J=8.8Hz,1H),4.21-4.17(m,1H),3 .98-3.94(m,2H),3.10(t,J=6.3Hz,2H),1.54(d,J=7.0Hz,3H),0.63(s,6H).(ESI)m / z 497[M+H] + .

[0372] Example 78 (S)-3-(2-(((S)-1-(2-(3-fluorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0373] Trifluoromethoxyiodobenzene was replaced by m-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0374] 1 H NMR (500MHz, CDCl3) δ8.16(d,J=5.8Hz,1H),8.08(d,J=8.0Hz,1H),7.45(d,J=5.8Hz,1H),7. 36-7.30(m,2H),7.19(s,1H),7.16-7.12(m,2H),6.93(td,J=8.3,2.1Hz,1H),5.93(s,1H),5. 05(s,1H),4.56(s,1H),4.27(t,J=8.8Hz,1H),4.20(dd,J=9.0,2.6Hz,1H),3.95(t,J=6.5Hz ,2H),3.08(t,J=6.3Hz,2H),2.24-2.15(m,1H),1.55(d,J=7.0Hz,3H),0.65(s,6H).(ESI)m / z 490[M+H] + .

[0375] Example 79 (S)-3-(2-(((S)-1-(2-(3-chlorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0376] Trifluoromethoxyiodobenzene was replaced by m-chloroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0377] 1 H NMR (500MHz, CDCl3) δ8.16(d,J=5.8Hz,1H),8.07(d,J=8.0Hz,1H),7.45(d,J=5 .8Hz,1H),7.38(t,J=1.9Hz,1H),7.33-7.29(m,2H),7.28-7.26(m,1H),7.22-7. 18(m,2H),5.87(s,1H),5.05(s,1H),4.56(s,1H),4.29-4.17(m,2H),3.93(t,J= 6.5Hz,2H),3.08(t,J=6.4Hz,2H),1.55(d,J=7.0Hz,3H),0.65(s,6H).(ESI)m / z 507[M+H] + .

[0378] Example 80 (S)-3-(2-(((S)-1-(2-(2-chlorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0379] Trifluoromethoxyiodobenzene was replaced by o-chloroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0380] LRMS (ESI) m / z 507 [M+H] + .

[0381] Example 81 (S)-3-(2-(((S)-1-(2-(4-chlorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0382] Trifluoromethoxyiodobenzene was replaced by p-chloroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0383] 1H NMR (500MHz, CDCl3) δ8.16(d,J=5.8Hz,1H),8.07(d,J=8.0Hz,1H),7.45(d,J=5. 8Hz,1H),7.36-7.29(m,5H),7.19(s,1H),5.91(s,1H),5.05(s,1H),4.56(s,1H), 4.27(t,J=8.8Hz,1H),4.20(dd,J=8.9,2.5Hz,1H),3.92(t,J=6.5Hz,2H),3.08( t,J=6.3Hz,2H),2.77-2.45(m,1H),1.55(d,J=7.0Hz,3H),0.65(s,6H).(ESI)m / z 507[M+H] + .

[0384] Example 82 (S)-3-(2-(((S)-1-(1-carbonyl-2-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0385] Trifluoromethoxyiodobenzene was replaced with 4-iodo-2-(trifluoromethyl)pyridine. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0386] LRMS (ESI) m / z 541 [M+H] + .

[0387] Example 83 (S)-3-(2-(((S)-1-(2-(5-chloropyridin-3-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0388] Trifluoromethoxyiodobenzene was replaced with 3-chloro-5-iodopyridine. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0389] LRMS (ESI) m / z 507 [M+H] + .

