A (4R)-sulfonylamino-L-prolinamide compound, preparation method, application and pharmaceutical combination thereof

Abstract

The present invention relates to a (4R)-sulfonylamino-L-prolinamide compound having a general structure and a pharmaceutically acceptable salt or solvate thereof. The present invention also provides a method for preparing a (4R)-sulfonylamino-L-prolinamide compound and a pharmaceutically acceptable salt or solvate thereof. The present invention further provides the use of a (4R)-sulfonylamino-L-prolinamide compound and a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating a disease by inhibiting phosphatidylinositol 3-kinase α (PI3Kα). The present invention further provides a drug combination comprising a (4R)-sulfonylamino-L-prolinamide compound and a pharmaceutically acceptable salt or solvate thereof. The (4R)-sulfonylamino-L-prolinamide derivative according to the present invention has favorable pharmacological properties, for example, they can inhibit PI3Kα, and are superior to Alpelisib in activity and selectivity for PI3Kα.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and more specifically to a (4R)-sulfonylamino-L-prolineamide compound, a preparation method, an application and a pharmaceutical combination thereof. Background Art

[0002] The PI3K / Akt / mTOR signaling pathway, a crucial intracellular signaling pathway, plays a crucial role in cell growth, survival, proliferation, and apoptosis. However, disruptions in this pathway can lead to a range of diseases, including cancer, immune system disorders, and hematopoietic disorders. Studies have shown that PI3K, a key regulatory site in this pathway, is closely associated with tumor development and progression. Therefore, the development of anti-tumor drugs targeting PI3K has been a research hotspot in recent years (Nature Reviews Molecular Cell Biology 2012, 13:195-203).

[0003] Phosphoinositide 3-kinase (PI3K) is a multi-member lipid kinase family. Based on their structural characteristics, activation mechanisms, and lipid substrate selectivity, PI3K kinases can be broadly divided into three classes: I, II, and III. Class I PI3K kinases are the most thoroughly studied. Class I PI3K kinases comprise four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. Class I PI3K kinases can be further divided into classes IA and IB. Class IA PI3K includes the subtypes PI3Kα, PI3Kβ, and PI3Kδ, while class IB PI3K includes only the subtype PI3Kγ. All class I PI3K kinases consist of a catalytic subunit and a regulatory subunit. The catalytic subunits, p110α, p110β, p110δ, and p110γ, are encoded by the genes PIK3CA, PIK3CB, PIK3CD, and PIK3CG, respectively. Class IA PI3K regulatory subunits include p85α, p85β, p55α, and p55γ, whose functions are associated with kinase expression, activation, and localization. Class IB PI3K, or PI3Kγ, has regulatory subunits including p101 and p87. Class I PI3K kinases phosphorylate the 3-hydroxyl group of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to generate phosphatidyl-3,4,5-triphosphate (PtdIns(3,4,5)P3), which acts as an important second messenger in cells and interacts with the downstream serine / threonine protein kinase Akt (also known as protein kinase B, PKB). The activated Akt further acts on downstream effector proteins including the mammalian target of rapamycin (mTOR) to regulate various life activities in cells (Nature Reviews Drug Discovery 2009, 8: 627-644).

[0004] Of the four type I PI3K isoforms, PI3Kα and PI3Kβ are expressed in various organs, while PI3Kδ and PI3Kγ are primarily distributed in bone marrow cells (Cancer Science, 2008, 99:1734-1740). PI3Kα is most closely linked to the development and progression of tumors. The PIK3CA gene, encoding p110α, is one of the most mutated oncogenes, with mutations primarily occurring at three sites with the highest mutation frequency: glutamic acids E542 and E545 in the helical domain of PI3Ka and histidine H1047 in the kinase catalytic domain of PI3Kc. Glutamates E542 and E545 typically mutate to lysine, while histidine H1047 mutates to arginine. Tumors caused by these three mutations account for approximately 30% of all solid tumors (Science, 2004, 304:554). PI3Kα mutations cause abnormal activation of the PI3K / Akt / mTOR signaling pathway, leading to excessive cell proliferation and, in turn, the development of various malignancies, including breast, colon, endometrial, gastric, ovarian, and lung cancers (Aging, 2011, 3:192-222). The other three isoforms, PI3Kβ, PI3Kδ, and PI3Kγ, primarily play a role in the development of thrombosis, immune dysfunction, leukemia, allergies, and inflammation (Journal of Medicinal Chemistry, 2019, 62:4815-485).

[0005] To date, more than 38 ATP-competitive PI3K inhibitors have entered clinical trials, including pan-Class I PI3K inhibitors, dual PI3K / mTOR inhibitors, and a new generation of Class I PI3K isoform-selective inhibitors. Among them, isoform-selective inhibitors target only one or two Class I PI3K isoforms, significantly reducing the toxic side effects of pan-Class I PI3K inhibitors (Journal of Medicinal Chemistry, 2019, 62:4815-485).

[0006] Alpelisib (Norvartis) is the only currently marketed selective inhibitor of the PI3Kα isoform. It was approved by the U.S. Food and Drug Administration (FDA) on May 24, 2019, for the treatment of postmenopausal women and men with PIK3CA mutations, HR+ / HER2- advanced or metastatic breast cancer, and disease progression during or after endocrine therapy (Drugs, 2019, 79:1249-1253). Although alpelisib exhibits potent inhibitory activity against PI3Kα, it also exhibits some inhibitory activity against PI3Kβ, PI3Kδ, and PI3Kγ, leading to toxic side effects (Bioorganic & Medicinal Chemistry Letters, 2013, 23:3741-3748).

[0007] As can be seen from the above, highly selective PI3Kα inhibitors are particularly valuable in the treatment of proliferative diseases such as cancer. Therefore, there is an urgent need to find and discover new highly selective PI3Kα inhibitors that can retain high activity against PI3Kα while weakening its inhibitory effects on PI3Kβ, PI3Kδ, and PI3Kγ. Summary of the Invention

[0008] In order to solve the problem of poor selectivity of Alpelisib in the prior art for inhibiting PI3Kα, the present invention provides a (4R)-sulfonylamino-L-prolineamide compound, a preparation method, an application and a pharmaceutical combination thereof.

[0009] According to the present invention, the (4R)-sulfonylamino-L-prolinamide compounds of the structure and pharmaceutically acceptable salts or solvates thereof, wherein X, Y, and Z are all CH; or X, Y are CH, and Z is N; or X, Z are CH, and Y is N; or Y, Z are CH, and X is N; R1 is selected from C 1-6 Alkyl, fluorinated C 1-6 Alkyl, C 3-6 Cycloalkyl, fluorinated C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl or fluorinated C 3-6 Heterocycloalkyl; R2 is selected from hydrogen, halogen, C 1-6 Alkyl, fluorinated C 1-6 Alkyl, C 3-6 Cycloalkyl, fluorinated C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl; R3 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl, wherein the C 1-6 Alkyl, C3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl are each independently and optionally substituted with one substituent R4 or two substituents R4 and R5; or the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Two adjacent R4 and R5 substituents on a heterocycloalkyl, aryl or heteroaryl ring together with the atoms to which they are attached form a fused ring; R4, R5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, -OCF3, -CN, -NO2, -OR a 、-COR a 、-CO2R a 、-OCOR a 、-NR a R b 、-SO2R a 、-SOR a 、-NR a CO2R b 、-OCON a R b 、-NR a COR b 、-CONR a R b 、-NR a CONR b R c 、-SO2NR a R b 、-NR a SO2R b or -NR a SO2NR b R c ; R a 、R b 、R c may be the same or different, and are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Heterocycloalkyl, aryl or heteroaryl.

[0010] Preferably, R3 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl, wherein the C 1-6 Alkyl, C 3-8Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl are each independently and optionally substituted by one substituent R4 or two substituents R4 and R5; R4, R5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -OCF3, -CN, -NO2, -OR a 、-CO2R a or-SO2R a ; R a Selected from C 1-6 alkyl.

[0011] Preferably, R1 is selected from R2 is selected from methyl, chloro; R3 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluorophenyl, 3-trifluorophenyl, 4-trifluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-nitro-4-methylphenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyano-4-fluorophenyl, 4-cyanophenyl, 4-sulfonephenyl, 4-methylformylphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methylpyrazole, 1-methylimidazole,

[0012] Preferably, the (4R)-sulfonylamino-L-prolineamide compound and its pharmaceutically acceptable salt or solvate are selected from the target compounds of Examples 1 to 56.

[0013] The present invention also provides a method for preparing (4R)-sulfonylamino-L-prolinamide compounds and pharmaceutically acceptable salts or solvates thereof.

[0014] The present invention further provides the use of (4R)-sulfonylamino-L-prolinamide compounds and pharmaceutically acceptable salts or solvates thereof in the preparation of drugs for treating diseases by inhibiting phosphatidylinositol 3-kinase α (PI3Kα).

[0015] Preferably, the (4R)-sulfonylamino-L-prolinamide compounds and pharmaceutically acceptable salts or solvates thereof are used in the preparation of anti-proliferative disease drugs.

[0016] Preferably, the anti-proliferative disease includes cancer, hyperplasia spectrum, polycythemia vera, essential thrombocythemia and myelofibrosis with myeloid metaplasia.

[0017] Preferably, the cancer is selected from the group consisting of lung and bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon and rectal cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma / glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine corpus cancer, cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, small intestine cancer, non-Hodgkin's lymphoma, melanoma and villous colon adenoma, etc.

[0018] Preferably, the overgrowth lineage is an overgrowth lineage associated with a PIK3CA gene mutation.

[0019] The present invention further provides a pharmaceutical combination comprising a (4R)-sulfonylamino-L-prolinamide compound and a pharmaceutically acceptable salt or solvate thereof.

[0020] Preferably, the pharmaceutical combination comprises a therapeutically effective amount of the free form and a pharmaceutically acceptable salt or solvate.

[0021] Preferably, the pharmaceutical combination further comprises one or more pharmaceutically acceptable excipients.

[0022] Preferably, the pharmaceutical combination is a combined pharmaceutical composition suitable for simultaneous or sequential administration, comprising a (4R)-sulfonylamino-L-prolinamide compound and a pharmaceutically acceptable salt or solvate thereof; a therapeutically effective amount of one or more combination partners; and one or more pharmaceutically acceptable excipients.

[0023] Preferably, the pharmaceutical combination is used to treat protein tyrosine kinase-mediated diseases, particularly phosphatidylinositol 3-kinase-mediated diseases.

[0024] The (4R)-sulfonylamino-L-prolinamide derivatives according to the present invention possess favorable pharmacological properties, for example, they can inhibit PI3Kα. In particular, their activity and selectivity against PI3Kα are superior to those of the marketed drug alpelisib. This means that the (4R)-sulfonylamino-L-prolinamide derivatives according to the present invention can enhance therapeutic efficacy by reducing toxic side effects. DETAILED DESCRIPTION

[0025] This article generally involves four major categories of compounds: (4R)-sulfonylamino-L-prolinamide compounds; (4R)-acylamino-L-prolinamide compounds; (4R)-aromaticamino-L-prolinamide compounds; and 4-benzyloxy-L-prolinamide compounds.

[0026] The present invention provides (4R)-sulfonylamino-L-prolinamide compounds having a general formula (I) and pharmaceutically acceptable salts or solvates thereof.

[0027]

[0028] In a preferred embodiment, X, Y, and Z are all CH. In a preferred embodiment, X and Y are CH, and Z is N. In a preferred embodiment, X and Z are CH, and Y is N. In a preferred embodiment, Y and Z are CH, and X is N.

[0029] Wherein, R1 is selected from C 1-6 Alkyl, fluorinated C 1-6 Alkyl, C 3-6 Cycloalkyl, fluorinated C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl or fluorinated C 3-6 Heterocycloalkyl.

[0030] Wherein, R2 is selected from hydrogen, halogen, C 1-6 Alkyl, fluorinated C 1-6 Alkyl, C 3-6 Cycloalkyl, fluorinated C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl.

[0031] Wherein, R3 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl are each independently and optionally substituted with one substituent R4 or two substituents R4 and R5; or the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Two adjacent R4 and R5 substituents on a heterocycloalkyl, aryl or heteroaryl ring together with the atoms to which they are attached form a fused ring. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, -OCF3, -CN, -NO2, -OR a 、-COR a 、-CO2R a 、-OCOR a 、-NR a R b 、-SO2R a 、-SOR a 、-NRa CO2R b 、-OCON a R b 、-NR a COR b 、-CONR a R b 、-NR a CONR b R c 、-SO2NR a R b 、-NR a SO2R b or -NR a SO2NR b R c Here R a 、R b 、R c may be the same or different, and are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Heterocycloalkyl, aryl or heteroaryl.

[0032] In a preferred embodiment, R3 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl are each independently and optionally substituted by one substituent R4 or two substituents R4 and R5. Here, R4 and R5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -OCF3, -CN, -NO2, -OR a 、-CO2R a or-SO2R a More preferably, R a Selected from C 1-6 alkyl.

[0033] In a preferred embodiment, R1 is selected from R2 is selected from methyl, chloro; R3 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluorophenyl, 3-trifluorophenyl, 4-trifluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-nitro-4-methylphenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyano-4-fluorophenyl, 4-cyanophenyl, 4-sulfonephenyl, 4-methylformylphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methylpyrazole, 1-methylimidazole,

[0034] The term "alkyl" as used herein, unless a different number of atoms is specified, refers to a straight or branched hydrocarbon chain of 1 to 6 carbon atoms.

[0035] The term "cycloalkyl" used in the present invention refers to monocyclic alkyl, spirocyclic alkyl and bridged cycloalkyl groups consisting of 3 to 11 carbon atoms unless a different number of atoms is specified. The monocyclic alkyl, spirocyclic alkyl and bridged cycloalkyl groups may or may not contain alkyl substituents.

[0036] The term "heterocycloalkyl" as used in the present invention refers to a monocyclic heteroalkyl group, a spirocyclic heteroalkyl group and a bridged heteroalkyl group consisting of 2 to 9 carbon atoms and 1 to 2 heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms, etc.), unless a different number of atoms is specified. The monocyclic heteroalkyl group, the spirocyclic heteroalkyl group and the bridged heteroalkyl group may or may not contain an alkyl substituent.

[0037] The term "halogen" as used herein means fluorine, bromine, chlorine or iodine, especially fluorine and chlorine.

[0038] The term "fluoro" used in the present invention means that the alkyl, cycloalkyl and heterocycloalkyl groups substituted by fluorine may be mono-, poly- or per-halogenated.

[0039] The term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a completely conjugated π electron system.

[0040] The term "heteroaryl" as used herein refers to a non-all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a completely conjugated π electron system.

[0041] The "pharmaceutically acceptable salts" in the present invention include inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts and the like.

[0042] The compound of formula (I) in the present invention may exist in the form of hydrates, solvates, polymorphs and mixtures thereof.

[0043] The compound of formula (I) in the present invention may exist in an optically active form, in the form of a mixture of optical isomers, in the form of one or more atropisomers and a mixture thereof, or in the form of one or more tautomers and a mixture thereof.

[0044] The compounds of formula (I) provided by the present invention are suitable for treating diseases dependent on PI3K (especially PI3Kα), especially proliferative diseases, such as cancer, overgrowth lineage, polycythemia vera, essential thrombocythemia and myelofibrosis with myeloid metaplasia.

[0045] "Treatment" includes prophylactic (preventative) and therapeutic treatment, as well as the delaying of progression of the disease or disorder.

[0046] "PI3K-mediated diseases" (especially PI3Kα-mediated diseases) are especially such diseases that respond to the inhibition of PI3K, especially the inhibition of PI3Kα, in a beneficial manner (e.g., improvement of one or more symptoms, delay of disease onset, up to temporary or complete cure of the disease) (among the diseases treated, especially cancer, overgrowth lineages, polycythemia vera, essential thrombocythemia and myelofibrosis with myeloid metaplasia, etc.).

[0047] The present invention relates to cell proliferation diseases mediated by PI3K, and in particular, the compounds can be used to treat cancers in humans or animals (e.g., mice), including, for example, lung and bronchial cancer; prostate cancer; breast cancer; pancreatic cancer; colon and rectal cancer; thyroid cancer; liver and intrahepatic bile duct cancer; hepatocellular carcinoma; gastric cancer; glioma / glioblastoma; endometrial cancer; melanoma; kidney and renal pelvis cancer; bladder cancer; uterine corpus cancer; cervical cancer; ovarian cancer; multiple myeloma; esophageal cancer; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; brain cancer; oral and pharyngeal cancer; laryngeal cancer; small intestine cancer; non-Hodgkin's lymphoma; melanoma and villous colon adenoma, etc.

[0048] The present invention includes all combinations and subgroups of the specific groups defined herein, including substituents defined in the brief description below, exemplified in the various examples throughout the specification, and described in the appended claims.

[0049] The term "combination" refers to a fixed combination in dosage unit form, or a kit of parts for combined administration, wherein the compound of formula (I) and the combination partner (e.g., another drug) can be administered independently simultaneously or separately within time intervals, especially when these time intervals allow the combination partners to exhibit a synergistic effect (e.g., a synergistic effect). Such administration provides therapeutically effective levels of two or more drugs (compounds) in the patient (e.g., cocktail therapy).

[0050] The present invention provides a method for treating a cell proliferative disease such as cancer, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) alone or in combination with one or more other anticancer agents. In particular, the components are formulated together as a combination therapy or administered separately. Anticancer agents suitable for use with the compound of formula (I) include, but are not limited to, one or more selected from kinase inhibitors (such as gefitinib, erlotinib, etc.), antiestrogens (such as fulvestrant, tamoxifen, toremifene, raloxifene, anastrozole, etc.), antiandrogens (such as flutamide, bicalutamide, finasteride, aminoglutethimide, ketoconazole and corticosteroids, etc.), cancer chemotherapy drugs, alkylating agents, chelating agents, biological effect modifiers, cancer vaccines, compounds of substances used for antisense therapy, etc.

[0051] The present invention has confirmed through multiple experiments that the (4R)-sulfonylamino-L-prolineamides synthesized by the present invention can inhibit PI3Kα with high selectivity.

[0052] The preparation method of the (4R)-sulfonylamino-L-prolinamide compound having the general structural formula (I) provided by the present invention is prepared by the following steps, but is not limited to the following methods.