[0390] Example 84 (S)-3-(2-(((S)-1-(2-(6-chloropyridin-2-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0391] Trifluoromethoxyiodobenzene was replaced with 2-chloro-6-iodopyridine. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0392] 1 H NMR(500MHz, CDCl3)δ8.18(d,J=5.6Hz,1H),8.11(d,J=8.0Hz,1H),8.05(d,J=8.2Hz,1H), 7.66(t,J=7.9Hz,1H),7.48(d,J=5.7Hz,1H),7.32(d,J=8.0Hz,1H),7.21(s,1H),7.10(d,J =7.7Hz,1H),5.80(s,1H),5.05(s,1H),4.56(s,1H),4.31-4.25(m,3H),4.20(d,J=6.9Hz,1 H),3.06(t,J=6.3Hz,2H),2.27-2.14(m,1H),1.57(d,J=7.0Hz,3H),0.64(s,6H).(ESI)m / z 507[M+H] + .

[0393] Example 85 (S)-3-(2-(((S)-1-(2-(5-chloro-2-fluorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0394] Trifluoromethoxyiodobenzene was replaced with 5-chloro-2-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0395] LRMS (ESI) m / z 524 [M+H] + .

[0396] Example 86 (S)-3-(2-(((S)-1-(2-(3-chloro-4-fluorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0397] Trifluoromethoxyiodobenzene was replaced with 2-chloro-1-fluoro-4-iodobenzene. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0398] LRMS (ESI) m / z 524 [M+H] + .

[0399] Example 87 (S)-3-(2-(((S)-1-(2-(3-chloro-2-fluorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one

[0400] Trifluoromethoxyiodobenzene was replaced with 3-chloro-2-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods were the same as those in Example 74.

[0401] LRMS (ESI) m / z 524 [M+H] + .

[0402] Example 88 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0403] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced with (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and the remaining required raw materials, reagents and preparation methods are the same as Example 74.

[0404] LRMS (ESI) m / z 560 [M+H] + .

[0405] Example 89 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-methoxyphenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0406] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 3-iodoanisole. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0407] LRMS (ESI) m / z 506 [M+H] + .

[0408] Example 90 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0409] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by meta-iodotrifluorotoluene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0410] 1 H NMR (500MHz, CDCl3) δ8.18(d,J=5.8Hz,1H),8.09(d,J=8.0Hz,1H),7.64(s,1H),7.59(d,J=7 .6Hz,1H),7.53-7.48(m,2H),7.47(d,J=5.8Hz,1H),7.33(d,J=8.0Hz,1H),7.21(s,1H),5.7 4(s,1H),5.06(s,1H),4.57(s,1H),4.28(t,J=8.8Hz,1H),4.21(d,J=8.6Hz,1H),3.99(t,J= 6.5Hz,2H),3.12(t,J=6.4Hz,2H),1.98(s,1H),1.56(d,J=7.0Hz,3H),0.66(s,6H).(ESI)m / z 544[M+H] + .

[0411] Example 91 3-(6-((S)-1-((4-((R)-4-((S)-1-fluoroethyl)-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-1-carbonyl-3,4-dihydroisoquinolin-2(1H)-yl)benzonitrile

[0412] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 3-iodobenzonitrile. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0413] LRMS (ESI) m / z 501 [M+H] + .

[0414] Example 92 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-fluorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0415] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by m-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0416] LRMS (ESI) m / z 494 [M+H] + .

[0417] Example 93 (R)-3-(2-(((S)-1-(2-(3-chlorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0418] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by m-chloroiodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0419] LRMS (ESI) m / z 510 [M+H] + .

[0420] Example 94 (R)-3-(2-(((S)-1-(2-(2-chlorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0421] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by o-chloroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0422] LRMS (ESI) m / z 510 [M+H] + .

[0423] Example 95 (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0424] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by p-chloroiodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0425] LRMS (ESI) m / z 510 [M+H] + .

[0426] Example 96 (R)-3-(2-(((S)-1-(1-carbonyl-2-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0427] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by p-chloroiodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0428] LRMS (ESI) m / z 545 [M+H] + .

[0429] Example 97 (R)-3-(2-(((S)-1-(2-(5-chloropyridin-3-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0430] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 3-chloro-5-iodopyridine. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0431] LRMS (ESI) m / z 511 [M+H] + .

[0432] Example 98 (R)-3-(2-(((S)-1-(2-(6-chloropyridin-2-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0433] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 2-chloro-6-iodopyridine. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0434] LRMS (ESI) m / z 511 [M+H] + .