[0053] Synthesis of intermediate I

[0054]

[0055] A 2-aminothiazole derivative (raw material I) undergoes a substitution reaction with phenyl chloroformate to produce a carbamate compound (intermediate I). The base used in the reaction is diisopropylethylamine (DIPEA), the solvent is 1,4-dioxane, the reaction temperature is 40°C, and the reaction time is 12 hours.

[0056] An example of the synthesis of intermediate I is given below.

[0057] Synthesis of intermediate I-1

[0058] Phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate

[0059]

[0060] At room temperature, 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole (250 mg, 0.83 mmol) and DIPEA (360 μL, 2.07 mmol) were dissolved in anhydrous 1,4-dioxane. The temperature was raised to 40°C, and phenyl chloroformate (156 μL, 1.24 mmol) was slowly added dropwise. The reaction was continued for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was then dissolved in ethyl acetate and washed twice with 1N sodium hydroxide. The organic layer was collected and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 150 mg of an off-white solid in a 45% yield. 1 H NMR(400MHz,DMSO-d6)δ12.53(s,1H,NH),8.63(d,J=5.1Hz,1H,Ar-H),7.59(s,1H,Ar-H),7.50–7.41 (m,3H,Ar-H),7.36–7.21(m,3H,Ar-H),2.44(s,3H,CH3),1.62(s,6H,CH3×2); ESI-MS:m / z=422[M+H] + .

[0061] Synthesis of intermediate I-2

[0062] Phenyl(5-(2-(tert-butyl)pyridin-4-yl)-4-methylthiazol-2-yl)carbamate

[0063]

[0064] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 5-(2-(tert-butyl)pyridin-4-yl)-4-methylthiazol-2-amine. 120 mg of an off-white solid was obtained in a 47% yield. ESI-MS: m / z = 368 [M+H] + .

[0065] Synthesis of intermediate I-3

[0066] Phenyl (5-(2-cyclobutylpyridin-4-yl)-4-methylthiazol-2-yl)carbamate

[0067]

[0068] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 5-(2-cyclobutylpyridin-4-yl)-4-methylthiazol-2-amine. 132 mg of an off-white solid was obtained in a 51% yield. ESI-MS: m / z = 366 [M+H] + .

[0069] Synthesis of intermediate I-4

[0070] Phenyl(4-methyl-5-(2-(1-methylcyclopropyl)pyridin-4-yl)thiazol-2-yl)carbamate

[0071]

[0072] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 4-methyl-5-(2-(1-methylcyclopropyl)pyridin-4-yl)thiazol-2-amine. 126 mg of an off-white solid was obtained in a 48% yield. ESI-MS: m / z = 366 [M+H] + .

[0073] Synthesis of intermediate I-5

[0074] Phenyl(5-(2-(1-cyanocyclopropyl)pyridin-4-yl)-4-methylthiazol-2-yl)carbamate

[0075]

[0076] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 1-(4-(2-amino-4-methylthiazol-5-yl)pyridin-2-yl)cyclopropane-1-carbonitrile. 106 mg of an off-white solid was obtained in a 58% yield. ESI-MS: m / z = 377 [M+H]. + .

[0077] Synthesis of intermediate I-6

[0078] Phenyl(4-methyl-5-(2-(1-(trifluoromethyl)cyclopropyl)pyridin-4-yl)thiazol-2-yl)carbamate

[0079]

[0080] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1,-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 4-methyl-5-(2-(1-(trifluoromethyl)cyclopropyl)pyridin-4-yl)thiazol-2-amine. 125 mg of an off-white solid was obtained in a 47% yield. ESI-MS: m / z = 420 [M+H] + .

[0081] Synthesis of intermediate I-7

[0082] Phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrimidin-4-yl)thiazol-2-yl)carbamate

[0083]

[0084] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrimidin-4-yl)thiazol-2-amine. 118 mg of an off-white solid was obtained in a 51% yield. ESI-MS: m / z = 423 [M+H] + .

[0085] Synthesis of intermediate I-8

[0086] Phenyl(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate

[0087]

[0088] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-amine. 145 mg of an off-white solid was obtained in a 55% yield. ESI-MS: m / z = 369 [M+H] + .

[0089] Synthesis of intermediate I-9

[0090] Phenyl (5-(2-cyclopropylpyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate

[0091]

[0092] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 5-(2-cyclopropylpyrimidin-4-yl)-4-methylthiazol-2-amine. 135 mg of an off-white solid was obtained in a 51% yield. ESI-MS: m / z = 353 [M+H] + .

[0093] Synthesis of intermediate I-10

[0094] Phenyl(4-methyl-5-(2-(1-methylcyclopropyl)pyrimidin-4-yl)thiazol-2-yl)carbamate

[0095]

[0096] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 4-methyl-5-(2-(1-methylcyclopropyl)pyrimidin-4-yl)thiazol-2-amine. 128 mg of an off-white solid was obtained in a 52% yield. ESI-MS: m / z = 367 [M+H]. + .

[0097] Synthesis of intermediate I-11

[0098] Phenyl(5-(2-(azetidin-1-yl)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate

[0099]

[0100] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 5-(2-(azetidin-1-yl)pyrimidin-4-yl)-4-methylthiazol-2-amine. 133 mg of an off-white solid was obtained in a 49% yield. ESI-MS: m / z = 368 [M+H]. + .

[0101] Synthesis of intermediate I-12

[0102] Phenyl (5-(2-(diethylamino)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate

[0103]

[0104] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 5-(2-(diethylamino)pyrimidin-4-yl)-4-methylthiazol-2-amine. 111 mg of an off-white solid was obtained in a 32% yield. ESI-MS: m / z = 384 [M+H] + .

[0105] Synthesis of intermediate I-13

[0106] Phenyl(4-chloro-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate

[0107]

[0108] The synthesis method was the same as that for intermediate I-1, except that 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole was replaced with 4-chloro-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole-2-amine. 127 mg of an off-white solid was obtained in a 52% yield. ESI-MS: m / z = 442 [M+H]. + .

[0109] Synthesis of Intermediate II

[0110]

[0111] Tert-butyloxycarbonyl-protected (4R)-hydroxy-L-proline methyl ester (1) undergoes substitution reaction with methanesulfonic acid to obtain tert-butyloxycarbonyl-protected (4S)-methanesulfonate-L-proline methyl ester (2). The reagents used in the reaction are diisopropyl azodicarboxylate (DIDA), triethylamine (TEA), triphenylphosphine (PPh3), and toluene. The reaction temperature is 0-70°C and the reaction time is 6 hours.

[0112] The obtained product is then reacted with sodium azide (NaN3) to obtain tert-butyloxycarbonyl-protected (4R)-azido-L-proline methyl ester (3). The solvent used is N,N-dimethylformamide (DMF), the reaction temperature is 80°C, and the reaction time is 16 hours.

[0113] The tert-butyloxycarbonyl-protected (4R)-azido-L-proline methyl ester is then hydrolyzed with a base (sodium hydroxide, NaOH) to give the tert-butyloxycarbonyl-protected (4R)-azido-L-proline (4).

[0114] Subsequently, the tert-butyloxycarbonyl-protected (4R)-azido-L-proline was reacted with isobutyl chloroformate and ammonia (NH3·H2O) to obtain the tert-butyloxycarbonyl-protected (4R)-azido-L-prolineamide (5).

[0115] The tert-butyloxycarbonyl-protected (4R)-azido-L-prolinamide was reduced with hydrogen on palladium carbon to give the key intermediate II, namely the tert-butyloxycarbonyl-protected (4R)-amino-L-prolinamide (6).

[0116] An example of the synthesis of intermediate II is given below.

[0117] 1-(tert-Butyl)2-methyl(2S,4S)-4-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (2)

[0118]

[0119] This reaction was conducted in two parallel reactions: PPh3 (192.49 g, 733.88 mmol) was dissolved in 400 mL of toluene. Methanesulfonic acid (47.02 g, 489.25 mmol, 34.83 mL) and TEA (22.70 mL, 163.08 mmol) were then added to the solution. Compound 1 (100 g, 407.71 mmol) was dissolved in 400 mL of toluene. This solution was then added to the solution at 0-5°C. The temperature was maintained at 0-5°C, and DIAD (158.54 mL, 815.42 mmol) was slowly added dropwise. After addition, the temperature was raised to 70°C and the reaction was allowed to proceed for 6 hours. The reaction mixtures from the two parallel reactions were separated by 1 L of dichloromethane and 1 L of saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane three times, 1 L each time, and all the organic phases were combined and washed with brine twice, 1 L each time, and then dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude product. The crude product was triturated with 2 L of MTBE, the mixture was filtered, and the filtrate was concentrated to obtain a yellow oily mixture 2 (490 g, 37.60% yield).

[0120] 1-(tert-Butyl)2-methyl(2S,4R)-4-azidopyrrolidine-1,2-dicarboxylate (3)

[0121]

[0122] The reaction was conducted in two parallel reactions: Compound 3 (245 g, 757.67 mmol) was dissolved in 1 L of DMF. NaN3 (73.49 g, 1.13 mol) was added portionwise to the solution at 25°C. After addition, the temperature was raised to 80°C and the reaction was allowed to proceed for 16 hours. The reaction mixture was separated with 2 L of MTBE and 2 L of saturated sodium bicarbonate. The aqueous phase was extracted three times with 2 L of MTBE each time. All organic phases were combined and washed with brine twice (2 L each time), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was eluted by silica gel chromatography to obtain 3 (154 g, 569.77 mmol, 37.60% yield) as a yellow oil. 1 HNMR(400MHz, CDCl3)δ4.37-4.31(m,1H),4.28-4.23(m,1H),3.68(s,3H),3.54-3.49 (m,1H),3.43-3.38(m,1H),2.28-2.25(m,1H),2.02-1.96(m,1H),1.41-1.38(m,9H).

[0123] (2S,4R)-4-Azido-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (4)

[0124]

[0125] Compound 4 was dissolved in a mixed solvent of 1120 ml of THF and 560 ml of MeOH. NaOH (134.07 g, 3.35 mol) was dissolved in 560 ml of water. The sodium hydroxide solution was slowly added dropwise to the mixed solvent at 0-5°C. The temperature was raised to 25°C and the reaction was allowed to proceed for 16 hours. The organic solvent was removed by distillation under reduced pressure, and the aqueous layer was acidified to pH 3 with 5M hydrochloric acid. The reaction mixture was extracted with dichloromethane three times, 1 L each time. All organic phases were combined and washed with brine twice, 2 L each time, and then dried over anhydrous sodium sulfate. Filtered and distilled under reduced pressure to obtain 4 (125 g, 87% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ12.83-12.63(m,1H),4.38-4.30(m,1H),4.16-4.08(m,1H),3.63-3.57(m,1H),3. 56-3.46(m,1H),2.37-2.26(m,1H),2.17-2.04(m,1H),1.78-1.74(m,1H),1.39(s,4H),1.35-1.34(m,5H).

[0126] Tert-Butyl (2S,4R)-4-azido-2-carbamoylpyrrolidine-1-carboxylate (5)

[0127]

[0128] Compound 5 (125 g, 487.79 mmol) was dissolved in 1250 mL of THF. 4-Methylmorpholine (80.44 mL, 731.69 mmol) and isobutyl chloroformate (96.09 mL, 731.69 mmol) were added to the solution at -10°C. The reaction was allowed to proceed for 30 minutes while maintaining the temperature at -10°C. NH₃₃H₂O (134.18 mL, 975.58 mmol) was slowly added dropwise to the solution while maintaining the temperature at -10°C. After the addition was complete, the temperature was maintained and the reaction was continued for 30 minutes. The temperature was raised to 25°C and the reaction was continued for 2.5 hours. The reaction mixture was separated between 1 L of ethyl acetate and 0.8 L of water. The aqueous phase was extracted twice with 1 L of ethyl acetate. All organic phases were combined and washed with brine twice (1 L each time). The mixture was then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was eluted by silica gel chromatography to obtain compound 5 (113 g, 442.66 mmol, 90.75% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm 7.00-6.83(m,1H),6.18-5.53(m,1H),4.47-4.36(m,1H),4.24-4.15(m,1H), 3.72-3.35(m,2H),2.66-2.48(m,1H),2.40-2.06(m,1H),1.49-1.44(m,9H).

[0129] (2S,4R)-4-Amino-2-formylaminopyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate II, 6)

[0130]

[0131] This reaction was conducted in parallel: Compound 6 (44 g, 172.36 mmol) was dissolved in 440 mL of methanol. Pd / C (10.65 g, 6.65 mmol, 10% purity) was added to the solution under argon at 25°C. The reaction solution was degassed under vacuum, replaced with hydrogen several times, and allowed to react under H2 (15 psi) at 25°C for 16 hours. The reaction solution was filtered through a Celite pad, and the filter cake was washed three times with 1 L of methanol. The organic phase was collected and the solvent was removed by distillation under reduced pressure to yield 6 (60 g, 261.69 mmol, 75.91% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ7.36-7.19(m,1H),6.93-6.76(m,1H),5.75-5.74(m,1H),4.09-4.03(m,1H),3 .50-3.38(m,2H),3.17(s,1H),3.00-2.89(m,1H),2.21(s,1H),1.89-1.77(m,2H),1.41-1.32(m,9H).

[0132] Synthesis of intermediate III

[0133]

[0134] A tert-butyloxycarbonyl-protected (4R)-amino-L-prolinamide (6) undergoes a substitution reaction with xanthoxyl chloride or sulfonic anhydride to yield a sulfonylamino-containing compound (Intermediate III, 7). The base used in the reaction is diisopropylethylamine (DIPEA), the solvent is dichloromethane (DCM), the reaction temperature is room temperature, and the reaction time is 2 hours.

[0135] An example of the synthesis of intermediate III is given below.

[0136] Synthesis of intermediate III-1

[0137]

[0138] tert-Butyl (2S,4R)-2-Formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylate

[0139] At room temperature, tert-butyl (2S,4R)-4-amino-2-formylaminopyrrolidine-1-carboxylate (100 mg, 0.44 mmol) was dissolved in anhydrous dichloromethane, and methanesulfonic anhydride (76 mg, 0.44 mmol) was slowly added dropwise in an ice bath. The reaction was carried out at room temperature for two hours to obtain a crude product, which was purified by silica gel chromatography to obtain 120 mg of an off-white solid with a yield of 88%. 1 H NMR(400MHz,DMSO-d6)δ7.45–7.34(m,2H,NH),7.04–6.92(m,1H,NH),4.14–4.03(m,1H,CH),3.96–3.85(m,1H,CH),3.67–3.57(m ,1H,CH),3.20–3.08(m,1H,CH),2.93(s,3H,CH3),2.14–1.92(m,2H,CH),1.39(s,4H,CH),1.34(s,5H,CH); ESI-MS: m / z=308[M+H] + .

[0140] Synthesis of intermediate III-2

[0141] tert-Butyl (2S,4R)-2-Formylamino-4-(ethylsulfonylamino)pyrrolidine-1-carboxylate

[0142]

[0143] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by ethanesulfonyl chloride, to obtain 123 mg of an off-white solid with a yield of 87%. 1 H NMR(400MHz,DMSO-d6)δ7.45–7.32(m,2H,NH),7.01–6.89(m,1H,NH),4.13–4.06(m,1H,CH),3.93–3.84(m,1H,CH),3.65–3.57(m,1H,CH),3.20–3.1 2(m,1H,CH),3.01(q,J=7.3Hz,2H,CH2),2.15–1.95(m,2H,CH),1.39(s,4H,CH),1.34(s,5H,CH),1.18(t,J=7.3Hz,3H,CH3); ESI-MS:m / z=322[M+H] + .

[0144] Synthesis of intermediate III-3

[0145] tert-Butyl (2S,4R)-2-Formylamino-4-(cyclopropylsulfonylamino)pyrrolidine-1-carboxylate

[0146]

[0147] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by cyclopropylsulfonyl chloride, to obtain 120 mg of an off-white solid with a yield of 82%. 1 H NMR(400MHz,DMSO-d6)δ7.46–7.33(m,2H,NH),7.02–6.90(m,1H,NH),4.14–4.06(m,1H,CH),3.99–3.88(m,1H,CH),3.67–3.59(m,1H,CH),3.21 –3.13(m,1H,CH),2.60–2.52(m,1H,CH),2.18–1.97(m,2H,CH),1.39(s,4H,CH),1.34(s,5H,CH),1.00–0.85(m,4H,CH); ESI-MS: m / z=334[M+H] + .

[0148] Synthesis of intermediate III-4

[0149] tert-Butyl (2S,4R)-2-Formylamino-4-(cyclobutylsulfonylamino)pyrrolidine-1-carboxylate

[0150]

[0151] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by cyclobutanesulfonyl chloride, to obtain 112 mg of an off-white solid with a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ7.45–7.24(m,2H,NH),7.00–6.90(m,1H,NH),4.12–4.01(m,1H,CH),3.92–3.77(m,2H,CH),3.63–3.51(m,1 H,CH),3.16–3.03(m,1H,CH),2.31–2.14(m,4H,CH),2.05–1.81(m,4H,CH),1.39(s,4H,CH),1.34(s,5H,CH); ESI-MS: m / z=348[M+H] + .

[0152] Synthesis of intermediate III-5

[0153] tert-Butyl (2S,4R)-2-Formylamino-4-(cyclopentylsulfonylamino)pyrrolidine-1-carboxylate

[0154]

[0155] The synthesis method is the same as that of intermediate III-1, except that methanesulfonic anhydride is replaced with cyclopentylsulfonyl chloride to obtain 110 mg of an off-white solid with a yield of 63%. ESI-MS: m / z = 362 [M+H] + .

[0156] Synthesis of intermediate III-6

[0157] tert-Butyl (2S,4R)-2-Formylamino-4-(cyclohexylsulfonylamino)pyrrolidine-1-carboxylate

[0158]

[0159] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by cyclohexylsulfonyl chloride, to obtain 20 mg of an off-white solid with a yield of 12%. 1H NMR(400MHz,DMSO-d6)δ7.40–7.30(m,2H,NH),7.00–6.88(m,1H,NH),4.12–4.01(m ,1H,CH),3.90–3.80(m,1H,CH),3.62–3.54(m,1H,CH),3.16–3.06(m,1H,CH),2.92 –2.83(m,1H,CH),2.00–1.91(m,3H,CH),1.79–1.70(m,2H,CH),1.63–1.57(m,1H,C H),1.39(s,4H,CH),1.34(s,5H,CH),1.28–1.19(m,6H,CH); ESI-MS: m / z=376[M+H] + .

[0160] Synthesis of intermediate III-7

[0161] tert-Butyl (2S,4R)-2-carbamoyl-4-((tetrahydro-2H-pyran)-4-sulfonylamino)pyrrolidine-1-carboxylate

[0162]

[0163] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced with tetrahydropyran-4-sulfonyl chloride, to obtain 120 mg of an off-white solid with a yield of 69%. 1 H NMR(400MHz,DMSO-d6)δ7.57–7.46(m,1H,NH),7.43–7.33(m,1H,NH),7.03–6.92(m,1H,NH),4 .13–4.05(m,1H,CH),3.96–3.86(m,3H,CH),3.66–3.58(m,1H,CH),3.39–3.34(m,1H,CH),3.29 –3.23(m,1H,CH),3.17–3.09(m,1H,CH),2.14–2.05(m,1H,CH),2.03–1.96(m,1H,CH),1.87–1 .79(m,2H,CH),1.63–1.48(m,2H,CH),1.39(s,4H,CH),1.34(s,5H,CH); ESI-MS:m / z=378[M+H] + .

[0164] Synthesis of intermediate III-8

[0165] tert-Butyl (2S,4R)-2-Formylamino-4-(phenylsulfonylamino)pyrrolidine-1-carboxylate

[0166]

[0167] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by benzenesulfonyl chloride, to obtain 130 mg of an off-white solid with a yield of 80%. 1 H NMR(400MHz,DMSO-d6)δ8.08–8.02(m,1H,NH),7.84–7.77(m,2H,Ar-H),7.73–7.57( m,3H,Ar-H),7.40–7.27(m,1H,NH),6.99–6.85(m,1H,NH),4.06–3.98(m,1H,CH),3. 77–3.65(m,1H,CH),3.39–3.33(m,1H,CH),3.02–2.94(m,1H,CH),2.05–1.88(m,1H, CH),1.83–1.74(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=370[M+H] + .

[0168] Synthesis of intermediate III-9

[0169] tert-Butyl (2S,4R)-2-Formylamino-4-((2-fluorophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0170]

[0171] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 2-fluorobenzenesulfonyl chloride, to obtain 128 mg of an off-white solid with a yield of 75%. 1 H NMR(400MHz,DMSO-d6)δ8.46–8.29(m,1H,Ar-H),7.87–7.67(m,2H,NH),7.55 –7.28(m,3H,Ar-H),7.05–6.80(m,1H,NH),4.15–3.95(m,1H,CH),3.93–3.75( m,1H,CH),3.47–3.38(m,1H,CH),3.10–2.95(m,1H,CH),2.15–1.93(m,1H,CH ),1.92–1.73(m,1H,CH),1.32(d,J=9.2Hz,9H,CH3×3); ESI-MS:m / z=388[M+H] + .

[0172] Synthesis of intermediate III-10

[0173] tert-Butyl (2S,4R)-2-Formylamino-4-((3-fluorophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0174]

[0175] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 3-fluorobenzenesulfonyl chloride, to obtain 120 mg of an off-white solid with a yield of 70%. 1 H NMR(400MHz,DMSO-d6)δ8.25–8.16(m,1H,NH),7.75–7.64(m,2H,Ar-H),7.63–7.5 1(m,2H,Ar-H),7.42–7.30(m,1H,NH),7.03–6.85(m,1H,NH),4.09–3.99(m,1H,CH) ,3.78–3.68(m,1H,CH),3.37(s,1H,CH),3.05–2.95(m,1H,CH),2.07–1.87(m,1H,C H),1.87–1.75(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=388[M+H] + .

[0176] Synthesis of intermediate III-11

[0177] tert-Butyl (2S,4R)-2-Formylamino-4-((4-fluorophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0178]

[0179] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 4-fluorobenzenesulfonyl chloride, to obtain 125 mg of an off-white solid with a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ8.15–8.04(m,1H,NH),7.92–7.81(m,2H,Ar-H),7.51–7.42( m,2H,Ar-H),7.39–7.31(m,1H,NH),7.00–6.87(m,1H,NH),4.07–3.97(m,1H,CH),3. 74–3.63(m,1H,CH),3.41–3.35(m,1H,CH),3.04–2.89(m,1H,CH),2.04–1.90(m,1H, CH),1.85–1.72(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=388[M+H]+ .

[0180] Synthesis of intermediate III-12

[0181] tert-Butyl (2S,4R)-2-Formylamino-4-((2-(trifluoromethyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0182]

[0183] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 2-trifluoromethylbenzenesulfonyl chloride, to obtain 128 mg of an off-white solid with a yield of 64%. 1 H NMR (400MHz, DMSO-d6) δ8.48–8.37(m,1H,NH),8.10(d,J=7.6Hz,1H,Ar-H),8.00(d,J=7.3H z,1H,Ar-H),7.96–7.82(m,2H,Ar-H),7.42–7.30(m,1H,NH),7.01–6.87(m,1H,NH),4.12–4. 02(m,1H,CH),3.87–3.73(m,1H,CH),3.49–3.39(m,1H,CH),3.15–3.02(m,1H,CH),2.18–1.9 8(m,1H,CH),1.94–1.81(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=438[M+H] + .

[0184] Synthesis of intermediate III-13

[0185] tert-Butyl (2S,4R)-2-Formylamino-4-((3-(trifluoromethyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0186]

[0187] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 3-trifluoromethylbenzenesulfonyl chloride, to obtain 110 mg of an off-white solid with a yield of 57%. 1H NMR(400MHz,DMSO-d6)δ8.36–8.27(m,1H,NH),8.16–8.04(m,3H,Ar-H),7.89(t,J =7.4Hz,1H,Ar-H),7.40–7.31(m,1H,NH),7.01–6.88(m,1H,NH),4.08–3.98(m,1H ,CH),3.82–3.69(m,1H,CH),3.32–3.23(m,1H,CH),3.08–2.87(m,1H,CH),2.08–1 .89(m,1H,CH),1.86–1.77(m,1H,CH),1.31(s,9H,CH3×3); ESI-MS:m / z=438[M+H] + .

[0188] Synthesis of intermediate III-14

[0189] tert-Butyl (2S,4R)-2-Formylamino-4-((4-(trifluoromethyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0190]

[0191] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 4-trifluoromethylbenzenesulfonyl chloride, to obtain 120 mg of an off-white solid with a yield of 62%. 1 H NMR(400MHz,DMSO-d6)δ8.40–8.30(m,1H,NH),8.10–7.95(m,4H,Ar-H),7.44–7.32(m,1H,NH),7.03–6.88(m,1H),4.13–3.99(m,1H,CH),3.80–3.6 9(m,1H,CH),3.32–3.24(m,1H,CH),3.08–2.85(m,1H,CH),2.09–1.91(m,1H,CH),1.89–1.75(m,1H,CH),1.31(s,9H,CH3×3); ESI-MS: m / z=438[M+H] + .

[0192] Synthesis of intermediate III-15

[0193] tert-Butyl (2S,4R)-2-Formylamino-4-((2,4-dichlorophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0194]

[0195] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 2,4-dichlorobenzenesulfonyl chloride, to obtain 118 mg of an off-white solid with a yield of 61%. 1 H NMR(400MHz,DMSO-d6)δ8.52–8.40(m,1H,NH),8.04–7.95(m,1H,Ar-H),7.94–7.87(m,1H, Ar-H),7.71–7.61(m,1H,Ar-H),7.41–7.29(m,1H,NH),7.01–6.86(m,1H,NH),4.12–4.00( m,1H,CH),3.85–3.70(m,1H,CH),3.48–3.35(m,1H,CH),3.13–2.95(m,1H,CH),2.16–1.95 (m,1H,CH),1.89–1.74(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=438[M+H] + .

[0196] Synthesis of intermediate III-16

[0197] tert-Butyl (2S,4R)-2-Formylamino-4-((3,4-dichlorophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0198]

[0199] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 3,4-dichlorobenzenesulfonyl chloride, to obtain 115 mg of an off-white solid with a yield of 60%. 1 H NMR(400MHz,DMSO-d6)δ8.34–8.22(m,1H,NH),8.00(s,1H,Ar-H),7.92(d,J=8.1Hz,1H,Ar -H),7.77(d,J=8.6Hz,1H,Ar-H),7.44–7.32(m,1H,NH),7.03–6.89(m,1H,NH),4.09–3.99( m,1H,CH),3.80–3.68(m,1H,CH),3.43–3.36(m,1H,CH),3.10–2.92(m,1H,CH),2.10–1.91 (m,1H,CH),1.90–1.79(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=438[M+H] + .

[0200] Synthesis of intermediate III-17

[0201] tert-Butyl (2S,4R)-2-Formylamino-4-((2,5-dichlorophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0202]

[0203] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 2,5-dichlorobenzenesulfonyl chloride, to obtain 132 mg of an off-white solid with a yield of 68%. 1 H NMR(400MHz,DMSO-d6)δ8.62–8.50(m,1H,NH),7.93(s,1H,Ar-H),7.83–7.69(m,2 H,Ar-H),7.40–7.30(m,1H,NH),7.04–6.88(m,1H,NH),4.14–4.01(m,1H,CH),3.89 –3.76(m,1H,CH),3.45–3.37(m,1H,CH),3.10–3.01(m,1H,CH),2.17–1.96(m,1H,C H),1.91–1.77(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=438[M+H] + .

[0204] Synthesis of intermediate III-18

[0205] tert-Butyl (2S,4R)-2-Formylamino-4-((2-(trifluoromethoxy)phenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0206]

[0207] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 2-(trifluoromethoxy)benzenesulfonyl chloride to obtain 125 mg of an off-white solid with a yield of 63%. 1H NMR(400MHz,DMSO-d6)δ8.34–8.26(m,1H,NH),7.94(d,J=7.6Hz,1H,Ar-H),7.80(t,J=7.8Hz ,1H,Ar-H),7.63–7.54(m,2H,Ar-H),7.39–7.30(m,1H,NH),6.99–6.88(m,1H,NH),4.10–4.0 0(m,1H,CH),3.87–3.77(m,1H,CH),3.44–3.37(m,1H,CH),3.07–2.97(m,1H,CH),2.13–1.97 (m,1H,CH),1.89–1.77(m,1H,CH),11.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=454[M+H] + .

[0208] Synthesis of intermediate III-19

[0209] tert-Butyl (2S,4R)-2-Formylamino-4-((3-(trifluoromethoxy)phenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0210]

[0211] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced with 3-(trifluoromethoxy)benzenesulfonyl chloride to obtain 122 mg of an off-white solid with a yield of 61%. 1 H NMR(400MHz,DMSO-d6)δ8.34–8.26(m,1H,NH),7.87–7.68(m,4H,Ar-H),7.39–7.31(m,1H,NH),6.99–6.88(m,1H,NH),4.06–3.99(m,1H,CH),3.79–3. 68(m,1H,CH),3.40–3.35(m,1H,CH),3.04–2.90(m,1H,CH),2.05–1.88(m, 1H,CH),1.85–1.75(m,1H,CH),1.31(s,9H,CH3×3); ESI-MS: m / z=454[M+H] + .

[0212] Synthesis of intermediate III-20

[0213] tert-Butyl (2S,4R)-2-Formylamino-4-((4-(trifluoromethoxy)phenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0214]

[0215] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 4-(trifluoromethoxy)benzenesulfonyl chloride to obtain 133 mg of an off-white solid with a yield of 67%. 1 H NMR(400MHz,DMSO-d6)δ8.26–8.18(m,1H,NH),7.94(d,J=8.5Hz,2H,Ar-H),7.62(d,J =8.2Hz,2H,Ar-H),7.44–7.31(m,1H,NH),7.03–6.84(m,1H,NH),4.09–3.96(m,1H,CH) ,3.79–3.65(m,1H,CH),3.41–3.36(m,1H,CH),3.05–2.88(m,1H,CH),2.04–1.91(m,1 H,CH),1.86–1.75(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=454[M+H] + .

[0216] Synthesis of intermediate III-21

[0217] tert-Butyl (2S,4R)-2-Formylamino-4-((2-methoxyphenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0218]

[0219] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 2-methoxybenzenesulfonyl chloride, to obtain 116 mg of an off-white solid with a yield of 67%. 1 H NMR(400MHz,DMSO-d6)δ7.80–7.71(m,1H,NH),7.70–7.57(m,2H,Ar-H),7.40–7.19(m,2 H,Ar-H),7.14–7.04(m,1H,NH),7.00–6.84(m,1H,NH),4.09–3.98(m,1H,CH),3.89(s,3H ,CH3),3.84–3.70(m,1H,CH),3.31–3.25(m,1H,CH),3.03–2.91(m,1H,CH),2.10–1.87(m ,1H,CH),1.83–1.65(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=400[M+H] + .

[0220] Synthesis of intermediate III-22

[0221] tert-Butyl (2S,4R)-2-Formylamino-4-((3-methoxyphenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0222]

[0223] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 3-methoxybenzenesulfonyl chloride, to obtain 125 mg of an off-white solid with a yield of 71%. 1 H NMR(400MHz,DMSO-d6)δ8.09–8.00(m,1H,NH),7.58–7.48(m,1H,Ar-H),7.43–7.27(m,3 H,Ar-H),7.27–7.19(m,1H,NH),7.01–6.85(m,1H,NH),4.08–3.97(m,1H,CH),3.83(s,3H ,CH3),3.74–3.61(m,1H,CH),3.42–3.35(m,1H,CH),3.07–2.93(m,1H,CH),2.07–1.85(m ,1H,CH),1.85–1.72(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=400[M+H] + .

[0224] Synthesis of intermediate III-23

[0225] tert-Butyl (2S,4R)-2-Formylamino-4-((4-methoxyphenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0226]

[0227] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 4-methoxybenzenesulfonyl chloride, to obtain 129 mg of an off-white solid with a yield of 73%. 1H NMR(400MHz,DMSO-d6)δ7.92–7.81(m,1H,NH),7.73(d,J=8.6Hz,2H,Ar-H),7.42–7.29(m, 1H,NH),7.13(d,J=8.7Hz,2H,Ar-H),7.00–6.86(m,1H,NH),4.07–3.97(m,1H,CH),3.84(s ,3H,CH3),3.71–3.56(m,1H,CH),3.40–3.35(m,1H,CH),3.03–2.89(m,1H,CH),2.05–1.86 (m,1H,CH),1.84–1.72(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=400[M+H] + .

[0228] Synthesis of intermediate III-24

[0229] tert-Butyl (2S,4R)-2-formylamino-4-((4-methyl-3-nitrophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0230]

[0231] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced with 4-methyl-3-nitrobenzenesulfonyl chloride to obtain 116 mg of an off-white solid with a yield of 62%. 1 H NMR(400MHz,DMSO-d6)δ8.37–8.35(m,1H,Ar-H),8.34–8.29(m,1H,NH),8.07–7.97(m,1H,Ar-H ),7.83–7.72(m,1H,Ar-H),7.43–7.29(m,1H,NH),7.01–6.85(m,1H,NH),4.09–3.97(m,1H,CH) ,3.80–3.66(m,1H,CH),3.45–3.34(m,1H,CH),3.11–2.93(m,1H,CH),2.61(s,3H,CH3),2.12–1 .90(m,1H,CH),1.89–1.76(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=429[M+H] + .

[0232] Synthesis of intermediate III-25

[0233] tert-Butyl (2S,4R)-2-formylamino-4-((4-nitrophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0234]

[0235] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 4-nitrobenzenesulfonyl chloride, to obtain 134 mg of an off-white solid with a yield of 77%. 1 H NMR(400MHz,DMSO-d6)δ8.50–8.47(m,1H,NH),8.46–8.41(m,2H,Ar-H),8.06(d,J=8 .3Hz,2H,Ar-H),7.45–7.29(m,1H,NH),7.06–6.83(m,1H,NH),4.11–3.96(m,1H,CH), 3.83–3.70(m,1H,CH),3.46–3.38(m,1H,CH),3.10–2.95(m,1H,CH),2.10–1.90(m,1H ,CH),1.89–1.77(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=415[M+H] + .

[0236] Synthesis of intermediate III-26

[0237] tert-Butyl (2S,4R)-2-Formylamino-4-((2-cyanophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0238]

[0239] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 2-cyanobenzenesulfonyl chloride, to obtain 126 mg of an off-white solid with a yield of 73%. 1H NMR(400MHz,DMSO-d6)δ8.65–8.55(m,1H,NH),8.18–8.09(m,1H,Ar-H),8.08–8.00(m,1H,Ar-H) ,7.98–7.90(m,1H,Ar-H),7.89–7.82(m,1H,Ar-H),7.42–7.29(m,1H,NH),7.00–6.87(m,1H,NH), 4.12–4.02(m,1H,CH),3.90–3.75(m,1H,CH),3.50–3.38(m,1H,CH),3.13–3.01(m,1H,CH),2.20 –1.96(m,1H,CH),1.94–1.81(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS: m / z=395[M+H] + .

[0240] Synthesis of intermediate III-27

[0241] tert-Butyl (2S,4R)-2-Formylamino-4-((3-cyano-4-fluorophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0242]

[0243] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 3-cyano-4-fluorobenzenesulfonyl chloride, to obtain 127 mg of an off-white solid with a yield of 70%. 1 H NMR(400MHz,DMSO-d6)δ8.40–8.33(m,1H,Ar-H),8.32–8.25(m,1H,Ar-H),8.23–8.11(m,1 H,Ar-H),7.87–7.72(m,1H,NH),7.41–7.28(m,1H,NH),7.03–6.87(m,1H,NH),4.11–3.96( m,1H,CH),3.82–3.67(m,1H,CH),3.47–3.35(m,1H,CH),3.15–2.92(m,1H,CH),2.12–1.93 (m,1H,CH),1.90–1.76(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=413[M+H] + .

[0244] Synthesis of intermediate III-28

[0245] tert-Butyl (2S,4R)-2-Formylamino-4-((4-cyanophenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0246]

[0247] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 4-cyanobenzenesulfonyl chloride, to obtain 122 mg of an off-white solid with a yield of 70%. 1 H NMR(400MHz,DMSO-d6)δ8.45–8.31(m,1H,NH),8.11(d,J=7.8Hz,2H,Ar-H),7.97(d,J =8.1Hz,2H,Ar-H),7.42–7.27(m,1H,NH),7.00–6.84(m,1H,NH),4.11–3.95(m,1H,CH) ,3.82–3.66(m,1H,CH),3.43–3.35(m,1H,CH),3.07–2.89(m,1H,CH),2.10–1.88(m,1 H,CH),1.87–1.75(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=395[M+H] + .