[0435] Example 99 2-(6-((S)-1-((4-((R)-4-((S)-1-fluoroethyl)-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-1-carbonyl-3,4-dihydroisoquinolin-2(1H)-yl)isonicotinenitrile

[0436] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 4-cyano-2-iodoarsidine. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0437] LRMS (ESI) m / z 502 [M+H] + .

[0438] Example 100 (R)-3-(2-(((S)-1-(1-carbonyl-2-(thiophen-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0439] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 3-iodothiophene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0440] LRMS (ESI) m / z 482 [M+H] + .

[0441] Example 101 (R)-3-(2-(((S)-1-(2-(1-isopropyl-1H-pyrazol-5-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0442] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 5-iodo-1-isopropyl-1H-pyrazole. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0443] LRMS (ESI) m / z 508 [M+H] + .

[0444] Example 102 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(1-isopropyl-1H-pyrazol-4-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0445] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-isopropyl-4-iodopyrazole. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0446] LRMS (ESI) m / z 508 [M+H] + .

[0447] Example 103 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0448] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 4-iodo-1-(trifluoromethyl)-1H-pyrazole. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0449] LRMS (ESI) m / z 534 [M+H] + .

[0450] Example 104 (R)-3-(2-(((S)-1-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0451] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-cyclopropyl-4-iodo-1H-pyrazole. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0452] LRMS (ESI) m / z 506 [M+H] + .

[0453] Example 105 (R)-3-(2-(((S)-1-(2-(1-methyl-1H-pyrazol-4-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0454] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-methyl-4-iodo-pyrazole. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0455] LRMS (ESI) m / z 480 [M+H] + .

[0456] Example 106 (R)-3-(2-(((S)-1-(2-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0457] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-ethyl-4-iodo-3-(trifluoromethyl)-1H-pyrazole. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0458] LRMS (ESI) m / z 562 [M+H] + .

[0459] Example 107 (R)-3-(2-(((S)-1-(2-(5-chloro-2-fluorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0460] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 5-chloro-2-fluoroiodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0461] LRMS (ESI) m / z 528 [M+H] + .

[0462] Example 108 (R)-3-(2-(((S)-1-(2-(3-chloro-4-fluorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0463] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 2-chloro-1-fluoro-4-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0464] LRMS (ESI) m / z 528 [M+H] + .

[0465] Example 109 (R)-3-(2-(((S)-1-(2-(3-chloro-2-fluorophenyl)-1-carbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0466] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 3-chloro-2-fluoroiodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0467] LRMS(ESI)m / z 528[[M+H] + .

[0468] Example 110 (R)-3-(2-(((S)-1-(5-carbonyl-6-(3-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0469] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0470] LRMS (ESI) m / z 561 [M+H]+ .

[0471] Example 111 (R)-3-(2-(((S)-1-(6-(3-methoxyphenyl)-5-carbonyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0472] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and trifluoromethoxyiodobenzene is replaced by 3-iodoanisole. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0473] LRMS (ESI) m / z 507 [M+H] + .

[0474] Example 112 (R)-3-(2-(((S)-1-(5-carbonyl-6-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0475] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and trifluoromethoxyiodobenzene is replaced by meta-iodotrifluorotoluene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0476] LRMS (ESI) m / z 545 [M+H] + .

[0477] Example 113 3-(2-((S)-1-((4-((R)-4-((S)-1-fluoroethyl)-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-5-carbonyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)benzonitrile

[0478] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and trifluoromethoxyiodobenzene is replaced by 3-iodobenzonitrile. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0479] LRMS (ESI) m / z 502 [M+H] + .

[0480] Example 114 (R)-3-(2-(((S)-1-(6-(3-fluorophenyl)-5-carbonyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0481] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and trifluoromethoxyiodobenzene is replaced by m-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0482] LRMS (ESI) m / z 495 [M+H] + .

[0483] Example 115 (R)-3-(2-(((S)-1-(6-(3-chlorophenyl)-5-carbonyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0484] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 2-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine, and trifluoromethoxyiodobenzene is replaced by m-chloroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0485] LRMS (ESI) m / z 511 [M+H] + .