[0248] Synthesis of intermediate III-29

[0249] tert-Butyl (2S,4R)-2-Formylamino-4-((4-(methylsulfonyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0250]

[0251] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with 4-(methylsulfonyl)benzenesulfonyl chloride to obtain 96 mg of an off-white solid with a yield of 62%. ESI-MS: m / z = 448 [M+H] + .

[0252] Synthesis of intermediate III-30

[0253] tert-Butyl (2S,4R)-2-Formylamino-4-((4-(methoxycarbonyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylate

[0254]

[0255] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with methyl 4-(chlorosulfonyl)benzoate to obtain 90 mg of an off-white solid with a yield of 68%. ESI-MS: m / z = 428 [M+H] + .

[0256] Synthesis of intermediate III-31

[0257] tert-Butyl (2S,4R)-2-formylamino-4-(pyridine-2-sulfonylamino)pyrrolidine-1-carboxylate

[0258]

[0259] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by pyridine-2-sulfonyl chloride, to obtain 106 mg of an off-white solid with a yield of 65%. 1 H NMR(400MHz,DMSO-d6)δ8.82–8.70(m,1H,Ar-H),8.34–8.20(m,1H,NH),8.10(t,J=7.3Hz,1H,Ar-H ),7.95(d,J=8.1Hz,1H,Ar-H),7.75–7.65(m,1H,Ar-H),7.42–7.27(m,1H,NH),6.99–6.84(m,1H,N H),4.10–3.99(m,1H,CH),3.99–3.87(m,1H,CH),3.46–3.36(m,1H,CH),3.07–2.96(m,1H,CH),2.1 1–1.93(m,1H,CH),1.90–1.75(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=371[M+H] + .

[0260] Synthesis of intermediate III-32

[0261] tert-Butyl (2S,4R)-2-Formylamino-4-(pyridine-3-sulfonylamino)pyrrolidine-1-carboxylate

[0262]

[0263] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by pyridine-3-sulfonyl chloride, to obtain 110 mg of an off-white solid with a yield of 67%. 1H NMR(400MHz,DMSO-d6)δ8.98(d,J=2.0Hz,1H,Ar-H),8.86(dd,J=4.8,1.5Hz,1H,Ar-H),8.47–8.37(m ,1H,NH),8.28–8.18(m,1H,NH),7.69(dd,J=8.0,4.8Hz,1H,Ar-H),7.45–7.35(m,1H,NH),7.03–6.85( m,1H,NH),4.10–4.02(m,1H,CH),3.82–3.73(m,1H,CH),3.64–3.57(m,1H,CH),3.08–2.99(m,1H,CH), 2.09–1.94(m,1H,CH),1.89–1.78(m,1H,CH),1.34(s,4H,CH),1.31(s,5H,CH); ESI-MS:m / z=371[M+H] + .

[0264] Synthesis of intermediate III-33

[0265] tert-Butyl (2S,4R)-2-Formylamino-4-(pyridine-4-sulfonylamino)pyrrolidine-1-carboxylate

[0266]

[0267] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with pyridine-4-sulfonyl chloride to obtain 101 mg of an off-white solid with a yield of 65%. ESI-MS: m / z = 371 [M+H] + .

[0268] Synthesis of intermediate III-34

[0269] tert-Butyl (2S,4R)-2-formylamino-4-((1-methyl-1H-pyrazole)-4-sulfonylamino)pyrrolidine-1-carboxylate

[0270]

[0271] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced with 1-methyl-1H-pyrazole-4-sulfonyl chloride to obtain 121 mg of an off-white solid with a yield of 74%. 1H NMR(400MHz,DMSO-d6)δ8.39–8.14(s,1H,Ar-H),7.81–7.75(m,1H,NH),7.74–7.69(s,1 H,Ar-H),7.46–7.27(m,1H,NH),7.08–6.81(m,1H,NH),4.11–3.99(m,1H,CH),3.89(s,3H ,CH3),3.75–3.61(m,1H,CH),3.52–3.39(m,1H,CH),3.18–3.03(m,1H,CH),2.14–1.93(m ,1H,CH),1.91–1.80(m,1H,CH),1.37(s,4H,CH),1.32(s,5H,CH); ESI-MS:m / z=374[M+H] + .

[0272] Synthesis of intermediate III-35

[0273] tert-Butyl (2S,4R)-2-Formylamino-4-((1-methyl-1H-pyrazole)-3-sulfonylamino)pyrrolidine-1-carboxylate

[0274]

[0275] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced by 1-methylpyrazole-3-sulfonyl chloride, to obtain 133 mg of an off-white solid with a yield of 81%. 1 H NMR(400MHz,DMSO-d6)δ8.10–7.98(m,1H,NH),7.89(s,1H,Ar-H),7.42–7.29(m,1H,N H),7.01–6.85(m,1H,NH),6.61(s,1H,Ar-H),4.10–4.00(m,1H,CH),3.92(s,3H,CH3) ,3.87–3.73(m,1H,CH),3.50–3.39(m,1H,CH),3.12–2.99(m,1H,CH),2.10–1.93(m,1 H,CH),1.92–1.81(m,1H,CH),1.37(s,4H,CH),1.32(s,5H,CH).ESI-MS:m / z=374[M+H] + .

[0276] Synthesis of intermediate III-36

[0277] tert-Butyl (2S,4R)-2-formylamino-4-((1-methyl-1H-imidazole)-4-sulfonylamino)pyrrolidine-1-carboxylate

[0278]

[0279] The synthesis method is the same as that of the synthetic intermediate III-1, except that methanesulfonic anhydride is replaced with 1-methyl-1H-imidazole-4-sulfonyl chloride to obtain 35 mg of an off-white solid with a yield of 21%. 1 H NMR(400MHz,DMSO-d6)δ7.82(d,J=9.3Hz,2H,Ar-H),7.40–7.36(m,1H,NH),7.24–7.12( m,1H,NH),6.99–6.87(m,1H,NH),4.58–4.47(m,1H,CH),4.10–4.02(m,1H,CH),3.71(s, 3H,CH3),3.45–3.39(m,1H,CH),3.09–3.01(m,1H,CH),2.66(s,3H,CH3),2.25–2.13(m, 1H,CH),1.83–1.75(m,1H,CH),1.37(s,4H,CH),1.32(s,5H,CH); ESI-MS:m / z=374[M+H] + .

[0280] Synthesis of intermediate III-37

[0281] tert-Butyl (2S,4R)-2-Formylamino-4-(thiophene-4-sulfonylamino)pyrrolidine-1-carboxylate

[0282]

[0283] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with thiophene-2-sulfonyl chloride to obtain 111 mg of an off-white solid with a yield of 55%. ESI-MS: m / z = 376 [M+H] + .

[0284] Synthesis of intermediate III-38

[0285] tert-Butyl (2S,4R)-2-Formylamino-4-(thiazole-4-sulfonylamino)pyrrolidine-1-carboxylate

[0286]

[0287] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with thiazole-2-sulfonyl chloride to obtain 98 mg of an off-white solid with a yield of 57%. ESI-MS: m / z = 377 [M+H] + .

[0288] Synthesis of intermediate III-39

[0289] tert-Butyl (2S,4R)-2-formylamino-4-((3,5-dimethylisoxazole)-4-sulfonylamino)pyrrolidine-1-carboxylate

[0290]

[0291] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride to obtain 98 mg of an off-white solid with a yield of 65%. ESI-MS: m / z = 389 [M+H] + .

[0292] Synthesis of intermediate III-40

[0293] tert-Butyl (2S,4R)-2-formylamino-4-((1,3,5-trimethyl-1H-pyrazole)-4-sulfonylamino)pyrrolidine-1-carboxylate

[0294]

[0295] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with pyridine-4-sulfonyl chloride to obtain 91 mg of an off-white solid with a yield of 59%. ESI-MS: m / z = 402 [M+H] + .

[0296] Synthesis of intermediate III-41

[0297] tert-Butyl (2S,4R)-2-Formylamino-4-(naphthalene-2-sulfonylamino)pyrrolidine-1-carboxylate

[0298]

[0299] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with naphthalene-2-sulfonyl chloride to obtain 101 mg of an off-white solid with a yield of 66%. ESI-MS: m / z = 420 [M+H] + .

[0300] Synthesis of intermediate III-42

[0301] tert-Butyl (2S,4R)-2-Formylamino-4-(quinoline-3-sulfonylamino)pyrrolidine-1-carboxylate

[0302]

[0303] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with quinoline-3-sulfonyl chloride to obtain 110 mg of an off-white solid with a yield of 59%. ESI-MS: m / z = 421 [M+H] + .

[0304] Synthesis of intermediate III-43

[0305] tert-Butyl (2S,4R)-2-Formylamino-4-(quinoline-6-sulfonylamino)pyrrolidine-1-carboxylate

[0306]

[0307] The synthesis method is the same as that for intermediate III-1, except that methanesulfonic anhydride is replaced with quinoline-6-sulfonyl chloride to obtain 115 mg of an off-white solid with a yield of 63%. ESI-MS: m / z = 421 [M+H] + .

[0308] Synthesis of intermediate III-44

[0309] tert-Butyl (2S,4R)-4-(benzo[d][1,3]dioxolane-5-sulfonylamino)-2-carbamoylpyrrolidine-1-carboxylate

[0310]

[0311] The synthesis method was the same as that for intermediate III-1, except that methanesulfonic anhydride was replaced with benzo[d][1,3]dioxole-5-sulfonyl chloride. 95 mg of an off-white solid was obtained with a yield of 56%. ESI-MS: m / z = 414 [M+H] + .

[0312] Synthesis of (4R)-sulfonylamino-L-prolinamide compounds (Examples 1-56)

[0313]

[0314] Intermediate III (7) is hydrolyzed under the action of trifluoroacetic acid (TFA) to obtain intermediate IV (8). The solvent used is dichloromethane (DCM), the reaction temperature is from zero to room temperature, and the reaction time is 1 hour.

[0315]

[0316] Intermediate I and intermediate IV (8) undergo a substitution reaction under alkaline conditions to obtain (4R)-sulfonylamino-L-prolinamides having the general structural formula (I). The base used in the reaction is diisopropylethylamine (DIPEA), the solvent used is 1,4-dioxane, the reaction temperature is 60°C, and the reaction time is 20 hours.

[0317] Synthesis of (4R)-amido-L-prolinamide compounds (Comparative Examples 1-6)

[0318]

[0319] An example of the synthesis of intermediate V is given below.

[0320] Synthesis of intermediate V-1

[0321] tert-Butyl (2S,4R)-2-carbamoyl-4-(4-(methoxycarbonyl)benzamido)pyrrolidine-1-carboxylate

[0322]

[0323] Monomethyl terephthalate (143 mg, 0.80 mmol), HOBT (108 mg, 0.80 mmol), and EDCI (230 mg, 1.20 mmol) were dissolved in anhydrous dichloromethane at room temperature and allowed to react for 2 hours. DIPEA (351 μL, 2.0 mmol) was then added to the solution at room temperature. After 10 minutes, tert-butyl (2S,4R)-4-amino-2-carbamoylpyrrolidine-1-carboxylate (200 mg, 0.87 mmol) was added at room temperature. The reaction was continued at room temperature for 3 hours. The reaction mixture was washed twice with saturated sodium bicarbonate. The organic layer was collected, concentrated in vacuo, and purified by column chromatography to obtain 170 mg of the target intermediate in a 55% yield. 1 H NMR(400MHz,DMSO-d6)δ8.78–8.71(m,1H,NH),8.03(d,J=8.3Hz,2H,Ar-H),7.99–7.92(m, 2H,Ar-H),7.40(d,J=4.9Hz,1H,NH),7.00(d,J=14.1Hz,1H,NH),4.61–4.43(m,1H,CH),4.2 5–4.12(m,1H,CH),3.87(s,3H,CH3),3.75–3.64(m,1H,CH),3.34–3.22(m,1H,CH),2.31–2. 13(m,1H,CH),2.15–2.02(m,1H,CH),1.37(d,J=13.8Hz,9H,CH3×3); ESI-MS:m / z=392[M+H] + .

[0324] Synthesis of intermediate V-2

[0325] tert-Butyl (2S,4R)-2-carbamoyl-4-(2-(4-(methoxycarbonyl)phenyl)acetylamino)pyrrolidine-1-carboxylate

[0326]

[0327] The synthesis method is the same as that of the synthetic intermediate V-1, except that monomethyl terephthalate is replaced by 4-(methoxycarbonyl)phenylacetic acid, to obtain 131 mg of an off-white solid with a yield of 33%. 1 H NMR (400MHz, DMSO-d6) δ8.44–8.36 (m, 1H, NH), 7.90 (d, J = 8.2Hz, 2H, Ar-H), 7.39 (d, J = 8. 1Hz,2H,Ar-H),7.37–7.34(m,1H,NH),6.97(d,J=19.9Hz,1H,NH),4.34–4.17(m,1H,CH),4 .19–4.04(m,1H,CH),3.84(s,3H,CH3),3.63–3.53(m,1H,CH),3.50(s,2H,CH2),3.19–3. 06(m,1H,CH),2.17–1.75(m,2H,CH),1.36(d,J=9.1Hz,9H,CH3×3); ESI-MS:m / z=406[M+H] + .

[0328] Synthesis of intermediate V-3

[0329] tert-Butyl (2S,4R)-2-carbamoyl-4-(8-methoxy-8-oxooctanoylamino)pyrrolidine-1-carboxylate

[0330]

[0331] The synthesis method is the same as that of the synthetic intermediate V-1, except that monomethyl terephthalate is replaced by monomethyl suberate, to obtain 98 mg of an off-white solid with a yield of 46%. 1H NMR (400MHz, DMSO-d6) δ8.03–7.96(m,1H,NH),7.35(d,J=11.2Hz,1H,NH),6.96(d,J=17.5Hz,1H ,NH),4.31–4.15(m,1H,CH),4.17–3.97(m,1H,CH),3.58(s,3H,CH3),3.56–3.50(m,1H,CH),3.14 –3.03(m,1H,CH),2.28(t,J=7.4Hz,2H,CH),2.03(t,J=7.3Hz,2H,CH),2.02–1.90(m,2H,CH),1. 53–1.43(m,4H,CH),1.36(d,J=16.2Hz,9H,CH3×3),1.28–1.18(m,4H,CH); ESI-MS:m / z=400[M+H] + .

[0332] Synthesis of intermediate V-4

[0333] tert-Butyl (2S,4R)-4-Benzoylamino-2-carbamoylpyrrolidine-1-carboxylate

[0334]

[0335] The synthesis method is the same as that of the synthetic intermediate V-1, except that monomethyl terephthalate is replaced by monomethyl suberate, to obtain 240 mg of an off-white solid with a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ8.64–8.49(m,1H,NH),7.87(d,J=5.2Hz,2H,Ar-H),7.59–7.53(m,1 H,Ar-H),7.53–7.45(m,2H,Ar-H),7.45–7.37(m,1H,NH),7.02(d,J=13.8Hz,1H,NH),4.61–4 .46(m,1H,CH),4.27–4.15(m,1H,CH),3.80–3.50(m,1H,CH),3.34–3.24(m,1H,CH),2.30–2 .15(m,1H,CH),2.15–2.03(m,1H,CH),1.40(d,J=13.9Hz,9H,CH3×3); ESI-MS:m / z=334[M+H] + .

[0336] Synthesis of intermediate V-5

[0337] tert-Butyl (2S,4R)-2-carbamoyl-4-(nicotinylamino)pyrrolidine-1-carboxylate

[0338]

[0339] The synthesis method is the same as that of the synthetic intermediate V-1, except that monomethyl terephthalate is replaced by nicotinic acid, to obtain 124 mg of an off-white solid with a yield of 62%. 1 H NMR(400MHz,DMSO-d6)δ8.99(s,1H,Ar-H),8.81–8.73(m,1H,NH),8.70(d,J=4.6Hz,1H,Ar-H),8. 18(d,J=7.9Hz,1H,Ar-H),7.54–7.47(m,1H,Ar-H),7.44–7.37(m,1H,NH),7.01(d,J=15.3Hz,1H, NH),4.57–4.43(m,1H,CH),4.23–4.13(m,1H,CH),3.77–3.64(m,1H,CH),3.33–3.21(m,1H,CH),2 .29–2.13(m,1H,CH),2.13–2.01(m,1H,CH),1.37(d,J=14.4Hz,9H,CH3×3); ESI-MS:m / z=335[M+H] + .

[0340] Synthesis of intermediate V-6

[0341] tert-Butyl (2S,4R)-2-carbamoyl-4-(isonicotinamido)pyrrolidine-1-carboxylate

[0342]

[0343] The synthesis method is the same as that of intermediate V-1, except that monomethyl terephthalate is replaced by isonicotinic acid, to obtain 130 mg of an off-white solid with a yield of 63%. 1H NMR(400MHz,DMSO-d6)δ8.99(s,1H,Ar-H),8.79–8.73(m,1H,NH),8.71(dd,J=4.8,1.6Hz,1H,Ar-H), 8.18(dd,J=7.9,1.7Hz,1H,Ar-H),7.51(dd,J=7.9,4.8Hz,1H,Ar-H),7.40(d,J=5.7Hz,1H,NH),7.00 (d,J=14.4Hz,1H,NH),4.62–4.42(m,1H,CH),4.31–4.11(m,1H,CH),3.84–3.63(m,1H,CH),3.20–3.0 4(m,1H,CH),2.28–2.15(m,1H,CH),2.16–2.00(m,1H,CH),1.40(s,9H,CH3×3); ESI-MS:m / z=335[M+H] + .

[0344] (4 R Synthesis of )-Aromatic Amino-L-Prolinamide Compounds (Comparative Example 7-Comparative Example 10)

[0345] Route 1:

[0346]

[0347] An example of the synthesis of intermediate VII is given below.

[0348] Synthesis of intermediate VII-1

[0349] tert-Butyl (2S,4R)-2-carbamoyl-4-(pyrimidin-2-ylamino)pyrrolidine-1-carboxylate

[0350]

[0351] Tert-butyl (2S,4R)-4-amino-2-carbamoylpyrrolidine-1-carboxylate (180 mg, 0.78 mmol) and 2-chloropyrimidine (75 mg, 0.66 mmol) were dissolved in isopropanol. DIPEA (228 μL, 1.32 mmol) was added to the solution at room temperature. The temperature was raised to 130°C and the reaction was continued for 10 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain the target intermediate (43 mg, 0.14 mmol, 20% yield). 1H NMR(400MHz,DMSO-d6)δ8.29(d,J=4.8Hz,2H,Ar-H),7.43–7.35(m,2H,NH),6.96(d,J=19.1Hz,1H,NH),6.61(t,J=4.8Hz,1H,Ar-H),4.51–4.38(m,1H, CH),4.19–4.12(m,1H,CH),3.75–3.63(m,1H,CH),3.25–3.13(m,1H,CH),2.19–2.01(m,2H,CH),1.36(d,J=11.9Hz,9H,CH3×3); ESI-MS:m / z=308[M+H] + .

[0352] Synthesis of intermediate VII-2

[0353] Methyl 2-(((3R,5S)-1-(tert-Butoxycarbonyl)-5-carbamoylpyrrolidin-3-yl)amino)pyrimidine-5-carboxylate

[0354]

[0355] Tert-butyl (2S,4R)-4-amino-2-carbamoylpyrrolidine-1-carboxylate (200 mg, 0.87 mmol) and methyl 2-chloropyrimidine-5-carboxylate (136 mg, 0.80 mmol) were dissolved in 1,4-dioxane. Triethylamine (330 μl, 2.38 mmol) was added to the solution at room temperature. The temperature was raised to 50°C and the reaction was continued for 2 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain the target intermediate (146 mg, 0.40 mmol, 50% yield). 1 HNMR(400MHz,DMSO-d6)δ8.74(d,J=22.3Hz,2H,Ar-H),8.41–8.33(m,1H,NH) ,7.45–7.35(m,1H,NH),7.05–6.90(m,1H,NH),4.63–4.43(m,1H,CH),4.19–4. 06(m,1H,CH),3.77(s,3H,CH3),3.72–3.64(m,1H,CH),3.25–3.14(m,1H,CH) ,2.20–2.00(m,2H,CH),1.34(d,J=11.9Hz,9H,CH3×3); ESI-MS:m / z=366[M+H] + .

[0356] Synthesis of intermediate VII-3

[0357] 6-(((3R,5S)-1-(tert-Butoxycarbonyl)-5-carbamoylpyrrolidin-3-yl)amino)nicotinate

[0358]

[0359] Tert-butyl (2S,4R)-4-amino-2-carbamoylpyrrolidine-1-carboxylate (500 mg, 2.18 mmol) and methyl 6-chloronicotinate (451 mg, 2.62 mmol) were dissolved in isopropanol. DIPEA (1.2 mL, 6.55 mmol) was added to the solution at room temperature. The temperature was raised to 150°C and the reaction was continued for 12 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain the target intermediate (76 mg, 0.21 mmol, 10% yield). 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H,Ar-H),7.81(d,J=8.9Hz,1H,NH),7.63(dd,J=12.9,6.4H z,1H,Ar-H),7.39(d,J=6.9Hz,1H,NH),6.97(d,J=19.8Hz,1H,NH),6.55–6.47(m,1H,Ar-H), 4.57–4.37(m,1H,CH),4.19–4.08(m,1H,CH),3.75(s,3H,CH3),3.73–3.63(m,1H,CH),3.22– 3.09(m,1H,CH),2.17–2.04(m,2H,CH),1.34(d,J=10.1Hz,9H,CH3×3); ESI-MS:m / z=307[M+H] + .

[0360] Route 2:

[0361]

[0362] Synthesis of intermediate X

[0363] tert-Butyl (2S,4R)-2-carbamoyl-4-(pyridin-2-ylamino)pyrrolidine-1-carboxylate

[0364]

[0365] Tert-butyl (2S,4R)-4-amino-2-carbamoylpyrrolidine-1-carboxylate (200 mg, 0.87 mmol) and 2-chloropyridine N-oxide (113 mg, 0.87 mmol) were dissolved in 2-methyl-2-butanol. Sodium bicarbonate (367 mg, 4.37 mmol) was added to the solution at room temperature. The temperature was raised to 120°C and the reaction was continued for 12 hours. After the reaction, the solid residue was removed by filtration and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated and purified by column chromatography to obtain the N-oxide intermediate IX (138 mg, 0.43 mmol, 20% yield). 1 H NMR (400 MHz, DMSO-d6) δ8.12 (d, J = 6.3 Hz, 1H, Ar-H), 7.44–7.32 (m, 1H, NH), 7.23 (t, J = 7.7 Hz,1H,Ar-H),7.15–6.95(m,2H,Ar-H),6.88–6.80(m,1H,NH),6.72–6.58(m,1H,NH),4.23–4.07(m,2H,CH) ,3.77–3.63(m,1H,CH),3.30–3.18(m,1H,CH),2.38–2.22(m,1H,CH),2.11–2.02(m,1H,CH),1.34(d,J=9.6 Hz,9H,CH3×3).

[0366] The resulting nitrogen oxide (50 mg, 0.16 mmol) and zinc were dissolved in 2 mL of tetrahydrofuran. 1 mL of aqueous ammonium chloride (200 mg / mL) was added to the solution at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 10 hours. After completion of the reaction, the pH was adjusted to approximately 8. The solid residue was removed by filtration, and the water and tetrahydrofuran were removed by vacuum distillation to obtain a crude product. The crude product was then separated and purified by column chromatography to yield the target intermediate X (39 mg, 0.13 mmol, 80% yield). 1 H NMR(400 MHz,dmso)δ7.95(s,1H,NH),7.42–7.26(m,2H.Ar-H),6.98–6.85(m,1H,NH),6.70(s,1H,NH),6.52–6.40(m,2H,Ar-H),4.46 –4.30(m,1H,CH),4.16–4.05(m,1H,CH),3.72–3.60(m,1H,CH),3.20–3.08(m,1H,CH),2.11–1.92(m,2H,CH),1.34(d,J=10.5 Hz, 9H, CH3×3); ESI-MS: m / z=307[M+H] + .

[0367] 4 - Synthesis of Benzyloxy-L-Prolinamide Compounds (Comparative Example 11-Comparative Example 16)

[0368]

[0369] An example of the synthesis of intermediate XI is given below.

[0370] Synthesis of intermediate XI-1

[0371] Benzyl (2S,4R)-1-(tert-Butyloxycarbonyl)-4-(benzyloxy)pyrrolidine-2-carboxylate

[0372]

[0373] (2S,4R)-1-(tert-Butyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (250 mg, 1.08 mmol) and NaH (52 mg, 2.16 mmol) were dissolved in DMF and reacted in an ice bath for 30 minutes. Benzyl bromide (193 μL, 1.62 mmol) was added and allowed to react at room temperature for 12 hours. After the reaction, ethyl acetate was added and the solution was washed with water. The organic layer was collected, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain the target intermediate (180 mg, 0.44 mmol, 41% yield). 1 H NMR(400MHz,DMSO-d6)δ7.57–7.02(m,10H,Ar-H),5.25–5.00(m,2H,CH),4.55–4.41(m,2H,CH),4.31–4.22(m,1H,CH),4.19–4.12(m ,1H,CH),3.50–3.40(m,2H,CH),2.45–2.30(m,1H,CH),2.12–1.85(m,1H,CH),1.32(d,J=46.8Hz,9H,CH3×3); ESI-MS:m / z=412[M+H] + .

[0374] Synthesis of intermediate XI-2

[0375] (2S,4R)-1-(tert-Butoxycarbonyl)-4-(3-trifluoromethylbenzyloxy)pyrrolidine-2-carboxylic acid (3-trifluoromethyl)benzyl ester

[0376]

[0377] The synthesis method was the same as that of the synthetic intermediate XI-1, and 300 mg of an off-white solid was obtained with a yield of 51%. 1H NMR(500MHz,DMSO-d6)δ7.92–7.42(m,8H,Ar-H),5.32–5.21(m,2H,CH),4.73–4.50(m,2H,CH),4.38–4.25(m,1H,CH),4.26–4.19(m ,1H,CH),3.57–3.43(m,2H,CH),2.49–2.37(m,1H,CH),2.19–1.94(m,1H,CH),1.30(d,J=69.2Hz,9H,CH3×3); ESI-MS:m / z=548[M+H] + .

[0378] Synthesis of intermediate XI-3

[0379] (2S,4R)-4-(4-trifluoromethyl)benzyl 1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylate

[0380]

[0381] The synthesis method was the same as that of the synthetic intermediate XI-1, and 250 mg of an off-white solid was obtained with a yield of 42%. 1 H NMR(500MHz,DMSO-d6)δ7.79–7.67(m,4H,Ar-H),7.64–7.52(m,4H,Ar-H),5.37–5.15(m,2H,CH),4.70–4.55(m,2H,CH),4.37–4.27(m,1H,Ar-H),4 .25–4.17(m,1H,Ar-H),3.59–3.44(m,2H,CH),2.49–2.42(m,1H,CH),2.14–1.99(m,1H,CH),1.31(d,J=60.9Hz,9H,CH3×3); ESI-MS:m / z=548[M+H] + .

[0382] Synthesis of intermediate XI-4

[0383] (2S,4R)-1-(tert-Butyloxycarbonyl)-4-(2,4-difluorobenzyloxy)pyrrolidine-2-carboxylic acid (2,4-difluoro)benzyl ester

[0384]

[0385] The synthesis method was the same as that of the synthetic intermediate XI-1, and 280 mg of an off-white solid was obtained with a yield of 54%. 1H NMR(400MHz,DMSO-d6)δ7.71–6.92(m,6H,Ar-H),5.44–5.08(m,2H,CH),4.68–4.46(m,2H,CH),4.33–4.12(m,2H,CH),3. 56–3.39(m,2H,CH),2.47–2.31(m,1H,CH),2.13–1.89(m,1H,CH),1.31(d,J=46.3Hz,9H,CH3×3); ESI-MS:m / z=484[M+H] + .

[0386] Synthesis of intermediate XI-5

[0387] (2S,4R)-1-(tert-Butyloxycarbonyl)-4-(3,4-difluorobenzyloxy)pyrrolidine-2-carboxylic acid (3,4-difluoro)benzyl ester

[0388]

[0389] The synthesis method was the same as that of the synthetic intermediate XI-1, and 270 mg of an off-white solid was obtained with a yield of 52%. 1 H NMR(400MHz,DMSO-d6)δ7.59–7.36(m,4H,Ar-H),7.35–7.13(m,2H,Ar-H),5.27–5.04(m,2H,CH),4.63–4.47(m,2H,CH),4.40–4.30(m,1H,CH),4 .27–4.17(m,1H,CH),3.60–3.44(m,2H,CH),2.45–2.30(m,1H,CH),2.17–1.95(m,1H,CH),1.37(d,J=47.9Hz,9H,CH3×3); ESI-MS:m / z=484[M+H] + .

[0390] Synthesis of intermediate XI-6

[0391] Benzyl (2S,4S)-1-(tert-Butyloxycarbonyl)-4-(benzyloxy)pyrrolidine-2-carboxylate

[0392]

[0393] The synthesis method was the same as that of the synthetic intermediate XI-1, and 300 mg of an off-white solid was obtained with a yield of 68%. 1H NMR(500MHz,DMSO-d6)δ7.59–7.05(m,10H,Ar-H),5.18–4.94(m,2H,CH),4.44–4.38(m,2H,CH),4.35(dd,J=9.3,3.1Hz,1H,CH),4.20–4.11(m,1H,C H),3.59–3.50(m,1H,CH),3.39–3.37(m,1H,CH),2.48–2.30(m,1H,CH),2.24–2.12(m,1H,CH),1.34(d,J=60.5Hz,9H,CH3×3); ESI-MS: m / z=412[M+H] + .

[0394] Provide the embodiment of synthetic final product below.These embodiment and above example are for illustration only, should not be construed as limiting the scope of the invention.In addition, should be understood that after reading content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the application's appended claims.

[0395] Example 1

[0396] (2S,4R)-4-(methylsulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0397]

[0398] Dissolve tert-butyl (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylate in anhydrous dichloromethane. Add an equal volume of trifluoroacetic acid dropwise with stirring in an ice bath. Allow to react at room temperature for 2 hours. Remove the solvent by distillation under reduced pressure to obtain (2S,4R)-4-(methylsulfonylamino)pyrrolidine-2-carboxamide (Intermediate IV). ESI-MS: m / z = 208 [M+H] + .

[0399] Phenyl (4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate (35 mg, 0.08 mmol) and DIPEA (42 μL, 0.16 mmol) were dissolved in anhydrous 1,4-dioxane at room temperature. The temperature was raised to 60°C, and (2S,4R)-4-(methylsulfonylamino)pyrrolidine-2-carboxamide (17 mg, 0.08 mmol) was slowly added dropwise. The reaction was allowed to react for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain 30 mg of an off-white solid in a 70% yield. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H,NH),8.61(d,J=5.1Hz,1H,Ar-H),7.56(s,1H,Ar-H) ,7.55–7.45(m,2H,NH),7.42(d,J=4.4Hz,1H,Ar-H),7.13–6.94(s,1H,NH),4.45–4.25(m, 1H,CH),4.10–3.97(m,1H,CH),3.95–3.82(m,1H,CH),3.45–3.37(m,1H,CH),2.98(s,3H, CH3),2.42(s,3H,CH3),2.20–2.03(m,2H,CH),1.62(s,6H,CH3×2); ESI-MS:m / z=535[M+H] + .

[0400] Example 2

[0401] (2S,4R)-4-(ethylsulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0402]

[0403] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(ethylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 33 mg of an off-white solid with a yield of 75%. 1H NMR(400MHz,DMSO-d6)δ11.11(s,1H,NH),8.61(d,J=5.1Hz,1H,Ar-H),7.61–7.58(m,1H,NH),7.56(s,1H, Ar-H),7.52–7.45(m,1H,NH),7.42(dd,J=5.2,1.3Hz,1H,Ar-H),7.09–6.98(m,1H,NH),4.42–4.26(m,1H, CH),4.06–3.94(m,1H,CH),3.93–3.83(m,1H,CH),3.66–3.54(m,1H,CH),3.05(q,J=7.2Hz,2H,CH2),2.42 (s,3H,CH3),2.21–1.98(m,2H,CH),1.62(s,6H,CH3×2),1.21(d,J=7.4Hz,3H,CH3); ESI-MS:m / z=549[M+H] + .

[0404] Example 3

[0405] (2S,4R)-4-(cyclopropylsulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0406]

[0407] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(cyclopropylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 31 mg of an off-white solid with a yield of 70%. 1H NMR(400MHz,DMSO-d6)δ11.11(s,1H,NH),8.61(d,J=5.1Hz,1H,Ar-H),7.56(s,1H,Ar-H),7.54(s,1H,NH), 7.55–7.52(m,1H,NH),7.42(dd,J=5.2,1.5Hz,1H,Ar-H),7.09–7.00(m,1H,NH),4.43–4.27(m,1H,CH),4.13 –3.97(m,1H,CH),3.95–3.85(m,1H,CH),3.46–3.40(m,1H,CH),2.63–2.55(m,1H,CH),2.42(s,3H,CH3),2.2 0–2.05(m,2H,CH),1.62(s,6H,CH3×2),1.29–1.22(m,3H,CH),1.04–0.99(m,1H,CH); ESI-MS:m / z=561[M+H] + .

[0408] Example 4

[0409] (2S,4R)-4-(cyclobutylsulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0410]

[0411] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(cyclobutylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 31 mg of an off-white solid with a yield of 70%. 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H,NH),8.60(d,J=4.4Hz,1H,Ar-H),7.55(s,1H,Ar-H),7.53 –7.44(m,2H,Ar-H),7.43–7.36(m,1H,NH),7.08–6.94(m,1H,NH),4.42–4.28(m,1H,CH),4.04–3 .94(m,1H,CH),3.93–3.78(m,2H,CH),3.31–3.24(m,1H,CH),2.41(s,3H,CH3),2.34–2.19(m,4 H,CH),2.14–2.00(m,2H,CH),1.97–1.82(m,2H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=575[M+H] + .

[0412] Example 5

[0413] (2S,4R)-4-(cyclopentylsulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0414]

[0415] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(cyclopentylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 25 mg of an off-white solid is obtained with a yield of 60%. ESI-MS: m / z = 589 [M+H] + .

[0416] Example 6

[0417]

[0418] (2S,4R)-4-(cyclohexylsulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0419] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(cyclohexylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 25 mg of an off-white solid with a yield of 52%. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H,NH),8.60(d,J=4.9Hz,1H,Ar-H),7.55(s,1H,Ar-H),7.53–7.44( m,2H,NH),7.41(d,J=3.6Hz,1H,Ar-H),7.08–6.98(m,1H,NH),4.42–4.21(m,1H,CH),4.08–3.92(m,1H ,CH),3.88–3.70(m,1H,CH),3.43–3.38(m,1H,CH),2.97–2.86(m,1H,CH),2.41(s,3H,CH3),2.14–1.9 6(m,4H,CH),1.84–1.73(m,2H,CH),1.61(s,6H,CH3×2),1.39–1.20(m,6H,CH); ESI-MS:m / z=603[M+H] + .

[0420] Example 7

[0421] (2S,4R)-4-((tetrahydro-2H-pyranyl)-4-sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0422]

[0423] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-carbamoyl-4-((tetrahydro-2H-pyran)-4-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 25 mg of an off-white solid with a yield of 52%. 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H,NH),8.60(d,J=5.0Hz,1H,Ar-H),7.66–7.58(m,1H,NH),7.55(s,1H,Ar-H),7. 51–7.45(m,1H,NH),7.41(d,J=4.3Hz,1H,Ar-H),7.08–6.97(m,1H,NH),4.41–4.27(m,1H,CH),4.07–3.99(m,1H,CH) ,3.94(dd,J=16.1,6.7Hz,2H,CH),3.89–3.78(m,1H,CH),3.44–3.37(m,2H,CH),3.29–3.18(m,1H,CH),2.41(s,3H,C H3),2.16–2.03(m,2H,CH),1.92–1.81(m,2H,CH),1.61(s,6H,CH3×2),1.60–1.49(m,2H,CH); ESI-MS:m / z=605[M+H] + .