[0486] Example 116 (R)-3-(2-(((S)-1-(8-carbonyl-7-(3-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0487] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 3-bromo-5,6,7,8-tetrahydro-1,7-naphthyridine. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0488] LRMS (ESI) m / z 561 [M+H] + .

[0489] Example 117 (R)-3-(2-(((S)-1-(7-(3-methoxyphenyl)-8-carbonyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0490] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 3-bromo-5,6,7,8-tetrahydro-1,7-naphthyridine, and trifluoromethoxyiodobenzene is replaced by 3-iodoanisole. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0491] LRMS (ESI) m / z 507 [M+H] + .

[0492] Example 118 (R)-3-(2-(((S)-1-(8-carbonyl-7-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0493] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 3-bromo-5,6,7,8-tetrahydro-1,7-naphthyridine, and trifluoromethoxyiodobenzene is replaced by meta-iodotrifluorotoluene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0494] LRMS (ESI) m / z 545 [M+H] + .

[0495] Example 119 3-(3-((S)-1-((4-((R)-4-((S)-1-fluoroethyl)-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-8-carbonyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)benzonitrile

[0496] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 3-bromo-5,6,7,8-tetrahydro-1,7-naphthyridine, and trifluoromethoxyiodobenzene is replaced by 3-iodobenzonitrile. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0497] LRMS (ESI) m / z 502 [M+H] + .

[0498] Example 120 (R)-3-(2-(((S)-1-(7-(3-fluorophenyl)-8-carbonyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0499] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 3-bromo-5,6,7,8-tetrahydro-1,7-naphthyridine, and trifluoromethoxyiodobenzene is replaced by m-fluoroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0500] LRMS LRMS(ESI)m / z 495[M+H] + .

[0501] Example 121 (R)-3-(2-(((S)-1-(7-(3-chlorophenyl)-8-carbonyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0502] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, 6-bromo-1,2,3,4-tetrahydroisoquinoline is replaced by 3-bromo-5,6,7,8-tetrahydro-1,7-naphthyridine, and trifluoromethoxyiodobenzene is replaced by m-chloroiodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0503] LRMS (ESI) m / z 511 [M+H] + .

[0504] Example 122 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(trifluoromethyl)-4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0505] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-fluoro-4-iodo-2-(trifluoromethyl)benzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 74.

[0506] LRMS (ESI) m / z 562 [M+H] + .

[0507] Example 123 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(2-fluoro-5-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0508] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 4-chloro-1-fluoro-2-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0509] LRMS (ESI) m / z 528 [M+H] +.

[0510] Example 124 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-chloro-4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0511] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 2-chloro-1-fluoro-4-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0512] LRMS (ESI) m / z 528 [M+H] + .

[0513] Example 125 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0514] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-chloro-4-iodo-2-(trifluoromethyl)benzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0515] LRMS (ESI) m / z 578 [M+H] + .

[0516] Example 126 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(difluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0517] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 3-(difluoromethyl)-1-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0518] LRMS (ESI) m / z 526 [M+H] + .

[0519] Example 127 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3,5-bis(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0520] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-iodo-3,5-bis(trifluoromethyl)benzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0521] LRMS (ESI) m / z 612 [M+H] + .

[0522] Example 128 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-chloro-5-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0523] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 3-chloro-1-fluoro-5-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0524] LRMS (ESI) m / z 528 [M+H] + .

[0525] Example 129 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0526] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-bromo-3-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0527] LRMS (ESI) m / z 555 [M+H] + .

[0528] Example 130 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-difluoromethoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0529] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-difluoromethoxy-3-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0530] LRMS (ESI) m / z 541 [M+H] + .

[0531] Example 131 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0532] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-fluoro-4-iodo-2-trifluoromethoxybenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 74.

[0533] LRMS (ESI) m / z 504 [M+H] + .

[0534] Example 132 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

[0535] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 3-chloro-1-fluoro-5-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 74.

[0536] LRMS (ESI) m / z 578 [M+H] + .