[0424] Example 8

[0425] (2S,4R)-4-(phenylsulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0426]

[0427] This example adopts the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(phenylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 36 mg of off-white solid with a yield of 75%. NMR(400MHz,DMSO-d6)δ11.03(s,1H,NH),8.60(d,J=5.1Hz,1H,Ar-H),8.23–8.12(m,1H,NH),7.86–7.79(m ,2H,Ar-H),7.70–7.59(m,3H,Ar-H),7.54(s,1H,Ar-H),7.45–7.42(m,1H,NH),7.42–7.37(m,1H,Ar-H)7.0 4–6.90(m,1H,NH),4.40–4.15(m,1H,CH),3.90–3.74(m,1H,CH),3.72–3.60(m,1H,CH),3.47–3.37(m,1H,C H),2.40(s,3H,CH3),2.06–1.92(m,1H,CH),1.88–1.72(m,1H,CH),1.61(s,CH3×2); ESI-MS: m / z=597[M+H] + .

[0428] Example 9

[0429] (2S,4R)-4-((2-Fluorophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0430]

[0431] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((2-fluorophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 40 mg of an off-white solid with a yield of 75%. 1H NMR(400MHz,DMSO-d6)δ11.11(s,1H,NH),8.67–8.56(m,1H,Ar-H),8.54–8.41(m,1H,NH),7.90–7.78(m,1H, Ar-H),7.77–7.65(m,1H,Ar-H),7.60–7.53(m,1H,Ar-H),7.52–7.46(m,1H,NH),7.45–7.35(m,3H,Ar-H),7.0 7–6.87(m,1H,NH),4.46–4.20(m,1H,CH),4.06–3.85(m,1H,CH),3.77–3.57(m,1H,CH),3.45–3.37(m,1H,CH ),2.40(s,3H,CH3),2.12–1.96(m,1H,CH),1.93–1.73(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=615[M+H] + .

[0432] Example 10

[0433] (2S,4R)-4-((3-Fluorophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0434]

[0435] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((3-fluorophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 35 mg of an off-white solid with a yield of 71%. 1H NMR(400MHz,DMSO-d6)δ11.09(s,1H,NH),8.60(d,J=4.9Hz,1H,Ar-H),8.38–8.25(m,1H,NH),7.73–7 .66(m,2H,Ar-H),7.64–7.51(m,3H,Ar-H),7.49–7.43(m,1H,NH),7.42–7.36(m,1H),7.09–6.93(m,1H ,NH),4.42–4.20(m,1H,CH),3.94–3.76(m,1H,CH),3.73–3.58(m,1H,CH),3.43–3.37(m,1H,CH),2.40 (s,3H,CH3),2.06–1.94(m,1H,CH),1.90–1.76(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=615[M+H] + .

[0436] Example 11

[0437] (2S,4R)-4-((4-Fluorophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0438]

[0439] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((4-fluorophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 32 mg of an off-white solid with a yield of 69%. 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H,NH),8.60(d,J=4.7Hz,1H,Ar-H),8.28–8.17(m,1H,NH),7. 94–7.84(m,2H,Ar-H),7.60–7.52(m,1H,NH),7.50–7.35(m,4H,Ar-H),7.08–6.88(m,1H,NH),4.3 7–4.19(m,1H,CH),3.89–3.75(m,1H,CH),3.73–3.58(m,1H,CH),3.34–3.21(m,1H,CH),2.40(s,3 H,CH3),2.06–1.93(m,1H,CH),1.89–1.73(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=615[M+H] + .

[0440] Example 12

[0441] (2S,4R)-4-((2-(trifluoromethyl)phenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0442]

[0443] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((2-(trifluoromethyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 30 mg of an off-white solid with a yield of 56%. 1H NMR(400MHz,DMSO-d6)δ11.13(s,1H,NH),8.60(d,J=4.9Hz,1H,Ar-H),8.57–8.48(m,1H,NH),8.11(d,J=7.6Hz,1H, Ar-H),8.01(d,J=7.4Hz,1H,Ar-H),7.97–7.82(m,2H,Ar-H),7.55(s,1H,Ar-H),7.48–7.43(m,1H,NH),7.43–7.36(m ,1H,Ar-H),7.06–6.91(m,1H.NH),4.43–4.26(m,1H,CH),4.00–3.84(m,1H,CH),3.78–3.65(m,1H,CH),3.48–3.37(m ,1H,CH),2.40(s,3H,CH3),2.20–2.03(m,1H,CH),1.97–1.80(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=665[M+H] + .

[0444] Example 13

[0445] (2S,4R)-4-((3-(trifluoromethyl)phenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0446]

[0447] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((3-(trifluoromethyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 37 mg of an off-white solid with a yield of 70%. 1H NMR(400MHz,DMSO-d6)δ11.09(s,1H,NH),8.60(d,J=4.9Hz,1H,Ar-H),8.52–8.39(m,1H,NH),8.19–8.0 5(m,3H,Ar-H),7.89(t,J=7.7Hz,1H,Ar-H),7.60–7.52(m,1H,NH),7.50–7.37(m,2H,Ar-H),7.08–6.93( m,1H,NH),4.50–4.21(m,1H,CH),3.95–3.80(m,1H,CH),3.76–3.60(m,1H,CH),3.47–3.38(m,1H,CH),2. 40(s,3H,CH3),2.10–1.96(m,1H,CH),1.90–1.73(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=665[M+H] + .

[0448] Example 14

[0449] (2S,4R)-4-((4-(trifluoromethyl)phenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0450]

[0451] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((4-(trifluoromethyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 34 mg of an off-white solid with a yield of 64%. 1H NMR(400MHz,DMSO-d6)δ11.16(s,1H,NH),8.60(d,J=4.5Hz,1H,Ar-H),8.59–8.40(m,1H,NH),8.11(d,J=7.6Hz,1H, Ar-H),8.01(d,J=7.5Hz,1H,Ar-H),7.97–7.82(m,2H,Ar-H),7.55(s,1H,Ar-H),7.51–7.43(m,1H,NH),7.43–7.36(m ,1H,Ar-H),7.08–6.93(m,1H,NH),4.48–4.26(m,1H,CH),4.02–3.86(m,1H,CH),3.83–3.67(m,1H,CH),3.53–3.42(m ,1H,CH),2.40(s,3H,CH3),2.21–2.07(m,1H,CH),2.03–1.80(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=665[M+H] + .

[0452] Example 15

[0453] (2S,4R)-4-((2,4-dichlorophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0454]

[0455] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((2,4-dichlorophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 35 mg of an off-white solid with a yield of 66%. 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H,NH),8.60(d,J=4.8Hz,1H,Ar-H),8.58–8.49(m,1H,NH),8.03–7.95(m,1H,A r-H),7.86(s,1H,Ar-H),7.64(d,J=8.4Hz,1H,Ar-H),7.54(s,1H,Ar-H),7.48–7.42(m,1H,NH),7.42–7.37(m,1H, Ar-H),7.06–6.91(s,1H,NH),4.49–4.26(m,1H,CH),3.99–3.85(m,1H,CH),3.72–3.54(m,1H,CH),3.44–3.35(m,1 H,CH),2.40(s,3H,CH3),2.19–2.07(m,1H,CH),1.95–1.77(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=665[M+H] + .

[0456] Example 16

[0457] (2S,4R)-4-((3,4-dichlorophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0458]

[0459] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((3,4-dichlorophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 33 mg of an off-white solid with a yield of 62%. 1H NMR (400MHz, DMSO-d6) δ11.04 (s, 1H, NH), 8.60 (d, J = 4.1Hz 1H,Ar-H),8.46–8.35(m,1H,NH),7.99(s,1H,Ar-H),7.90(d,J=8.1Hz,1H,Ar-H),7.81–7.72(m,1H ,Ar-H),7.54(s,1H,Ar-H),7.48–7.43(m,1H,NH),7.42–7.37(m,1H,Ar-H),7.17–6.88(m,1H,NH), 4.38–4.21(m,1H,CH),3.95–3.76(m,1H,CH),3.74–3.56(m,1H,CH),3.43–3.37(m,1H,CH),2.40(s ,3H,CH3),2.12–1.97(m,1H,CH),1.92–1.78(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=665[M+H] + .

[0460] Example 17

[0461] (2S,4R)-4-((2,5-dichlorophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0462]

[0463] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((2,5-dichlorophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 30 mg of an off-white solid with a yield of 56%. 1H NMR(400MHz,DMSO-d6)δ11.07(s,1H,NH),8.71–8.63(m,1H,NH),8.60(d,J=4.8Hz,1H,Ar-H),7.95(s,1H,A r-H),7.80–7.68(m,2H,Ar-H),7.54(s,1H,Ar-H),7.49–7.43(m,1H,NH),7.43–7.35(m,1H,Ar-H),7.09–6. 91(m,1H,NH),4.50–4.20(m,1H,CH),4.08–3.81(m,1H,CH),3.84–3.54(m,1H,CH),3.47–3.387(m,1H,CH), 2.40(s,3H,CH3),2.19–2.03(m,1H,CH),1.94–1.77(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=665[M+H] + .

[0464] Example 18

[0465] (2S,4R)-4-((2-(trifluoromethoxy)phenyl)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0466]

[0467] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((2-(trifluoromethoxy)phenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 35 mg of an off-white solid with a yield of 64%. 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H,NH),8.58(d,J=5.1Hz,1H,Ar-H),8.45–8.35(m,1H,NH),7.94(d,J=7.3Hz,1H, Ar-H),7.78(t,J=7.6Hz,1H,Ar-H),7.62–7.55(m,2H,Ar-H),7.53(s,1H,Ar-H),7.46–7.41(m,1H,NH),7.40–7.35(m ,1H,Ar-H),7.02–6.93(m,1H,NH),4.38–4.23(m,1H,CH),4.01–3.85(m,1H,CH),3.76–3.66(m,1H,CH),3.42–3.37(m ,1H,CH),2.39(s,3H,CH3),2.11–1.99(m,1H,CH),1.90–1.77(m,1H,CH),1.59(s,6H,CH3×2); ESI-MS: m / z=681[M+H] + .

[0468] Example 19

[0469] (2S,4R)-4-((3-(trifluoromethoxy)phenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0470]

[0471] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((3-(trifluoromethoxy)phenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 32 mg of an off-white solid with a yield of 59%. 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H,NH),8.60(d,J=4.9Hz,1H,Ar-H),8.47–8.35(m,1H,NH),7.89–7 .68(m,4H,Ar-H),7.55(s,1H,Ar-H),7.47–7.43(m,1H,NH),7.42–7.35(m,1H,Ar-H),7.04–6.92(m,1H ,NH),4.36–4.21(m,1H,CH),3.92–3.78(m,1H,CH),3.73–3.59(m,1H,CH),3.43–3.36(m,1H,CH),2.40 (s,3H,CH3),2.05–1.92(m,1H,CH),1.87–1.73(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=681[M+H] + .

[0472] Example 20

[0473] (2S,4R)-4-((4-(trifluoromethoxy)phenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0474]

[0475] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((4-(trifluoromethoxy)phenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 29 mg of an off-white solid with a yield of 53%. 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H,NH),8.60(d,J=5.1Hz,1H,Ar-H),8.34(d,J=4.8Hz,1H,Ar-H),7.95(d,J= 8.6Hz,2H,Ar-H),7.61(d,J=8.2Hz,2H,Ar-H),7.54(s,1H,Ar-H),7.49–7.43(m,1H,NH),7.42–7.35(m,1H,Ar-H ),7.05–6.85(m,1H,NH),4.43–4.17(m,1H,CH),3.91–3.77(m,1H,CH),3.74–3.54(m,1H,CH),3.44–3.37(m,1H, CH),2.40(s,3H,CH3),2.09–1.93(m,1H,CH),1.89–1.72(m,1H,CH),1.61(s,6H,CH3×3); ESI-MS: m / z=681[M+H] + .

[0476] Example 21

[0477] (2S,4R)-4-((2-methoxyphenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0478]

[0479] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((2-methoxyphenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 35 mg of an off-white solid with a yield of 69%. 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H,NH),8.59(d,J=4.8Hz,1H,Ar-H),7.83–7.73(m,2H,Ar-H),7.62(t,J=7.7Hz,1 H,Ar-H),7.54(s,1H,Ar-H),7.47–7.37(m,2H,NH),7.24(d,J=8.3Hz,1H,Ar-H),7.08(t,J=7.5Hz,1H,Ar-H),7.04–6 .92(m,1H,NH),4.40–4.20(m,1H,CH),3.92(s,3H,CH3),3.91–3.85(m,1H,CH),3.76–3.64(m,1H,CH),3.39–3.36(m ,1H,CH),2.40(s,3H,CH3),2.07–1.93(m,1H,CH),1.79–1.67(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=627[M+H] + .

[0480] Example 22

[0481] (2S,4R)-4-((3-methoxyphenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0482]

[0483] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((3-methoxyphenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 33 mg of an off-white solid with a yield of 66%. 1H NMR(400MHz,DMSO-d6)δ11.13(s,1H,NH),8.60(d,J=4.0Hz,1H,Ar-H),8.24–8.12(m,1H,NH),7.58–7.49(m, 2H,Ar-H),7.47–7.36(m,3H,Ar-H),7.35–7.27(m,1H,NH),7.23(d,J=7.7Hz,1H,Ar-H),7.06–6.88(m,1H,NH) ,4.37–4.22(m,1H,CH),3.83(s,3H,CH3),3.81–3.75(m,1H,CH),3.75–3.60(m,1H,CH),3.43–3.37(m,1H,CH ),2.40(s,3H,CH3),2.08–1.94(m,1H,CH),1.84–1.70(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=627[M+H] + .

[0484] Example 23

[0485] (2S,4R)-4-((4-methoxyphenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0486]

[0487] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-4-((4-methoxyphenyl)sulfonamide)pyrrolidine-2-carboxamide to obtain 37 mg of an off-white solid with a yield of 73%. 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H,NH),8.60(s,1H,Ar-H),7.99(d,J=2.0Hz,1H,Ar-H),7.74(d,J= 4.3Hz,2H,Ar-H),7.54(s,1H,Ar-H),7.46–7.37(m,2H,NH),7.13(d,J=4.2Hz,2H,Ar-H),7.02–6.91(m ,1H,NH),4.34–4.19(m,1H,CH),3.84(s,3H,CH3),3.79–3.59(m,2H,CH),3.31–3.24(m,1H,CH),2.40 (s,3H,CH3),2.03–1.91(m,1H,CH),1.83–1.72(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=627[M+H] + .

[0488] Example 24

[0489] (2S,4R)-4-((4-methyl-3-nitrophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0490]

[0491] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((4-methyl-3-nitrophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 34 mg of an off-white solid with a yield of 65%. 1H NMR(400MHz,DMSO-d6)δ11.03(s,1H,NH),8.60(d,J=4.2Hz,1H,Ar-H),8.48–8.41(m,1H,NH),8.37(s,1H,Ar-H),8.02( d,J=7.6Hz,1H,Ar-H),7.76(d,J=7.9Hz,1H,Ar-H),7.54(s,1H,Ar-H),7.47–7.43(m,1H,NH),7.42–7.35(m,1H,Ar-H), 7.04–6.90(m,1H,NH),4.40–4.22(m,1H,CH),3.92–3.79(m,1H,CH),3.67–3.55(m,1H,CH),3.43–3.36(m,1H,CH),2.59 (s,3H,CH3),2.40(s,3H,CH3),2.10–1.99(m,1H,CH),1.89–1.78(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=656[M+H] + .

[0492] Example 25

[0493] (2S,4R)-4-((4-nitrophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0494]

[0495] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((4-nitrophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 34 mg of an off-white solid with a yield of 65%. 1H NMR(400MHz,DMSO-d6)δ11.03(s,1H,NH),8.60(d,J=4.2Hz,1H,Ar-H),8.48–8.41(m,1H,NH),8.37(s,1H,Ar-H),8.02( d,J=7.6Hz,1H,Ar-H),7.76(d,J=7.9Hz,1H,Ar-H),7.54(s,1H,Ar-H),7.47–7.43(m,1H,NH),7.42–7.35(m,1H,Ar-H), 7.04–6.90(m,1H,NH),4.40–4.22(m,1H,CH),3.92–3.79(m,1H,CH),3.67–3.55(m,1H,CH),3.43–3.36(m,1H,CH),2.59 (s,3H,CH3),2.40(s,3H,CH3),2.10–1.99(m,1H,CH),1.89–1.78(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=642[M+H] + .

[0496] Example 26

[0497] (2S,4R)-4-((2-cyanophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0498]

[0499] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((2-cyanophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 37 mg of an off-white solid with a yield of 74%. 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H,NH),8.79–8.68(m,1H,NH),8.60(d,J=3.4Hz,1H,Ar-H),8.14(t,J=8.0Hz,1H,Ar-H),8. 05(d,J=7.7Hz,1H,Ar-H),8.01–7.88(m,1H,Ar-H),7.85(t,J=7.3Hz,1H,Ar-H),7.63–7.52(m,1H,Ar-H),7.49–7.43(m,1H,N H),7.42–7.36(m,1H,Ar-H),7.07–6.95(m,1H,NH),4.39–4.25(m,1H,CH),4.11–3.92(m,1H,CH),3.77–3.64(m,1H,CH),3.47 –3.39(m,1H,CH),2.40(s,3H,CH3),2.17–2.05(m,1H,CH),2.00–1.87(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=622[M+H] + .

[0500] Example 27

[0501] (2S,4R)-4-((3-cyano-4-fluorophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0502]

[0503] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((3-cyano-4-fluorophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 28 mg of an off-white solid with a yield of 55%. 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H,NH),8.60(d,J=4.0Hz,1H,Ar-H),8.42(d,J=3.5Hz,1H,Ar-H),8.34(d,J=3.3Hz ,1H,Ar-H),8.20–8.13(m,1H,Ar-H),7.77(t,J=8.7Hz,1H,NH),7.55(s,1H,Ar-H),7.49–7.43(m,1H,NH),7.42–7.36( m,1H,Ar-H),7.06–6.93(m,1H,NH),4.37–4.21(m,1H,CH),3.96–3.83(m,1H,CH),3.64–3.52(m,1H,CH),3.35–3.28( m,1H,CH),2.41(s,3H,CH3),2.11–2.00(m,1H,CH),1.94–1.79(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=640[M+H] + .

[0504] Example 28

[0505] (2S,4R)-4-((4-cyanophenyl)sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0506]

[0507] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((4-cyanophenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 33 mg of an off-white solid with a yield of 66%. 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H,NH),8.60(d,J=3.4Hz,1H,Ar-H),8.56–8.45(m,1H,NH),8.10(d,J =5.5Hz,2H,Ar-H),7.98(d,J=4.7Hz,2H,Ar-H),7.55(s,1H,Ar-H),7.47–7.43(m,1H,NH),7.42–7.32(m, 1H,Ar-H),7.03–6.92(m,1H,NH),4.36–4.24(m,1H,CH),3.98–3.79(m,1H,CH),3.65–3.51(m,1H,CH),2. 41(s,3H,CH3),2.05–1.97(m,1H,CH),1.90–1.75(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=622[M+H] + .

[0508] Example 29

[0509] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-((4-(methylsulfonyl)phenyl)sulfonamido)pyrrolidine-1,2-dicarboxamide

[0510]

[0511] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((4-(methylsulfonyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 30 mg of an off-white solid is obtained in a 61% yield. ESI-MS: m / z = 675 [M+H]. + .

[0512] Example 30

[0513] Methyl 4-(N-((3R,5S)-5-carbamoyl-1-((4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidin-3-yl)aminosulfonyl)benzoate

[0514]

[0515] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((4-(methoxycarbonyl)phenyl)sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 31 mg of an off-white solid is obtained in a 60% yield. ESI-MS: m / z = 655 [M+H]. + .

[0516] Example 31

[0517] (2S,4R)-4-(pyridine-2-sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0518]

[0519] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(pyridine-2-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 28 mg of an off-white solid with a yield of 60%. 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H,NH),8.79–8.71(m,1H,Ar-H),8.60(d,J=4.9Hz,1H,Ar-H),8.42–8.34(m,1H,NH),8 .17–8.03(m,1H,Ar-H),7.99–7.89(m,1H,Ar-H),7.72–7.63(m,1H,Ar-H),7.54(s,1H,Ar-H),7.46–7.42(m,1H,NH),7.42 –7.35(m,1H,Ar-H),7.03–6.95(m,1H,NH),4.39–4.23(m,1H,CH),4.16–3.99(m,1H,CH),3.85–3.63(m,1H,CH),3.43–3. 36(m,1H,CH),2.40(s,3H,CH3),2.13–1.96(m,1H,CH),1.93–1.77(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=598[M+H] + .

[0520] Example 32

[0521] (2S,4R)-4-(pyridine-3-sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0522]

[0523] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(pyridine-3-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 30 mg of an off-white solid with a yield of 63%. 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H,NH),8.99(d,J=1.9Hz,1H,Ar-H),8.86(dd,J=4.8,1.5Hz,1H,Ar-H),8.60(d,J=5.1Hz,1H,A r-H),8.53–8.43(m,1H,NH),8.27–8.16(m,1H,Ar-H),7.68(dd,J=8.0,4.9Hz,1H,Ar-H),7.55(s,1H,Ar-H),7.47–7.43(m,1H,NH ),7.41(dd,J=5.1,1.0Hz,1H,Ar-H),7.05–6.90(m,1H,NH),4.45–4.20(m,1H,CH),3.95–3.80(m,1H,CH),3.71–3.56(m,2H,CH), 3.20–3.07(m,2H,CH),2.41(s,3H,CH3),2.10–1.96(m,1H,CH),1.94–1.80(m,1H,CH),1.62(s,6H,CH3×2); ESI-MS: m / z=598[M+H] + .

[0524] Example 33

[0525] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(pyridine-4-sulfonylamino)pyrrolidine-1,2-dicarboxamide

[0526]

[0527] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(pyridine-4-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 25 mg of an off-white solid is obtained in a 55% yield. ESI-MS: m / z = 598 [M+H] + .

[0528] Example 34

[0529] (2S,4R)-4-((1-methyl-1H-pyrazole)-4-sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0530]

[0531] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((1-methyl-1H-pyrazole)-4-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 30 mg of an off-white solid with a yield of 63%. 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H,NH),8.60(d,J=4.3Hz,1H,Ar-H),8.26(s,1H,Ar-H),7.97–7.87(m,1H,NH ),7.77–7.70(m,1H,Ar-H),7.55(s,1H,Ar-H),7.51–7.43(m,1H,NH),7.43–7.36(m,1H,Ar-H),7.05–6.94(m,1H ,NH),4.38–4.23(m,1H,CH),3.90(s,3H,CH3),3.86–3.78(m,1H,CH),3.76–3.65(m,1H,CH),3.43–3.38(m,1H, CH),2.40(s,3H,CH3),2.09–1.99(m,1H,CH),1.96–1.79(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=601[M+H] + .

[0532] Example 35

[0533] (2S,4R)-4-((1-methyl-1H-pyrazole)-3-sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0534]

[0535] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((1-methyl-1H-pyrazole)-3-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 33 mg of an off-white solid with a yield of 68%. 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H,NH),8.60(d,J=5.0Hz,1H,Ar-H),8.23–8.13(m,1H,NH),7.95–7.82(m,1H,A r-H),7.55(s,1H,Ar-H),7.51–7.44(m,1H,NH),7.40(d,J=3.7Hz,1H,Ar-H),7.12–6.90(m,1H,NH),6.67–6.58(m, 1H,Ar-H),4.40–4.24(m,1H,CH),3.94(s,3H,CH3),3.93–3.87(m,1H,CH),3.81–3.67(m,1H,CH),3.64–3.51(m,1 H,CH),2.40(s,3H,CH3),2.11–1.98(m,1H,CH),1.93–1.78(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=601[M+H] + .

[0536] Example 36

[0537] (2S,4R)-4-((1-methyl-1H-imidazole)-4-sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0538]

[0539] This example adopts the same implementation method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((1-methyl-1H-imidazole)-4-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 25 mg of an off-white solid with a yield of 50%. 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H,NH),8.60(d,J=4.8Hz,1H,Ar-H),7.97–7.89(m,1H,NH),7.80(s,1H ,Ar-H),7.75(s,1H,Ar-H),7.54(s,1H,Ar-H),7.46–7.42(m,1H,NH),7.42–7.37(m,1H,Ar-H),7.02–6.92 (m,1H,NH),4.37–4.20(m,1H,CH),3.94–3.83(m,1H,CH),3.71(s,3H,CH3),3.71–3.66(m,1H,CH),3.41– 3.37(m,1H,CH),2.09–1.97(m,1H,CH),1.93–1.79(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=601[M+H] + .

[0540] Example 37

[0541] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(thiophene-2-sulfonylamino)pyrrolidine-1,2-dicarboxamide

[0542]

[0543] This example adopts the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(thiophene-4-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain 21 mg of an off-white solid with a yield of 50%. ESI-MS: m / z = 603 [M+H] + .

[0544] Example 38

[0545] (2S,4R)-N 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(thiazole-2-sulfonylamino)pyrrolidine-1,2-dicarboxamide

[0546]

[0547] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(thiazole-4-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 31 mg of an off-white solid is obtained with a yield of 62%. ESI-MS: m / z = 604 [M+H]. + .

[0548] Example 39

[0549] (2S,4R)-4-((3,5-dimethylisoxazole)-4-sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0550]

[0551] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((3,5-dimethylisoxazole)-4-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 29 mg of an off-white solid is obtained in a 60% yield. ESI-MS: m / z = 616 [M+H] + .

[0552] Example 40

[0553] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-((1,3,5-trimethyl-1H-pyrazole)-4-sulfonylamino)pyrrolidine-1,2-dicarboxamide

[0554]

[0555] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-((1,3,5-trimethyl-1H-pyrazole)-4-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 27 mg of an off-white solid is obtained in a 59% yield. ESI-MS: m / z = 629 [M+H] + .

[0556] Example 41

[0557] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(naphthalene-2-sulfonylamino)pyrrolidine-1,2-dicarboxamide

[0558]

[0559] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(naphthalene-2-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 27 mg of an off-white solid is obtained in a 54% yield. ESI-MS: m / z = 647 [M+H]. + .

[0560] Example 42

[0561] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(quinoline-3-sulfonylamino)pyrrolidine-1,2-dicarboxamide

[0562]

[0563] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(quinoline-3-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 33 mg of an off-white solid is obtained in a 58% yield. ESI-MS: m / z = 648 [M+H]. + .

[0564] Example 43

[0565] (2S,4R)-N 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(quinoline-6-sulfonylamino)pyrrolidine-1,2-dicarboxamide

[0566]

[0567] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-2-formylamino-4-(quinoline-6-sulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. 31 mg of an off-white solid is obtained with a yield of 56%. ESI-MS: m / z = 648 [M+H]. + .

[0568] Example 44

[0569] (2S,4R)-4-(Benzo[d][1,3]dioxolane-5-sulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0570]

[0571] This example uses the same method as Example 1, except that (2S,4R)-2-formylamino-4-(methylsulfonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2S,4R)-4-(benzo[d][1,3]dioxole-5-sulfonylamino)-2-carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester. 31 mg of an off-white solid is obtained with a yield of 57%. ESI-MS: m / z = 641 [M+H]. + .

[0572] Example 45

[0573] (2S,4R)-N 1 -(5-(2-(tert-butyl)pyridin-4-yl)-4-methylthiazol-2-yl)-4-(cyclopropanesulfonylamino)pyrrolidine-1,2-dicarboxamide

[0574]

[0575] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(5-(2-(tert-butyl)pyridin-4-yl)-4-methylthiazol-2-yl)carbamate. 27 mg of an off-white solid is obtained, with a yield of 51%. ESI-MS: m / z = 507 [M+H]. + .

[0576] Example 46

[0577] (2S,4R)-N 1 -(5-(2-cyclobutylpyridin-4-yl)-4-methylthiazol-2-yl)-4-(cyclopropanesulfonylamino)pyrrolidine-1,2-dicarboxamide

[0578]

[0579] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(5-(2-cyclobutylpyridin-4-yl)-4-methylthiazol-2-yl)carbamate. 25 mg of an off-white solid is obtained in a 49% yield. ESI-MS: m / z = 505 [M+H]. + .

[0580] Example 47

[0581] (2S,4R)-4-(cyclopropylsulfonylamino)-N 1 -(4-methyl-5-(2-(1-methylcyclopropyl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0582]

[0583] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(4-methyl-5-(2-(1-methylcyclopropyl)pyridin-4-yl)thiazol-2-yl)carbamate. 20 mg of an off-white solid is obtained in a 45% yield. ESI-MS: m / z = 505 [M+H]. + .

[0584] Example 48

[0585] (2S,4R)-N 1-(5-(2-(1-cyanocyclopropyl)pyridin-4-yl)-4-methylthiazol-2-yl)-4-(cyclopropylsulfonamido)pyrrolidine-1,2-dicarboxamide

[0586]

[0587] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(5-(2-(1-cyanocyclopropyl)pyridin-4-yl)-4-methylthiazol-2-yl)carbamate. 25 mg of an off-white solid is obtained in a 48% yield. ESI-MS: m / z = 516 [M+H]. + .

[0588] Example 49

[0589] (2S,4R)-4-(cyclopropylsulfonylamino)-N 1 -(4-methyl-5-(2-(1-(trifluoromethyl)cyclopropyl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0590]

[0591] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(4-methyl-5-(2-(1-(trifluoromethyl)cyclopropyl)pyridin-4-yl)thiazol-2-yl)carbamate. 23 mg of an off-white solid is obtained, with a yield of 46%. ESI-MS: m / z = 559 [M+H]. + .

[0592] Example 50

[0593] (2S,4R)-4-(cyclopropylsulfonylamino)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyrimidin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0594]

[0595] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyrimidin-4-yl)thiazol-2-yl)carbamate. 20 mg of an off-white solid is obtained in a 44% yield. ESI-MS: m / z = 562 [M+H]. + .

[0596] Example 51

[0597] (2S,4R)-N 1 -(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)-4-(cyclopropanesulfonylamino)pyrrolidine-1,2-dicarboxamide

[0598]

[0599] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate. 25 mg of an off-white solid is obtained in a 50% yield. ESI-MS: m / z = 508 [M+H]. + .

[0600] Example 52

[0601] (2S,4R)-4-(cyclopropanesulfonylamino)-N 1 -(5-(2-cyclopropylpyrimidin-4-yl)-4-methylthiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0602]

[0603] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(5-(2-cyclopropylpyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate. 28 mg of an off-white solid is obtained in a 52% yield. ESI-MS: m / z = 492 [M+H]. + .

[0604] Example 53

[0605] (2S,4R)-4-(cyclopropylsulfonylamino)-N 1 -(4-methyl-5-(2-(1-methylcyclopropyl)pyrimidin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0606]

[0607] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(4-methyl-5-(2-(1-methylcyclopropyl)pyrimidin-4-yl)thiazol-2-yl)carbamate. 28 mg of an off-white solid is obtained, with a yield of 52%. ESI-MS: m / z = 506 [M+H]. + .

[0608] Example 54

[0609] (2S,4R)-N 1 -(5-(2-(azetidin-1-yl)pyrimidin-4-yl)-4-methylthiazol-2-yl)-4-(cyclopropylsulfonylamino)pyrrolidine-1,2-dicarboxamide

[0610]

[0611] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(5-(2-(azetidin-1-yl)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate. 21 mg of an off-white solid is obtained in a 44% yield. ESI-MS: m / z = 507 [M+H]. + .

[0612] Example 55

[0613] (2S,4R)-4-(cyclopropanesulfonylamino)-N 1 -(5-(2-(diethylamino)pyrimidin-4-yl)-4-methylthiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0614]

[0615] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(5-(2-(diethylamino)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate. 21 mg of an off-white solid is obtained in a 44% yield. ESI-MS: m / z = 523 [M+H]. + .

[0616] Example 56

[0617] (2S,4R)-N 1 -(4-chloro-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(cyclopropylsulfonylamino)pyrrolidine-1,2-dicarboxamide

[0618]

[0619] This example uses the same method as Example 1, except that phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate is replaced with phenyl(4-chloro-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate. 26 mg of an off-white solid is obtained, with a yield of 51%. ESI-MS: m / z = 581 [M+H]. + .

[0620] Comparative Example 1

[0621] Methyl 4-(((3R,5S)-5-carbamoyl-1-((4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidin-3-yl))carbamoyl)benzoate

[0622]

[0623] This example adopts the same method as Example 1 to obtain 40 mg of off-white solid, with a yield of 50%. 1HNMR (400MHz, DMSO-d6) δ11.18(s,1H,NH),8.85(d,J=5.9Hz,1H,Ar-H),8.60(d,J=5.0Hz,1H,Ar-H),8.04(d,J= 8.2Hz,2H,Ar-H),7.97(d,J=8.2Hz,2H,Ar-H),7.55(s,1H,NH),7.48(s,1H,NH),7.41(d,J=4.9Hz,1H,Ar-H),7.0 4(s,1H,NH),4.67–4.53(m,1H,CH),4.47–4.33(m,1H),3.95–3.90(m,1H,CH),3.88(s,3H,CH3),3.60–3.47(m,1H ,CH),2.41(s,3H,CH3),2.34–2.20(m,1H,CH),2.18–2.03(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=619[M+H] + .

[0624] Comparative Example 2

[0625] Methyl 4-(2-(((3R,5S)-5-carbamoyl-1-((4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidin-3-yl)amino)-2-oxoethyl)benzoate

[0626]

[0627] This example adopts the same method as Example 1 to obtain 42 mg of off-white solid, with a yield of 58%. 1 HNMR(400MHz,DMSO-d6)δ11.05(s,1H,NH),8.61(d,J=5.1Hz,1H,Ar-H),8.50(d,J=6.2Hz,1H,Ar-H) ,7.87(d,J=8.0Hz,2H,Ar-H),7.56(s,1H,Ar-H),7.46(s,1H,NH),7.43–7.36(m,3H,Ar-H),7.02(s,1 H,NH),4.50–4.27(m,2H,CH),3.81(s,3H,CH3),3.77–3.69(m,1H,CH),3.54–3.48(m,2H,CH),3.46– 3.38(m,1H,CH),2.41(s,3H,CH3),2.15–1.94(m,2H,CH),1.62(s,6H,CH3×2); ESI-MS:m / z=633[M+H]+ .

[0628] Comparative Example 3

[0629] Methyl 8-(((3R,5S)-5-carbamoyl-1-((4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidin-3-yl)amino)-8-oxooctanoate

[0630]

[0631] This example adopts the same method as Example 1 to obtain 38 mg of off-white solid, with a yield of 50%. 1 HNMR (400MHz, DMSO-d6) δ11.17(s,1H,NH),8.60(d,J=5.1Hz,1H,Ar-H),8.07(d,J=7.0Hz,1H,Ar-H),7 .55(s,1H,Ar-H),7.47–7.35(m,2H,NH),7.06–6.96(m,1H,NH),4.45–4.20(m,2H,CH),3.87–3.65(m,1 H,CH),3.57(s,3H,CH3),3.40–3.35(m,1H,CH),2.41(s,3H,CH3),2.27(t,J=7.4Hz,2H,CH),2.10–1.9 5(m,4H,CH),1.62(s,6H,CH3×2),1.53–1.41(m,4H,CH),1.27–1.19(m,4H,CH); ESI-MS:m / z=627[M+H] + .

[0632] Comparative Example 4

[0633] (2S,4R)-4-Benzoylamino-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0634]

[0635] This example adopts the same method as Example 1 to obtain 33 mg of off-white solid, with a yield of 50%. 1HNMR (400MHz, DMSO-d6) δ11.24(s,1H,NH),8.64(d,J=7.0Hz,1H,Ar-H),8.61(d,J=5.1Hz,1H,Ar-H),7.87(s,1H,Ar -H),7.85(d,J=1.4Hz,1H,Ar-H),7.66(s,1H,NH),7.59–7.51(m,2H,Ar-H),7.51–7.44(m,3H,Ar-H),7.42(dd,J=5. 2,1.5Hz,1H,Ar-H),7.05(s,1H,NH),7.03(s,1H,NH),4.76–4.34(m,2H,CH),4.00–3.79(m,1H,CH),3.59–3.51(m,1 H,CH),2.42(s,3H,CH3),2.33–2.23(m,1H,CH),2.18–2.06(m,1H,Ar-H),1.62(s,6H,CH3×2); ESI-MS: m / z=561[M+H] + .