[0537] Example 133 3-(6-((S)-1-((4-((R)-4-((S)-1-fluoroethyl)-2-carbonyloxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)-3,4-dihydroisoquinolin-2(1H)-yl)benzonitrile

[0538] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene was replaced by 3-iodobenzonitrile. The remaining raw materials, reagents and preparation methods were the same as those required in Example 56.

[0539] LRMS (ESI) m / z 487 [M+H] + .

[0540] Example 134 (R)-3-(2-(((S)-1-(2-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0541] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-chloro-4-iodo-2-trifluoromethylbenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 56.

[0542] LRMS (ESI) m / z 564 [M+H] + .

[0543] Example 135 (R)-3-(2-(((S)-1-(2-(2-chloro-5-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0544] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one was replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene was replaced by 1-chloro-4-fluoro-2-iodobenzene. The remaining raw materials, reagents and preparation methods were the same as those required in Example 56.

[0545] LRMS (ESI) m / z 514 [M+H] + .

[0546] Example 136 (R)-3-(2-(((S)-1-(2-(3-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0547] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-ethyl-3-iodobenzene. The remaining required raw materials, reagents and preparation methods are the same as those in Example 56.

[0548] LRMS (ESI) m / z 490 [M+H] + .

[0549] Example 137 (R)-3-(2-(((S)-1-(2-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0550] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-fluoro-4-iodo-2-trifluoromethoxybenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 56.

[0551] LRMS (ESI) m / z 564 [M+H] + .

[0552] Example 138 (R)-3-(2-(((S)-1-(2-(3-(difluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

[0553] The intermediate (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one, and trifluoromethoxyiodobenzene is replaced by 1-difluoromethoxy-3-iodobenzene. The remaining raw materials, reagents and preparation methods are the same as those required in Example 56.

[0554] LRMS (ESI) m / z 528 [M+H] + .

[0555] Example 139 (S)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0556] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced with (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and the other required raw materials, reagents and preparation methods are the same as Example 90.

[0557] LRMS (ESI) m / z 546 [M+H] + .

[0558] Example 140 (S)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0559] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one was replaced with (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 67.

[0560] LRMS (ESI) m / z 532 [M+H] + .

[0561] Example 141 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0562] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced with (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and the other required raw materials, reagents and preparation methods are the same as Example 90.

[0563] LRMS (ESI) m / z 546 [M+H] + .

[0564] Example 142 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0565] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one was replaced with (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 67.

[0566] LRMS (ESI) m / z 532 [M+H] + .

[0567] Example 143 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0568] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-iodo-3-trifluoromethoxybenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0569] LRMS (ESI) m / z 562 [M+H] + .

[0570] Example 144 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0571] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-iodo-3-trifluoromethoxybenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 67.

[0572] LRMS (ESI) m / z 548 [M+H] + .

[0573] Example 145 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0574] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-fluoro-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0575] LRMS (ESI) m / z 496 [M+H] + .

[0576] Example 146 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0577] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-fluoro-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 67.

[0578] LRMS (ESI) m / z 482 [M+H] + .

[0579] Example 147 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0580] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-fluoro-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0581] LRMS (ESI) m / z 512 [M+H] + .

[0582] Example 148 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-(3-chlorophenyl)-4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0583] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-fluoro-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 67.

[0584] LRMS (ESI) m / z 499 [M+H] + .

[0585] Example 149 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-cyanophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0586] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 3-iodobenzonitrile. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0587] LRMS (ESI) m / z 503 [M+H] + .

[0588] Example 150 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-cyanophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0589] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one was replaced with (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene was replaced with 3-iodobenzonitrile. The remaining raw materials, reagents, and preparation methods were the same as those in Example 67. (ESI) m / z 489 [M+H] + .

[0590] Example 151 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(difluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0591] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-difluoromethyl-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0592] LRMS (ESI) m / z 528 [M+H] + .

[0593] Example 152 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-(difluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0594] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-difluoromethyl-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 67.

[0595] LRMS (ESI) m / z 514 [M+H] + .