[0636] Comparative Example 5

[0637] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(nicotinylamino)pyrrolidine-1,2-dicarboxamide

[0638]

[0639] This example adopts the same method as Example 1 to obtain 40 mg of off-white solid with a yield of 70%. 1HNMR (400MHz, DMSO-d6) δ11.05(s,1H,NH),9.00(d,J=1.7Hz,1H,Ar-H),8.84(d,J=6.6Hz,1H,Ar-H),8.71(dd,J=4.8,1.6Hz,1H ,Ar-H),8.60(d,J=5.1Hz,1H),8.18(dt,J=7.9,1.9Hz,1H,Ar-H),7.55(s,1H,NH),7.51(dd,J=7.9,4.8Hz,1H,NH),7.47(s,1H, NH),7.41(dd,J=5.2,1.3Hz,1H,Ar-H),7.03(s,1H,NH),4.70–4.55(m,1H,CH),4.50–4.35(m,1H,CH),3.95–3.83(m,1H,CH),3. 60–3.47(m,1H,CH),2.41(s,3H,CH3),2.31–2.19(m,1H,CH),2.17–2.05(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=562[M+H] + .

[0640] Comparative Example 6

[0641] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(isonicotinamido)pyrrolidine-1,2-dicarboxamide

[0642]

[0643] This example adopts the same method as Example 1 to obtain 20 mg of off-white solid with a yield of 80%. 1HNMR(400MHz,DMSO-d6)δ11.06(s,1H,NH),8.94(d,J=6.8Hz,1H,Ar-H),8.73(dd,J=4.5,1.6Hz,2H,Ar-H),8.61 (d,J=5.1Hz,1H,Ar-H),7.76(dd,J=4.5,1.6Hz,2H,Ar-H),7.56(s,1H,NH),7.47(s,1H,NH),7.42(dd,J=5.2,1.5 Hz,1H,Ar-H),7.04(s,1H),4.68–4.55(m,1H,CH),4.50–4.35(m,1H,CH),4.04–3.74(m,1H,CH),3.60–3.50(m,1H ,CH),2.41(s,3H,CH3),2.36–2.23(m,1H,CH),2.20–2.05(m,1H,CH),1.62(s,6H,CH3×2); ESI-MS:m / z=562[M+H] + .

[0644] Comparative Example 7

[0645] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(pyrimidin-2-ylamino)pyrrolidine-1,2-dicarboxamide

[0646]

[0647] This example adopts the same method as Example 1 to obtain 38 mg of off-white solid, with a yield of 60%. 1 HNMR(400MHz,DMSO-d6)δ11.06(s,1H,NH),8.60(d,J=4.5Hz,1H,Ar-H),8.31(d,J=3.8Hz,2H,Ar-H), 7.55(s,1H,Ar-H),7.51–7.47(m,1H,CH),7.46(s,1H,NH),7.41(d,J=3.6Hz,1H,Ar-H),7.01(s,1H,N H),6.66–6.58(m,1H,NH),4.62–4.50(m,1H,CH),4.48–4.31(m,1H,CH),3.96–3.84(m,1H,CH),3.51– 3.40(m,1H,CH),2.40(s,3H,CH3),2.27–2.01(m,2H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=535[M+H] +.

[0648] Comparative Example 8

[0649] 2-(((3R,5S)-5-carbamoyl-1-((4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carboxylic acid methyl ester

[0650]

[0651] This example adopts the same method as Example 1 to obtain 39 mg of off-white solid, with a yield of 55%. 1 HNMR(400MHz,DMSO-d6)δ11.03(s,1H,NH),8.84–8.71(m,2H,Ar-H),8.60(d,J=5.1Hz,1H,Ar-H),8. 48(d,J=4.7Hz,1H,Ar-H),7.55(s,1H,NH),7.47(s,1H,NH),7.41(d,J=4.7Hz,1H,Ar-H),7.03(s,1H ,NH),4.72–4.59(m,1H,CH),4.48–4.31(m,1H,CH),3.96–3.86(m,1H,CH),3.80(s,3H,CH3),3.55–3 .42(m,1H,CH),2.40(s,3H,CH3),2.28–2.04(m,2H,CH),1.62(s,6H,CH3×2); ESI-MS:m / z=593[M+H] + .

[0652] Comparative Example 9

[0653] Methyl 2-(((3R,5S)-5-carbamoyl-1-((4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidin-3-yl)amino)pyridine-5-carboxylate

[0654]

[0655] This example adopts the same method as Example 1 to obtain 32 mg of off-white solid, with a yield of 50%. 1HNMR(400MHz, CDCl3-d6)δ8.62(s,1H,NH),8.57–8.41(m,1H,Ar-H),7.81(d,J=6.7Hz,1H,Ar-H),7.6 7–7.35(m,2H,Ar-H),7.33–7.24(m,1H,Ar-H),7.20(s,1H,NH),7.09(s,1H,NH),6.36(d,J=6.3Hz,1H, Ar-H),6.20(s,1H,NH),4.80–4.66(m,1H,CH),4.64–4.50(m,1H,CH),4.18–3.98(m,1H,CH),3.74(s, 3H,CH3),3.62(s,1H),2.62–2.44(m,1H,CH),2.27(s,4H),1.57(s,6H,CH3×2); ESI-MS:m / z=592[M+H] + .

[0656] Comparative Example 10

[0657] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(pyridin-2-ylamino)pyrrolidine-1,2-dicarboxamide

[0658]

[0659] This example adopts the same method as Example 1 to obtain 32 mg of off-white solid, with a yield of 50%. 1 HNMR (400MHz, DMSO-d6) δ11.04(s,1H,NH),8.60(d,J=3.6Hz,1H,Ar-H),8.00(d,J=2.0Hz,1H,Ar-H),7.5 9–7.52(m,1H,Ar-H),7.51–7.43(m,1H,NH),7.43–7.30(m,2H,Ar-H),7.08–6.94(m,1H,NH),6.86–6.74(m ,1H,NH),6.55–6.43(m,2H,Ar-H),4.59–4.47(m,1H,CH),4.46–4.26(m,1H,CH),3.97–3.85(m,1H,CH),3 .49–3.39(m,1H,CH),2.40(s,3H,CH3),2.22–2.07(m,2H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=534[M+H] + .

[0660] Comparative Example 11

[0661] (2S,4R)-4-(Benzyloxy)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0662]

[0663] The target intermediate (70 mg, 0.13 mmol) and N-methylmorpholine (24 μL, 0.26 mmol) were dissolved in tetrahydrofuran at room temperature. Isopropyl chloroformate (23 μL, 0.17 mmol) was slowly added dropwise to the solution at room temperature. After a half-hour reaction at room temperature, aqueous ammonia (44 μL, 1.13 mmol) was added. The reaction was continued at room temperature for another four hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, the mixture was dissolved in ethyl acetate, and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and the ethyl acetate was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain the target product XII (46 mg, 0.08 mmol, 65% yield). 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H,NH),8.60(d,J=4.6Hz,1H,Ar-H),7.55(s,1H,Ar-H),7.4 9(s,1H,NH),7.41(d,J=3.7Hz,1H,Ar-H),7.39–7.23(m,5H,Ar-H),7.00(s,1H,NH),4.68–4.4 2(m,2H,CH),4.40–4.28(m,1H,CH),4.27–4.15(m,1H,CH),3.91–3.56(m,2H,CH),2.41(s,3H, CH3),2.36–2.23(m,1H,CH),2.05–1.85(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=548[M+H] + .

[0664] Phenyl(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate (70 mg, 0.17 mmol) and benzyl(2S,4R)-1-(tert-butoxycarbonyl)-4-(benzyloxy)pyrrolidine-2-carboxylate (100 mg, 0.32 mmol) were reacted using the same method as in Example 1 to obtain the target intermediate (50 mg, 0.08 mmol, 47% yield). 1HNMR(400MHz,DMSO-d6)δ11.24(s,1H,NH),8.61(d,J=4.2Hz,1H,Ar-H),7.56(s,1H,Ar-H ),7.43(d,J=3.4Hz,Ar-H),7.39–7.22(m,10H),5.24–5.08(m,2H,CH),4.57–4.49(m,2H,C H),4.48–4.43(m,1H,CH),4.34–4.24(m,1H,CH),3.84–3.75(m,1H,CH),3.74–3.63(m,1H ,CH),2.41(s,3H,CH3),2.14–1.80(m,2H,CH),1.62(s,6H,CH3×2); ESI-MS:m / z=639[M+H] + .

[0665] Comparative Example 12

[0666] (2S,4R)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-((3-(trifluoromethyl)benzyl)oxy)pyrrolidine-1,2-dicarboxamide

[0667]

[0668] This example adopts the same method as Comparative Example 11 to obtain 45 mg of off-white solid, with a yield of 74%. 1 HNMR(500MHz,DMSO-d6)δ11.08(s,1H,NH),8.60(d,J=4.8Hz,1H,Ar-H),7.69–7.53 (m,5H,Ar-H),7.49(s,1H,NH),7.41(d,J=4.0Hz,1H,Ar-H),7.00(s,1H,NH),4.72–4 .48(m,2H,CH),4.44–4.19(m,2H,CH),3.86–3.57(m,2H,CH),2.41(s,3H,CH3),2.37 –2.23(m,1H,CH),2.09–1.88(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS: m / z=616[M+H] + .

[0669] Comparative Example 13

[0670] (2S,4R)-N 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1,2-dicarboxamide

[0671]

[0672] This example adopts the same implementation method as Comparative Example 11 to obtain 40 mg of an off-white solid with a yield of 89%. 1 HNMR(500MHz,DMSO-d6)δ11.05(s,1H,NH),8.60(d,J=4.7Hz,1H,Ar-H),7.69(d,J=7.6Hz, 2H,Ar-H),7.60–7.51(m,3H,Ar-H),7.49(s,1H),NH,7.41(d,J=3.6Hz,1H,Ar-H),7.00(s,1 H,NH),4.71–4.54(m,2H,CH),4.44–4.09(m,2H,CH),3.91–3.52(m,2H,CH),2.40(s,3H,CH3 ),2.37–2.26(m,1H,CH),2.05–1.91(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=616[M+H] + .

[0673] Comparative Example 14

[0674] (2S,4R)-4-((2,3-difluorobenzyl)oxy)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0675]

[0676] This example adopts the same method as Comparative Example 11 to obtain 45 mg of off-white solid, with a yield of 56%. 1HNMR(400MHz,DMSO-d6)δ11.38(s,1H,NH),8.60(d,J=5.1Hz,1H,Ar-H),7.55(s,1H,Ar-H),7 .47(s,1H,NH),7.43–7.33(m,2H,Ar-H),7.28–7.16(m,2H,Ar-H),6.99(s,1H,NH),4.64–4.54 (m,2H,CH),4.39–4.22(m,2H,CH),3.83–3.71(m,1H,CH),3.70–3.59(m,1H,CH),2.41(s,3H,C H3),2.35–2.21(m,1H,CH),2.04–1.88(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=584[M+H] + .

[0677] Comparative Example 15

[0678] (2S,4R)-4-((3,4-difluorobenzyl)oxy)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0679]

[0680] This example adopts the same method as Comparative Example 11 to obtain 37 mg of off-white solid with a yield of 74%. 1 HNMR(400MHz,DMSO-d6)δ11.60(s,1H,NH),8.60(d,J=5.2Hz,1H,Ar-H),7.55(s,1H,Ar-H),7.48 (s,1H,NH),7.44–7.30(m,3H,Ar-H),7.24–7.11(m,1H,Ar-H),7.00(s,1H,NH),4.55–4.41(m,2H, CH),4.41–4.29(m,1H,CH),4.28–4.17(m,1H,CH),3.77–3.68(m,1H,CH),3.67–3.57(m,1H,CH), 2.41(s,3H,CH3),2.31(s,1H),2.36–2.23(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=584[M+H] + .

[0681] Comparative Example 16

[0682] (2S,4S)-4-(Benzyloxy)-N 1 -(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0683]

[0684] This example adopts the same method as Comparative Example 11 to obtain 55 mg of off-white solid, with a yield of 60%. 1 HNMR(500MHz,DMSO-d6)δ11.01(s,1H,NH),8.60(d,J=3.7Hz,1H,Ar-H),7.55(s,1H,Ar-H),7 .41(s,1H,NH),7.38–7.16(m,6H,Ar-H),7.02(s,1H,NH),4.55–4.39(m,2H,CH),4.38–4.26( m,1H,CH),4.24–4.10(m,1H,CH),3.85–3.72(m,1H,CH),3.67–3.53(m,1H,CH),2.41(s,3H,C H3),2.35–2.26(m,1H,CH),2.22–2.06(m,1H,CH),1.61(s,6H,CH3×2); ESI-MS:m / z=548[M+H] + .

[0685] Inhibitory activity of the compounds of the present invention against PI3Kα

[0686] The inhibitory activity of the compounds of the present invention against PI3Kα was determined using the Kinase-Glo Plus Luminescent Kinase Assay (European Journal of Medicinal Chemistry, 2015, 99:36-50). The test compound was first diluted to the desired concentration, and 2.5 μL of each was added to a 384-well plate. PI3Kα was then diluted to 1.65 nM using kinase buffer (50 mM HEPES pH 7.5, 3 mM MgCl2, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, 2 mM DTT), and 2.5 μL was added to each well of the 384-well plate. Similarly, the substrates PIP2 and ATP were diluted to 50 μM and 25 μM, respectively, using kinase buffer, and 5 μL was added to each well of the 384-well plate. After a 1-hour reaction, 10 μL of Kinase-Glo reagent was added to each well to terminate the reaction. After centrifugation and other treatments, the RLU values ​​were read using a microplate reader. Inhibition rate was calculated using the following formula: Inhibition rate (%) = (sample RLU - min) / (max - min) × 100, where "min" represents the RLU of the control well without enzyme, and "max" represents the RLU of the control well containing DMSO.

[0687] Table 1 Inhibitory activity of the inventive compounds against PI3Kα

[0688]

[0689]

[0690] “++++” represents 0.5-4.9 nM; “+++” represents 5-9.9 nM; “++” represents 10-100 nM; “+” represents >100 nM.

[0691] As shown in the inhibitory activity data in Table 1, (4R)-sulfonylamino-L-prolinamide compounds all exhibit strong PI3Kα inhibitory activity, and their inhibitory activity is superior to that of the marketed drug Alpelisib. However, the other three major classes of compounds involved in the present invention, namely (4R)-acylamino-L-prolinamide compounds, (4R)-aromaticamino-L-prolinamide compounds, and 4-benzyloxy-L-prolinamide compounds, do not have an inhibitory activity against PI3Kα that is superior to that of the marketed drug Alpelisib. Therefore, (4R)-sulfonylamino-L-prolinamide compounds have good development and application prospects.

[0692] Inhibitory activity of the compounds of the present invention against Class I PI3Ks

[0693] The inhibitory activity of the compounds of the present invention against PI3Kβ, γ, and δ was determined using the ADP-Glo ​​Kinase assay (European Journal of Medicinal Chemistry, 2015, 99:36-50). The test compound was diluted to the desired concentration range, and 2.5 μL of each was added to a 384-well plate. PI3Kβ, γ, and δ were then diluted to 4.8 nM, 7.6 nM, and 5.7 nM, respectively, using kinase buffer (50 mM HEPES pH 7.5, 3 mM MgCl2, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, 2 mM DTT), and then 2.5 μL was added to each well of the 384-well plate. Similarly, the substrates PIP2 and ATP were diluted to 50 μM and 25 μM, respectively, using kinase buffer, and 5 μL was added to each well of the 384-well plate. After 1 hour of reaction, 5 μL of the reaction mixture was transferred to a new 384-well plate and 5 μL of ADP-Glo ​​reagent was added to stop the reaction. After centrifugation and equilibration for 40 minutes, 10 μL of Kinase Detection reagent was added and equilibrated for another hour. After centrifugation and other treatments, the RLU values ​​were read using a microplate reader. The inhibition rate was calculated according to the following formula: Inhibition rate (%) = (sample RLU - min) / (max - min) × 100, where "min" represents the RLU of the no-enzyme control well and "max" represents the RLU of the DMSO control well. IC50 values ​​were obtained using Graphpad 5.0 software.

[0694] The following data (Table 2) demonstrating the inhibitory activity of representative (4R)-sulfonylamino-L-prolinamide compounds of the present invention against Class I PI3Ks demonstrates their highly selective action against PI3Kα, with selectivity significantly exceeding that of the marketed PI3Kα selective inhibitor, alpelisib. The inhibitory activity of the (4R)-sulfonylamino-L-prolinamide compounds of the present invention against Class I PI3Ks should not be construed as limited to the aforementioned representative compounds.

[0695] Table 2 Inhibitory activity (selectivity) of (4R)-sulfonylamino-L-prolinamide compounds against Class I PI3Ks

[0696]

[0697] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of the present invention. Various modifications are possible. In other words, any simple, equivalent changes and modifications made in accordance with the claims and description of the present invention are within the scope of protection of the patent claims. Anything not fully described in this invention constitutes conventional technology.

Claims

1. A (4R)-sulfonylamino-L-prolinamide compound having the general formula (I) and a pharmaceutically acceptable salt thereof, X, Y, and Z are all CH; or X and Y are CH, and Z is N; or X and Z are CH, and Y is N; or Y and Z are CH, and X is N; R1 is selected from C 1-6 Alkyl, fluorinated C 1-6 Alkyl, C 3-6 Cycloalkyl, R2 is a methyl group; R3 is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, phenyl or 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methylpyrazole, 1-methylimidazole, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl and phenyl are each independently and optionally substituted with one substituent R4; R4 is selected from hydrogen, fluorine, methyl or -OCF3.

2. The (4R)-sulfonylamino-L-prolinamide compound and its pharmaceutically acceptable salt according to claim 1, characterized in that: R1 is selected from R3 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl.

3. The (4R)-sulfonylamino-L-prolinamide compound and its pharmaceutically acceptable salt according to claim 1, characterized in that: The (4R)-sulfonylamino-L-prolinamide compound is selected from:

4. Use of a (4R)-sulfonylamino-L-prolinamide compound and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a medicament for treating a disease by inhibiting phosphatidylinositol 3-kinase α (PI3Kα), wherein the disease is an antiproliferative disease.

5. The use according to claim 4, characterized in that The antiproliferative disease is selected from the group consisting of cancer, hyperplasia, polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia.

6. A drug, characterized in that The drug includes the (4R)-sulfonylamino-L-prolineamide compound according to any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof.

7. The drug according to claim 6, characterized in that The medicament further comprises one or more pharmaceutically acceptable excipients.

Images