[0596] Example 153 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0597] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-chloro-2-fluoro-4-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0598] LRMS (ESI) m / z 530 [M+H] + .

[0599] Example 154 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0600] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-chloro-2-fluoro-4-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 67.

[0601] LRMS (ESI) m / z 516 [M+H] + .

[0602] Example 155 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(5-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0603] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 4-chloro-1-fluoro-2-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0604] LRMS (ESI) m / z 530 [M+H] +.

[0605] Example 156 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(5-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0606] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 4-chloro-1-fluoro-2-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 67.

[0607] LRMS (ESI) m / z 516 [M+H] + .

[0608] Example 157 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0609] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-ethyl-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0610] LRMS (ESI) m / z 506 [M+H] + .

[0611] Example 158 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0612] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-ethyl-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 67.

[0613] LRMS (ESI) m / z 492 [M+H] +.

[0614] Example 159 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-carbonyl-2-(3-(difluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0615] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-difluoromethoxy-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 90.

[0616] LRMS (ESI) m / z 544 [M+H] + .

[0617] Example 160 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(3-(difluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one-5,5-d2

[0618] The intermediate (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one is replaced by (R)-3-(2-chloropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one-d2, and 1-iodo-3-trifluoromethylbenzene is replaced by 1-difluoromethoxy-3-iodobenzene. The other required raw materials, reagents and preparation methods are the same as those in Example 67.

[0619] LRMS (ESI) m / z 530 [M+H] + .

[0620] Pharmacological activity test examples

[0621] Pharmacological Example 1 Test of the inhibitory activity of the compound on IDH1 R132H enzyme

[0622] The enzyme inhibitory activity was evaluated as follows: 5 μL of enzyme system (150 mM NaCl, 20 mM Tris 7.5, 10 mM MgCl2, 0.05% (w / v) bovine serum albumin, 0.012 μL enzyme), 2.5 μL of compound, and 2.5 μL of a mixture of substrates α-KG and NADPH (final concentration of substrate α-KG 1 mM, final concentration of NADPH 4 μM) were added to a 384-well plate and incubated at room temperature in the dark for 60 minutes. 5 μL of 0.01 unit diaphroase and 5 μM resazurin diluted in 1x detection buffer were added to each well and incubated at room temperature in the dark for 10 minutes. Florescence was read on a PerkinElmer at Ex 544Em 590. Test board. IC 50 The values ​​were calculated using GraphPad Prism software.

[0623] Table 1: IC of some compounds 50 data IDH305 * and DS-1001b * Positive control compound tested in the same batch as the compound

[0624] Experimental conclusion: Through molecular level enzyme inhibition activity screening, it was found that the above compounds have good inhibitory effects on IDH1R132H enzyme. 48 compounds are more active than clinical drugs IDH305 and DS-1001b; the most active compound IC 50 It reached 8.7 nM, which was about eight times more active than the positive control IDH305.

[0625] Pharmacological Example 2. Evaluation of the inhibitory activity of 2-HG production using HT1080 cells

[0626] HT-1080 (IDH1R132C), a human fibrosarcoma cell line harboring an IDH1 mutant, was seeded at appropriate density in 6-well culture plates. After overnight culture, various concentrations of compounds were added for 48 hours. Cells were harvested by trypsinization, resuspended in pre-chilled PBS, counted, and centrifuged at 500 g for 5 minutes at 4°C. The supernatant was discarded, and the cell pellet was stored at -80°C until analysis. Intracellular 2-HG was quantified using gas chromatography-mass spectrometry (Intuvo 9000 5977B GC / MSD).

[0627] Experimental results:

[0628] Table 2: IC of some compounds 50 data IDH305 * Positive control compound tested in the same batch as the compound

[0629] Experimental conclusion: Through cell-level inhibitory activity screening, it was found that the above compounds can effectively inhibit the production of 2-HG in HT1080 cells. The inhibitory activity of 22 compounds is better than that of the positive control IDH305. Among them, the compound with the best activity IC 50 Reached 21nM.

[0630] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. An oxazolone-substituted pyrimidineamine compound, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The structure of the compound is shown in general formula I: in: X can be selected from the following groups: none (i.e., N is directly connected to ring A), CH2, C=O or SO2; Huanhe The rings are independently selected from the following groups: substituted or unsubstituted C6 to C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocyclic group, or substituted or unsubstituted 10-20 membered aromatic condensed ring; R 1 、R 1' 、R 2 、R 2' 、R 3 and R 4 can be independently selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10 Straight chain or branched alkoxy, C2-C6 straight chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 Membered carbocyclic group, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amino group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; wherein the heterocyclic group may be saturated or unsaturated, but not aromatic; R 5 and R 6 are located in Huanhe 1, 2, 3 or 4 substituents on the ring may be independently selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, thiol, -S(O)2OH, C1-C6 alkyl-sulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, aryl or heteroaromatic ring-substituted C1-C6 alkyl, C3-C 10 C1-C6 alkyl, C1-C6 alkylamino, C3-C8 cycloalkyl, C3-C8 halogenated cycloalkyl, C6-C 10 Aryl, 3-12 membered heterocyclic group, substituted or unsubstituted C1-C6 alkyl; wherein the cycloalkane or heterocyclic group may be unsaturated or saturated, but not aromatic; or R 4 and R 5 It can be connected end to end with the connected groups to form a 5-8 membered saturated or unsaturated heterocyclic or heteroaromatic ring; Unless otherwise specified, the heteroaromatic ring, heterocondensed ring or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the heterocyclic group includes a saturated or partially unsaturated ring; The substitution in the substituted or unsubstituted group means that the group is substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group, and 5- to 12-membered heteroaryl; The halogen is F, Cl, Br or I.

2. The oxazolone-substituted pyrimidineamine compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The ring is selected from the following group: substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted 5- to 12-membered heteroaryl; The ring is selected from the following group: substituted or unsubstituted C6~C 10 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl.

3. The oxazolone-substituted pyrimidineamine compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein: The R 4 and R 5 Can be connected end to end with the connected groups, thus The rings together form a bicyclic backbone selected from the group consisting of: Among them, R 7 The substituents may be selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, sulfhydryl, -S(O)2OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 straight or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 a membered carbocyclic group, a substituted or unsubstituted C2-C6 acyl group, a substituted or unsubstituted C2-C6 ester group, a substituted or unsubstituted C0-C6 amino group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted C1-C6 alkyl-sulfonyl group or a substituted or unsubstituted C1-C6 alkyl-sulfinyl group; n = 0, 1, 2; Preferably, the R 4 and R 5 Can be connected end to end with the connected groups, thus The rings together form a bicyclic backbone selected from the group consisting of:

4. The oxazolone-substituted pyrimidineamine compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein: The Huanhe The rings are each independently selected from the group consisting of a substituted or unsubstituted phenyl group, and a substituted or unsubstituted 5- to 9-membered heteroaryl group.

5. The oxazolone-substituted pyrimidineamine compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The Huanhe The rings are each independently selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 9-membered heteroaryl; and R 5 and R 6 are located in Huanhe 1, 2, 3 or 4 substituents on the ring may be independently selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, thiol, -S(O)2OH, C1-C6 alkyl-sulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocyclyl.

6. The oxazolone-substituted pyrimidineamine compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein: The compound has a structure selected from the group consisting of:

7. Use of the oxazolone-substituted pyrimidineamine compound according to any one of claims 1 to 6, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The compound can be used to prepare a pharmaceutical composition for treating diseases related to IDH protease mutation.

8. The use according to claim 7, characterized in that The disease associated with IDH protease mutation is a tumor disease; preferably selected from the following group: glioma, acute myeloid leukemia, chondrosarcoma and bile duct cancer; more preferably, it is glioma.

9. A pharmaceutical composition, characterized in that include: (i) a therapeutically effective amount of the compound according to any one of claims 1 to 6, or its various crystal forms, or pharmaceutically acceptable inorganic or organic salts, or hydrates or solvates; and (ii) a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, wherein The administration of the pharmaceutical composition includes, but is not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

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